Agent for prophylaxis and treatment of neuropathy

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

 

The technical field to which the invention relates

The present invention relates to an agent for the prevention or treatment of neuropathy, or a means to enhance the production or secretion of neurotrophic factor.

In addition, the present invention relates to new 5-membered aromatic heterocyclic compound which has a reinforcing production or secretion of neurotrophic factor action, which can be used for prevention or treatment of neuropathy and the like.

The level of technology

As for the 5-membered aromatic heterocyclic compounds, have been reported following compounds.

(1) as a receptor antagonist of adenosine A1, the compound represented by the formula:

where A represents an aromatic ring; X, Y and Z are each carbon, nitrogen, oxygen or sulfur; R1represents optionally substituted aryl or optionally substituted heteroaryl; R2, R3and R4are the same or different and each represents hydrogen, lower alkyl, lower alkenyl, lower quinil and the like; R5and R6are the same or different and each represents hydrogen or lower alkyl; B before the hat is oxygen or sulfur; R7and R8are the same or different and each represents hydrogen, lower alkyl, lower alkoxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaromatic not necessarily protected carboxyethyl and the like (see European patent EP-A-630894).

(2) as protivoepidemicheskaja tools and protivoateroskleroticheskim means a compound represented by the formula:

where R1represents a C1-6alkyl; R2and R5are each, independently, hydrogen, C1-4alkyl, C1-4alkoxy (except tert-butoxy), trifluoromethyl, fluorine, chlorine, phenyl, phenoxy or benzyloxy; R3and R6are each, independently, hydrogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy; R4and R7are each, independently, hydrogen, C1-3alkyl, C1-2alkoxy, fluorine or chlorine;

X represents -(CH2)m- or -(CH2)qCH=CH(CH2)q(m is 0, 1, 2 or 3, q is 0 or one is 0 and the other is equal to 1); and

Z represents a-CH(OH)-CH2-C(OH)R10-CH2-COOH (R10represents in the location or C 1-3alkyl);

provided that each of rings A and B can only have one group selected from trifloromethyl, phenoxy and benzyloxy, and-X-Z is at the 4 - or 5-position of the pyrazol ring in the ortho-position with respect to R1(see application for international patent WO 86/00307).

(3) as a promoter of production or secretion neurotrophin compound represented by the formula:

where R1represents a halogen atom, optionally substituted heterocyclic group, optionally substituted by a hydroxy-group, optionally substituted Tilney group or optionally substituted by an amino group, A represents an optionally substituted acyl group, optionally substituted heterocyclic group, optionally substituted by a hydroxy-group or optionally esterified or amidinophenoxy carboxyl group, B represents an optionally substituted aromatic group, X represents an oxygen atom, a sulfur atom or optionally substituted nitrogen atom, and Y represents divalent hydrocarbon group or heterocyclic group, (see application for international patent WO 01/14372).

(4) as a regulator of the action of receptor-specific retinoids, the compound represented by the formula:

where R1represents an optionally substituted aromatic hydrocarbon group or optionally substituted aromatic heterocyclic group; R2represents hydrogen or optionally substituted hydrocarbon group; X represents O, S or a group represented by-NR4-where R4represents hydrogen or optionally substituted alkyl group; A represents an optionally substituted aromatic hydrocarbon group or optionally substituted aromatic heterocyclic group; R3represents a group represented by the formula: -OR5-where R5represents hydrogen or optionally substituted hydrocarbon group, or-NR6R7where R6and R7are the same or different and each represents hydrogen or optionally substituted hydrocarbon group, or R6and R7may form a ring together with the adjacent nitrogen atom (see application for international patent WO 00/01679).

The invention

The object of the present invention is an agent for the prevention or treatment of neuropathy and means to enhance the production or secretion of neurotrophic factors, which have an excellent effect and malaoxon is.

The next object of the present invention is 5-membered aromatic heterocyclic compound which has excellent preventive or therapeutic effect on the neuropathy, and which is low toxic.

The authors of the present invention have found that the compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X, Z, Y and R1are as defined below,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

which is structurally characterized by the fact that the group represented by the formula: -X-Z-Y-R1[X is divalent acyclic hydrocarbon group; Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group); Y represents a bond or divalent acyclic hydrocarbon group; R1is a it is certainly substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group] attached to and constituting a ring carbon atom of a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, demonstrates an excellent effect on the production or secretion of neurotrophic factor defined by the features of chemical structure, and on the basis of these data, created present invention.

Thus the present invention relates to

1) the agent for the prevention or treatment of neuropathy, which contains a compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle,

containing 2 or more nitrogen atoms, which, in addition, may have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cycle which economic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salt;

2) means on one of the above 1), where the 5-membered aromatic heterocycle represented by ring A is a pyrazol, oxadiazoline, thiadiazoline, triazole or tetrazole ring;

3) means on one of the above 1), where optionally substituted cyclic group represented by R1represents a group represented by the formula:

where D is a ring, optionally having, in addition, the Deputy (deputies); Y1represents a bond or divalent acyclic hydrocarbon group; R3' represents a group of the formula: -SO2R4, -SOR4or-PO3R4R5where R4and R5are the same or different and each represents a hydrogen atom, a hydrocarbon group or heterocyclic group, and R4and R5may form a heterocycle together with the adjacent oxo-substituted phosphorus atom and two oxygen atoms, or optionally substituted heterocyclic group;

4) redtwo enhance the production or secretion of neurotrophic factor which contains a compound of the formula

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salt;

5) the tool on one of the above 4), where the 5-membered aromatic heterocycle represented by ring A is a pyrazol, oxadiazoline, thiadiazoline, triazole or tetrazole ring;

6) the remedy for the relief of pain containing compound, not only the TES by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salt;

7) the tool on one of the above 6), where the 5-membered aromatic heterocycle represented by ring A is a pyrazol, oxadiazoline, thiadiazoline, triazole or tetrazole ring;

8) neuroprotective agent containing the compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salt;

9) the compound represented by the formula

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or neobyazatel is substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y and Y1are the same or different and each is a bond or divalent acyclic hydrocarbon group; and

D is a ring, also not necessarily have a Deputy (deputies);

R3represents an optionally substituted acyl group or optionally substituted heterocyclic group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

and provided that when the 5-membered aromatic heterocycle represented by ring A is a pyrazole, X represents methylene, Z represents-S-, and Y is a bond, then ring represented by D, should not be oxadiazol,

or its salt;

10) the compound according to the above 9), where the 5-membered aromatic heterocycle represented by ring A is a pyrazol, oxadiazoline, thiadiazoline, triazole or tetrazole ring;

11) the compound according to the above 9), where obazatelno substituted acyl group, presents R3represents a group of the formula: -SO2R4, -SOR4or-PO3R4R5where R4and R5are the same or different and each represents a hydrogen atom, a hydrocarbon group or heterocyclic group, and R4and R5may form a heterocycle together with the adjacent oxo-substituted phosphorus atom and two atoms of oxygen;

12) the compound according to the above 9), where the 5-membered aromatic heterocycle represented by ring A is a pyrazol ring;

13) the compound according to the above 9), where B represents an optionally substituted aromatic hydrocarbon group or optionally substituted aromatic heterocyclic group;

14) the compound according to the above 9), where X represents divalent C1-8aliphatic hydrocarbon group;

15) the compound according to the above 9)where Z is a-CONR2- (R2represents a hydrogen atom or optionally substituted alkyl group);

16) the compound according to the above 9)where Y is a bond or C1-4alkylen;

17) the compound according to the above 9), where Y1is a bond or C1-4alkylen;

18) the compound according to the above 9), where the ring represented by D, the pre is is a C 6-14aromatic hydrocarbon ring;

19) the compound according to the above 9)which is a diethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate;

(2E)-N-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide;

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-imidazol-1-ylmethyl)phenyl]acrylamide;

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-pyrazole-1-ylmethyl)phenyl]acrylamide;

diethyl [4-({(2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate;

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(3-methyl-2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}acrylamide;

(2E)-N-[4-(1H-benzimidazole-1-ylmethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide;

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(methylsulphonyl)methyl]phenyl}acrylamide;

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[hydroxy(2-pyridinyl)methyl]phenyl}acrylamide;

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(4-morpholinylmethyl)phenyl]acrylamide; or

(2E)-N-{4-[(ethylsulfonyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide;

20) a pharmaceutical agent containing the compound according to the above 9), or its prodrug;

21) a method for preventing or treating neuropathy in a mammal, which includes the introduction of compounds represented by FD is moloi:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salt, the specified mammal;

22) a method of enhancing the production or secretion of neurotrophic factor in a mammal, which comprises introducing the compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing or more nitrogen atoms, which can, in addition, to have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salts, specified mammal;

23) a method of reducing pain in a mammal, which comprises introducing the compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted of heteros Klionsky group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salts, specified mammal;

24) the method of protection of the nerve in a mammal, which comprises introducing the compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents the volume of hydrogen or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salts, specified mammal;

25) the use of compounds represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally Zam is placed acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salts, to obtain means for the prevention or treatment of neuropathy;

26) use of the compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salts, to obtain when estva, enhancing the production or secretion of neurotrophic factor;

27) use of the compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salts, to obtain funds for the relief of pain;

28) use of the compound represented by the formula:

where

ring A represents a 5-clenn the second aromatic heterocycle, containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group;

X represents divalent acyclic hydrocarbon group;

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group);

Y represents a bond or divalent acyclic hydrocarbon group; and

R1represents an optionally substituted cyclic group, optionally substituted by an amino group or optionally substituted acyl group,

provided that when the 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-,

or its salt to obtain neuroprotective agents;

29) the method of obtaining the compound represented by the formula:

where

ring A represents a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies);

B represents an optionally substituted hydrocarbon group or optionally substituted Goethe is acyclically group;

X represents divalent acyclic hydrocarbon group;

R2represents a hydrogen atom or optionally substituted alkyl group;

Y and Y1are the same or different and each is a bond or divalent acyclic hydrocarbon group;

D is a ring optionally having, in addition, the Deputy (deputies); and

R3represents an optionally substituted acyl group or optionally substituted heterocyclic group,

or its salt, which comprises the interaction of the compounds represented by the formula:

wherein each symbol is as defined above, or its salt, with a compound represented by the formula:

wherein each symbol is as defined above, or its salt;

30) the method of obtaining the compound represented by the formula:

where

B represents an optionally substituted hydrocarbon group or optionally substituted heterocyclic group, and

ALK4represents a C1-6alkyl group or a C7-13aracelio group,

or its salt, which comprises the interaction of the compounds represented by f is rmulas:

where W represents-OH or-N(ALK2)(ALK3), where ALK2and ALK3are the same or different and each represents a C1-6alkyl group, and B is as defined above, or its salt, with C1-6acylhydrazines or C7-13aralkylamines, in the presence of acid; and the like.

Detailed description of the invention

The terms used in the present description, hereinafter defined more specifically.

In the "5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may in addition have a Deputy (deputies)," defined as the ring A, as the "5-membered aromatic heterocycle containing 2 or more nitrogen atoms can be considered, for example, 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, besides carbon atoms, as atoms constituting a part of the ring, and optionally, additionally containing 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom.

As specific examples of the "5-membered aromatic heterocycle containing 2 or more nitrogen atoms, may be mentioned, for example, imidazole ring, pyrazole nucleus ring, oxadiazole ring, thiadiazole ring, triazole ring, tetrazole Kohl is on and the like. Among them pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring and tetrazole ring are preferred, and pyrazol ring is especially preferred.

"5-membered aromatic heterocycle containing 2 or more nitrogen atoms may also have 1 or 2 substituent in the substituted provisions. As such a substituent can be mentioned, for example, halogen atom, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted hydroxy-group, optionally substituted Tolna group, optionally substituted amino group and the like.

As the above "halogen atom" may be specified, for example, fluorine atom, chlorine atom, bromine atom and iodine atom. Among them, a fluorine atom and a chlorine atom are preferred.

As the "hydrocarbon group"in the above "optionally substituted hydrocarbon group" can be mentioned, for example, aliphatic hydrocarbon group, alicyclic hydrocarbon group, aromatic hydrocarbon group, an aromatic aliphatic hydrocarbon group, alicyclic aliphatic hydrocarbon group and the like.

As the aliphatic hydrocarbon group can be mentioned, for example,aliphatic hydrocarbon group with a straight chain or branched chain, containing 1-15 carbon atoms, particularly an alkyl group, Alchemilla group, Alchemilla group and the like.

As preferred examples of the alkyl groups can be specified C1-10alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.

As the preferred examples alkenyl groups can be specified C2-10alkeneamine groups such as ethynyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.

As the preferred examples etkinlik groups can be specified C2-10alkyline groups, such as ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.

As the alicyclic hydrocarbon group can be mentioned, for example, saturated or unsaturated alicyclic hydrocarbon groups containing 3 to 12 carbon atoms, the particular cycloalkyl group, cycloalkenyl group, cycloalkenyl group and the like.

As the preferred examples cycloalkyl groups can be specified C3-10cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and the like.

As the preferred examples cycloalkenyl groups can be specified C3-10cycloalkenyl groups such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.

As the preferred examples cycloalkenyl groups can be specified C4-10cycloalkenyl groups, such as 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl and the like.

As the aromatic hydrocarbon group can be mentioned, for example, C6-14aryl group and the like. As preferred examples of the aryl group may include phenyl, naphthyl, antril, tenantry, acenaphthylene, biphenylyl, indenyl and the like. Among them, phenyl, naphthyl and the like, are preferred. Aryl group may be partially saturated, and as the partially saturated with the Oh aryl group, may be considered, for example, dihydroindeno and the like.

As the aromatic aliphatic hydrocarbon group can be mentioned, for example, C7-13the aromatic aliphatic hydrocarbon group, and specifically, kalkilya group, arylalkylamine group and the like.

As the preferred examples aranceles group can be specified in C7-13kalkilya group, such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, benzhydryl and the like.

As the preferred examples arylalkylamines group can be specified C8-13arylalkylamine group, such as styryl and the like.

As the alicyclic aliphatic hydrocarbon group can be mentioned, for example, C4-13alicyclic aliphatic hydrocarbon group, and specifically, cycloalkylation group, cycloalkenyl group and the like.

As the preferred examples cycloalkylation group can be specified C4-13cycloalkylation group, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl and the like.

As the preferred examples cycloalkylcarbonyl group can be specified C5-13cycloalkylcarbonyl group, such as cycloprop Setenil, cyclopentylacetyl, cyclohexylethyl and the like.

The above "hydrocarbon group" may have 1-3 substituent in the substituted provisions. As such a substituent can be mentioned, for example, halogen atom, nitro, oxo, C1-3alkylenedioxy, optionally substituted aromatic heterocyclic group, optionally substituted non-aromatic heterocyclic group, optionally substituted amino, optionally substituted hydroxy-group, optionally substituted Tolna group, optionally substituted acyl group and the like.

As the halogen atoms can be mentioned, for example, fluorine atom, chlorine atom, bromine atom and iodine atom. Especially preferred are a fluorine atom and a chlorine atom.

As C1-3alkylenedioxy can be specified, for example, methylenedioxy, Ethylenedioxy and the like.

As the "aromatic heterocyclic group" of the "optionally substituted aromatic heterocyclic group"may be mentioned, for example, a 5-7-membered monocyclic aromatic heterocyclic group that contains, as atoms constituting a part of the ring, except the carbon atoms, 1-4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, or a condensed aromatic heterocyclic gruppa as a condensed aromatic heterocyclic group may be specified, for example, a group where these 5-7-membered monocyclic aromatic heterocyclic group condensed with a 6-membered ring containing 1 or 2 nitrogen atom, benzene ring, a 5-membered ring containing 1 sulfur atom and the like.

As preferable examples of the "aromatic heterocyclic group" can be specified furyl (e.g. 2-furyl, 3-furyl), thienyl (for example, 2-thienyl, 3-thienyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (for example, 2-pyrazinyl), pyrrolyl (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (for example, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (for example, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), oxazolyl (for example, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl, thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolin, oxadiazolyl (for example, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazole-2-yl), triazolyl (for example, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-2-yl, 1,2,3-triazole-4-yl), tetrazolyl (for example, tetrazol-1-yl, tetrazol-5-yl), chinolin (for example, 2-chinolin, 3-chinolin, 4-chinolin), chinadoll (for example, 2-chinadoll, 4-chinadoll), hin Kalil (for example, 2-Minoxidil), benzofuran (for example, 2-benzofuran, 3-benzofuran), sensational (for example, 2-benzothiazyl, 3-benzothiazol), benzoxazolyl (for example, 2-benzoxazolyl), benzothiazolyl (for example, 2-benzothiazolyl), benzimidazolyl (for example, the benzimidazole-1-yl, benzimidazole-2-yl), indolyl (e.g., indol-1-yl, indol-3-yl), 1H-indazole (for example, 1H-indazol-3-yl), 1H-pyrrolo[2,3-b]pyrazinyl (for example, 1H-pyrrolo[2,3-b]pyrazin-2-yl), 1H-pyrrolopyridine (for example, 1H-pyrrolo[2,3-b]pyridine-6-yl), 1H-imidazopyridine (for example, 1H-imidazo[4,5-b]pyridine-2-yl, 1H-imidazo[4,5-c]pyridine-2-yl), 1H-imidazopyridine (for example, 1H-imidazo[4,5-b]pyrazin-2-yl), triazinyl, ethanolic, benzoxadiazole, benzothiadiazole, benzotriazole and the like.

As the "nonaromatic heterocyclic group" of the "optionally substituted non-aromatic heterocyclic group"may be mentioned, for example, a 5-7-membered monocyclic non-aromatic heterocyclic group which contains 1-4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, as atoms constituting the ring part, in addition to carbon atoms, or a condensed non-aromatic heterocyclic group. As the condensed non-aromatic heterocyclic group can be mentioned, for example, a group where these 5-7-membered monocyclic non-aromatic, heterocycle the definition of the group condensed with a 6-membered ring, containing 1 or 2 nitrogen atom from the benzene ring, 5-membered ring containing 1 sulfur atom and the like.

As preferred examples of non-aromatic heterocyclic group can be specified pyrrolidinyl (for example, 1-pyrrolidinyl), piperidinyl (for example, piperidine), morpholinyl (for example, morpholino), thiomorpholine (for example, thiomorpholine), piperazinil (for example, 1-piperazinil), hexamethylenimine (for example, hexamethylenimine-1-yl), oxazolidinyl (for example, oxazolidin-3-yl), diazolidinyl (for example, thiazolidin-3-yl), imidazolidinyl (for example, imidazolidin-3-yl), imidazolyl (for example, imidazolin-1-Il, imidazolin-2-yl), oxazolyl (e.g., oxazoline-2-yl), thiazolyl (for example, thiazolin-2-yl), oxazinyl (for example, oxazin-2-yl), tetrahydrofuranyl, azepane, tetrahydropyridine (e.g., 1,2,3,6-tetrahydropyridine-1-yl), dihydrobenzofuranyl, DIOXOLANYL, dithiolane, dioxothiazolidine, dioxoimidazolidin and the like.

The above aromatic heterocyclic group and non-aromatic heterocyclic group may have 1-3 substituent in the substituted provisions. As such a substituent can be mentioned, for example, nitro, hydroxy, amino, oxo, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkyl, optionally substituted with 1-3 atoms of g is lagena (for example, fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and ethyl, C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy, C6-14aryl (e.g. phenyl) and the like.

As the "optionally substituted amino group" may be mentioned, for example, amino group, optionally mono - or di-substituted C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group, C1-13acyl group or heteroaryl group, each optionally have substituents.

Here, as C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, and C7-13aranceles group can be mentioned groups represented by the "hydrocarbon group" of the "optionally substituted hydrocarbon group"represented as the substituents for ring A.

As the above C1-13acyl groups can be mentioned groups represented as the acyl group of the "optionally substituted acyl group", which will be described later. Acyl group prefer is Ino represents formyl, C1-10alkylsulphonyl, C1-6alkoxycarbonyl, C6-14arylcarbamoyl, C7-13aralkylamines, 5 - or 6-membered aromatic heterocyclicamines, 5 - or 6-membered nonaromatic heterocyclicamines and the like.

Here, as the preferred examples of C1-10alkylcarboxylic may be mentioned acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like.

As preferred examples of C1-6alkoxycarbonyl can be specified, for example, tert-butoxycarbonyl and the like.

As preferred examples of C6-14arylcarbamoyl may be mentioned benzoyl, and the like.

As preferred examples of C7-13aralkylamines can be specified benzylcarbamoyl, ventilkappen and the like.

As preferred examples of 5 - or 6-membered aromatic heterocultural can be specified fullcarbon, pyrrolidinones, thienylboronic, pyridylcarbonyl and the like.

As preferred examples of 5 - or 6-membered nonaromatic of heterocultural can be specified tetrahydrofuranyl and the like.

As mentioned above the heteroaryl group can be specified, for example, aromatic heterocyclic group, provided the Lenna as substituents of "optionally substituted hydrocarbon group", presented as the substituents for ring A. Among them, pyridyl, imidazolyl, triazolyl, pyrimidinyl and the like, are preferred.

These C1-10alkyl group, a C2-10Alchemilla group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13kalkilya group, C1-13acyl group and heteroaryl group may have 1 to 6, preferably 1 or 2 substituent in the substituted provisions. As such a substituent can be mentioned, for example, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and trifluoromethyl, C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy, hydroxy, nitro, amino, C1-6alkylsulfonyl group (for example, methylsulphonyl) and the like.

As the substituted amino group can be specified, for example, mono - or di-C1-10alkylamino (for example, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, propylamino, dibutylamino), mono - or di-C2-10alkanolamine (for example, diallylamine), mono - or di-C3-10 cyclooctylamino (for example, cyclohexylamine), mono - or di-C1-10alkylcarboxylic (for example, acetylamino, propionamido), mono - or di-C6-14arylamino (for example, phenylamino), N-C1-10alkyl-N-C6-14arylamino (for example, N-methyl-N-phenylamino), N-C1-10alkyl-N-C7-13aralkylamines (for example, N-methyl-N-benzylamino), mono - or di-C1-6alkoxycarbonyl (for example, tert-butoxycarbonyl), mono - or di-C6-14arylcarboxamide (for example, phenolcarboxylic), mono - or di-C7-13aralkylated (for example, benzylcarbamoyl, finetimberlake), mono - or di-5 - or 6-membered aromatic heterocyclization (for example, fullcircle, pyrrolidinone, taylormomsen, pyridinecarboxamide), mono - or di-5 - or 6-membered non-aromatic heterocyclization (for example, tetrahydropyranyloxy) and the like.

As the "optionally substituted hydroxy-group" can be mentioned, for example, the hydroxy-group, optionally substituted C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group, C1-13acyl group or heteroaryl group, each of which is optionally substituted, and the like.

Here, as C 1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, and C7-13aranceles group can be mentioned groups represented by the "hydrocarbon group", "optionally substituted hydrocarbon group"represented as the substituents for ring A.

As C1-13acyl groups can be specified groups, represented as a Deputy of the above "optionally substituted amino group".

As the heteroaryl group can be specified, for example, aromatic heterocyclic group, represented as substituents of "optionally substituted hydrocarbon group"represented as the substituents for ring A. Among them, pyridyl, imidazolyl, triazolyl, pyrimidinyl and the like are preferred.

These C1-10alkyl group, a C2-10Alchemilla group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13kalkilya group, C1-13acyl group and heteroaryl group may have 1 or 2 substituent in the substituted provisions. As such a substituent can be mentioned, for example, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkyl group, optionally C is displaced by 1 to 3 halogen atoms (for example, fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and trifluoromethyl, C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy, hydroxy, nitro, amino, C1-6alkylsulfonyl group (for example, methylsulphonyl) and the like.

As substituted hydroxy-group can be specified, for example, alkoxy group, alkenylamine group, cycloalkane group, cycloalkenyl group, aryloxy group, aralkylated group, acyloxy group, heteroaromatic group, each of which is optionally substituted, and the like.

As preferred examples of the alkoxy group can be specified in C1-10alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy, heptyloxy, nonyloxy and the like.

As preferred examples of alkenylamine group can be specified in C2-10alkenylamine group, such as allyloxy, krotylov, 2-pentyloxy, 3 hexenoate and the like.

As preferred examples of cycloalkane group can be specified in C3-10cycloalkane group, such as CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy the and and the like.

As preferred examples of cycloalkenyl group can be specified in C3-10cycloalkenyl group, such as 2-cyclopentyloxy, 2-cyclohexyloxy and the like.

As preferred examples of aryloxy group can be specified in C6-14aryloxy group, such as phenoxy, naphthyloxy and the like.

As preferred examples of aralkylated group can be specified in C7-13aralkylated group, such as benzyloxy, penetrate, naphthalenyloxy and the like.

As preferred examples of acyloxy group can be specified C2-13acyloxy group, such as C1-6alkylcarboxylic group (for example, atomic charges, propionyloxy, butyryloxy, isobutyryloxy) and the like.

As preferred examples of heteroaromatic group can be specified 5-7-membered monocyclic heteroaromatic group, such as 2-pyridyloxy, 3 pyridyloxy, 2-imidazolidone, 2-pyrimidinone, 1,2,4-triazole-5-yloxy and the like.

The above alkoxy group, alkenylamine group, cycloalkane group, cycloalkenyl group, aryloxy group, aralkylated group, acyloxy group, heteroaromatic group may have 1 to 3, preferably 1 or 2 substituent in the substituted provisions. As such a substituent can be specified, n is the sample, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and trifluoromethyl, C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy, hydroxy, nitro, amino, C1-6alkylsulfonyl group (for example, methylsulphonyl) and the like.

As optionally substituted Tilney group can be specified, for example, Tolna group, optionally substituted C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group, C1-13acyl group or heteroaryl group, each of which is optionally substituted, and the like.

Here, as C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group, C1-13acyl group and heteroaryl group may be specified groups, respectively, presented in the above "optionally substituted hydroxy groups is". These groups may have 1 or 2 substituent in the substituted provisions. As such a substituent can be mentioned, for example, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and trifluoromethyl, C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy, hydroxy, nitro, amino, C1-6alkylsulfonyl group (for example, methylsulphonyl), oxo and the like.

As substituted Tilney groups can be specified, for example, alkylthio group, alkanity group, cycloalkyl group, cycloalkenyl group, aaltio group, Uralkali group, atillio group, heteroaromatic group, each of which is optionally substituted, and the like.

As preferred examples of alkylthio group can be specified C1-10alkylthio group, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, isopentyl, neopentyl, hexylthio, Reptilia, Nonito and the like.

As preferred examples of alkanity group can be specified C 2-10alkanity group, such as allylthio, cruelty, 2-pentylthio, 3 hexanite and the like.

As preferred examples of cycloalkyl group can be specified C3-10cycloalkyl group, such as cyclobutyl, cyclopentyl, cyclohexylthio and the like.

As preferred examples of cycloalkenyl group can be specified C3-10cycloalkenyl group, such as 2-cyclopentenyl, 2-cyclohexenyl and the like.

As preferred examples of aaltio group can be specified C6-14aaltio group, such as phenylthio, naphthylthio and the like.

As preferred examples of Uralkali group can be specified C7-13Uralkali group, such as benzylthio, penetito, naphthylmethyl and the like.

As preferred examples of achilty group can be specified C2-13atillio group, such as C1-6alkylcarboxylic group (for example, acetylthio, propositio, butylthio, isobutyronitrile) and the like.

As preferred examples of heteroaromatic group can be specified 5-7-membered monocyclic heteroaromatic group, such as 2-pyridylthio, 3 pyridylthio, 2-imidazoline, 2-pyrimidinyl, 1,2,4-triazole-5-ylthio and the like.

Above alkylthio group, alkene the thio group, cycloalkyl group, cycloalkenyl group, aaltio group, Uralkali group, atillio group, heteroaromatic group may have 1 or 2 substituent in the substituted provisions. As such a substituent can be mentioned, for example, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkyl, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and trifluoromethyl, C1-6alkoxy, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy, hydroxy, nitro, amino, C1-6alkylsulfonyl (for example, methylsulphonyl), oxo and the like.

As the acyl group of the "optionally substituted acyl group" may be mentioned, for example, a group represented by the formula: -COR4, -CO-OR4, -SO2R4, -SOR4, -PO3R4R5[that is, -P(=O)(OR4)(OR5)], -CO-NR4aR5a, -CS-NR4aR5aand-SO2-NR4aR5awhere R4and R5are the same or different and each represents a hydrogen atom, a hydrocarbon group or heterocyclic group, or R4and R5may form a heterocycle together with the adjacent oxo-substituted phosphorus atom and 2 and the ohms of oxygen; R4aand R5aare the same or different and each represents a hydrogen atom, a hydrocarbon group or heterocyclic group, or R4aand R5amay form a nitrogen-containing heterocycle together with the adjacent nitrogen atom and the like.

As the "hydrocarbon group" for R4, R5, R4aor R5acan be specified groups, presented as the "hydrocarbon group" of the "optionally substituted hydrocarbon group"represented as the substituents for ring A.

The hydrocarbon group preferably represents a C1-10alkyl group (preferably methyl, ethyl, propyl, butyl, tert-butyl, pentyl, 1-ethylpropyl, 2,2-dimethylpropyl); C2-10quinil group (preferably 2-PROPYNYL); C3-10cycloalkyl group which may be condensed with a benzene ring (preferably cyclopropyl, cyclohexyl); C6-14aryl group which may be condensed with C3-10cycloalkanes (preferably a cyclopentane) (preferably phenyl, dihydroindeno, biphenylyl); C7-13aracelio group (preferably benzyl, phenethyl, phenylpropyl, naphthylmethyl, benzhydryl) and the like.

As the "heterocyclic group" for R4, R5, R4aor R5acan be specified aromatizes the traveler heterocyclic group and non-aromatic heterocyclic group, presented as substituents of "optionally substituted hydrocarbon group" represented as the substituents for ring A.

The heterocyclic group preferably is thiazolyl, oxazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, hinely, ethanolic, pyrrolidinyl, piperidinyl, piperazinil and the like.

As the heterocycle formed by R4and R5together with the adjacent oxo-substituted phosphorus atom and 2 oxygen atoms, may be considered, for example, 4-7-membered heterocycle containing oxo-substituted phosphorus atom and 2 oxygen atom in addition to carbon atoms, as atoms constituting a part of the ring which can optionally contain 1 or 2 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom and the like. As preferred examples of such heterocycle can be considered 2-oxide-1,3,2-dioxaphosphinan; 2-oxide-1,3,2-dioxaphospholane, 2-oxide-4,7-dihydro-1,3,2-dioxaphosphinan and the like.

As the "nitrogen-containing heterocycle"formed by R4aand R5atogether with the adjacent nitrogen atom, may be considered, for example, a 5-7 membered nitrogen-containing heterocycle containing at least one nitrogen atom besides carbon atoms, as atoms, composing the th part of the ring, which can also contain 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom and the like. As preferred examples of such a nitrogen-containing heterocycle can be specified, pyrrolidin, imidazolidin, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.

Acyl group can have 1-3 substituent in the substituted provisions. As such a substituent may be considered, for example, C1-6alkyl, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and ethyl, C1-6alkoxy, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), nitro, hydroxy, amino optionally mono - or di-substituted C1-6the alkyl (for example, stands, ethyl and the like.

As preferred examples of the acyl group can be specified formyl, carboxyl, carbarnoyl, thiocarbamoyl, C1-10alkylsulphonyl (for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl), C2-10alkenylboronic (for example, crotonoyl), C3-10cycloalkylcarbonyl (for example, cyclobuta is carbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cyclohexylcarbonyl), C3-10cycloalkylcarbonyl (for example, 2-cyclohexanecarbonyl), C6-14arylcarbamoyl (for example, benzoyl, 1-naphtol, 2-naphtol), C7-13aralkylamines (for example, benzylcarbamoyl, ventilkappen), an aromatic heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl), non-aromatic heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, piperidinylcarbonyl), C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl), C6-14aryloxyalkyl (for example, vinyloxycarbonyl, naphthalocyanines), C7-13Uralelectromed (for example, benzyloxycarbonyl, ventilatsioonil), mono - or di-(C1-6alkyl optionally having 1-3 substituent selected from a halogen atom and C1-6alkoxycarbonyl)carbarnoyl (for example, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino, propellerblades, triptoreline), mono - or di-(C1-6alkyl, optionally substituted by 1 to 3 halogen atoms)thiocarbamoyl (for example, methylthiocarbamate, etildiocolmain), C6-14arylcarbamoyl (for example, phenylcarbamoyl), C3-10cycloalkylcarbonyl (for example, cyclopropanecarbonyl), C7-13aralkylamines (for example, benzo is carbamoyl), C1-6alkoxycarbonyl (for example, methoxycarbonyl), C1-10alkylsulfonyl group (for example, methylsulfinyl, ethylsulfinyl), C1-10alkylsulfonyl group (for example, methylsulphonyl, ethylsulfonyl), C6-14arylsulfonyl (for example, phenylsulfonyl), (mono - or di-C1-10alkyl)phosphono group optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan), mono - or di-(C1-6alkyl, optionally substituted by 1 to 3 halogen atoms)sulfamoyl (for example, methylsulfonyl, ethylsulfonyl) and the like.

"Hydrocarbon group" of the "optionally substituted hydrocarbon group"represented as the substituents for ring A, preferably represents C1-10alkyl group, a C6-14aryl group, a C3-10cycloalkyl group, C7-13aracelio group, C8-13arylalkyl group, C4-13cycloalkylcarbonyl group and the like. Hydrocarbon group, more preferably represents a C1-10alkyl group, a C6-14aryl group and the like.

Deputy "optionally substituted hydrocarbon group" preferably represents C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom, the bromine atom, iodine atom)such as methoxy, ethoxy, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), nitro, hydroxy, amino, C1-3alkylenedioxy (for example, methylenedioxy, Ethylenedioxy) and the like. The number of substituents is, for example, 1-3.

As the "heterocyclic group" of the "optionally substituted heterocyclic group"represented as the substituents for ring A can be mentioned groups represented as the above "heterocyclic group" for the above R4.

The heterocyclic group preferably is asailing group optionally condensed with a benzene ring, such as pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl and the like.

The above heterocyclic group may have 1-3 substituent in the substituted provisions. As such a substituent can be mentioned, for example, optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, optionally substituted aromatic hydrocarbon group, optionally substituted aromatic heterocyclic group, optionally substituted non-aromatic courtesans is a cyclic group, halogen atom, nitro, optionally substituted amino, optionally substituted hydroxy-group, optionally substituted Tolna group, optionally substituted acyl group, a C1-3alkylenedioxy, oxo and the like.

Here, as the "aliphatic hydrocarbon groups, alicyclic hydrocarbon group" and "aromatic hydrocarbon group" of the "optionally substituted aliphatic hydrocarbon group", "optionally substituted alicyclic hydrocarbon group" and "optionally substituted aromatic hydrocarbon group"can be mentioned groups represented by the "hydrocarbon group" of the "optionally substituted hydrocarbon group"represented as the substituents for ring A.

As substituents of the "aliphatic hydrocarbon groups, alicyclic hydrocarbon group" and "aromatic hydrocarbon group" can be mentioned groups represented by the "Deputy" of the "optionally substituted hydrocarbon group"represented as the substituents for ring A. the Position of substitution and the number of substitutions are not in any way limited. The number of substitutions is preferably 1-3.

As the "optionally substituted aromatic heterocyclic group" and "optionally substituted non-aromatic GE is eroticlinks group" can be mentioned groups, presented as substituents of "optionally substituted hydrocarbon group"represented as the substituents for ring A.

In addition, as the "halogen atom", the "optionally substituted amino", "optionally substituted hydroxy-group", "optionally substituted Tilney group", "optionally substituted acyl group" and "C1-3alkylenedioxy", can be mentioned groups represented as substituents of "optionally substituted hydrocarbon group"represented as the substituents for ring A.

As the "optionally substituted hydroxy-group", "optionally substituted Tilney group" and "optionally substituted amino group"represented as the substituents for ring A can be mentioned groups represented as substituents of "optionally substituted hydrocarbon group"represented as the substituents for ring A.

Deputy for ring A is preferably an optionally substituted hydrocarbon group, more preferably, C1-10alkyl group, a C6-14aryl group, a C7-13aracelio group and the like. Deputy for ring A is especially preferably, C1-6alkyl group (preferably, methyl and the like).

Ring A is preferably an imidazole is also, pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring or tetrazole ring (preferably pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring or tetrazole ring, more preferably pyrazol ring), each of which may have 1 or 2 substituent (preferably, C1-6alkyl group such as methyl and the like)selected from C1-10alkyl group, a C6-14aryl group, and C7-13aranceles group.

As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for B, respectively, are used of a group presented as the substituents for ring A. Here, the hydrocarbon group of the "optionally substituted hydrocarbon group" is preferably an alicyclic hydrocarbon group or aromatic hydrocarbon group. In addition, the heterocyclic group of the "optionally substituted heterocyclic group" is preferably an aromatic heterocyclic group.

B preferably represents an optionally substituted aromatic hydrocarbon group or optionally substituted aromatic heterocyclic group.

B, in addition, it is preferable to depict is to place an optionally substituted C 6-14aryl group, optionally substituted 5-7-membered monocyclic aromatic heterocyclic group and the like. As preferred specific examples of B, can be specified C6-14aryl group (preferably phenyl, naphthyl) and a 5-7 membered monocyclic aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl), each of them has optional 1-3 substituent selected from C1-6the alkyl, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and ethyl, C1-6alkoxy, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), nitro, formyl, and C1-3alkylenedioxy (for example, methylendioxy).

Among them, C6-14aryl group (preferably, phenyl) and a 5-7 membered monocyclic aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl), each of them has optional 1-3 substituent selected from C1-6the alkyl, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkoxy, optional what about substituted by 1-3 halogen atoms (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), halogen atom (preferably, fluorine atom, chlorine atom, bromine atom), are preferred.

B particularly preferably represents C6-14aryl group (preferably phenyl), optionally having halogen atom (preferably, fluorine atom).

"Dimalanta acyclic hydrocarbon group for X may be divalent hydrocarbon group with straight chain or branched chain, saturated or unsaturated, insofar as it is acyclic.

As divalent acyclic hydrocarbon group" can be mentioned, for example, "dimalanta aliphatic hydrocarbon group". In particular, it is preferable divalently C1-8aliphatic hydrocarbon group represented by the following groups.

(1) C1-8alkylene (for example, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -CH(CH3)-, -C(CH3)2-, -(CH(CH3))2-, -(CH2)2C(CH3)2-, -(CH2)3C(CH3)2and the like);

(2) C2-8Alcanena (for example, -CH=CH-, -CH2-CH=CH-, -C(CH3)2-CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=CHCH=CH-, -CH=CH-CH2-CH2-CH2and the like) and so on.

C2-8albaniles includes both its E-form and Z-form.

"Dimalanta acyclic hydrocarbon group preferably represents a C1-4alkylene or C2-4albaniles, more preferably, -CH2-, -(CH2)2-, -CH=CH - and the like. X is particularly preferably-CH=CH - and the like.

Z represents-O-, -S-, -NR2-, -CONR2- or-NR2CO- (R2represents a hydrogen atom or optionally substituted alkyl group).

In the optionally substituted alkyl group for R2as the alkyl group, may be mentioned, for example, C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl). The alkyl group can have 1-3 substituent. As such a substituent, may be considered, for example, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkoxy, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom) such as methoxy, ethoxy, hydroxy, nitro, amino and the like.

R2preferably represents a hydrogen atom or a C1-6alkyl group, more preferably a hydrogen atom.

Z preferably represents-CONR2- (Rsup> 2is the same as defined above), more preferably-CONH- (in the present invention, the carbon atom (C)- CONR2is associated with X and the nitrogen atom (N) is related to Y).

As divalent acyclic hydrocarbon group for Y may be mentioned groups represented as the above X.

Y preferably represents a bond, C1-4alkylene, more preferably a bond, -CH2-, -(CH2)2-, -(CH2)3- and the like. Y particularly preferably represents a connection.

As the "cyclic group" of the "optionally substituted cyclic group" for R1may be specified, for example, alicyclic hydrocarbon group, aromatic hydrocarbon group, aromatic heterocyclic group, non-aromatic heterocyclic group and the like.

Here, as an "alicyclic hydrocarbon group" and "aromatic hydrocarbon group" can be mentioned groups represented by the "hydrocarbon group" of the "optionally substituted hydrocarbon group"represented as the substituents for ring A.

As the "aromatic heterocyclic group" and "non-aromatic heterocyclic group" can be mentioned groups represented as substituents of "optionally substituted carbohydrate is native group", presented as the substituents for ring A.

A cyclic group preferably represents optionally partially saturated C6-14aryl group (preferably phenyl, dihydroindeno), C3-10cycloalkyl group (preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), C3-10cycloalkenyl group (preferably cyclohexenyl), 5 - or 6-membered aromatic heterocyclic group optionally condensed with a benzene ring (preferably furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, indolyl, hinely, ethanolic and benzothiadiazole), 5 - or 6-membered non-aromatic heterocyclic group optionally condensed with a benzene ring (preferably pyrrolidinyl, tetrahydrofuranyl, thiazolyl, oxazolyl, diazolidinyl, oxazolidinyl, DIOXOLANYL, piperidinyl, piperazinil, morpholinyl, thiomorpholine, dihydrobenzofuranyl, oxidehydrogenation) and the like. A cyclic group is a, more preferably, C6-14aryl group, and phenyl is particularly preferred.

"Cyclic group" for R1may have 1-4 substituent in the substituted provisions. As such a substituent can be mentioned, for example,

(1) nitro;

(2) oxo;

(3) hydroxy;

(4) cyano;

(5) a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(6) C1-6alkylenedioxy (for example, methylenedioxy, Ethylenedioxy);

(7) carboxyl;

(8) C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl) optionally substituted by 1 to 3 substituents selected from a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom); hydroxy; cyano; C1-6alkoxy (e.g. methoxy), amino, optionally mono - or di-substituted C1-6the alkyl and C1-6alkylcarboxylic (for example, acetyl, propionyl, Boutillon, isobutyryl, isovaleryl), such as amino, methylamino, dimethylamino, acetylamino, bucillamine, isobutylamino, isovaleramide; 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl); aromatic fused heterocyclic group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, hinely, indazole), optional ameena 1-3 substituents, selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl); 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuryl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl, dioxideequivalent), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl); non-aromatic fused heterocyclic group (for example, oxidehydrogenation, tetrahydrolipstatin), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl); carboxyl group; C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl); (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan); carbarnoyl, optionally substituted amino; mono - or di-C1-6 allylcarbamate, optionally substituted by 1-3 substituents selected from halogen atom, hydroxy and C1-6alkoxycarbonyl, such as methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino, propellerblades, triptoreline, methoxycarbonylaminophenyl, 2-hydroxy-1-methoxycarbonylaminophenyl and 2-hydroxy-1-methoxycarbonylpropionyl; mono - or di-C6-14arylcarbamoyl, optionally substituted by 1-3 substituents selected from optionally halogenated C1-6the alkyl and C1-6alkoxy, such as phenylcarbamoyl, methoxyphenylacetyl and cryptomaterial; mono - or di-C7-13aralkylamines, optionally substituted by 1-3 substituents selected from amino, optionally mono - or di-substituted C1-6the alkyl, optionally halogenated C1-6the alkyl, hydroxy and C1-6alkoxycarbonyl, such as benzylcarbamoyl, phenetically, dimethylaminobenzylidene, methoxycarbonylmethylene and triftormetilfullerenov; sulfamoyl; optionally halogenated mono - or di-C1-6alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl); C1-6alkylthio (for example, methylthio, ethylthio and tert-butylthio); C1-6alkylsulfonyl (for example, methylsulfinyl, ethylsulfinyl and tert-butylsulfonyl);C 1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl and tert-butylsulfonyl); C1-6alkylsulphonyl (for example, acetyl); mono - or di-C6-14arylcarboxamide (for example, phenolcarboxylic); C6-14aaltio (for example, phenylthio); 5 - or 6-membered aromatic heterocyclic thio (e.g., triazolyl, tetrazolyl) optionally substituted C1-6the alkyl, C6-14arylsulfonyl (for example, phenylsulfinyl); 5 - or 6-membered aromatic heterocyclic sulfinil (for example, triazolylmethyl and tetraallyltin), optionally substituted C1-6the alkyl, C6-14arylsulfonyl (for example, phenylsulfonyl); 5 - or 6-membered aromatic heterocyclic sulfonyl (for example, triazolylmethyl and tetraallylsilane), optionally substituted C1-6by alkyl;

(9) C3-10cycloalkyl group (e.g. cyclohexyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(10) C6-14aryl (e.g. phenyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(11) C7-13aralkyl (e.g., benzyl), optionally substituted by 1-3 substituents selected from a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom and hydroxy;

(12 5 - or 6-membered aromatic heterocyclic group (for example, thiadiazolyl and imidazolyl), optionally substituted by 1-3 substituents selected from a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6the alkyl and C6-14aryl (e.g. phenyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom and iodine atom);

(13) C1-6alkoxy group (e.g. methoxy, ethoxy), optionally substituted by 1-3 substituents selected from a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl and pyrimidinyl), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl); aromatic fused heterocyclic group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, chinosol and indazole), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl); 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahed furyl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl, dioxideequivalent), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl); non-aromatic fused heterocyclic group (for example, oxidehydrogenation and tetrahydrolipstatin), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl);

(14) C1-6alkylthio (for example, methylthio), optionally substituted by 1-3 substituents selected from 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl), optionally substituted C1-6the alkyl and a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(15) C6-14aryloxy (for example, phenoxy), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(16) amino, optionally mono - or di-substituted C1-6the alkyl, such as amino, methylamino, di is ethylamino, ethylamino, diethylamino, ethylmethylamino, propylamino, dibutylamino;

(17) phosphono-C1-6alkylamino, optionally mono - or di-substituted C1-10the alkyl, such as phosphonomethylglycine, diethyltoluenediamine;

(18) mono - or di-C1-6alkylcarboxylic, optionally substituted by 1-6, preferably 1-3, substituents selected from a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6the alkyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl and ethoxycarbonyl), such as acetylamino, hexanamine, triptorelin, N-acetyl-N-methylamino, pentafluoropropionate, ethoxycarbonylpyrimidine;

(19) (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan);

(20) C1-6alkylsulphonyl (for example, acetyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(21) C1-6alkylsulfonyl (for example, methylsulfinyl), optionally substituted 5 - or 6-membered aromatic heterocyclic group (e.g., thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl), optionally substituted C1-6by alkyl;

(22) C1-6alkylsulfonyl, (e.g. the, methylsulphonyl and ethylsulfonyl), optionally substituted 5 - or 6-membered aromatic heterocyclic group (e.g., thiazolium, oxazolium, triazolium, tetrazolium, pyridium, pyrimidinyl), optionally substituted C1-6by alkyl;

(23) C3-10cycloalkylcarbonyl (for example, cyclohexylcarbonyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(24) C6-14arylcarbamoyl (e.g., benzoyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(25) C7-13aralkylamines (for example, benzylcarbamoyl and geneticarmor), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(26) C6-14aryl-C2-6alkenylboronic (for example, strikeball), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(27) C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(28) 5 - or 6-membered aromatic heterocyclicamines (for example, furoyl, pyrrolidinones and pyridylcarbonyl), optional replacement of the military C 1-6by alkyl;

(29) 5 - or 6-membered nonaromatic heterocyclicamines (for example, tetrahydrofuroyl), optionally substituted C1-6by alkyl;

(30) carbarnoyl, optionally mono - or di-substituted C1-6the alkyl, such as carbarnoyl and dimethylcarbamoyl;

(31) sulfamoyl, optionally substituted by 1 or 2 substituents selected from 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl), optionally substituted C1-6the alkyl, C1-6the alkyl such as sulfamoyl and dimethylsulphamoyl;

(32) C7-13uralelektromedi (for example, benzyloxycarbonyl, ventilatsioonile), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom);

(33) C1-6alkoxycarbonyl (for example, tert-butoxycarbonyl);

(34) C6-14arylsulfonyl (for example, phenylsulfonyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom and iodine atom); and the like.

Deputy for the above-mentioned "cyclic group" is preferably a

(1) C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl), optionally substituted by 1-3 substituents, select nimi from hydroxy; 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl and pyrimidinyl), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl; aromatic fused heterocyclic group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, chinosol and indazole), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl; 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuryl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxideequivalent), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl; non-aromatic fused heterocyclic group (for example, oxidehydrogenation and tetrahydrolipstatin), optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6alkyl is, carboxyl, carbamoyl and C1-6alkoxycarbonyl; (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan); C1-6alkylthio; C1-6alkylsulfonyl; and (C1-6alkylsulfonyl;

(2) a 5 - or 6-membered aromatic heterocyclic group (for example, thiadiazolyl and imidazolyl), optionally substituted by 1-3 substituents selected from a halogen atom, a C1-6the alkyl and C6-14aryl, optionally substituted by 1 to 3 halogen atoms; or

(3) C1-6alkylsulfonyl (for example, methylsulphonyl and ethylsulfonyl), optionally substituted 5 - or 6-membered aromatic heterocyclic group (e.g., thiazolium, oxazolium, triazolium, tetrazolium, pyridium and pyrimidinyl), optionally substituted C1-6the alkyl.

Deputy for the "cyclic group" is more preferably represents a C1-6alkyl group, optionally substituted by 1-3 substituents selected from 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl and pyrimidinyl), optionally substituted C1-6by alkyl; aromatic fused heterocyclics the group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, chinosol and indazole), optionally substituted C1-6by alkyl; a 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuryl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxideequivalent), optionally substituted C1-6by alkyl; (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan); C1-6alkylsulfonyl; and (C1-6alkylsulfonyl.

As the "optionally substituted amino" and "optionally substituted acyl group" for R1use of a group presented as substituents of "optionally substituted hydrocarbon group"represented as the substituents for ring A.

As preferable examples of the "optionally substituted amino group" for R1can be specified

1) amino, optionally mono - or di-substituted by substituents selected from C1-6the alkyl, optionally substituted hydroxy, C6-14the aryl and 5 - or 6-membered aromatic heterocyclic group (EmOC is emer, pyridium), optionally substituted by nitro, such as amino, methylamino, dimethylamino, diisopropylamino, phenylamino and N-phenyl-N-methylamino;

2) mono - or di-C1-6alkylcarboxylic, optionally substituted by 1-3 substituents selected from a halogen atom (e.g. fluorine, chlorine, bromine, iodine) and (C1-6of alkyl, such as acetylamino, hexanamine, triptorelin, N-acetyl-N-methylamino, pentafluoropropionate;

3) C1-6alkoxycarbonyl, optionally substituted C1-6the alkyl, such as tert-butoxycarbonyl and N-tert-butoxycarbonyl-N-methylamino;

4) C6-14arylcarboxamide (for example, phenolcarboxylic), optionally substituted C1-6by alkyl;

5) C7-13aralkylated (for example, benzylcarbamoyl and finetimberlake), optionally substituted C1-6by alkyl;

6) a 5 - or 6-membered aromatic heterocyclization (for example, fullcircle, pyrrolidinone, taylormomsen, pyridinecarboxamide), optionally substituted C1-6by alkyl;

7) a 5 - or 6-membered non-aromatic heterocyclization (for example, tetrahydropyranyloxy), optionally substituted C1-6by alkyl; and the like.

As preferable examples of the "optionally substituted acyl group" for R1can be specified

(1) carboxyl;

(2 C 1-6alkylsulphonyl (for example, acetyl);

(3) C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl);

(4) C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl);

(5) carbarnoyl, optionally mono - or di-substituted C1-6the alkyl, such as carbarnoyl and dimethylcarbamoyl;

(6) sulfamoyl, optionally mono - or di-substituted C1-6the alkyl, such as sulfamoyl and dimethylsulphamoyl;

(7) mono - or di-C6-14arylcarbamoyl (for example, phenylcarbamoyl);

(8) mono - or di-C7-13aralkylamines (for example, benzylcarbamoyl);

(9) (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutylamino); 2-oxide-1,3,2-dioxaphosphinan; and the like.

R1preferably represents optionally substituted cyclic group, and more preferably, C6-14aryl group (preferably phenyl), optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl and pyrimidinyl), optionally substituted C1-6by alkyl; aromaticas the fused heterocyclic group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, chinosol and indazole), optionally substituted C1-6by alkyl; a 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuryl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxideequivalent), optionally substituted C1-6by alkyl; (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan); C1-6alkylsulfonyl; and (C1-6alkylsulfonyl.

When, in the formula (I), 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not be a-O-.

As preferable examples of compounds represented by formula (I)can be mentioned the following compounds.

The compound in which ring A is an imidazole ring, a pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring or tetrazole ring (preferably, a pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring and tetrazole ring is more preferable, pyrazol ring), each of which may have 1 or 2 substituent selected from C1-10alkyl group, a C6-14aryl group, and C7-13aranceles group;

B represents a C6-14aryl group (preferably, phenyl) or a 5-7 membered monocyclic aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl), each of them has optional 1-3 substituent selected from C1-6the alkyl, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkoxy, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), halogen atom (preferably, fluorine atom, chlorine atom, bromine atom);

X represents a C1-4alkylene or C2-4albaniles;

Z is a-CONR2- (where R2is the same as defined above, preferably a hydrogen or C1-6alkyl group, and the carbon atom (C)- CONR2is associated with X and the nitrogen atom (N) is related to Y);

Y is a bond or C1-4alkylen; and

R1represents a C6-14aryl group (preferably phenyl), optionally substituted C1-6alkyl group, optionally substituted by 1-3 mandated what teli, selected from 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl and pyrimidinyl), optionally substituted C1-6by alkyl; aromatic fused heterocyclic group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, chinosol and indazole), optionally substituted C1-6by alkyl; a 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuryl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxideequivalent), optionally substituted C1-6by alkyl; (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan); C1-6alkylsulfonyl; and (C1-6alkylsulfonyl.

As the optionally substituted cyclic group for R1preferred is a group represented by the formula:

where, as hereinafter defined, D is a ring optionally having, in addition, the Deputy (deputies the Fort worth); Y1represents a bond or divalent acyclic hydrocarbon group; R3' represents a group of the formula: -SO2R4, -SOR4or-PO3R4R5where R4and R5are the same or different and each represents a hydrogen atom, a hydrocarbon group or heterocyclic group, and R4and R5may form a heterocycle together with the adjacent oxo-substituted phosphorus atom and two oxygen atoms, or optionally substituted heterocyclic group.

"Hydrocarbon group" for R4or R5is the same as defined above.

"Heterocyclic group" for R4or R5is the same as defined above.

The heterocycle formed by R4and R5together with the adjacent oxo-substituted phosphorus atom and two oxygen atoms, is the same as defined above.

As divalent acyclic hydrocarbon group for Y1can be specified groups, represented as specified above X.

Y1preferably represents a bond or C1-4alkylene, more preferably a bond, -CH2-, -(CH2)2-, -(CH2)3- and the like.

As the rings "ring, optionally, in addition, has a Deputy (deputies)", D, can the t to be considered, for example, a ring corresponding to the "cyclic group" for the above R1.

Ring D preferably represents optionally partially saturated C6-14aromatic hydrocarbon ring (preferably benzene, dihydroindeno), C3-10cycloalkane (preferably cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane), C3-10cycloalkane (preferably cyclohexane), 5 - or 6-membered aromatic heterocycle, optionally condensed with a benzene ring (preferably furan, thiophene, oxazole, thiazole, isoxazol, imidazole, pyrazole, pyridine, pyrazin, indole, quinoline, isoquinoline and benzothiadiazole), 5 - or 6-membered nonaromatic a heterocycle, optionally condensed with a benzene ring (preferably pyrrolidine, tetrahydrofuran, thiazoline, oxazoline, thiazolidine, oxazolidine, dioxolane, piperidine, piperazine, morpholine, thiomorpholine, dihydrobenzofuran and oxidehydrogenation) and the like. Above the ring, more preferably represents a C6-14aromatic hydrocarbons, and benzene is particularly preferred.

The above ring may have 1-3 substituent in the substituted provisions. As such a substituent can be mentioned, for example, halogen atom (e.g. fluorine atom, chlorine atom, and the om bromine, the iodine atom), C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and trifluoromethyl, C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy and the like.

As the "optionally substituted acyl group" for R3can be specified, for example, of a group presented as substituents of "optionally substituted hydrocarbon group"represented as the substituents for ring A. as the "optionally substituted heterocyclic group" for R3or R3' can be specified, for example, of a group presented as the substituents for ring A.

As preferable examples of the "optionally substituted acyl group" for R3can be specified carboxyl group; C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl); (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan); carbarnoyl, optionally substituted amino; mono - or di-C1-6allylcarbamate, neoba is consequently substituted by 1-3 substituents, selected from halogen atom, hydroxy and C1-6alkoxycarbonyl, such as methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino, propellerblades, triptoreline, methoxycarbonylaminophenyl, 2-hydroxy-1-methoxycarbonylaminophenyl and 2-hydroxy-1-methoxycarbonylpropionyl; mono - or di-C6-14arylcarbamoyl, optionally substituted by 1-3 substituents selected from optionally halogenated C1-6the alkyl and C1-6alkoxy, such as phenylcarbamoyl, methoxyphenylacetyl and cryptomaterial; mono - or di-C7-13aralkylamines, optionally substituted by 1-3 substituents selected from amino, optionally mono - or di-substituted C1-6the alkyl, optionally halogenated C1-6the alkyl, hydroxy and C1-6alkoxycarbonyl, such as benzylcarbamoyl, phenetically, dimethylaminobenzylidene, methoxycarbonylmethylene and triftormetilfullerenov; sulfamoyl; optionally halogenated mono - or di-C1-6alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl); C1-6alkylsulfonyl (for example, methylsulfinyl, ethylsulfinyl, tert-butylsulfonyl); C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl, tert-butylsulfonyl); C1-6alkylsulphonyl (for example, AC is Teal); 5 - or 6-membered aromatic heterocyclic sulfinil (for example, triazolylmethyl and tetraallyltin), optionally substituted C1-6the alkyl, C6-14arylsulfonyl (for example, phenylsulfonyl); 5 - or 6-membered aromatic heterocyclic sulfonyl (for example, triazolylmethyl and tetraallylsilane), optionally substituted C1-6by alkyl; and the like. As the "optionally substituted acyl group" for R3preferred are groups of the formula: -SO2R4, -SOR4or-PO3R4R5(wherein each symbol is as defined above).

"Optionally substituted acyl group" for R3especially preferably represents C1-6alkylsulfonyl; and (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan).

Preferred examples of the "optionally substituted heterocyclic group" for R3or R3' include 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl); aromatic fused heterocyclic group (for example, benzimidazo the sludge, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, hinely, indazole); 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuryl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl, dioxideequivalent); and non-aromatic fused heterocyclic group (for example, oxidehydrogenation, tetrahydrolipstatin), each of which is optionally substituted by 1-3 substituents selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl (for example, methoxycarbonyl).

Among them, 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl), an aromatic fused heterocyclic group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, hinely, indazole), and 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuranyl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, voxopop azinil, dioxideequivalent), each of which is optionally substituted C1-6the alkyl, are preferred.

When, in the formula (II), 5-membered aromatic heterocycle represented by ring A is an imidazole, then Z should not represent-O-; when the 5-membered aromatic heterocycle represented by ring A is a pyrazole, X represents methylene, Z represents-S-, and Y is a bond, then ring represented by D, should not be oxadiazol.

As preferable examples of compounds represented by formula (II)may be considered following connection.

[Compound A]

The compound in which the ring A is an imidazole ring, a pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring or tetrazole ring (preferably pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring and tetrazole ring, more preferably pyrazol ring), each of which may have 1 or 2 substituent selected from C1-10alkyl group, a C6-14aryl group, and C7-13aranceles group;

B represents an optionally substituted aromatic hydrocarbon group or optionally substituted aromatic Goethe is acyclically group, more preferably, C6-14aryl group (preferably, phenyl) or a 5-7 membered monocyclic aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl), each of them has optional 1-3 substituent selected from C1-6the alkyl, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkoxy, optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), halogen atom (preferably fluorine atom, chlorine atom, bromine atom);

X represents divalent C1-8aliphatic hydrocarbon group, more preferably, C1-4alkylene or C2-4albaniles;

Z is a-CONR2- (where R2is as defined above and preferably represents a hydrogen atom or a C1-6alkyl group, and the carbon atom (C)- CONR2is associated with X and the nitrogen atom (N) is related to Y);

Y and Y1are the same or different and each is a bond or C1-4alkylen;

D represents C6-14aromatic hydrocarbon group optionally, in addition, has a Deputy (deputies), more preferably, C6-14aroma is slavogorod (preferably, benzene) optionally having 1-3 substituent selected from a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methyl and trifluoromethyl, and C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom)such as methoxy, ethoxy;

R3is a (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan); or 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl), or 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuryl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin), each of which is optionally substituted 1-3 C1-6alkilani.

[Compound B]

The compound in which the ring A is an imidazole ring, a pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring or tetrazole ring (preferably, irazola ring, oxadiazoline ring, thiadiazole ring, triazole ring or tetrazole ring, more preferably pyrazol ring), each of which may have 1 or 2 substituent selected from C1-10alkyl group, a C6-14aryl group, and C7-13aranceles group (preferably, C1-6alkyl groups such as methyl and the like);

B represents a C6-14aryl group (preferably, phenyl) or a 5-7 membered monocyclic aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl), each of them has optional 1-3 substituent selected from C1-6the alkyl, optionally substituted by 1-3 halogen atoms, C1-6alkoxy, optionally substituted by 1 to 3 halogen atoms, and halogen atom; more preferably, C6-14aryl group (preferably, phenyl)optionally having halogen atom (preferably, fluorine atom);

X represents a C1-4alkylene or C2-4albaniles; more preferably, -CH2-, -(CH2)2-, -CH=CH -, particularly preferably-CH=CH-;

Z is a-CONR2- (where R2is the same as defined above, and the carbon atom (C)- CONR2is associated with X and the nitrogen atom (N) is related to Y); more preferably-CONH-;

Y represents the ligature or C 1-4alkylene; more preferably a bond, -CH2-, -(CH2)2-, -(CH2)3-; particularly preferably, the connection;

Y1is a bond or C1-4alkylene; more preferably, a bond, -CH2-, -(CH2)2-, -(CH2)3-;

D represents C6-14aromatic hydrocarbon (preferably, benzene) optionally having 1-3 substituent selected from a halogen atom, a C1-6alkyl group optionally substituted by 1 to 3 halogen atoms and C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms; and

R3represents a carboxyl group; C1-6alkoxycarbonyl; (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan); carbarnoyl, optionally substituted amino; mono - or di-C1-6allylcarbamate, optionally substituted by 1-3 substituents selected from halogen atom, hydroxy and C1-6alkoxycarbonyl; mono - or di-C6-14arylcarbamoyl, optionally substituted by 1-3 substituents selected from optionally halogenated C1-6the alkyl and C1-6alkoxy; mono - or di-C7-13aralkylamines, optionally substituted by 1-3 substituents selected from amino, long is the super mono - or di-substituted C 1-6the alkyl, optionally halogenated C1-6the alkyl, hydroxy and C1-6alkoxycarbonyl; sulfamoyl; optionally halogenated mono - or di-C1-6alkylsulfanyl; C1-6alkylsulfanyl; C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl); C1-6alkylsulphonyl; 5 - or 6-membered aromatic heterocyclic sulfinil (for example, triazolylmethyl, tetraallyltin), optionally substituted C1-6the alkyl, C6-14arylsulfonyl (for example, phenylsulfonyl); 5 - or 6-membered aromatic heterocyclic sulfonyl (for example, triazolylmethyl, tetraallylsilane), optionally substituted C1-6by alkyl; more preferably, C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl); (mono - or di-C1-10alkyl)phosphono group, optionally forming a ring (e.g., dimethylphosphino; diethylphosphino; Diisopropylamine; dibutyltin; 2-oxide-1,3,2-dioxaphosphinan).

[Compound C]

The compound in which the ring A is an imidazole ring, a pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring or tetrazole ring (preferably, a pyrazol ring, oxadiazole ring, thiadiazole ring, triazole ring and tetrazole ring, more preferably pyrazol to what izo), each of which may have 1 or 2 substituent selected from C1-10alkyl group, a C6-14aryl group, and C7-13aranceles group (preferably, C1-6alkyl groups such as methyl and the like);

B represents a C6-14aryl group (preferably, phenyl) or a 5-7 membered monocyclic aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl), each of them has optional 1-3 substituent selected from C1-6the alkyl, optionally substituted by 1-3 halogen atoms, C1-6alkoxy, optionally substituted by 1 to 3 halogen atoms, and halogen atom; more preferably, C6-14aryl group (preferably phenyl), optionally having halogen atom (preferably, fluorine atom);

X represents a C1-4alkylene or C2-4albaniles; more preferably, -CH2-, -(CH2)2-, -CH=CH -, particularly preferably-CH=CH-;

Z is a-CONR2- (where R2is the same as defined above, and the carbon atom (C)- CONR2is associated with X and the nitrogen atom (N) is related to Y); more preferably-CONH-;

Y is a bond or C1-4alkylene; more preferably, a bond, -CH2-, -(CH2)2-, -(CH2)3-; particularly preferably, the IDE;

Y1is a bond or C1-4alkylene; more preferably, a bond, -CH2-, -(CH2)2-, -(CH2)3-;

D represents C6-14aromatic hydrocarbon (preferably, benzene)optionally having 1-3 substituent selected from a halogen atom, a C1-6alkyl group optionally substituted by 1 to 3 halogen atoms, and C1-6alkoxy group optionally substituted by 1 to 3 halogen atoms; and

R3represents 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl); aromatic fused heterocyclic group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, hinely, indazole); 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuryl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl, dioxideequivalent); non-aromatic fused heterocyclic group (e.g., oxidehydrogenation, tetrahydrolipstatin), each of which is optionally substituted by 1-3 substituents selected from C1-6 of alkyl, hydroxy-C1-6of alkyl, carboxyl, carbamoyl and C1-6alkoxycarbonyl;

more preferably, 5 - or 6-membered aromatic heterocyclic group (for example, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl), an aromatic fused heterocyclic group (for example, benzimidazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, hinely, indazole) or 5 - or 6-membered nonaromatic heterocyclic group (for example, tetrahydrofuranyl, morpholinyl, thiomorpholine, piperidine, pyrrolidine, piperazinil, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl, dioxideequivalent), each of which is optionally substituted C1-6the alkyl.

[Connection D]

Diethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate (Example No. 2);

(2E)-N-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide (Example No. 60);

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-imidazol-1-ylmethyl)phenyl]acrylamide (Example No. 159);

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-pyrazole-1-ylmethyl)phenyl]acrylamide (Example No. 161);

diethyl [4-({(2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzylphosphonate (Example No. 149);

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(3-methyl-2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}acrylamide (Example No. 110);

(2E)-N-[4-(1H-benzimidazole-1-ylmethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide (Example No. 185);

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(methylsulphonyl)methyl]phenyl}acrylamide (Example No. 222);

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[hydroxy(2-pyridinyl)methyl]phenyl}acrylamide (Example No. 49);

(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(4-morpholinylmethyl)phenyl]acrylamide (Example No. 192); and

(2E)-N-{4-[(ethylsulfonyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide (Example No. 223).

Salts of the compounds represented by formula (I) or (II), the compound used in the synthesis of compounds represented by formula (I) or (II), and the compound used in the present invention, preferably represent a pharmacologically acceptable compounds and may constitute, for example, a salt with inorganic base, a salt with organic base, salt with inorganic acid, salt with organic acid, salt with basic or acidic amino acid.

Preferred examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; salts of alkaline earth metals such as calcium salt, with the l magnesium and the like; and an aluminium salt, ammonium salt and the like.

Preferred examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenziletilendiaminom and the like.

Preferred examples of the salt with inorganic acid include salts with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid and the like.

Preferred examples of the salt with organic acid include salts with formic acid, acetic acid, triperoxonane acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid and the like.

Preferred examples of salts with basic amino acid include salts with arginine, lysine and ornithine, and the like.

Preferred examples of salts with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

Among these salts, sodium salt, potassium salt, hydrochloride and the like are preferable.

Proletar is in connection represented by formula (I) or (II)or its salt (hereinafter sometimes abbreviated referred to as the compound of the present invention means a compound capable of conversion into a compound of the present invention in vivo by the action of an enzyme or gastric juice and the like, in physiological conditions, namely, a compound capable of conversion into a compound of the present invention in enzymatic oxidation, restoring or hydrolysis, and the like, or a compound capable of conversion into a compound of the present invention during the hydrolysis and the like, with the help of gastric juice and the like. As prodrugs of the compounds of the present invention may include the compounds derived by acylation, alkylation or postlarvae amino compounds of the present invention (e.g., compounds derived by eicosapolyene, alanalanalana, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofurfurylamine, pyrrolidinedione, pivaloyloxymethyl or tert-bottled amino compounds of the present invention, and the like); compounds derived by acylation, alkylation, postlarvae or Borisovna hydroxy-group is soedineniya of the present invention (for example, compounds obtained by acetylation, palmitoleate, propanolamine, pihlajasaari, succinylcholine, fumariaceae, alanalanalana or dimethylaminoethylacrylate hydroxy-group of the compounds of the present invention, and the like); and compounds obtained by esterification or amidation of the carboxyl group of the compounds of the present invention (e.g., compounds derived by ethyl esterification, phenyl esterification, carboxymethylate esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonylmethylene esterification, teledramas esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, cyclohexyloxycarbonyloxy esterification, or methylaminopropane carboxyl group connection the present invention, and the like) and so on. These compounds can be obtained from the compounds of the present invention using methods known in themselves.

The prodrug compounds of the present invention may constitute one of the compounds capable of conversion into a compound of the present invention under physiological conditions, as described in "Iyakuhin no Kaihatsu (Development of Drugs)", vol. 7, Molecular Designing, published by Hirokawa Shoten, 1990, pages 163-198.

The connection is really the invention may be labeled with an isotope (for example, 3H,14C,35S125I and the like) and the like.

In addition, the compound of the present invention may be an anhydride or a hydrate.

The compound of the present invention and its prodrug are low-toxic and can be used for mammals (e.g. human, mouse, rat, rabbit, dog, cat, cattle, horses, pigs, monkeys and the like), as a means for prevention or treatment of neuropathy, tools that enhance the production or secretion of neurotrophic factors and the like, either alone or in a mixture with a pharmaceutically acceptable carrier, or the like, to obtain a pharmaceutical composition.

As indicated above pharmacologically acceptable carrier can be given various organic or inorganic carriers which are generally used as materials for pharmaceutical preparations. They are included as fillers, lubricants, binders, disintegrating agents or the like, in solid preparations; solvents, solubilization, suspendida funds, isotonic means superyoshi funds, sedatives, or the like, in liquid preparations. Where necessary, can the additives to be used, such as preservatives, antioxidants, coloring tools, sweeteners and the like.

As preferred examples of the fillers may be mentioned lactose, sucrose, D-mannitol, D-sorbitol, starch, pre-gelatinizing starch, dextrin, crystalline cellulose, hydroxypropylcellulose with a low degree of substitution, sodium carboxymethyl cellulose, powdered gum, pullulan, silicic anhydride, low density, synthetic aluminum silicate, magnesium alumosilicate and the like.

As preferred examples of the lubricants can be specified stearate, calcium stearate, talc, colloidal silica and the like.

As preferred examples of binders can be pre-specified gelatinizing starch, sucrose, gelatin, powdered gum, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sugar, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone and the like.

As preferred examples of disintegrating agents may be mentioned lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium crosscarmellose, sodium carboxymethyl Rahman, silicic anhydride, low density, hydroxypropylcellulose with a low degree of substitution and the like.

As preferred examples of the solvents may be mentioned water for injection, physiological saline, ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

As preferred examples of solubilization can be mentioned polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, Tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.

As the preferred examples suspendida funds can be specified surfactants, such as steartrimonium, sodium laurylsulfate, lauramidopropyl acid, lecithin, benzalconi chloride, benzethonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates, polyoxyethylene-utverjdenie castor oil and the like.

As preferred examples of isotonic among the STV can be mentioned sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.

As the preferred examples superyoshi funds can be specified buffer solutions of phosphate, acetate, carbonate, citrate and the like.

As preferred examples of sedatives may be mentioned benzyl alcohol and the like.

As preferred examples of preservatives can be specified pair-hydroxybenzoate, chlorbutanol, benzyl alcohol, finitely alcohol, dehydroacetic acid, sorbic acid and the like.

As preferred examples of the antioxidants can be specified sulfites, ascorbates and the like.

As preferred examples of the dye can be mentioned water-soluble edible dye-based resins (e.g., food colors such as Food Color Red No. 2 and No. 3, Food Color Yellow No. 4 and No. 5, Food Color Blue No. 1 and No. 2), water-insoluble lacquer dyes (e.g., aluminum salt of the aforementioned water-soluble edible dye-based resins, and the like), natural dyes (for example, β-carotene, chlorophyll, red iron oxide, and the like) and so on.

As preferred examples of the sweeteners can be specified sodium saccharin, zikali the glycyrrhizinate, aspartame, Peconic krapivinsky and the like.

In the operation of standard dosage forms on the basis of the above pharmaceutical compositions may be specified oral drugs such as tablets (including sublingual tablet and tablet, disintegrating in the mouth), capsules (including soft capsules and microcapsules), granules, powders, coated tablets, syrups, emulsions, suspensions and the like; or a parenteral drugs, such as drugs for injection (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, and the like), external agents (e.g., transdermal preparations, ointments and the like), suppositories (e.g. rectal suppositories, vaginal suppositories, and the like), pellets, transnasal funds transpulmonary funds (inhaled), eye drops and so on and so forth, and these drugs can be safely administered orally or parenterally.

These drugs can be a drugs controlled release (e.g., microcapsules with a slow release, and the like), such as drugs with quick release, drugs with a slow release, and the like.

The pharmaceutical composition may be obtained using methods well known in the technology of pharmaceutical production, for example, using methods described in the Pharmacopoeia of Japan, and the like. Next, some specific ways of receiving the Oia such preparations are described in detail. The content of compounds of the present invention in the pharmaceutical composition varies depending on the dosage forms, doses of the compounds of the present invention and the like, but it is, for example, about 0.1-100 wt.%.

For example, the preparation for oral administration can be obtained by adding a filler (e.g. lactose, sucrose, starch, D-mannitol and the like), baking powder (e.g., calcium carboxymethylcellulose, and the like), binders (for example, pre-gelatinizing starch, powdered gum, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and the like), lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000 and the like) and so forth, to the active ingredient and molding by compressing the mixture, and then, if desired, by coating on the formed product, in a manner known per se, from the basics to cover, for the purpose of taste masking or give enteric property or durability to destruction.

As the basis for coverage can be specified, for example, sugar basis for cover, the basis for coverage in the form of a water-soluble film, the basis for coverage in the form of enteric film, the basis for coverage in the form of a film with samedl the authorized release, and the like.

As sugar basics of coverage uses sucrose and, in addition, in combination, can be used one or more kinds of ingredients selected from talc, precipitated calcium carbonate, gelatin, powdered gum, pullulan, Carnauba wax and the like.

As the basis for coverage in the form of a water-soluble film can be specified, for example, cellulose polymers such as hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers, such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), Rohm Pharma], polyvinylpyrrolidone and the like; polysaccharides, such as pullulan and the like and so forth.

As the basis for coverage in the form of enteric film can be specified, for example, cellulose polymers, such as phthalate of hydroxypropylmethylcellulose, acetate succinate of hydroxypropylmethylcellulose, karboksimetiltselljuloza, acetate phthalate cellulose and the like; polymers of acrylic acid such as methacrylic acid copolymer L [Eudragit L (trade name), Rohm Pharma], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma], methacrylic acid copolymer S [Eudragit S (trade name is tion), Rohm Pharma] and the like; natural products such as shellac and so on and so forth.

As the basis for coverage in the form of a film with a slow release can be specified, for example, cellulose polymers such as ethylcellulose and the like; polymers of acrylic acid such as a copolymer of aminoalkyl methacrylate RS [Eudragit RS (trade name), Rhom Pharma], the suspension of a copolymer of acrylate-methyl methacrylate [Eudragit NE (trade name), Rohm Pharma] and so on and so forth.

Two or more of the above bases for coatings can be used in a mixture with the corresponding proportions. In the case of coating can be used bleaching agent, such as titanium oxide, iron oxide, and the like.

The preparation for injection get through dissolution, suspension or emulsion of the active ingredient in an aqueous solvent (e.g. distilled water, physiological solution, ringer's solution) or in an oil solvent (for example, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil and the like; propylene glycol and the like), together with a dispersant (e.g., Polysorbate 80, polyoxyethylene-utverzhdennym castor oil 60, polyethylene glycol, carboxymethylcellulose, alginate n is sodium and the like), preservatives (such as methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol, phenol and the like), isotonic agents (e.g. sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like) and so on. If so desired, may be used, such additives as soljubilizatory (e.g., sodium salicylate, sodium acetate and the like), stabilizers (for example, serum albumin, human and the like), sedatives (e.g., benzyl alcohol and the like) and so on.

The compound of the present invention has an excellent effect of enhancing the production or secretion of neurotrophic factor.

As a neurotrophic factor can be specified, for example, neurotrophin, the superfamily of TGF-βfamily neurokinin, growth factor and the like.

Neurotrophin is a common name of the gene family of growth factor nerve (NGF) and refers to a protein that plays an important role in differentiation and functional homeostasis of the cells of the Central and peripheral nervous systems, the formation of synapses, regeneration and repairing damage, and the like. As specific examples neurotrophin can be specified NGF, BDNF (derived neurotrophic factor, obtained from the brain), NT-3 (neurotrophin-3), NT-4/5 (neurot the OPIN-4/5), NT-6 (neurotrophin-6), and the like. Neurotrophin preferably includes NGF, BDNF, NT-3, and the like.

The superfamily of TGF-β means the group of proteins known that it has a structure that differs by the position of the cysteine in the Mature molecule, and exhibits a great variety of effects on various cells and tissues. As specific examples can be given of TGF-β1, TGF-β2, TGF-β3, BMP (osteogenic factor, bone morphogenetic protein)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8A, BMP-8B, BMP-14 (GDF-5), GDNF (derived neurotrophic factor derived from line glial cells), neurturin, artemin, persephin, GDF-1, GDF-8, GDF (growth factor/differentiation)-15, inhibin αinhibin β, DAF (formation phase delay) 7 and the like. The superfamily of TGF-β preferably represents GDNF, GDF-15, and the like.

As a family neurokinin can be specified, for example, ciliary neurotrophic factor (CNTF), interleukin 6 (IL-6), and the like.

As a growth factor can be specified, for example, the growth factor insulin-1 (IGF-1), growth factor, basic fibroblast, and the like.

Neurotrophic factor preferably is neurotrophin, the superfamily of TGF-β and the like, more preferably NGF, BDNF, NT-3, GDNF, GDF-15, and the like.

The compound of the present invention has the hcpa the op perate, improve functioning of nerves.

In addition, the compound of the present invention has the effect of improving the speed signal of the motor nerve or sensory nerve action, debilitating pain (e.g. neuropathic pain) and neuroprotective.

Here, "neuroprotective effect" refers to the action of neurite growth, the effect of forming naritai network, the effect of suppressing reduction of neurite, the effect of suppressing the degeneration of nerve endings and the like.

The connection according to the present invention can be used as a means to prevent or treat, for example, neuropathies (e.g., peripheral neuropathies, such as diabetic neuropathy, neuropathy caused by cancer treatment, and the like, Guillain-Barre syndrome); neurodegerative diseases (e.g., senile dementia of Alzheimer, Parkinson's, Horai Huntington, side microfische sclerosis (ALS), down syndrome); diabetic cardiac myopathy; damage to the peripheral nervous system; spinal cord injuries; spinal stenosis channel; multiple sclerosis; cerebral ischemic disease; epilepsy; depression; tremor; syndrome restless legs; inflammatory bowel disease (e.g., inflammatory colitis); neuropatic the ski pain (for example, painful neuropathy, post herpetic neuralgia, back pain, trigeminal neuralgia, their carpal canal syndrome, phantom pain, spinal injury, multiple sclerosis), chronic pain (such as pain in cancer); behavioral anomalies, followed by dementia (e.g., wandering, aggressive behavior); disorders of the neurosis of fear; the muscles caused by injury; Autonomous anomalies (e.g., diabetic autonomic disorder, asymptomatic hypoglycemia, gastroparesis, neuropathic diarrhea and constipation, erectile dysfunction, orthostatic hypotension, arrhythmia, heart failure, painless heart attack, dyshidrosis, neuropathic bladder, sudden deafness, chronic obstruction of the arteries, tides blood to a person); bladder dysfunction (e.g., disorder of reflex bladder); the weakening of hearing, diabetic damage to the feet; bone diseases (e.g. osteoporosis); diseases of the joints (e.g., Charcot joint, osteoarthritis, rheumatic fever); diseases of Hirshprung and the like.

In addition, the compound of the present invention can also be used as a means for prevention or treatment of diseases such as diabetes (for example diabetes, type 1 diabetes, type 2, gestational diabetes and that is similar) weakened glucose tolerance (IGT), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, Hypo-HDL-emii, postprandial hyperlipidemia), hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases (e.g. atherosclerosis), and the like; or syndrome (e.g., syndrome X, visceral syndrome obesity), including a combination of some of these diseases.

In addition, the compound of the present invention is used for secondary prevention or suppression of development (for example, suppression of the development weakened glucose tolerance in diabetes) the above various diseases (e.g. heart attack).

In addition, the compound of the present invention can be used as debilitating remedies for peripheral neuropathy or metabolic disorders of the brain; the promoter for the treatment of skin damage caused by disease of metabolic or endocrine system such as diabetes, and wound; means for regeneration of the pancreas (the means to restore pancreatic function; means for regeneration of the kidney (tools for recovery of renal function); means for attenuating or suppressing pain (e.g. neuropathic pain); prophylactic agent for amputation of the lower limb; p is operationsmore funds from sudden death, and the like.

Although the dose of a compound of the present invention varies depending on subject of administration, route of administration, target disease, condition and the like, it is, for example, in the case of oral administration to an adult patient with peripheral neuropathy (e.g., diabetic neuropathy), as a rule, is about 0.01 to 100 mg/kg body weight, preferably 0.05 to 30 mg/kg body weight, more preferably 0.1 to 2 mg/kg of body weight, per dose, this amount is preferably administered from one to 3 times a day.

The compound of the present invention can be used in combination with a pharmaceutical vehicle (hereinafter will be abbreviated to be referred to as a combination drug), such as a therapeutic agent for diabetes, a therapeutic agent of diabetic complications, antiepileptic agent, an antidepressant, an agonist opioids, protivogipertonicheskoe tool, protivogipertonicheskoe tool, anti-arrhythmia, anti-obesity, diuretic, a chemotherapeutic agent, immunotherapy agent, antithrombotic agent, a therapeutic agent of osteoporosis, a remedy for dementia, the means to mitigate erectile dysfunction therapeutic agent from incontinence or fast urination, therapeutic agents is from dysuria, non-steroidal anti-inflammatory drug, a local anesthetic, vitamins and the like. These combination medicines can be a low molecular weight compound, or may be a high molecular weight protein, polypeptide, antibody, vaccine and the like.

As a therapeutic agent for diabetes may include insulin preparations (e.g., animal insulin preparations obtained by extraction from bovine or porcine pancreas); preparations of human insulin synthesized by genetic engineering using Escherichia coli or a yeast; insulin zinc; Protamine-insulin-zinc, fragment or derivative of insulin (e.g., INS-1 and the like, for oral insulin preparations and the like), insulin sensitizers (e.g., pioglitazone or its salt (preferably hydrochloride), rosiglitazone or its salt (preferably maleate), regexen (JTT-501), GI-262570, netoglitazone (MCC-555), YM-440, DRF-2593, BM-131258, KRP-297, R-119702, CS-011, FK-614, compounds described in the application for international patent WO 99/58510 (e.g., (E)-4-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzylamino]-4-fenilalanina acid), compounds described in the application for an international patent WO 01/38325, tesaglitazar (AZ-242), ragaglitazar (NN-622), BMS-298585, ONO-5816, BM-13-1258, LM-4156, MBX-102, LY-519818,MX-6054, LY-510929, balaglitazone (NN-2344), T-131 or its salt, THR-0921 and the like), inhibitors α-glucosidase (e.g., voglibose, acarbose, miglitol, emiglitate and the like), biguanides (e.g., phenformin, Metformin, buformin and the like), stimulants of insulin secretion, [sulfonylureas (e.g. tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole and the like), Repaglinide, sinapinic, nateglinide, mitiglinide or hydrate of its calcium salt and the like], GPR40 agonists, receptor agonists GLP-1 [e.g., GLP-1, GLP-1MR, NN-2211, AC-2993 (basis 4), BIM-51077, Aib(8,35)hGLP-1(7,37)NH2, CJC-1131, and the like], agonists of amerina (for example, pramlintide and the like), inhibitors phosphotyrosine phosphatase (for example, vanadium acid and the like), inhibitors dipeptidylpeptidase IV (for example, NVP-DPP-278, PT-100, P32/98, NVP-DDP-728, LAF237, TS-021, and the like), agonists β3 (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 and the like), inhibitors of gluconeogenesis (e.g., inhibitors of glycogen phosphorylase inhibitors of glucose-6-phosphatase, glucagon antagonists, and the like), SGLT inhibitors (superelastic sodium-glucose) (e.g., T-1095 etc.), inhibitors of 11β-hydroxysteroid dehydrogenase (e.g., BVT-3498 etc.), adiponectin or agonists, an inhibitor of the IKK (e.g., AS-2868, and the like), medicines for high resistance to leptin agonists receptor simastatin (compounds described in International patent applications WO 01/25228 and WO 03/42204, the compounds described in the International patent applications WO 98/44921, WO 98/45285 and WO 99/22735, etc.), glucokinase activators (e.g., Ro-28-1675) and the like.

As a therapeutic agent from complications of diabetes can be specified inhibitors aldose reductase (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CTPET-112 and the like), neurotrophic factors and drugs to increase their levels (e.g., NGF, NT-3, BDNF, promoters production or secretion neurotrophin described in the application for international patent WO 01/14372 (for example, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole and the like), and so on), the accelerator nerve regeneration (e.g., Y-128, and the like), PKC inhibitors (e.g., LY-333531 and the like), AGE inhibitors (e.g., ALT946, pimagedine, picrotoxinin, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridorin, pyridoxamine, and the like), scavengers of active oxygen (e.g., thioctic acid, and the like), cerebral vasodilators (e.g., tiaprid, meksiletin and the like), agonists of the receptors somatostatin is on (BIM23190), inhibitors of kinase-1, regulatory signals apoptosis (ASK-1), and the like.

As antiepileptic drugs may be indicated, for example, gabapentin, gabapentin MR, trileptal, keppra has, zonegran, pregabalin, harcore, carbamazepine, and the like.

As antidepressants may be indicated, for example, amitriptyline, imipramine, and the like.

As agonist opioids may be indicated, for example, morphine and the like.

As protivoepidemicheskaja funds may be specified, connection statin (for example, tseriwastatina, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, and their salts (for example sodium salt) and the like), inhibitors of squalene synthase (e.g., compounds described in the application for international patent WO 97/10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid, and the like), compounds of fibrate (for example, bezafibrat, clofibrate, simfibrate, clinofibrate and the like), antioxidants (for example, lipoic acid, probucol) and the like.

As protivogipertonicheskoe funds can be indicated inhibitors angiotensin-converting enzyme (for example, captopril, enalapril, delapril and the like) or ant is honesty angiotensin II (e.g., candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1-[[2'-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acids and the like), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, and the like), clonidine and the like.

As anti-arrhythmia can be specified, for example, meksiletin and the like.

As a remedy against obesity can be specified, for example, drugs against obesity, affecting the Central nervous system (for example, dexfenfluramin, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP-7941; compounds included in the applications for International patents WO 01/82925 and WO 01/87834 and the like); antagonists of neuropeptide Y (e.g., CP-422935, and the like); antagonists of the receptor for cannabinoids (e.g., SR-141716, SR-147778, and the like); ghrelin antagonists; inhibitors of 11β-hydroxysteroid dehydrogenase (e.g., BVT-3498 and the like, and so on), inhibitors of pancreatic lipase (e.g., orlistat, ALT-962 and the like)agonists β3 (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 and the like), anorectics pepti the s (for example, leptin, CNTF (ciliary-derived neurotrophic factor) and the like), cholecystokinin agonists (e.g., lintitript, FPL-15849 etc.), anorectic (e.g., P-57, and the like) and so on.

As a diuretic can be specified, for example, xanthine derivatives (e.g., sodium salicylate and theobromine, calcium salicylate and theobromine, and the like), drugs thiazide (for example, atiase, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydroxylamine, panflutes, polythiazide, methyclothiazide and the like), protivoallergennye drugs (eg, spironolactone, triamterene and the like), inhibitors of carbonic carbonic anhydrase (e.g., acetazolamide and the like), drugs chlorobenzenesulfonamide (e.g., chlorthalidone, mefruside, indapamide etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

As chemotherapeutic agents can be specified, for example, alkylating tools (e.g., cyclophosphamide, ifosfamide, etc.), antagonists of metabolism (e.g., methotrexate, 5-fluorouracil, and the like), anticancer antibiotics (e.g., mitomycin, adriamycin etc.), anticancer agents of vegetable origin (e.g., vincristine, vindesine, Taxol etc.), cisplatin, carboplatin, etoposide and the like. Among them, furtulon and neopentylene, which are derivatives of 5-fluorouracil and the like, are preferred.

As immunotherapy may be indicated, for example, components of microorganisms or bacteria (for example, a derivative of the dipeptide muramira, picibanil and the like), polysaccharides having the activity of increasing immunity (e.g., lentinan, sizofiran, christenings and the like), cytokines obtained by genetic engineering (e.g., interferon, interleukin (IL), and the like), the factors stimulating the growth of the colonies (for example, the factor stimulating the growth of colonies of granulocytes, erythropoietin and the like) and so forth, with preference given to interleukins such as IL-1, IL-2, IL-12, and the like.

As antithrombotic funds may be specified, for example, heparin (e.g., sodium heparin, calcium heparin, sodium dalteparin and the like), warfarin (e.g., potassium warfarin, and the like), protivotumanki medicines (for example, argatroban and the like), thrombolytic tools (e.g., urokinase, isocynate, alteplase, reteplase, monteplase, pamiteplase and the like), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride Cilostazol, ethyl icosapentate, sodium beraprost, sarpogrelate hydrochloride and the like) and so on.

As a therapeutic agent for osteoporosis can be specified, for example, alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, disodium pamidronate, sodium alendronate hydrate, disodium encadrant and the like.

As a means of dementia can be specified, for example, taken, donepezil, rivastigmine, galantamine and the like.

As a means to alleviate erectile dysfunction can be specified, for example, apomorphine, sildenafil citrate and the like.

As a therapeutic agent from incontinence or fast urination can be specified, for example, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.

As a therapeutic agent from dysuria can be specified inhibitors of acetylcholine esterase (e.g., distigmine) and the like.

As a non-steroidal anti-inflammatory drugs may be indicated, for example, aspirin, acetaminophen, indomethacin, and the like.

As a local anesthetic can be specified, for example, lidocaine, capsaicin, and the like.

As vitamins can be specified, for example, vitamin B1, vitamin B12 and so on is one.

In addition, drugs that have the effect of weakening cachexia, established in animal models or in clinical situations, such as cyclo-oxygenase inhibitors (e.g., indomethacin and the like) [Cancer Research, Vol. 49, 5935-5939, 1989], the derivatives of progesterone (for example, megestrol acetate) [Journal of Clinical Oncology, Vol. 12, 213-225, 1994], glucosteroid (for example, dexamethasone and the like), metoclopramide funds tetrahydrocannabinol funds (ibid), agents, improving fat metabolism (e.g., eicosapentanoic acid and the like) [British Journal of Cancer, Vol. 68, 314-318, 1993], growth hormones, IGF-1, or antibodies to factor induces cachexia, such as TNF-α, LIF, IL-6, Oncostatin M and the like, may also be used in combination with the compound of the present invention.

Combined drug preferably is a drug insulin sensitizer insulin, inhibitor α-glucosidase, biguanide, a stimulator of insulin secretion (preferably a sulfonylurea), an inhibitor of aldose reductase inhibitor, a PKC inhibitor, an antiepileptic agent, an antidepressant, anti-arrhythmia, agonist opioids, antioxidant, non-steroidal anti-inflammatory drug, and the like.

Time of introduction of the above combined with drug is estva not limited to, and the connection according to the present invention and the combination drug can be administered to a subject, introducing at the same time, or they can be entered Paladino. The combined dosage of the medicinal product may be determined in accordance with the clinically used dose, and can be selected appropriately, depending on subject of administration, route of administration, disease, combination and the like.

The method of introduction of the combined drugs is not in any way limited insofar as the compound of the present invention and a combination drug are combined in administration. Examples of such injection mode include the following methods: (1) the compound of the present invention and a combination drug are processed simultaneously with the receipt of a single drug that is injected. (2) the Compound of the present invention and a combination drug are processed separately to obtain two kinds of preparations which are administered simultaneously, using the same method of administration. (3) the Compound of the present invention and a combination drug are processed separately to obtain two kinds of preparations which are administered through the same is the procedure of introducing Paladino. (4) the Compound of the present invention and a combination drug are processed together with the receipt of two kinds of preparations which are administered simultaneously by different routes of administration. (5) the Compound of the present invention and a combination drug are processed separately to obtain two kinds of preparations which are administered through various routes of administration, Paladino (for example, the compound of the present invention and a combination drug are entered in this order or in reverse order) and the like.

The proportion of compounds of the present invention to the combination drug can be selected appropriately, depending on subject of administration, route of administration, diseases and the like. For example, when the subject of this introduction is people, from 0.01 to 100 mass parts of the combined drugs are used to 1 part of weight of compounds of the present invention.

When the compound of the present invention is used in conjunction with the combined drug, the dosage of both components can be reduced within a safe range, given the opposite effects of the components. In particular, a combination of drugs is, such as a sensitizer to insulin, a stimulator of insulin secretion (preferably a sulfonylurea), biguanide, an inhibitor of aldose reductase inhibitor, a PKC inhibitor, an antiepileptic agent, an antidepressant, anti-arrhythmia, agonist opioids, antioxidant, non-steroidal anti-inflammatory drug, and the like, may be reduced in number compared with the normal dose. Thus, the opposing effects of these combined drugs can be safely avoided.

The compound of the present invention can be used in combination with the treatment method, which includes non-pharmacological means, such as spinal electrical stimulation, acupuncture and acupuncture with moxibustion, and the like.

Then explains how to obtain the compounds of the present invention.

The compound (I) can be obtained in accordance with the method, which is in itself known, such as method A, method D and method F, which will be described hereinafter, or in a manner analogous to them.

The compound (Ia) of the formula (I), where Z is a-CONR2- (R2is the same as defined above) can be obtained in accordance with the following method A.

[Method A]

In this method, compound (III) is subjected to amidation reaction of obtaining compound (Ia). This reaction is carried out in accordance with the method, which is in itself known, such as the method of directly condensing compound (III) with compound (IV), the way of interaction of the reactive derivative of compound (III) with compound (IV) and the like.

The method of directly condensing compound (III) with compound (IV)is generally carried out in the presence of a condensation catalyst in a solvent that does not adversely affect the reaction.

As the condensation catalyst may be specified conventional means, such as reagents for condensation-based carbodiimides, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or its hydrochloride and the like; agents for condensation on the basis of metaphosphoric acid such as the diethyl RIANovosti, diphenylphosphoryl azide and the like; carbonyl diimidazole, 2-chloro-1,3-dimethylimidazole tetrafluoroborate and the like.

As the solvent that does not adversely affect the reaction, can be specified, for example, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; galogenidov the haunted hydrocarbons, such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; ethyl acetate, water and the like. Two or more kinds of these solvents can be used in a mixture with the corresponding relations.

The amount of compound (IV)to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (III).

The amount of the condensation catalyst to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (III).

When the above reagent for condensing type carbodiimide is used as the condensation catalyst, the reaction efficiency can be improved by the use of the condensation promoter (e.g., 1-hydroxy-1H-1,2,3-benzotriazole hydrate, 1-hydroxy-7-isobenzofuranone, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide and the like)where it is necessary. When the above reagent for condensing type phosphoric acid is used as the condensation catalyst, the reaction efficiency can be improved is and, as a rule, by adding a base type of organic amine such as triethylamine and the like.

The number of the above promoter condensation of organic bases amine to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (III).

The reaction temperature is usually -30°C-100°C.

The reaction time is usually 0.5 to 60 hours.

As the reactive derivative of the above compound (III) can be specified, for example, acid anhydride, galogenangidridy (acid chloride, bromohydrin), imidazole, or a mixed acid anhydride (e.g., anhydride with methylcarbonate, ethylcarbonate or isobutylketone and the like) and so on.

For example, when an acid anhydride or galogenangidridy is used as the reactive derivative, the reaction is usually carried out in the presence of a base, in a solvent that does not adversely affect the reaction.

As the base can be specified, for example, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N,N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate on the matter, potassium carbonate, cesium carbonate and the like.

As the solvent that does not adversely affect the reaction, can be specified, for example, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; ethyl acetate, acetonitrile, water and the like. Two or more kinds of these solvents can be used in a mixture with the corresponding relations. When the above amides are used as the solvent that does not adversely influence the reaction, the reaction can also be carried out in the absence of base.

The amount of compound (IV)to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (III).

The amount of base to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (III).

The reaction temperature is usually -30°C-100°C.

The reaction time is usually 0.5 to 20 hours

When a mixed acid anhydride is used as the reactive derivative, the compound (III) interacts with a complex ester harpalinae acid in the presence of a base, and then interacts with the compound (IV).

As of ester harpalinae acids may be mentioned, for example, methylcarbonate, ethylchloride, isobutylparaben and the like.

As the base can be specified, for example, triethylamine, aniline, N-methylmorpholine, N,N-dimethylaniline, 4-dimethylaminopyridine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like.

The amount of compound (IV)to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (III).

The reaction temperature is usually -30°C-100°C.

The reaction time is usually 0.5 to 20 hours.

The compound (Ia)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

The compound (IV), which is is to be used as a starting compound in the above method A, can be obtained by using method, which is in itself known.

The compound (III), which should be used as a starting compound in the above method And may be obtained, for example, the following further method B.

[Method B]

where R6represents an optionally substituted hydrocarbon group, optionally substituted heterocyclic group or optionally substituted acyl group, and other symbols are as defined above.

As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for R6can be used by groups, respectively, represented as the above B.

As the "optionally substituted acyl group" for R6can be used to group presented as those of the above R1.

R6preferably represents C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, tert-butyl), C7-13aracelio group (e.g. benzyl), C6-14aryl group (e.g. phenyl) and the like.

In this method, the compound (V) is subjected to hydrolysis to obtain compound (III).

This reaction is carried out in accordance with the conventional method, in the presence of the iSlate, in a solvent containing water.

The acid can be mentioned, for example, hydrochloric acid, sulfuric acid, acetic acid, Hydrobromic acid and the like.

As the base can be specified, for example, carbonates of alkali metals such as potassium carbonate, sodium carbonate, cesium carbonate and the like; carbonates of alkaline earth metals such as barium carbonate, calcium carbonate and the like; alkali metal alkoxide such as sodium methoxide and the like; alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; hydroxides of alkaline earth metals such as barium hydroxide, calcium hydroxide and the like; and the like.

The amount of acid or base that must be used is, as a rule, an excess amount relative to the compound (V). Preferably, the amount of acid to be used is about 2 to about 50 equivalents relative to the compound (V), and the number base to be used is about 1.2 to about 10 equivalents relative to the compound (V).

As a solvent containing water, can be specified, for example, a mixed solvent of water and one or nakolkanerov solvents, selected from alcohols, such as methanol, ethanol and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; dimethyl sulfoxide and acetone and the like, and so on. When hydrolysis is acid, the solvent can be used an excessive amount of acid.

The reaction temperature is usually from about -20 to about 150°C, preferably from about -10 to about 100°C.

The reaction time is generally about 0.1 - about 20 hours.

The compound (III)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

The compound (V), which should be used as a starting compound in the above method B, can be obtained by using method, which is in itself known. For example, from compounds (V), compounds where X represents-CH=CH - or -(CH2)2- [accordingly, the compound (V-1) or (V-2)]can be obtained in accordance with the following method C.

[Method C]

where R7represents the t an optionally substituted hydrocarbon group, optionally substituted heterocyclic group or optionally substituted acyl group, and other symbols are as defined above.

As the "optionally substituted hydrocarbon group", "optionally substituted heterocyclic group" and "optionally substituted acyl group" for R7use groups, respectively, represented as the above R6.

R7preferably represents C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, tert-butyl), C7-13aracelio group (e.g. benzyl), C6-14aryl group (e.g. phenyl) and the like.

(Stage 1a)Reaction recovery

This reaction is carried out in accordance with the conventional method in the presence of a reducing agent in a solvent that does not adversely affect the reaction.

As the reducing agent can be specified, for example, sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminium hydride, dihydrobis(2 methoxyethoxy)sodium aluminate, borane and its complexes (for example, borane-tetrahydrofuran, borane-pyridine, borane-dimethyl sulfide, and the like) and so on.

The amount of reducing agent to be used, is preferably the ome 0.5 to about 10 molar equivalents relative to the compound (VI).

As the solvent that does not adversely affect the reaction, can be specified, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; water; alcohols such as methanol, ethanol, isopropanol and the like; and so forth. Two or more kinds of these solvents can be used in a mixture, in the relevant respect.

The reaction temperature is usually about -50 about 150°C, preferably from about -10 to about 100°C.

The reaction time is usually from about 0.5 to about 20 hours.

The compound (VII)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like. Is it possible to use the reaction mixture containing the compound (VII)as a starting material for the next reaction without isolation or purification of the compound (VII).

The compound (VI)to be used as starting compounds in the above stage 1a, can be obtained in accordance with the method, which is in itself known, such as the methods described in Tetrahedron Letters, Vol. 41, p. 5453 (2000), the application for international patent WO 99/52882, Journal of Chemical Society, Perkin Trans. Vol. 1, No. 2, pp. 642-645 (1981), and the like, or in accordance with the method similar to them.

(Stage 1b)Reactions of halogenation, hydroxylation

At this stage, the compound (VIII) is subjected to halogenation reaction, and then hydroxylation reactions with obtaining the compound (VII).

Here the halogenation reaction is carried out in the presence of a halogenation means and, when necessary, appropriate reaction initiator, in a solvent that does not adversely affect the reaction.

As halogenation funds may be specified, for example, N-halogenated imides, such as N-bromosuccinimide, N-chlorosuccinimide and the like, and so on.

The amount of halogenation tool that should be used is preferably about 1 - about 10 molar equivalents relative to the compound (VIII).

As the initiator of the reaction can be specified, for example, organic azo compounds, such as azobisisobutyronitrile and the like; the body is ical peroxides, such as benzoyl peroxide and the like, and so on.

The amount of initiator in the reaction, which should be used is preferably about 0.001 to about 1 molar equivalent relative to the compound (VIII).

As the solvent that does not adversely affect the reaction, can be specified, for example, ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; halogenated hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane, chloroform, dichloromethane and the like, acetonitrile, ethyl acetate, N,N-dimethylformamide and the like. Two or more kinds of these solvents can be used in a mixture, in the relevant respect.

The reaction temperature is usually 50-200°C, preferably, 0-120°C.

The reaction time is usually 0.1 to 48 hours.

The hydroxylation reaction can conveniently be in the presence of an appropriate base, in a solvent that does not adversely affect the reaction.

As the base can be specified, for example, acetate or formate, alkali metal such as sodium acetate, potassium acetate, sodium formate and the like; carbonates of alkali metals such as potassium carbonate, sodium carbonate, cesium carbonate and the like; carbonates u is lonesomely metals, such as barium carbonate, calcium carbonate and the like; alkoxides of alkali metals such as sodium methoxide and the like; hydroxides of alkali metals such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; hydroxides of alkaline earth metals such as barium hydroxide, calcium hydroxide and the like, and so on.

The amount of base that should be used is, as a rule, an excess amount relative to the compound (VIII). The amount of base that should be used is preferably about 1.2 to about 30 equivalents, relative to compound (VIII).

As the solvent that does not adversely affect the reaction, can be specified, for example, alcohols such as methanol, ethanol and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; dimethyl sulfoxide, acetone and the like. Two or more kinds of these solvents can be used in a mixture, in appropriate ways, or may be used in mixture with water. When the above solvent is used in a mixture with water, the mixing ratio of water is, for example, 0.1 to 1000%, preferably 1-100%, by volume, relative to the solvent.

The reaction temperature pillar is t, usually about -20 to about 150°C, preferably from about -10 to about 100°C.

The reaction time is generally about 0.1 - about 20 hours.

The compound (VII)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like. It is also possible to use a reaction mixture containing the compound (VII)as a starting material for the next reaction step, without isolation or purification of the compound (VII).

(Stage 1c)The reaction dihalogenoalkane and hydrolysis

At this stage, the compound (VIII) is subjected to reaction dihalogenoalkane, and then hydrolysis to obtain the compound (IX).

The reaction dihalogenoalkane carried out in the presence of a halogenation means and, when necessary, appropriate reaction initiator, in a solvent that does not adversely affect the reaction.

As halogenation tools can be used by the initiator of the reaction and the solvent that does not adversely affect the reaction, connections, respectively, the compounds represented for the above reaction Galaga is investing in stage 1b.

The amount of halogenation tools that should be used, preferably represents about 2 to about 20 molar equivalents, relative to compound (VIII).

The amount of initiator in the reaction, which should be used is preferably about 0.001 to about 1 molar equivalent relative to the compound (VIII).

The reaction temperature is usually 50-200°C, preferably, 0-120°C.

The reaction time is usually 0.1 to 48 hours.

The reaction of the hydrolysis is carried out in the same manner as the reaction of hydroxylation at the above stage 1b.

The compound (IX)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like. It is also possible to use a reaction mixture containing the compound (IX)as a starting material for the next reaction step, without isolation or purification of the compound (IX).

The compound (VIII)to be used as a starting compound in the above stages 1b and 1c, may be obtained in accordance with the method, which is in itself known, for example, methods which, described in Journal of Organic Chemistry, Vol. 51, p. 4075 (1986), and the like, or in accordance with the method similar to them.

(Stage 2)The oxidation reaction

This reaction is carried out in accordance with the conventional method, in the presence of an oxidant in a solvent that does not adversely affect the reaction.

As oxidant can be specified, for example, oxidizing agents based on metals, such as manganese dioxide, pyridine chlorproma, pyridine dichromate, ruthenium oxide, and the like, and so on.

The amount of oxidizer, which should be used is preferably about 1 - about 10 molar equivalents relative to the compound (VII).

As the solvent that does not adversely affect the reaction, may be mentioned aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; and so forth. Two or more kinds of these solvents can be used in a mixture with the corresponding relations.

The reaction temperature is usually about -50 - about 150°C, preferably from about -10 to about 100°C.

The reaction time is usually about 0.5 to about 20 hours.

In addition, the compound (IX) can also be obtained by adding a reactive reagent, such as a complex of sulfur trioxide and pyridine or oxalyl chloride and the like, to the compound (VII)in a mixed solvent of sulfoxidov, such as dimethyl sulfoxide and the like, and halogenated hydrocarbons such as chloroform, dichloromethane and the like, and then interact with an organic base, such as triethylamine, N-methylmorpholine and the like.

The number of the reactive reagent, which should be used is preferably about 1 - about 10 molar equivalents, relative to compound (VII).

The amount of organic base, which should be used is preferably about 1 - about 10 molar equivalents, relative to compound (VII).

The reaction temperature is usually about -50 to about 150°C, preferably from about -10 to about 100°C.

The reaction time is generally about 0.5 to about 20 hours.

The compound (IX)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction Rast is orichalum, crystallization, recrystallization, transfer phase, chromatography and the like. It is also possible to use a reaction mixture containing the compound (IX)as a starting material for the next reaction step, without isolation or purification of the compound (IX).

(Stage 3)The reaction of carbon addition

At this stage, the compound (V-1) are obtained by reaction of compound (IX) with a reagent on the basis of organic phosphorus compounds in the presence of a base in a solvent that does not adversely affect the reaction.

As a reagent in organic phosphorus compounds can be specified, for example, methyl diethylphosphonoacetate, ethyl diethylphosphonoacetate, ethyl diethylphosphonoacetate and the like.

The amount of organic reagent based on phosphorus, which should be used is preferably about 1 - about 10 molar equivalents relative to the compound (IX).

As the base can be specified, for example, alkali metal salts, such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and the like; salts of alkaline earth metals such as barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-Diaz is bicyclo[5,4,0]undec-7-ene and the like; metal hydrides such as potassium hydride, sodium hydride and the like; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like, and so on.

The amount of these bases, which should be used is preferably about 1 - about 5 molar equivalents relative to the compound (IX).

As the solvent that does not adversely affect the reaction, can be specified, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; amides such as N,N-dimethylformamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like; and so forth. Two or more kinds of these solvents can be used in a mixture with the corresponding relations.

The reaction temperature is usually about -50 to about 150°C, preferably about -10 to about 100°C.

The reaction time is generally about 0.5 to about 20 hours.

The compound (V-1)thus obtained can be isolated and purified by known means of separation and purification such as concentrated is e, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like. It is also possible to use a reaction mixture containing the compound (V-1), as the source material for the next reaction step, without isolation or purification of the compound (V-1).

(Stage 4)The hydrogenation reaction

This reaction is carried out in accordance with the usual way in an atmosphere of hydrogen or in the presence of sources of hydrogen from formic acid and the like, and based catalyst metal, in a solvent that does not adversely affect the reaction.

As the catalyst based on metal can be mentioned, for example, catalysts based on transition metals, such as palladium on charcoal, palladium on barium carbonate, palladium black, platinum oxide, platinum on coal, Nickel Raney catalyst, the catalyst Wilkinson and the like, and so on.

The amount of catalyst based on metal that should be used is preferably about 0.01 to about 10 molar equivalents, relative to compound (V-1).

As the solvent that does not adversely affect the reaction, can be specified, for example, aromatic hydrocarbons such as benzene, then the Wal, xylene and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; amides such as N,N-dimethylformamide and the like; alcohols such as methanol, ethanol, isopropanol and the like; and so forth. Two or more kinds of these solvents can be used in a mixture, in the relevant respect.

The reaction temperature is usually about -50 to about 150°C, preferably from about -10 to about 100°C.

The reaction time is generally about 0.5 to about 20 hours.

The compound (V-2)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

The compound (Ib) of the formula (I)where Z represents Za [Za represents-O-, -S - or-NR2- (R2is the same as defined above] can be obtained, for example, using the following method D.

[Method D]

where L represents a removable group, and other symbols are as defined above.

In catasterismi group L can be specified for example, a halogen atom, -OSO2R8(R8represents a hydrogen atom, a C1-4alkyl group, a C6-10aryl group, optionally substituted C1-4alkyl group, a C7-14aracelio group, optionally substituted C1-4alkyl group), and the like.

Here, as the halogen atom may include fluorine, chlorine, bromine, iodine and the like.

As C1-4alkyl group "C1-4alkyl groups", "C6-10aryl group, optionally substituted C1-4alkyl group" and "C7-14aranceles group, optionally substituted C1-4alkyl group" for R8may be mentioned methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Among them, methyl is preferred.

As C6-10aryl group "C6-10aryl group, optionally substituted C1-4alkyl group" for R8may be mentioned phenyl and naphthyl. Among them, phenyl is preferred.

As C7-14Uralkaliy "C7-14aranceles group, optionally substituted C1-4alkyl group" for R8may be mentioned benzyl, phenethyl and naphthylmethyl. Among them, benzyl is preferred.

Delete group L preferably represents a halogen atom (site is preferably, chlorine), methanesulfonate and the like.

The compound (Ib) can be obtained, for example, by treatment of the compound (X) and the compound (XI) reaction of Mitsunobu.

This reaction is carried out in accordance with the conventional method in the presence of phosphine and azo compounds in a solvent that does not adversely affect the reaction.

As phosphine compounds may be mentioned, for example, trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, diphenylpyridine, cyanomethylene tributylphosphine and the like.

As the azo compounds can be specified, for example, diethyl-azodicarboxylate, aminobutiramida azodicarboxylate, azodicarbonamide and the like.

When cyanomethylene tributylphosphane used as a phosphine compound, the reaction can be carried out in the absence of azo compounds.

The amount of compound (XI)to be used is generally 1 to 20 equivalents, preferably 1-10 equivalents, relative to compound (X).

The amount of phosphine compounds and azo compounds to be used is generally 1-50 equivalents, preferably 1-10 equivalents, relative to compound (X).

As the solvent that does not adversely affect the reaction, can is to be specified, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; amides such as N,N-dimethylformamide and the like; and so forth. Two or more kinds of these solvents can be used in a mixture with the corresponding relations.

The reaction temperature is generally about -20 to about 150°C, preferably from about -10 to about 100°C.

The reaction time is generally about 0.1 - about 20 hours.

The compound (Ib)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

The compound (Ib) can also be obtained by converting compound (X) in its reactive derivative, compound (XII) and the interaction of the compound (XII) with compound (XI).

The compound (XII) can be obtained by reacting compound (X) with an appropriate activating reagent in a solvent that does not adversely impact the Oia reaction, when it is necessary, in the presence of a base.

Here as the activating reagent can be used reagents corresponding to the above delete group L. Specific examples of the activating reagents include thionyl chloride, methanesulfonyl chloride and the like.

The amount of an activating reagent, which should be used is preferably about 1 - about 10 molar equivalents, relative to compound (X).

As the base can be specified, for example, alkali metal salts, such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and the like; salts of alkaline earth metals such as barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5,4,0]undec-7-ene and the like; metal hydrides such as potassium hydride, sodium hydride and the like; alkoxides of alkali metals, such as the sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like; and so forth.

The amount of these bases, which should be used is preferably about 1 - about 10 molar equivalents, relative to compound (X).

As the solvent that does not adversely affect the reaction is s, can be specified, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; amides such as N,N-dimethylformamide and the like; and so forth. Two or more kinds of these solvents can be used in a mixture in appropriate ways, or may be used in mixture with water. When the above solvent is used in a mixture with water, the mixing ratio of water is, for example, 0.1 to 1000%, preferably 1-100%, by volume, relative to the solvent.

The reaction temperature is generally about -20 to about 150°C, preferably from about -10 to about 100°C.

The reaction time is generally about 0.1 - about 20 hours.

The compound (XII)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like. It is also possible to use a reaction mixture containing the compound (XII), as the source material for following the th reaction, without isolating or purifying the compound (XII).

The interaction of the compound (XII) with compound (XI) is carried out in a solvent that does not adversely affect the reaction, when necessary, in the presence of a base.

As the base can be specified, for example, alkali metal salts, such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and the like; salts of alkaline earth metals such as barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5,4,0]undec-7-ene and the like; metal hydrides such as potassium hydride, sodium hydride and the like; alkoxides of alkali metals, such as the sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like; and so forth.

The amount of these bases, which should be used is preferably about 1 - about 10 molar equivalents relative to the compound (XII).

As the solvent that does not adversely affect the reaction, can be specified, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, simple diethyl ether and the like; halogenated hydrocarbon is, such as chloroform, dichloromethane and the like; amides such as N,N-dimethylformamide and the like; and so forth. Two or more kinds of these solvents can be used in a mixture in appropriate ways, or may be used in mixture with water. When the above solvent is used in a mixture with water, the mixing ratio of water is, for example, 0.1 to 1000%, preferably 1-100%, by volume, relative to the solvent.

The amount of compound (XI)to be used is generally 1 to 20 equivalents, preferably 1-10 equivalents, relative to compound (XII).

The reaction temperature is generally about -20 to about 150°C, preferably from about -10 to about 100°C.

The reaction time is generally about 0.1 - about 20 hours.

The compound (Ib)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

The compound (X) and the compound (XI)to be used as a starting compound in the above method D can be obtained by using method, which is in itself known,or way, similar to him.

Of the compounds (X), the compound (Xa), where X represents -(CH2)3-can be obtained, for example, using the following method E.

[Method E]

where the symbols are as defined above.

In this method, the compound (V-2) is subjected to reduction reaction of obtaining compound (Xa).

This reaction is carried out in the same way as in stage 1a of the above method C.

The compound (Xa)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

Of the compounds (X) compound, where X is other than -(CH2)3-can also be obtained using the above method E, or manner analogous to him.

The compound (Ic) of the formula (I)where Z represents-NR2CO- (R2is the same as defined above)can be obtained, for example, using the following method F.

[Method F]

where the symbols are as defined above.

In this method, compound (XIII) is subjected to amidation reaction of obtaining compound (Ic). This reacts the Yu carried out in the same way, as in the above method A.

The compound (XIII) and compound (XIV) can be obtained by using method, which is in itself known.

The compound (Ic)thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

Of the above compounds (Ia), compound (Iaa) is represented by the formula:

wherein each symbol is as defined above, can be obtained by reacting the above compound (III) with the compound represented by the formula:

wherein each symbol is as defined above.

This reaction is carried out in the same manner as in the above method A. In this reaction, the compound (IV'), which should be used as a starting compound can be obtained by using method, which is in itself known.

Compound (Iaa)thus obtained can be isolated or purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, PE is crystallizatio, the transfer phase, chromatography and the like.

Of the above compounds (IX), the compound (IXa)in which the ring A is a pyrazole, substituted C1-6the alkyl group can also be obtained, for example, using the following method G.

[Method G]

where B is as defined above; W represents-OH or-N(ALK2)(ALK3); ALK1, ALK2, ALK3and ALK4are the same or different and each represents a C1-6alkyl group.

As C1-6alkyl groups for ALK1, ALK2, ALK3or ALK4can be specified, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Among them, methyl is preferred.

As C7-13aranceles group for ALK4can be specified, for example, benzyl and the like.

(Stage 1)

This stage can be carried out in accordance with the method, which is in itself known, such as the method described inInorganic Chemistry, 28, 1093(1989), or in accordance with the method similar to him.

First, the compound (XIV) interacts with a complex ester of formic acid (for example, the lower complex alkilany ether, such as methylformate, ethyl formate, paperformat and that of podobn the e) in the presence of a base to obtain the compound (XV), where W represents-OH.

This reaction is usually carried out in a solvent that does not adversely affect the reaction. As the solvent that does not adversely affect the reaction, is used, for example, alcohols (e.g. methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, methoxyethanol and the like), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and the like), aromatic hydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene and the like), ethers (for example, a simple ethyl ester, simple isopropyl ether, simple tert-butyl methyl ether, tetrahydrofuran, dioxane and the like), NITRILES (e.g. acetonitrile, propionitrile and the like), dimethylformamide, dimethylacetamide, N-organic, dimethylsulfoxide, hexamethylphosphoramide and the like. Two or more kinds of these solvents can be used in a mixture with the corresponding relations.

As the base used, for example, tertiary amines (e.g. trimethylamine, triethylamine, tributylamine, N-ethyldiethanolamine, N-methylmorpholine, DBU (1,8-diazabicyclo[5,4,0]-7-undecene), DBN (1,5-diazabicyclo[4,3,0]-5-nonen), and the like), carbonates of alkali metals (for example, bi is arbonet sodium, potassium carbonate, sodium carbonate, cesium carbonate and the like), hydroxides of alkali metals (e.g. potassium hydroxide, sodium hydroxide, calcium hydroxide and the like), alkoxides (e.g. sodium methoxide, ethoxide sodium, proposed sodium tert-piperonyl potassium tert-piperonyl sodium and the like), potassium hydride, sodium hydride, sodium amide, potassium metal, sodium metal, and the like.

The number of ester of formic acid and base to be used is generally 1-10 equivalents, preferably 1-5 equivalents, for each, relative to the compound (XIV).

The reaction temperature is generally-20-150°C, preferably of 10-100°C.

The reaction time is generally 30 minutes to 24 hours, preferably 1 hour to 15 hours.

In addition, the compound (XV), where W represents-N(ALK2)(ALK3) (ALK2and ALK3are the same or different and each represents a C1-6alkyl group)can be obtained by reaction of compound (XIV) with dimethylformamide di-C1-6allylacetate (for example, dimethylformamide by dimethylacetal, dimethylformamide by diethylacetal, dimethylformamide by dipropylacetate, dimethylformamide by diisopropylate and the like), bidimensionnelles the methane or christinamultimedia.

This reaction is usually carried out in a solvent that does not adversely affect the reaction. As the solvent that does not adversely affect the reaction, is used, for example, alcohols (e.g. methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, methoxyethanol and the like), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and the like), aromatic hydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene and the like), ethers (for example, a simple ethyl ester, simple isopropyl ether, simple tert-butyl methyl ether, tetrahydrofuran, dioxane and the like), NITRILES (e.g. acetonitrile, propionitrile and the like), dimethylformamide, dimethylacetamide, N-organic, dimethylsulfoxide, hexamethylphosphoramide and the like. Two or more kinds of these solvents can be used in a mixture with the corresponding relations. It is also possible to carry out the reaction without solvent.

The number above dimethylformamide di-C1-6allylacetate, bidimensionality and tridimensionality that should be used is generally 1-10 equivalents, preferably 1-5 equivalents, on which each I, with respect to the compound (XIV).

The reaction temperature is generally-20-200°C, preferably-10-150°C.

The reaction time is generally 30 minutes to 24 hours, preferably 1 hour to 15 hours.

The compound (XV)thus obtained can be isolated or purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like. The reaction mixture containing the compound (XV)can be used as source material for the next reaction step, without isolation or purification of the compound (XV).

The compound (XIV)is used as starting compound in this reaction, can be obtained by using method, which is in itself known.

(Stage 2)

Then the compound (XV) interacts with the C1-6acylhydrazines or C7-13aralkylamines in the presence of acid to obtain the compound (XVI).

As C1-6acylhydrazone can be specified, for example, methylhydrazine, acylhydrazone and the like.

As C7-13aralkylamines can be specified, for example, benzoylhydrazone and the like.

This reaction is usually carried out in a solvent that does not adversely hcpa is istia for the reaction. As the solvent that does not adversely affect the reaction, is used, for example, alcohols (e.g. methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, methoxyethanol and the like), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and the like), aromatic hydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene and the like), ethers (for example, a simple ethyl ester, simple isopropyl ether, simple tert-butyl methyl ether, tetrahydrofuran, dioxane and the like), NITRILES (e.g. acetonitrile, propionitrile and the like), esters (e.g. methyl acetate, ethyl acetate, ethylpropane and the like), dimethylformamide, dimethylacetamide, N-organic, dimethylsulfoxide, hexamethylphosphoramide and the like. Two or more kinds of these solvents can be used in a mixture with the corresponding relations.

As the acid to be used for this reaction can be specified, for example, inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid and the like), organic acids (e.g. formic acid, acetic acid, propionic acid, oil is acid, methansulfonate acid, econsultancy acid, benzolsulfonat acid, toluensulfonate acid and the like, camphorsulfonic acid and the like) and so on. Among them sulfonic acid are preferred, and p-toluensulfonate acid is especially preferred.

The number of C1-6acylhydrazone, C7-13aralkylamines and acids that should be used is generally 1-10 equivalents, preferably 1-5 equivalents, for each, relative to the compound (XV).

In this reaction, C1-6acylhydrazone and C7-13aralkylamines can be used as an acid additive salt. As such acid additive salts can be mentioned salts with inorganic acids (for example, hydrochloride, sulfate) and salts with organic acids (e.g. p-toluensulfonate), represented as salts of the compounds represented by formula (I). When C1-6acylhydrazone and C7-13aralkylamines used as the acid additive salts, the reaction can also be carried out without the addition of acid.

In this reaction, the amount of acid (including acid forming acid additive salt), which should be used is preferably 1 equivalent, relative to C1-6acylhydrazines C 7-13aralkylamines, and use this quantity leads to the production of target compounds with high output.

The reaction temperature is generally-20-150°C, preferably of 10-100°C.

The reaction time is generally 30 minutes to 24 hours, preferably 1 hour to 15 hours.

The compound (XVI)thus obtained can be isolated or purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like. The reaction mixture containing the compound (XVI)can be used as a starting material for the next reaction step, without isolation or purification of the compound (XVI).

(Stage 3)

In addition, compound (XVI) is subjected to reaction formirovaniya in the presence of a halogenation means (for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene and the like) and so forth to obtain the compound (IXa).

This reaction may be carried out in accordance with the reaction of Vilsmeier-khaak, known in itself, for example, in accordance with the method set forth inJ. Chem. Soc., Perkin I, 2334(1979) [D. Reid, R. Webster, S. McKenzie], or in accordance with a method similar to the th.

The reaction formirovaniya carried out using formuliruiutsia tools, such as dimethylformamide, N-methylacetanilide, N-ethylacetamide and the like.

This reaction is usually carried out in a solvent that does not adversely affect the reaction. As the solvent that does not adversely affect the reaction, is used, for example, halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and the like), aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene, nitrobenzene and the like), ethers (for example, a simple ethyl ester, simple isopropyl ether, simple tert-butyl methyl ether, simple bis(2-methoxyethoxy) ether, tetrahydrofuran, dioxane and the like), NITRILES (e.g. acetonitrile, propionitrile and the like), esters (e.g. methyl acetate, ethyl acetate, ethylpropane and the like) and so on. Two or more kinds of these solvents can be used in a mixture with the corresponding relations. In addition to the above formuliruiutsia tool can be used as solvent. As a combination of halogenation means and formuliruiutsia tools that should be used for this reaction, it is preferable from ETANA phosphorus oxychloride - dimethylformamide.

The number formuliruiutsia tools and halogenation tool that should be used is generally 1-10 equivalents, preferably 1-5 equivalents, for each, relative to the compound (XVI).

The reaction temperature is generally-20-200°C, preferably 10-150°C.

The reaction time is generally 30 minutes to 24 hours, preferably 1 hour to 15 hours.

The compound (IXa)thus obtained can be isolated or purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

Of the compounds (III), which should be used as a starting compound in the above method A, the compound (III-1), where X represents-CH=CH-, can be obtained in accordance with the following method H.

[Method H]

wherein each symbol is as defined above.

In this method, compound (IX) reacts with malonic acid to obtain compound (III-1). This reaction may be carried out in accordance with the method, which is in itself known, for example, in accordance with the methods described inNew Courses in Experimen Chemistry ; 14, Synthesis and Reaction of Organic Compounds [II] pp. 980-981;Organic Syntheses, Coll. Vol. 4, 731 (1963); J. Am. Chem. Soc., 80, 3645 (1958), and the like, or in accordance with the method similar to them.

For example, this reaction is carried out in the presence of a base, in a solvent that does not adversely affect the reaction.

As the base used, for example, aromatic amines (e.g. pyridine, lutidine, quinoline), secondary amines (e.g., piperidine, pyrrolidine, morpholine, dicyclohexylamine), tertiary amines (e.g. trimethylamine, triethylamine, tributylamine, N-ethyldiethanolamine, N-methylmorpholine, DBU (1,8-diazabicyclo[5,4,0]-7-undecene), DBN (1,5-diazabicyclo[4,3,0]-5-nonen), and the like), carbonates of alkali metals (e.g. sodium bicarbonate, potassium carbonate, sodium carbonate, the cesium carbonate and the like), hydroxides of alkali metals (e.g. potassium hydroxide, sodium hydroxide, calcium hydroxide and the like), alkoxides (e.g. sodium methoxide, ethoxide sodium, proposed sodium tert-piperonyl potassium tert-piperonyl sodium and the like), potassium hydride, sodium hydride, sodium amide, potassium metal, sodium metal, and the like. Of the above grounds of liquid amines can be used as a solvent.

As the solvent that does not adversely affect the reaction, is used, for example, alcohols (e.g. methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, methoxyethanol and the like), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and the like), aromatic hydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene and the like), ethers (for example, a simple ethyl ester, simple isopropyl ether, simple tert-butyl methyl ether, simple bis(2-methoxyethoxy) ether, tetrahydrofuran, dioxane and the like), NITRILES (e.g. acetonitrile, propionitrile and the like), dimethylformamide, dimethylacetamide, N-organic, dimethylsulfoxide, hexamethylphosphoramide, water and the like. Two or more kinds of these solvents can be used in a mixture with the corresponding relations.

The amount of malonic acid to be used is generally 1-10 equivalents, preferably 1-5 equivalents, relative to compound (IX).

The amount of base to be used is generally 1-10 equivalents, preferably 1-5 equivalents, relative to compound (IX).

The reaction temperature is generally-20-180°C, preferably, 0-120°C.

The reaction time is usually 30 minutes to 36 hours, prepact the tion 1 hour - 18 h.

The compound (III-1)thus obtained can be isolated or purified by known means of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer phase, chromatography and the like.

In each of the aforementioned reactions, when the original connection is amino, carboxy, hydroxy or carbonyl as a substituent, these groups may have a protective group, entered into them, such as the group generally used in the chemistry of peptides, and the like. The target compound can be obtained by removal of the protective group, if necessary, after the reaction.

As aminosidine groups can be specified, for example, formyl, C1-6alkylsulphonyl (for example, acetyl, propionyl and the like), C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), benzoyl, C7-13aralkylamines (for example, benzylcarbamoyl and the like), C7-13Uralelectromed (for example, benzyloxycarbonyl, 9-fertilitycare and the like), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl (for example, trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl and the like), C2-6al is Anil (for example, 1-allyl and the like), and so on. These groups are optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), C1-6alkoxy (e.g. methoxy, ethoxy, propoxy and the like) or nitro and the like.

As carboxyamide groups can be specified, for example, C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), C7-13aralkyl (for example, benzyl and the like), phenyl, trityl, silyl (for example, trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl and the like), C2-6alkenyl (e.g., 1-allyl and the like) and the like. These groups are optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), C1-6alkoxy (e.g. methoxy, ethoxy, propoxy and the like) or nitro and the like.

As hydroxyamino groups can be specified, for example, C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl, trityl, C7-13aralkyl (for example, benzyl and the like), formyl, C1-6alkylsulphonyl (for example, acetyl, propionyl and the like), benzoyl, C7-13aralkylamines (for example, benzylcarbamoyl and the like), 2-tetrahydropyranyl, 2-tetrahydrofur the Nile, silyl (for example, trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl and the like), C2-6alkenyl (e.g., 1-allyl and the like) and the like. These groups are optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), C1-6alkyl (e.g. methyl, ethyl, propyl and the like), C1-6alkoxy (e.g. methoxy, ethoxy, propoxy and the like) or nitro and the like.

As carbonintensity groups can be specified, for example, cyclic acetal (e.g., 1,3-dioxane, and the like), non-cyclic acetal (e.g., di-C1-6alkyl acetal and the like) and so on.

The method of removal of these protective groups can be carried out using methods known in themselves, for example, the methods described inProtective Groups in Organic Synthesis, John Wiley and Sons, 1980, and the like. For example, apply the methods using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide, and the like), and so forth; and the recovery method and the like.

When the original connection may form a salt in each of the above reactions,the connection can be used in salt form. As such salts can be used, for example, salts represented as the salt of the compound represented by formula (I).

When the compound of the present invention includes optical isomers, stereoisomers, regioisomers and rotational isomers, they are also included in the compound of the present invention and can be obtained as a separate connection using the method of synthesis and separation processes known in themselves. For example, when there are optical isomers of the compounds of the present invention, an optical isomer resolved from the compound, are also covered by the connection of the present invention.

The optical isomers can be obtained by using method, which is in itself known. Specifically, the optically active isomer can be obtained by using optically active synthetic intermediate compounds or by optical resolution of the final racemate through the normal method.

Optical resolution can be used in a manner that is itself known, such as the method of fractional recrystallization, the way with chiral column, diastereomer method and the like.

1) the Method of fractional recrystallization

The way in which the racemate and optically-active compound (for example, (+)-almond acid (--almond acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, and the like) to form a salt, which is then separated by fractional recrystallization, with subsequent impacts on salt, if desired, stage neutralization with getting a free optical isomer.

2) Method with chiral column

The method of separation through the application of the racemate or its salt in a column for the separation of optical isomers (chiral column). If, for example, liquid column chromatography, optical isomers are separated by coating a mixture of optical isomers by chiral column such as ENANTIO-OVM (manufactured Tosoh Corp.), CHIRAL SERIES (manufactured Daicel Co.) and the like, and manifestations of water, various buffers (e.g. phosphate buffer) and organic solvents (e.g. ethanol, methanol, isopropanol, acetonitrile, triperoxonane acid, diethylamino and the like), singly or in the form of their respective mixtures. If, for example, gas chromatography for separation can be used chiral column such as CP-Chirasil-DeX CB (GL Science Co.) and the like.

3) Diastereomeric way

Way, where racemic mixture chemically reacts with an optically active reagent to obtain the mixture is diastereomers, which is subjected to conventional means of separation (e.g., fractional recrystallization, chromatography and the like) with a separate connection, which is then subjected to chemical treatment (for example, hydrolysis and the like) to separate the active centre of the optically active reagent from connection with obtaining optical isomer. For example, when the compound of the present invention has in the molecule hydroxy or primary or secondary amino, the compound and an optically active organic acid (e.g., MTPA [α-methoxy-α-(trifluoromethyl)phenylacetic acid], (-)-metacercaria acid and the like), or the like, are subjected to the condensation reaction with receiving, respectively, the corresponding ester or amide of diastereoisomer. On the other hand, when the compound of the present invention is a carboxylic acid group, the compound and an optically active reagent amine or alcohol is subjected to the condensation reaction with getting amide or ester diastereoisomer. Selected diastereoisomer then subjected to the reaction of acidic or basic hydrolysis, whereby it is converted into an optical isomer of the original compound.

The best way of carrying out the invention

The present invention under the window explained below with reference to comparative examples, examples, experimental examples and preparation examples, which should not be construed as limiting.

In the following comparative examples and examples,"% " indicates the percentage of mass, unless specifically indicated otherwise. In addition, room temperature means a temperature 1-30°C.

In comparative examples and examples, HPLC is measured under the following conditions.

measuring instrument: system LC-10Avp, Shimadzu Seisakusho

column: CAPSEL PAK C18UG120 S-3 μm, 2,0×50 mm

solvent:

Solution A : water containing 0.1% triperoxonane acid

Solution B; acetonitrile containing 0.1% triperoxonane acid

the cycle of creation gradient: 0,00 min (Solution A/Solution B=90/10), 4,00 min (Solution A/Solution B=5/95), of 5.50 min (Solution A/Solution B=5/95), 5,51 min (Solution A/Solution B=90/10), 8,00 min (Solution A/Solution B=90/10)

the injected quantity: 2 μl, flow rate: 0.5 ml/min, method of detection: UV, 220 nm

In the comparative examples and the examples of mass spectrum (MS) was measured under the following conditions.

measuring instrument: Micromass Ltd., platform II, Waters Corporation ZQ, or Waters ZMD Corporation

the method of ionization, chemical ionization at atmospheric pressure (APCI) or electron spray ionization (ESI)

device for preparative HPLC: Gilson, Inc., high-performance cleaning system

column: YMC Combiprep ODS-A S-5 m is m, 20×50 mm

solvent:

Solution A : water containing 0.1% triperoxonane acid

Solution B; acetonitrile containing 0.1% triperoxonane acid

the cycle of creation gradient: 0,00 min (Solution A/Solution B=90/10), 1,20 min (Solution A/Solution B=90/10), and 4.75 min (Solution A/Solution B=0/100), 7,30 min (Solution A/Solution B=0/100), 7,40 min (Solution A/Solution B=90/10), 7,50 min (Solution A/Solution B=90/10)

flow rate: 25 ml/min, method of detection: UV, 220 nm

Comparative example 1

A mixture of ethyl 4-perbenzoate (20,0 g) and N,N-dimethylformamide of dimethylacetal (24.5 g) is stirred for 1 hour at reflux. The reaction mixture was concentrated, and add methylhydrazine (9.3 g) and ethanol (100 ml). The mixture is stirred for 3 hours while heating under reflux. The reaction mixture is concentrated, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated to obtain a yellow oil (20,1 g). This yellow oil was dissolved in tetrahydrofuran (100 ml) and carefully add lithium aluminum hydride (3,26 g) at 0°C. the Mixture was stirred at 0°C for 1 hour. Sodium sulfate decahydrate (38 g) is carefully added to the reaction mixture and the mixture is stirred at room temperature for 30 min and filtered. The filtrate is concentrated to receive the tion of 15.1 g of a yellow oil. 14.0 g of this yellow oil was dissolved in tetrahydrofuran (200 ml) and add to it activated manganese dioxide (50 g). The mixture is stirred at room temperature for 14 hours. The reaction mixture is filtered and the filtrate concentrated. The residue is subjected to column chromatography on silica gel to obtain 5-(4-forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde (4,25 g) as colorless crystals from the fraction, eluruumi hexane-ethyl acetate (2:1, volume/volume).

NMR (CDCl3) δ: 3,81 (3H, c), 7,2-7,3 (2H, m), 7,35-7,45 (2H, m), 8,03 (1H, c), a 9.60 (1H, c).

From the faction, eluruumi after the above connections, receive 3-(4-forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde (of 3.60 g) as colorless crystals.

NMR (CDCl3) δ: 3,99 (3H, c), and 7.1 to 7.2 (2H, m), 7,7-7,8 (2H, m), 7,98 (1H, c), for 9.90 (1H, c).

Using well-known complex β-keeeper (including commercially available products) as a starting material and in the same manner as in comparative example 1, get connections, described in comparative examples 2 to 13 and 16.

Comparative example 2

5-(4-Methoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde

Yield: 41%. Colorless prismatic crystals. Melting point: 82-83°C (recrystallized from ethyl acetate-hexane).

Comparative example 3

5-(4-Chlorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde

Yield: 28%. Bescot the s prismatic crystals. Melting point: 78-80°C (recrystallized from ethyl acetate-hexane).

Comparative example 4

5-(3-Chlorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde

Yield: 25%. Colorless prismatic crystals. Melting point: 91-92°C (recrystallized from ethyl acetate-hexane).

Comparative example 5

5-(4-Bromophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde

Yield: 36%. The colorless solid product.

Mr (CDCl3) δ: 3,82 (3H, c), 7,25-to 7.35 (2H, m), 7,7-of 7.75 (2H, m), with 8.05 (1H, c), 9,62 (1H, c).

Comparative example 6

1-Methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde

Yield: 31%. Colorless prismatic crystals. Melting point: 66-67°C (recrystallized from ethyl acetate-hexane).

Comparative example 7

5-(2-Forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde

Yield: 48%. Pale yellow oil.

H-NMR (CDCl3)δ: of 3.80 (3H, c), 7,25 to 7.4 (3H, m), and 7.5 and 7.6 (1H, m), of 8.06 (1H, c), being 9.61 (1H, c).

Comparative example 8

5-(3-Forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde

Yield: 20%. Colorless prismatic crystals. Melting point: 115-116°C (recrystallized from ethyl acetate-hexane).

Comparative example 9

1-Methyl-5-(4-were)-1H-pyrazole-4-carbaldehyde

Yield: 33%. Colorless prismatic crystals. Melting point: 55-56°C (recrystallized from ethyl acetate-hexane).

<> Comparative example 10

1-Methyl-5-(1-naphthyl)-1H-pyrazole-4-carbaldehyde

Yield: 60%. Colorless prismatic crystals. Melting point: 95-97°C (recrystallized from ethyl acetate-hexane).

Comparative example 11

1-Methyl-5-phenyl-1H-pyrazole-4-carbaldehyde

Yield: 34%. Colorless prismatic crystals. Melting point: 100-101°C (recrystallized from ethyl acetate-hexane).

Comparative example 12

5-(2-Furyl)-1-methyl-1H-pyrazole-4-carbaldehyde

Yield: 37%. Colorless prismatic crystals. Melting point: 121-122°C (recrystallized from ethyl acetate-hexane).

Comparative example 13

1-Ethyl-5-(4-forfinal)-1H-pyrazole-4-carbaldehyde

Yield: 24%. Pale yellow oil.

NMR (CDCl3) δ: of 1.42 (3H, t, J=7 Hz), 4,08 (2H, q, J=7 Hz), 7,2-7,3 (2H, m), 7,35-7,45 (2H, m), of 8.06 (1H, c), 9,58 (1H, c).

Comparative example 14

A mixture of ethyl 4-perbenzoate (10.0 g) and N,N-dimethylformamide of dimethylacetal (8,54 g) is stirred for 1 hour at reflux. The reaction mixture was concentrated and add benzylpiperazine-oxalate (15.2 g) and ethanol (100 ml). The mixture is stirred for 3 hours while heating under reflux. The reaction mixture is concentrated, water is added and extracted with a mixture of ethyl acetate. The organic layer was washed with water, dried over betw denim magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with a mixture (11,83 g), ethyl 1-benzyl-5-(4-forfinal)-1H-pyrazole-4-carboxylate and ethyl 1-benzyl-3-(4-forfinal)-1H-pyrazole-4-carboxylate from the faction, eluruumi hexane-ethyl acetate (4:1, volume/volume).

NMR (CDCl3) δ: 1,17 (3H×0,7, t, J=7.2 Hz), 1.26 in (3H×0,3, t, J=7.2 Hz), 4,10-to 4.28 (2H, m)to 5.17 (2H×0,7, c), 5,32 (2H×0,3, c)6,94-of 7.82 (9H, m), of 7.90 (1H×0,3, c), with 8.05 (1H×0,7, c).

This mixture (11,83 g) dissolved in tetrahydrofuran (200 ml), carefully add lithium aluminum hydride (1,38 g) at 0°C and the mixture was stirred at 0°C for 1 hour. 1H. aqueous sodium hydroxide solution is carefully added to the reaction mixture until then, until a solid product is no longer deposited. The mixture is stirred at room temperature for 30 min and filtered. The filtrate is concentrated to obtain 10,29 g yellow oil. This yellow oil was dissolved in tetrahydrofuran (200 ml), added activated manganese dioxide (30 g) and the mixture is stirred at room temperature for 14 hours. The reaction mixture is filtered and the filtrate concentrated. The residue is subjected to column chromatography on silica gel with a mixture (of 7.8 g, yield 59%) of 1-benzyl-5-(4-forfinal)-1H-pyrazole-4-carbaldehyde and 1-benzyl-3-(4-forfinal)-1H-pyrazole-4-carbaldehyde from the faction, eluruumi hexane-ethyl acetate (4:1-2:1, volume/volume).

I is R (CDCl 3) δ: 5,24 (2H×0,7, (c), to 5.35 (2H×0,3, c), 6,98-7,80 (9H, m), 7,92 (1H×0,3, c), 8,11 (1H×0,7, c), 9,59 (1H×0,7, c), 9,87 (1H×0,3, c).

Comparative example 15

A mixture of 4-fluoro-N-methylbenzonitrile (5.0 g), ethyl acetoacetate (4,84 g) and ethanol (140 ml) is stirred for 14 h at reflux. The reaction mixture is concentrated, water is added and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with obtaining oil from the faction, eluruumi hexane-ethyl acetate (4:1-1:1, volume/volume). This oil is dissolved in ethanol (50 ml), added 1,8-diazabicyclo[5,4,0]-7-undecene (0.5 ml) and the mixture is stirred for 4 hours while heating under reflux. The reaction mixture was added water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain ethyl 5-(4-forfinal)-1,3-dimethyl-1H-pyrazole-4-carboxylate (3,41 g, yield 44%) as colorless crystals.

NMR (CDCl3) δ: a 1.11 (3H, t, J=7.0 Hz), 2,50 (3H, c), 3,63 (3H, c), 4,11 (2H, q, J=7.0 Hz), 7,10-7,24 (2H, m), 7,26-7,38 (2H, m).

Ethyl 5-(4-forfinal)-1,3-dimethyl-1H-pyrazole-4-carboxylate (3.25 g) was dissolved in tetrahydrofuran (200 ml), carefully add lithium aluminum hydride (0,47 g), at 0°C and the mixture AC who're asked at room temperature, within 2 hours. 2n. Aqueous sodium hydroxide solution is carefully added to the reaction mixture until then, until a solid product is no longer deposited and after stirring at room temperature for 30 min the mixture is filtered. The filtrate is concentrated to obtain 2,59 g of pale yellow oil. This pale yellow oil is dissolved in tetrahydrofuran (200 ml) and added activated manganese dioxide (20 g). The mixture is stirred at room temperature for 14 hours. The reaction mixture is filtered and the filtrate concentrated. The residue is subjected to column chromatography on silica gel to obtain 5-(4-forfinal)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (1.63 g, yield 61%) as a colorless powder from the faction, eluruumi hexane-ethyl acetate (4:1-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 130-131°C.

Comparative example 16

5-Cyclohexyl-1-methyl-1H-pyrazole-4-carbaldehyde

Yield: 36%. Colorless prismatic crystals. Melting point: 83-84°C (recrystallized from ethyl acetate-hexane).

Comparative example 17-1

A mixture of 4-foronline (11.1 g), ethylformate (25,0 g) and ethanol (150 ml) was stirred at 65°C for 2 hours. In the reaction mix add toluensulfonate isocyanide (23,4 g)and the mixture is displaced is more within 2 hours. while heating under reflux. The reaction mixture was concentrated and poured into water. Precipitated solids are collected by filtration, washed with water and dried to obtain ethyl 1-(4-forfinal)-1H-imidazole-5-carboxylate (19,8 g, 85%). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 114-115°C.

Comparative example 17-2

To a solution of ethyl 1-(4-forfinal)-1H-imidazole-5-carboxylate (9,37 g) in tetrahydrofuran (100 ml) is added dropwise diisobutylaluminium hydride (1.5 mol/l toluene solution, 60 ml) at 0°C. the Mixture was stirred at 0°C for 1 hour., add sodium sulfate to decahydrate (13,0 g), and the mixture is stirred at room temperature for 1 hour. The reaction mixture was filtered, and the organic layer concentrated to obtain [1-(4-forfinal)-1H-imidazol-5-yl]methanol (4,10 g, 53%) as crystals. It recrystallization from ethyl acetate-simple isopropyl ether to give pale yellow prismatic crystals. Melting point: 96-98°C.

Comparative example 17-3

A mixture of [1-(4-forfinal)-1H-imidazol-5-yl]methanol (2.50 g), activated manganese dioxide (10 g) and tetrahydrofuran (150 ml) was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the organic layer concentrated to obtain 1-(forfinal)-1H-imidazole-5-carbaldehyde (2.20 g, 89%) as crystals. It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 131-133°C.

Comparative example 18

A mixture of 4'-forpromotion (7.50 g), p-toluensulfonyl hydrazide (of 9.30 g), ethanol (100 ml) and acetic acid (1 ml) is stirred for 1 hour. under reflux. The reaction mixture is cooled to room temperature, and the precipitated solids are collected by filtration and dried to obtain N'-[1-(4-forfinal)propylidene]-4-methylbenzenesulfonamide (12.0 g, yield 73%) as white crystals.

NMR (CDCl3) δ: of 1.09 (3H, t, J=7.5 Hz), 2,42 (3H, c), 2,58 (2H, q, J=7.5 Hz), 6,95-7,05 (2H, m), 7,32 (2H, d,J=8.5 Hz), 7,55-the 7.65 (2H, m), of 7.90 (2H, d, J=8.5 Hz), 8,07 (1H, users).

N'-[1-(4-Forfinal)propylidene]-4-methylbenzenesulfonamide (12.0 g) was dissolved in thionyl chloride (30 ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture was poured into 1N. an aqueous solution of sodium hydroxide. Precipitated solids are collected by filtration, washed with water and dried in a stream of air to obtain 4-(4-forfinal)-5-methyl-1,2,3-thiadiazole (to 6.19 g, 65%) as a yellow solid product.

NMR (CDCl3) δ: a 2.71 (3H, c), 7,15-of 7.25 (2H, m), 7,7-7,8 (2H, m).

A mixture of 4-(4-forfinal)-5-methyl-1,2,3-thiadiazole (to 6.19 g), N-bromosuccinimide (12.4 g), 2,2'-azobis(isobutyronitrile) (100 mg) and carbon tetrachloride (100 ml) is peremeshivayte for 6 hours while heating under reflux. The reaction mixture is washed with water, dried over anhydrous magnesium sulfate and concentrated. To the residue add sodium acetate (30 g) and acetic acid (100 ml)and the mixture is stirred for 12 hours under reflux. Add 6N. hydrochloric acid (50 ml)and the mixture is additionally stirred for 1 hour at reflux. The reaction mixture is concentrated, poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 4-(4-forfinal)-1,2,3-thiadiazole-5-carbaldehyde (360 mg, yield of 5.4%) as pale-yellow crystals from a fraction, eluruumi hexane-ethyl acetate (2:1, volume/volume).

NMR (CDCl3) δ: 7,25-to 7.35 (2H, m), 7,8-7,9 (2H, m), 10,11 (1H, c).

Comparative example 19

A mixture of ethyl diethoxyacetate (17.6 g), hydrazine monohydrate (5.50 g) and ethanol (100 ml) is stirred for 6 hours while heating under reflux. The reaction mixture was concentrated and the residue is dissolved in ethanol (50 ml). Add 4-forfinal isothiocyanate (15.3 g) and the mixture is stirred at room temperature for 15 minutes Add 2n. an aqueous solution of sodium hydroxide (200 ml) and the mixture is stirred during the iyo 90 minutes under reflux. The reaction mixture was poured into 6N. an aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 5-(diethoxylate)-4-(4-forfinal)-2,4-dihydro-3H-1,2,4-triazole-3-thione (29.3 g, yield: 99%) as a yellow oil.

NMR (CDCl3) δ: of 1.13 (6H, t, J=Hz), 3,45-3,5 (2H, m), 3,6-3,7 (2H, m), from 5.29 (1H, c), 7,15-of 7.25 (2H, m), 7.3 to 7.4 (2H, m), 11,21 (1H, users).

To 5-(diethoxylate)-4-(4-forfinal)-2,4-dihydro-3H-1,2,4-triazole-3-tion (25,7 g) add 3,5h. an aqueous solution of nitric acid (containing 0.3% sodium nitrite and the mixture is stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain a yellow oil (19,0 g). This yellow oil was dissolved in 10% aqueous solution of sulfuric acid (100 ml), heated to 70-75°C and stirred for 2 hours. The reaction mixture was poured into 10% aqueous solution of disodium hydrogen phosphate and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 4-(4-forfinal)-4H-1,2,4-triazole-3-carbaldehyde (7,25 g, 43%) as yellow crystals.

<> NMR (CDCl3) δ: 7,15-of 7.25 (2H, m), 7.3 to 7.4 (2H, m), scored 8.38 (1H, c), 10,14 (1H, c).

Comparative example 20

A mixture of methyl 4-perbenzoate (to 3.92 g), p-toluensulfonyl azide (4,00 g), triethylamine (2,02 g) and acetonitrile (30 ml) stirred at 0°C for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain a yellow oil. This yellow oil is added reagent Lawson (8,10 g) and tetrahydrofuran (50 ml)and the mixture heated under reflux for 16 hours. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel to obtain methyl 5-(4-forfinal)-1,2,3-thiadiazole-4-carboxylate (1,95 g, yield 41%) as colorless crystals from the fraction, eluruumi with ethyl acetate-hexane (1:3, vol/vol).

NMR (CDCl3) δ: 3,99 (3H, c), 7,15-of 7.25 (2H, m), 7,55 and 7.6 (2H, m).

To a solution of methyl 5-(4-forfinal)-1,2,3-thiadiazole-4-carboxylate (1.19 g) in tetrahydrofuran (30 ml) is added diisobutylaluminium hydride (1,5h toluene solution, 10 ml) at 0°C and the mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into an aqueous solution of diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over besod the first magnesium sulfate and concentrated to obtain [5-(4-forfinal)-1,2,3-thiadiazole-4-yl]methanol (0,80 g, yield 76%) as a yellow oil.

NMR (CDCl3) δ: of 5.05 (2H, c), 7,15-of 7.25 (2H, m), 7,55 and 7.6 (2H, m).

[5-(4-Forfinal)-1,2,3-thiadiazole-4-yl]methanol (0.75 g) was dissolved in tetrahydrofuran (30 ml) and added activated manganese dioxide (3 g). The mixture is stirred at room temperature for 16 hours. The reaction mixture is filtered and the filtrate concentrated. Add ethyl diethylphosphonoacetate (0.50 g) and N,N-dimethylformamide (10 ml) to the residue. To this mixture is added sodium hydride (60% in oil, 80 mg) at 0°C and the mixture was stirred at 0°C, for 1 hour. The reaction mixture was poured into an aqueous solution of diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain a yellow oil. This yellow oil is added 6N aqueous solution of hydrochloric acid (10 ml) and acetic acid (5 ml), and the mixture is stirred for 3 hours while heating under reflux. The reaction mixture is concentrated, poured into water and the precipitated solids are collected by filtration, washed with water and dried to obtain (2E)-3-[5-(4-forfinal)-1,2,3-thiadiazole-4-yl]acrylic acid (190 mg, yield: 21%) as pale yellow crystals.

NMR (DMSO-d6) δ: 6,98 (1H, d, J=15,5 Hz), 7,3-7,5 (3H, m), 7,6-7,8 (2H, m), 12,67 (1H, users).

Comparative example 21/u>

A mixture of 5-(4-forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde (350 mg), sodium hydride (60% in oil, 120 mg), ethyl diethylphosphonoacetate (673 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the precipitated solids are collected by filtration. After drying in air flow solids dissolved in a mixed solvent of tetrahydrofuran (10 ml) and ethanol (10 ml). Add 1H. an aqueous solution of sodium hydroxide (5 ml) and the mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into 10% aqueous citric acid solution and the precipitated solids are collected by filtration, washed with water and dried in a stream of air to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (354 mg, 84%) as crystals. It recrystallization from methanol-simple isopropyl ether gives colorless prismatic crystals. Melting point: 212-213°C.

In a similar way as in comparative examples 21, receive connections described in comparative examples 22-31, 33-35, 37, and 40.

Comparative example 22

(2E)-3-[5-(4-Methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]acrylic acid

Yield: 28%. Colorless prismatic crystals. Melting point: 190-192°C (recrystallized from methanol-simple diisopropyl ether is).

Comparative example 23

(2E)-3-[5-(3-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl]acrylic acid

Yield: 68%. Colorless prismatic crystals. Melting point: 185-187°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 24

(2E)-3-[5-(4-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl]acrylic acid

Yield: 59%. Colorless prismatic crystals. Melting point: 237-239°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 25

(2E)-3-(1-Methyl-5-phenyl-1H-pyrazole-4-yl)acrylic acid

Yield: 70%. Colorless prismatic crystals. Melting point: 215-216°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 26

(2E)-3-{1-Methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl}acrylic acid

Yield: 73%. Colorless prismatic crystals. Melting point: 195-196°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 27

(2E)-3-[5-(2-Forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid

Yield: 30%. Colorless prismatic crystals. Melting point: 186-187°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 28

(2E)-3-[5-(3-Forfinal)-1-methyl-1H-pyrazole-4-yl]Smoot the OIC acid

Yield: 38%. Colorless prismatic crystals. Melting point: 191-192°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 29

(2E)-3-[5-(4-Bromophenyl)-1-methyl-1H-pyrazole-4-yl]acrylic acid

Yield: 46%. Colorless prismatic crystals. Melting point: 246-247°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 30

(2E)-3-[1-Methyl-5-(1-naphthyl)-1H-pyrazole-4-yl]acrylic acid

Yield: 53%. Colorless prismatic crystals. Melting point: 216-217°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 31

(2E)-3-[1-Methyl-5-(4-were)-1H-pyrazole-4-yl]acrylic acid

Yield: 43%. Colorless prismatic crystals. Melting point: 221-222°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 32

A mixture of mixture of 3.9 g) 1-benzyl-5-(4-forfinal)-1H-pyrazole-4-carbaldehyde and 1-benzyl-3-(4-forfinal)-1H-pyrazole-4-carbaldehyde obtained in comparative example 14, sodium hydride (60% in oil, 667 mg), ethyl diethylphosphonoacetate (3,43 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. Organic SL is th washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain a mixture (4.0 g, 82%) of ethyl (2E)-3-[1-benzyl-5-(4-forfinal)-1H-pyrazole-4-yl]acrylate and ethyl (2E)-3-[1-benzyl-3-(4-forfinal)-1H-pyrazole-4-yl]acrylate.

NMR (CDCl3) δ: 1,20-1,30 (3H, m), 4,08-4,24 (2H, m), 5,20 (2H×0,7, c)5,33 (2H×0,3, c), between 6.08 (1H×0,3, d, J=16.2 Hz), 6,16 (1H×0,7, d, J=15,9 Hz), of 6.96-of 7.60 (10H, m), a 7.62 (1H×0,3, c)7,88 (1H×0,7, c).

Comparative example 33

(2E)-3-[1-Ethyl-5-(4-forfinal)-1H-pyrazole-4-yl]acrylic acid

Yield: 62%. Colorless prismatic crystals. Melting point: 160-161°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 34

(2E)-3-[5-(4-Forfinal)-1,3-dimethyl-1H-pyrazole-4-yl]acrylic acid

Yield: 63%. Colorless prismatic crystals. Melting point: 208-209°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 35

(2E)-3-(5-Cyclohexyl-1-methyl-1H-pyrazole-4-yl)acrylic acid

Yield: 85%. Colorless prismatic crystals. Melting point: 160°C (decomposition) (recrystallized from methanol-simple diisopropyl ether).

Comparative example 36

The mixture of the mixture (4.0 g) and ethyl (2E)-3-[1-benzyl-5-(4-forfinal)-1H-pyrazole-4-yl]acrylate and ethyl (2E)-3-[1-benzyl-3-(4-forfinal)-1H-pyrazole-4-yl]acrylate obtained in comparative example 32, 2n. in the aqueous sodium hydroxide solution (11 ml) and methanol (20 ml) was stirred at 60° C for 14 hours. The reaction mixture was poured 1H. hydrochloric acid (22 ml). Precipitated solids are collected by filtration, washed with water and simple with isopropyl ether and dried in a stream of air with the mixture (3.5 g, 95%) of (2E)-3-[1-benzyl-5-(4-forfinal)-1H-pyrazole-4-yl]acrylic acid and (2E)-3-[1-benzyl-3-(4-forfinal)-1H-pyrazole-4-yl]acrylic acid in powder form.

NMR (CDCl3) δ: a 5.25 (2H×0,7, c)5,38 (2H×0,3, c), 6,23 (1H×0,3, d, J=15.6 Hz), and 6.25 (1H×0,7, d, J=15,9 Hz), 6.90 to-7,60 (10H, m), 8,16 (1H×0,7, c), 8,51 (1H×0,3, c).

Comparative example 37

(2E)-3-[5-(2-Furyl)-1-methyl-1H-pyrazole-4-yl]acrylic acid

Yield: 63%. Colorless prismatic crystals. Melting point: 203-204°C (recrystallized from methanol-simple diisopropyl ether).

Comparative example 38

Potassium bis(trimethylsilyl)amide (20% toluene solution of 1.0 g) are added to a mixture of bis(2,2,2-triptorelin) (methoxycarbonylmethyl) phosphonate (318 mg), 18-crown-6 (1,32 g) and tetrahydrofuran (20 ml) at -78°C. Then add 5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (216 mg) and the mixture was stirred at -78°C for 4 hours. The reaction mixture was added an aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and end tryout. To the residue is added methanol (5 ml) and 1N. an aqueous solution of sodium hydroxide (5 ml)and the mixture stirred at 60°C for 1 hour. The reaction mixture is concentrated to residue type 1H. hydrochloric acid and extracted with a mixture of ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives (2Z)-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]acrylic acid in the form of crystals (77 mg, 30%yield). Melting point: 205-206°C.

Comparative example 39

A mixture of methyl (2Z)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylate (300 mg), methanol (5 ml) and 1N. an aqueous solution of sodium hydroxide (5 ml) was stirred at 60°C for 30 min. the reaction mixture was added 1N. hydrochloric acid and extracted with a mixture of ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives (2Z)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid in the form of crystals (220 mg, yield 78%). Melting point: 205-206°C.

Comparative example 40

(2E)-3-[1-(4-Forfinal)-1H-imidazol-5-yl]acrylic acid

Yield: 85%. Colorless crystals. The rate is temperature melting point: decomposition at 250° C.

NMR (DMSO-d6) δ: 6,17 (1H, d, J=15,5 Hz), 7,16 (1H, d, J=15,5 Hz), 7,35 and 7.6 (4H, m), 7,76 (1H, users), 8,02 (1H, users), 12,35 (1H, users).

Comparative example 41

A mixture of 4-(4-forfinal)-4H-1,2,4-triazole-3-carbaldehyde (3,83 g), ethyl diethylphosphonoacetate (the ceiling of 5.60 g), sodium hydride (60% in oil, 0.88 g) and tetrahydrofuran (130 ml) was stirred at 0°C for 1 hour. The reaction mixture was poured into an aqueous solution of diluted hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in 6N. aqueous hydrochloric acid (100 ml) and stirred for 2 hours while heating under reflux. To neutralize the reaction mixture of disodium hydrogen phosphate. Precipitated solids are collected by filtration, washed with water and dried to obtain (2E)-3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]acrylic acid (of 3.60 g, yield 76%) as pale yellow crystals. Melting point: 226-229°C (recrystallized from ethyl acetate-hexane).

Comparative example 42

Sodium hydride (60% in oil, 60 mg) is added at 0°C to a mixture of 4-(4-forfinal)-1-methyl-1H-pyrazole-5-carbaldehyde (168 mg), ethyl diethylphosphonoacetate (400 mg) and N,N-dimethylformamide (3 ml) and the mixture is stirred at room temperature during the 15 minutes The reaction mixture was poured into 1N. an aqueous solution of hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer is concentrated and the residue dissolved in a mixture of 6N. hydrochloric acid (18 ml) and acetic acid (2 ml). The mixture is stirred for 1 hour at reflux. The reaction mixture was concentrated and poured into water. To neutralize type 1H. the sodium hydroxide. Precipitated solids are collected by filtration, washed with water and dried to obtain (2E)-3-[4-(4-forfinal)-1-methyl-1H-pyrazole-5-yl]acrylic acid (159 mg, 78%) as colorless crystals.

NMR (DMSO-d6) δ: 3,99 (3H, c), 6,17 (1H, d, J=16 Hz), 7,2-7,3 (2H, m), 7,35-7,45 (2H, m), 7,49 (1H, d, J=16 Hz), to 7.61 (1H, c).

Comparative example 43

In accordance with the method presented in the comparative example 42, (2E)-3-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]acrylic acid are synthesized from 4-(4-forfinal)-1-methyl-1H-pyrazole-3-carbaldehyde. Yield: 56%. Colorless crystals.

NMR (DMSO-d6) δ: 3,91 (3H, c), 6,38 (1H, d, J=15,5 Hz), 7,2-7,3 (2H, m), 7.3 to 7.4 (2H, m), 7,41 (1H, d, J=15,5 Hz), 7,95 (1H, c).

Comparative example 44

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (0,80 g), 5% palladium on coal (0,30 g), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 6 hours in an atmosphere of hydrogen at atmospheric pressure the AI. Palladium on coal collected by filtration, and the filtrate is concentrated to obtain 3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]propionic acid (0,78 g, yield 97%) as a colorless solid product.

NMR (CDCl3) δ: of 2.50 (2H, t, J=7 Hz), 2,69 (2H, t, J=7 Hz), 3,71 (3H, c), 7,1-of 7.25 (2H, m), 7,25 of 7.3 (2H, m), 7,42 (1H, c).

Comparative example 45

A mixture of 2-(4-nitrophenyl)attentioned (1.50 g), 1-bromo-2-butanone (1,27G) and ethanol (50 ml) is heated under reflux for 30 minutes, the Reaction mixture was concentrated and ethyl acetate added to the residue. The mixture was sequentially washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive a 4-ethyl-2-(4-nitrobenzyl)-1,3-thiazole as a brown oil (1,59 g, yield 84%) of the fraction, eluruumi hexane-ethyl acetate (7:1-4:1, volume/volume).

NMR (CDCl3) δ: of 1.30 (3H, t, J=7,6 Hz), 2,80 (2H, apt d, J=7,6, 1.0 Hz), to 4.41 (2H, c), to 6.80 (1H, t, J=1.0 Hz), 7,44-7,51 (2H, m), 8,15 is 8.22 (2H, m).

Comparative example 46

A mixture of 2-(4-nitrophenyl)attentioned (1.50 g), ethyl bromopyruvate (1.64 g) and ethanol (50 ml) is heated under reflux for 30 minutes, the Reaction mixture was concentrated and ethyl acetate added to the residue. The mixture was sequentially washed with saturated aqueous sodium bicarbonate and feast upon the s ' solution of salt, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain ethyl 2-(4-nitrobenzyl)-1,3-thiazole-4-carboxylate as pale yellow crystals (1,79 g, yield 81%) of the fraction, eluruumi hexane-ethyl acetate (1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 122-123°C.

Comparative example 47

A mixture of 2-(4-nitrophenyl)attentioned (0.50 g), 1-bromo-2-propanone (0,43 g) and ethanol (20 ml) is heated under reflux for 1 hour. The reaction mixture was concentrated and to the residue is added saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive a 4-methyl-2-(4-nitrobenzyl)-1,3-thiazole in the form of pale yellow crystals (from 0.37 g, yield 63%) of the fraction, eluruumi hexane-ethyl acetate (2:1-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 81-82°C.

Comparative example 48

A mixture of 2-(4-nitrophenyl)attentioned (0,80 g), chloroacetaldehyde (40% aqueous solution, is 2.88 g) and ethanol (20 ml) is heated to reverse the fridge for 15 hours. The reaction mixture was added saturated aqueous sodium bicarbonate solution and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 2-(4-nitrobenzyl)-1,3-thiazole in the form of an orange oil (0.35 g, yield 39%) of the fraction, eluruumi hexane-ethyl acetate (9:1-2:1, volume/volume).

NMR (CDCl3) δ: of 4.45 (2H, c), 7,26 (1H, d, J=3.8 Hz), 7,45-7,52 (2H, m), 7,74 (1H, d, J=3.8 Hz), 8,16-8,23 (2H, m).

Comparative example 49

A mixture of 2-(4-nitrophenyl)acetohydrazide (2.50 g), triethyl of orthoformiate (5,69 g), methanesulfonic acid (0.25 g) and tetrahydrofuran (50 ml) is heated under reflux for 1 hour. The reaction mixture was diluted with ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 2-(4-nitrobenzyl)-1,3,4-oxadiazol in the form of pale yellow crystals (1.92 g, yield 73%) of the fraction, eluruumi hexane-ethyl acetate (3:1-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 104-105°C.

Comparative example 50

The mixture is 2-(4-nitrophenyl)acetohydrazide (7.0 g), trimethyl of ortobotanico (16,01 g), methanesulfonic acid (0,69 g) and tetrahydrofuran (200 ml) is heated under reflux for 2 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 2-(4-nitrobenzyl)-5-propyl-1,3,4-oxadiazol in the form of a colorless oil (7,73 g, yield 87%) of the fraction, eluruumi hexane-ethyl acetate (3:2-1:2, vol/vol).

NMR (CDCl3) δ: of 1.00 (3H, t, J=7.2 Hz), 1,69-1,89 (2H, m), and 2.79 (2H, t, J=7.2 Hz), 4,28 (2H, c), 7,47-7,53 (2H, m), 8,18 is 8.25 (2H, m).

Comparative example 51

A mixture of 4-nitrobenzaldehyde (15.1 g), 1,3-thiazolidin-2,4-dione (11,70 g), piperidine (1.70 g) and ethanol (300 ml) is heated under reflux for 24 hours. The reaction mixture was concentrated. The obtained residue was washed with ethanol to obtain 5-(4-nitrobenzylidene)-1,3-thiazolidin-2,4-dione as yellow crystals (14.8 g, yield 59%). It recrystallization from acetone-hexane gives pale yellow prismatic crystals. Melting point: 272-273°C.

Comparative example 52

To a mixture of 5-(4-nitrobenzylidene)-1,3-thiazolidin-2,4-dione (4.0 g) and N,N-dimethylformamide (100 ml) at room temperature is round, add sodium hydride (60% in oil, 0.7 g). The reaction mixture was stirred at room temperature for 30 min and added to the reaction mixture iodomethane (6.81 in). The mixture is additionally stirred at room temperature for 15 hours. The reaction mixture was added water and the precipitated crystals are collected by filtration to obtain 3-methyl-5-(4-nitrobenzylidene)-1,3-thiazolidin-2,4-dione as yellow crystals (as 4.02 g, yield 95%). It recrystallization from tetrahydrofuran-hexane gives yellow prismatic crystals. Melting point: 233-234°C.

Comparative example 53

To a mixture of 5-(4-nitrobenzylidene)-1,3-thiazolidin-2,4-dione (3.50 g) and N,N-dimethylformamide (100 ml) is added sodium hydride (60% in oil, of 0.62 g) at room temperature. The reaction mixture was stirred at room temperature for 30 min and the reaction mixture was added iodoethane (6,55 g). The mixture is stirred at room temperature for 15 hours. The reaction mixture was added water and the precipitated crystals are collected by filtration to obtain 3-ethyl-5-(4-nitrobenzylidene)-1,3-thiazolidin-2,4-dione as yellow crystals (3,81 g, yield 98%). It recrystallization from acetone-hexane gives yellow prismatic crystals. Melting point: 217-218°C.

Comparative example 54

A mixture of 3-methyl-5-(4-nitrobenzylidene)-1,3-thiazolidin-2,4-dione (1.0 g), 5% palladium on coal (1.0 g) and tetrahed is furane (150 ml) is subjected to catalytic recovery when the hydrogen pressure of 5.0 kgf· cm-2. The catalyst was removed by filtration and the filtrate concentrated to obtain 5-(4-aminobenzyl)-3-methyl-1,3-thiazolidin-2,4-dione as colorless crystals (0.71 g, yield 79%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 91-92°C.

Comparative example 55

A mixture of 3-ethyl-5-(4-nitrobenzylidene)-1,3-thiazolidin-2,4-dione (of 3.60 g), 5% palladium on coal (5.0 g) and tetrahydrofuran (300 ml) is subjected to catalytic recovery when the hydrogen pressure of 5.0 kgf·cm-2. The catalyst was collected by filtration and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and receive 5-(4-aminobenzyl)-3-ethyl-1,3-thiazolidin-2,4-dione as yellow crystals (3,05 g, yield 94%) of the fraction, eluruumi hexane-ethyl acetate (3:1-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives yellow prismatic crystals. Melting point: 103-104°C.

Comparative example 56

A mixture of 2-(4-nitrophenyl)acetohydrazide (0.50 g), ethyl chlorocarbonate (0.34 g) and N,N-dimethylacetamide (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was added water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, the tub over anhydrous magnesium sulfate and concentrated to obtain colorless crystals. A mixture of the obtained crystals, defector by (1.50 g), hexamethyldisiloxane (2,96 g) and 1,2-dichlorobenzene (10 ml) was stirred at 160°C for 2 hours. The reaction mixture was added water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-it is in the form of pale yellow crystals (0.29 grams, yield 50%). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 170-171°C.

Comparative example 57

To a mixture of 3-(4-nitrophenyl)propionic acid (3.00 g), 4-methylmorpholine (2,02 g) and tetrahydrofuran (100 ml) is added dropwise isobutyl chlorocarbonate (2,95 g) at 0°C. the Reaction mixture was stirred at 0°C for 1 hour and the insoluble material collected by filtration. The filtrate is added to a mixture of hydrazine hydrate (3,85 g) and tetrahydrofuran (100 ml) at 0°C. the Reaction mixture was stirred at 0°C for 1 hour and the reaction mixture was added saturated aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The mixture obtained about the TATKO, triethyl of orthopropionate (8,14 g), methanesulfonic acid (0,30 g) and tetrahydrofuran (100 ml) is heated under reflux for 1 hour. The reaction mixture was diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to column chromatography on silica gel to obtain 2-ethyl-5-[2-(4-nitrophenyl)ethyl]-1,3,4-oxadiazole in the form of colorless crystals (2.28 g, yield 60%) of the fraction, eluruumi hexane-ethyl acetate (1:2, vol/vol). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 65-66°C.

Comparative example 58

To a mixture of 3-(4-nitrophenyl)propionic acid (3.00 g), 4-methylmorpholine (2,02 g) and tetrahydrofuran (100 ml) at 0°C is added dropwise isobutyl chlorocarbonate (2,95 g). The reaction mixture was stirred at 0°C, within 1 hour, and the insoluble material collected by filtration. The filtrate is added to a mixture of hydrazine hydrate (3,85 g) and tetrahydrofuran (100 ml) at 0°C. the Reaction mixture was stirred at 0°C, for 1 hour and the reaction mixture was added saturated aqueous solution of ammonium chloride. The mixture is extracted with ethyl acetate. The organic layer was washed with a feast upon the s ' solution of salt, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, triethyl of orthoformiate (6,84 g), methanesulfonic acid (0,30 g) and tetrahydrofuran (100 ml) is heated under reflux for 1 hour. The reaction mixture was diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to column chromatography on silica gel to obtain 2-[2-(4-nitrophenyl)ethyl]-1,3,4-oxadiazole in the form of colorless crystals (2.70 g, yield 80%) of the fraction, eluruumi hexane-ethyl acetate (1:2, vol/vol). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 93-94°C.

Comparative example 59

A mixture of 4-chloromethyl-1,3-oxazole hydrochloride (5,16 g), potassium carbonate (4,19 g), water (60 ml) and ethyl acetate (60 ml) is stirred for 15 minutes, the Reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, triphenylphosphine (of 7.95 g) and acetonitrile (200 ml) is heated under reflux for 15 hours. The reaction mixture is cooled and the precipitated crystals are washed with a simple d is ethyl ether to obtain [(1,3-oxazol-4-yl)methyl]triphenylphosphonium chloride in the form of colorless crystals (8,11 g, yield 68%). Melting point: 268-270°C.

Comparative example 60

A mixture of 4-chloromethyl-2-ethyl-1,3-oxazole (4,87 g), triphenylphosphine (7,89 g) and acetonitrile (100 ml) is heated under reflux for 15 hours. The reaction mixture was concentrated and the resulting crystals are washed with simple diethyl ether to obtain [(2-ethyl-1,3-oxazol-4-yl)methyl]triphenylphosphonium chloride in the form of colorless crystals (10,02 g, yield 79%). It recrystallization from acetonitrile-simple diethyl ether gives colorless prismatic crystals. Melting point: 222-223°C.

Comparative example 61

A mixture of 4-nitrobenzaldehyde (0,42 g), potassium carbonate (0,58 g), [(1,3-oxazol-4-yl)methyl]triphenylphosphonium chloride (1.65 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 15 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to column chromatography on silica gel to obtain yellow crystals from a fraction, eluruumi hexane-tetrahydrofuran (1:1, volume/volume). The obtained crystals, 5% palladium on coal (1,00 g) and tetrahydrofuran (50 ml) is subjected to catalytic recovery in the atmosphere of hydrogen at atmospheric pressure. utilizator removed by filtration and the filtrate concentrated. The resulting residue is subjected to column chromatography on silica gel to obtain 4-[2-(1,3-thiazol-4-yl)ethyl]aniline in the form of colorless crystals (0.27 g, yield 47%) of the fraction, eluruumi hexane-ethyl acetate (2:1-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 69-70°C.

Comparative example 62

A mixture of 4-nitrobenzaldehyde (1.0 g), potassium carbonate (1,37 g), [(2-ethyl-1,3-oxazol-4-yl)methyl]triphenylphosphonium chloride (4,20 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 40 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to column chromatography on silica gel to obtain a yellow oil from a fraction, eluruumi hexane-ethyl acetate (3:1-2:1, volume/volume). The obtained oil, 5% palladium on coal (2.00 g) and tetrahydrofuran (200 ml) is subjected to catalytic recovery in the atmosphere of hydrogen at atmospheric pressure. The catalyst was removed by filtration and the filtrate concentrated. The resulting residue is subjected to column chromatography on silica gel to obtain 4-[2-(2-ethyl-1,3-thiazol-4-yl)ethyl]aniline as a brown oil (1,11 g, yield 73%) of fracc and, eluruumi hexane-ethyl acetate (2:1, volume/volume).

NMR (CDCl3) δ: of 1.39 (3H, t, J=7,6 Hz), 2,84-is 3.08 (6H, m), of 3.56 (2H, users), 6,59 of 6.66 (3H, m), 6,95-7,00 (2H, m).

Comparative example 63

A mixture of 5-(4-forfinal)-1H-pyrazole-4-carbaldehyde (1.0 g), malonic acid (0,67 g), piperidine (0.54 g) and simple bis(2-methoxyethanol) ether (10 ml) was stirred at 110°C for 6 hours. In the acidified reaction mixture was added water and 1N. hydrochloric acid and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to column chromatography on silica gel to obtain (2E)-3-[5-(4-forfinal)-1H-pyrazole-4-yl]acrylic acid in the form of colorless crystals (0.12 g, yield 10%) of the fraction, eluruumi hexane-ethyl acetate (1:9, vol/vol). It recrystallization from acetone-simple diisopropyl ether gives colorless prismatic crystals. Melting point: 276-277°C.

Comparative example 64

To a mixture of 3-(4-nitrophenyl)propionic acid (13,45 g), N,N-dimethylformamide (0.1 ml) and tetrahydrofuran (300 ml) at room temperature is added dropwise, oxalyl chloride (10.5 g). The reaction mixture was stirred at room temperature for 1 hour and concentrated. The resulting residue is dissolved in tetrahydrofur is not (50 ml) and at room temperature is added dropwise to a mixture of 25% aqueous ammonia (100 ml) and tetrahydrofuran (100 ml). The reaction mixture was stirred at room temperature for 2 hours and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 3-(4-nitrophenyl)propanamide in the form of colorless crystals (11,80 g, yield 88%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 177-178°C.

Comparative example 65

A mixture of 3-(4-nitrophenyl)propanamide (0.50 g), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (0,81 g) and pyridine (5 ml) was stirred at 50°C for 15 hours. The reaction mixture was concentrated and added dropwise to the obtained residue, 1N. hydrochloric acid and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with 3-(4-nitrophenyl)proportioned in the form of colorless crystals (0.40 g, yield 73%) of the fraction, eluruumi hexane-ethyl acetate (2:1-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 157-158°C.

Comparative example 66

A mixture of 3-(4-nitrophenyl)proportioned (1.0 g), chloroacetaldehyde (40% aqueous the solution, 2.83 g) and tert-butanol (20 ml) is heated under reflux for 2 hours. The reaction mixture was concentrated, and add to the residue saturated aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 2-[2-(4-nitrophenyl)ethyl]-1,3-thiazole in the form of pale yellow crystals (0.31 g, yield 28%) of the fraction, eluruumi hexane-ethyl acetate (3:1, volume/volume). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 92-93°C.

Comparative example 67

A mixture of 3-(4-nitrophenyl)proportioned (1,25 g), 1-bromo-2-butanone (0,98 g) and tert-butanol (30 ml) is heated under reflux for 30 minutes, the Reaction mixture was concentrated and added dropwise to the residue saturated aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 4-ethyl-2-[2-(4-nitrophenyl)ethyl]-1,3-thiazole as a yellow oil (1.48 g, yield 95%) of the fraction, eluruumi hexane-ethyl acetate (4:1-2:1, volume/volume).

NMR (CDCl3/sub> ) δ: of 1.29 (3H, t, J=7,6 Hz), 2,78 (2H, apt d, J=7,6, 1.0 Hz), 3,17-3,37 (4H, m), of 6.73 (1H, t, J=1.0 Hz), 7,32-7,39 (2H, m), 8,10-8,18 (2H, m).

Comparative example 68

A mixture of 4-NITROPHENOL (to 3.92 g), 4-chloromethyl-1,3-thiazole hydrochloride (4.0 g), potassium carbonate (8,13 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 40 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 4-[(4-nitrophenoxy)methyl]-1,3-thiazole in the form of colorless crystals (to 3.38 g, yield 61%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 175-176°C.

Comparative example 69

A mixture of 4-NITROPHENOL (5,48 g), 4-chloromethyl-2-ethyl-1,3-thiazole (yield of 7.40 g), potassium carbonate (of 5.45 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 15 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with 1N. aqueous sodium hydroxide solution and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 2-ethyl-4-[(4-nitrophenoxy)methyl]-1,3-thiazole in the form of colorless crystals (of 3.60 g, yield 35%)of the fraction, eluruumi hexane-ethyl acetate (4:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 79-80°C.

Comparative example 70

To a mixture of 2-(4-nitrophenoxy)acetic acid (5.0 g), 4-methylmorpholine (3,34 g) and tetrahydrofuran (100 ml) at 0°C is added dropwise isobutyl chlorocarbonate (a 4.86 g). The reaction mixture was stirred at room temperature for 1 hour and the insoluble material collected by filtration. The filtrate is added dropwise to a mixture of hydrazine monohydrate (6,36 g) and tetrahydrofuran (50 ml) at 0°C. the Reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was added saturated aqueous solution of ammonium chloride, and the precipitated crystals are collected by filtration to obtain 2-(4-nitrophenoxy)acetohydrazide in the form of colorless crystals (of 1.30 g, yield 24%). It recrystallization from tetrahydrofuran-hexane gives colorless prismatic crystals. Melting point: 191-192°C.

Comparative example 71

A mixture of 2-(4-nitrophenoxy)acetohydrazide (1.10 g), methanesulfonic acid (0.10 g), triethyl of orthoformiate (2,31 g) and tetrahydrofuran (50 ml) is heated under reflux for 1 hour. The reaction mixture was added water and extracted with a mixture of ethyl acetate. The organic layer is sequentially p is washed with saturated aqueous sodium bicarbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 2-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole in the form of colorless crystals (0,79 g, yield 69%) of the fraction, eluruumi hexane-ethyl acetate (1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 125-126°C.

Comparative example 72

A mixture of 2-(4-nitrophenyl)ndimethylacetamide (15.0 g), 1-bromo-2-propanone (of 19.03 g)and N,N-dimethylformamide (2 ml) was stirred at 120°C for 3 hours. Water, potassium carbonate and ethyl acetate is added for alkalizing the reaction mixture and extracted with a mixture of ethyl acetate. The insoluble material is collected by filtration and separated the organic layer. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 4-methyl-2-(4-nitrobenzyl)-1,3-oxazole in the form of orange crystals (1.50 g, yield of 8.2%) from the faction, eluruumi hexane-ethyl acetate (2:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 67-68°C.

Comparative example 73

To a mixture of 2-(4-nitrophenoxy)acetohydrazide (1,57 g) and N,N-dimethylacetamide (50 ml) at room temperature is added dropwise acetyl chloride (0,70 g). The reaction mixture is stirred for 2 hours. The reaction mixture was added water and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, defector by (1,76 g), hexamethyldisiloxane (a 4.03 g) and 1,2-dichlorobenzene (10 ml) was stirred at 140°C for 3 hours. The reaction mixture was added saturated aqueous sodium bicarbonate solution and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 2-methyl-5-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole in the form of colorless crystals (0,41 g, yield 56%) of the fraction, eluruumi hexane-ethyl acetate (3:2-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 105-106°C.

Comparative example 74

A mixture of 2-(4-nitrophenyl)ndimethylacetamide (14.6 g), 1-bromo-2-butanone (20,46 g) and N,N-dimethylformamide (2 ml) was stirred at 140°C for 2 hours. For alkalizing the reaction mixture, water is added, the potassium carbonate and ethyl acetate and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over besttranslator magnesium and concentrate. The residue is subjected to column chromatography on silica gel to obtain 4-ethyl-2-(4-nitrobenzyl)-1,3-oxazole in the form of brown crystals (2.65 g, yield 14%) of the fraction, eluruumi hexane-ethyl acetate (2:1, volume/volume). It recrystallization from ethyl acetate-hexane gives brown prismatic crystals. Melting point: 58-59°C.

Comparative example 75

To a mixture of ethyl (4-{[(benzyloxy)carbonyl]amino}phenyl)acetate (0,30 g) and tetrahydrofuran (10 ml) at 0°C is added dropwise 1 M methyl magnesium bromide (1 M solution in tetrahydrofuran, 10 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was added 1N. hydrochloric acid and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain benzyl 4-(2-hydroxy-2-methylpropyl)phenylcarbamate in the form of colorless crystals (0.17 g, yield 59%) of the fraction, eluruumi hexane-ethyl acetate (4:1-2:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 117-118°C.

Comparative example 76

To a mixture of ethyl (4-{[(benzyloxy)carbonyl]amino}phenyl)acetate (15.3 g) and tetrahydrofuran (100 ml) at 0° C is added dropwise 1 M ethyl magnesium bromide (1 M solution in tetrahydrofuran, 500 g). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was added 1N. hydrochloric acid and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain benzyl 4-(2-ethyl-2-hydroxybutyl)phenylcarbamate in the form of colorless crystals from the fraction, eluruumi hexane-ethyl acetate (2:1-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals (6,86 g, yield 43%). Melting point: 99-100°C.

Comparative example 77

A mixture of benzyl 4-(2-hydroxy-2-methylpropyl)phenylcarbamate (at 8.60 g), 10% palladium on coal (9.0 g) and tetrahydrofuran (300 ml) is subjected to catalytic recovery in the atmosphere of hydrogen at atmospheric pressure. The catalyst was removed by filtration and the filtrate concentrated. The residue is subjected to column chromatography on silica gel to obtain 1-(4-AMINOPHENYL)-2-methylpropan-2-ol as colorless crystals (3,54 g, 75%yield) of the fraction, eluruumi hexane-ethyl acetate (1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic Crist is lly. Melting point: 107-108°C.

Comparative example 78

A mixture of benzyl 4-(2-ethyl-2-hydroxybutyl)phenylcarbamate (6,30 g), 10% palladium on coal (5.0 g) and tetrahydrofuran (150 ml) is subjected to catalytic recovery in the atmosphere of hydrogen at atmospheric pressure. The catalyst was removed by filtration, and the filtrate is concentrated to obtain 3-(4-aminobenzyl)-3-pentanol in the form of colorless crystals (3.51 g, yield 95%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 85-86°C.

Comparative example 79

To a mixture of hydroxylamine hydrochloride (21,5 g) and dimethyl sulfoxide (50 ml) at room temperature is added dropwise 28% solution of sodium methoxide in methanol (59,6 g). In the reaction mixture is optionally added dropwise a solution (50 ml) of (4-nitrophenyl)acetonitrile (10.0 g) in dimethyl sulfoxide. The reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was added water and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain N'-hydroxy-2-(4-nitrophenyl)ethanamide in the form of brown crystals (yield of 7.10 g, yield 59%). It recrystallization from ethyl acetate-simple diisopropyl ether gives brown prismatic crystal is s. Melting point: 170-171°C.

Comparative example 80

To a mixture of N'-hydroxy-2-(4-nitrophenyl)ethanamide (2.38 g) and N,N-dimethylacetamide (30 ml) at room temperature add acetyl chloride (0.96 g) and the mixture is stirred at room temperature for 15 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue and xylene (100 ml) is heated under reflux for 24 hours. The reaction mixture was concentrated and to the residue is added ethyl acetate. The mixture was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 5-methyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole in the form of orange crystals (1,00 g, yield 37%) of the fraction, eluruumi hexane-ethyl acetate (4:1-3:1, volume/volume). It recrystallization from ethyl acetate-hexane gives orange prismatic crystals. Melting point: 66-67°C.

Comparative example 81

A mixture of 5-methyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole (to 3.89 g), Lindlar catalyst (2.0 g) and tetrahydrofuran (200 ml) is subjected to catalytic recovery in the atmosphere of hydrogen at atmospheric pressure. Produce the p removed by filtration and the filtrate concentrated. The residue is subjected to column chromatography on silica gel to obtain 4-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]aniline as a brown oil (0.33 g, yield 10%) of the fraction, eluruumi hexane-ethyl acetate (3:1-2:1, volume/volume).

NMR (CDCl3) δ: 2,52 (3H, c), 3,62 (2H, users), to 3.92 (2H, c), 6,62 of 6.66 (2H, m), 7,08 for 7.12 (2H, m).

Comparative example 82

A mixture of 1-bromo-3-(4-nitrophenyl)-2-propanone (0.50 g), proportioned (0.17 g) and ethanol (10 ml) is heated under reflux for 2 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 2-ethyl-4-(4-nitrobenzyl)-1,3-thiazole as a colorless oil (0.45 g, yield 96%) of the fraction, eluruumi hexane-ethyl acetate (9:1-4:1, volume/volume).

NMR (CDCl3) δ: to 1.38 (3H, t, J=7.5 Hz), to 3.02 (2H, q, J=7.5 Hz), 4,19 (2H, c), 6,74 (1H, c), 7,40-7,44 (2H, m), 8,15-8,18 (2H, m).

Comparative example 83

To a mixture of N'-hydroxy-2-(4-nitrophenyl)ethanamide (6,17 g) and N,N-dimethylacetamide (50 ml) add propionyl chloride (3,22 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. the content of inorganic fillers layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue and xylene (200 ml) is heated under reflux for 15 h with azeotropic the de-hydration. The reaction mixture was concentrated and the resulting residue is subjected to column chromatography on silica gel to obtain 5-ethyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole in the form of brown crystals (4,40 g, yield 60%) of the fraction, eluruumi hexane-ethyl acetate (3:1-2:1, volume/volume). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 69-70°C.

Comparative example 84

A mixture of 5-ethyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole (4,30 g), iron (restored, 5,14 g), calcium chloride (0.20 g) and 80% ethanol (50 ml) is heated under reflux for 2 hours. The insoluble material is collected by filtration and the filtrate concentrated. To the residue water is added and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 4-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]aniline as an orange oil (2,73 g, yield 73%) of the fraction, eluruumi hexane-ethyl acetate (2:1-1:1, volume/volume).

NMR (CDCl3) δ: of 1.35 (3H, t, J=7,6 Hz), of 2.86 (2H, q, J=7,6 Hz), 3,62 (2H, ears is .c), 3,93 (2H, c), 6,61 of 6.66 (2H, m), 7,08 for 7.12 (2H, m).

Comparative example 85

A mixture of 1-bromo-3-(4-nitrophenyl)-2-propanone (0,80 g), thioacetamide (0,23 g) and ethanol (20 ml) is heated under reflux for 2 hours. The reaction mixture was concentrated and to the residue is added saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 2-methyl-4-(4-nitrobenzyl)-1,3-thiazole in the form of pale yellow crystals (of 0.58 g, yield 79%) of the fraction, eluruumi hexane-ethyl acetate (3:1-2:1, volume/volume). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 118-119°C.

Comparative example 86

To a mixture of 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-she (1.0 g), iodomethane (0.97 g) and N,N-dimethylformamide (30 ml) is added sodium hydride (60% in oil, 0.20 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with recip is of 3-methyl-5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-it is in the form of colorless crystals (0.75 g, yield 71%) of the fraction, eluruumi hexane-ethyl acetate (3:1-2:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 115-116°C.

Comparative example 87

To a mixture of 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-she (1.50 g), iodoethane (1,59 g) and N,N-dimethylformamide (50 ml) at room temperature is added sodium hydride (60% in oil, of 0.30 g). The reaction mixture was stirred at room temperature for 3 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with 3-ethyl-5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-it is in the form of colorless crystals (0,99 g, yield 59%) of the fraction, eluruumi hexane-ethyl acetate (3:1-2:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 108-109°C.

Comparative example 88

To a mixture of 5-(4-nitrobenzyl)-1H-tetrazole (5.0 g) and N,N-dimethylformamide (200 ml) is added sodium hydride (60% in oil, 1,17 g) at 0°C. the Reaction mixture was stirred at 0°C for 1 hour and add iodoethane (5,69 g) at 0°C. the Reaction mixture was stirred at 0°C for 2 h is in the reaction mixture is poured onto water. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 2-ethyl-5-(4-nitrobenzyl)-2H-tetrazole in the form of a brown oil (2.70 g, yield 48%) of the fraction, eluruumi hexane-ethyl acetate (2:1-1:2, vol/vol).

NMR (CDCl3) δ: 1,63 (3H, t, J=7.5 Hz), 4,35 (2H, c), 4,63 (2H, q, J=7.5 Hz), of 7.48-7,52 (2H, m), 8,16-to 8.20 (2H, m).

In addition, 1-ethyl-5-(4-nitrobenzyl)-1H-tetrazol obtained as brown crystals (0.65 g, yield 11%) of eluruumi after this faction, consistently. It recrystallization from ethyl acetate-hexane gives brown prismatic crystals. Melting point: 104-105°C.

NMR (CDCl3) δ: of 1.44 (3H, t, J=7.4 Hz), 4,25 (2H, q, J=7,4 Hz), and 4.40 (2H, c), 7,40-7,44 (2H, m), 8,20-8,24 (2H, m).

Comparative example 89

A mixture of 2-(4-nitrophenyl)attentioned (1,11 g), 2-chloro-3-butanone (0.75 g) and tert-butanol (50 ml) is heated under reflux for 4 days. The reaction mixture was concentrated and to the residue is added water and saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel obtained with the eat 4,5-dimethyl-2-(4-nitrobenzyl)-1,3-thiazole in the form of pale yellow crystals (0,67 g, yield 47%) of the fraction, eluruumi hexane-ethyl acetate (2:1-1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 93-94°C.

Comparative example 90

A mixture of 2-(4-nitrophenyl)attentioned (7.0 g), 2-chloro-cyclohexanone (7,28 g) and tert-butanol (100 ml) is heated under reflux for 3 days. The reaction mixture was concentrated and to the residue is added saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 2-(4-nitrobenzyl)-4,5,6,7-tetrahydro-1,3-benzothiazole in the form of pale brown crystals (6,58 g, yield 66%) of the fraction, eluruumi hexane-ethyl acetate (3:1, volume/volume). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 118-119°C.

Comparative example 91

2-(4-Nitrobenzyl)-5-propyl-1,3,4-oxadiazol (of 7.70 g), 5% palladium on coal (7.0 g) and tetrahydrofuran (200 ml) is subjected to catalytic recovery in the atmosphere of hydrogen at atmospheric pressure. The catalyst was removed by filtration and the filtrate concentrated. The residue is subjected to column chromatograph and on silica gel to obtain 4-[(5-propyl-1,3,4-oxadiazol-2-yl)methyl]aniline in the form of pale yellow crystals (3,74 g, yield 55%) of the fraction, eluruumi hexane-ethyl acetate (1:1-1:2, vol/vol). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 60-61°C.

In the same way as in example 91, receive connections described in the examples 92-112.

Comparative example 92

5-(4-Aminobenzyl)-1,3,4-oxadiazol-2(3H)-he obtained as colorless crystals (yield 75%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 267-268°C.

Comparative example 93

4-[2-(5-Ethyl-1,3,4-oxadiazol-2-yl)ethyl]aniline obtained as colorless oil (yield 97%).

NMR (CDCl3) δ: of 1.35 (3H, t, J=7,6 Hz), and 2.83 (2H, q, J=7,6 Hz), 2,92-3,11 (4H, m), 3,61 (2H, users), 6,58 of 6.66 (2H, m), 6,95-7,02 (2H, m).

Comparative example 94

4-[2-(1,3,4-Oxadiazol-2-yl)ethyl]aniline obtained as colorless crystals (yield 77%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 73-74°C.

Comparative example 95

4-[2-(4-Ethyl-1,3-thiazol-2-yl)ethyl]aniline obtained as brown oil (yield 96%).

NMR (CDCl3) δ: of 1.29 (3H, t, J=7,6 Hz), 2,73-to 2.85 (2H, m), 2,93-of 3.07 (2H, m), 3,18-of 3.27 (2H, m)to 3.58 (2H, users), 6,59-of 6.71 (3H, m), 6.90 to-7,11 (2H, m).

Comparative example 96

4-(1,3-Thiazol-4-ylethoxy)aniline obtained as nl is the bottom-yellow crystals (yield 78%). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 114-115°C.

Comparative example 97

4-[(2-Ethyl-1,3-thiazol-4-yl)methoxy]aniline obtained as brown oil (yield 83%).

NMR (CDCl3) δ: of 1.40 (3H, t, J=7.2 Hz), 3.04 from (2H, q, J=7.2 Hz), 3,44 (2H, users), to 5.08 (2H, d, J=0.9 Hz), 6,60-of 6.65 (2H, m), 6,79-6,84 (2H, m), 7,14 (1H, d, J=0.9 Hz).

Comparative example 98

4-(1,3,4-Oxadiazol-2-ylethoxy)aniline obtained as colorless crystals (yield 83%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 56-57°C.

Comparative example 99

4-[(4-Methyl-1,3-oxazol-2-yl)methyl]aniline obtained as colorless crystals (yield 80%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 84-85°C.

Comparative example 100

4-[(5-Methyl-1,3,4-oxadiazol-2-yl)methoxy]aniline obtained as colorless oil (yield 87%).

NMR (CDCl3) δ: to 2.55 (3H, c), 3,49 (2H, users), 5,13 (2H, c), 6,60-of 6.65 (2H, m), 6,80-6,86 (2H, m).

Comparative example 101

4-[(4-Ethyl-1,3-oxazol-2-yl)methyl]aniline obtained as colorless oil (yield 94%).

NMR (CDCl3) δ: of 1.20 (3H, t, J=7.5 Hz), 2,52 (2H, q, J=7.5 Hz), 3,63 (2H, users), of 3.96 (2H, c), 6,61 of 6.66 (2H, m), 7,06-to 7.09 (2H, m), 7.23 percent (1H, c).

Comparative example 102

4-[(2-Ethyl-1,3-thiazol-4-yl)methyl]aniline obtained as colorless oil (yield 92%).

NMR (CDCl3) δ: of 1.37 (3H, t, J=7.5 Hz), 3,01 (2H, q, J=7.5 Hz)and 3.59 (2H, users), 3,98 (2H, c), 6,56 (1H, c), 6,62 is 6.67 (2H, m),? 7.04 baby mortality-was 7.08 (2H, m).

Comparative example 103

{4-[(2-Methyl-1,3-thiazol-4-yl)methyl]aniline obtained as colorless oil (yield 95%).

NMR (CDCl3) δ: of 2.68 (3H, c)and 3.59 (2H, users), of 3.97 (2H, c), 6,56 (1H, c), 6,63 is 6.67 (2H, m),? 7.04 baby mortality-7,07 (2H, m).

Comparative example 104

5-(4-Aminobenzyl)-3-ethyl-1,3,4-oxadiazol-2(3H)-he obtained as colorless crystals (yield 71%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 88-89°C.

Comparative example 105

4-[(1-Methyl-1H-tetrazol-5-yl)methyl]aniline obtained as pale-yellow crystals (yield 81%). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 104-105°C.

Comparative example 106

4-[(2-Methyl-2H-tetrazol-5-yl)methyl]aniline obtained as colorless oil (yield 94%).

NMR (CDCl3) δ: 3,61 (2H, users), 4,11 (2H, c), 4,28 (3H, c), 6,62-of 6.65 (2H, m), 7,08-7,13 (2H, m).

Comparative example 107

4-[(1-Ethyl-1H-tetrazol-5-yl)methyl]aniline obtained as pale-yellow crystals (yield 78%). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. The rate is temperature melting point: 94-95° C.

Comparative example 108

4-[(2-Ethyl-2H-tetrazol-5-yl)methyl]aniline obtained as colorless oil (yield 98%).

NMR (CDCl3) δ: 1,60 (3H, t, J=7.4 Hz), 3,61 (2H, users), of 4.12 (2H, c), 4,59 (2H, q, J=7.4 Hz), 6,60-of 6.65 (2H, m), 7,09-7,13 (2H, m).

Comparative example 109

6-Amino-1,3-benzoxazol-2(3H)-he obtained as colorless crystals (yield 96%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 205-207°C (decomposition).

Comparative example 110

4-(1,3-Benzoxazol-2-ylmethyl)aniline obtained as colorless crystals (yield 78%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 105-106°C.

Comparative example 111

4-[(4,5-Dimethyl-1,3-thiazol-2-yl)methyl]aniline obtained as colorless crystals (yield 82%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 91-92°C.

Comparative example 112

4-(4,5,6,7-Tetrahydro-1,3-benzothiazol-2-ylmethyl)aniline obtained as pale-yellow crystals (yield 95%).

NMR (CDCl3) δ: 1,80-1,85 (4H, m), 2,64 was 2.76 (4H, m), 3,62 (2H, users), of 4.12 (2H, c), 6,62 of 6.66 (2H, m), 7,08-7,20 (2H, m).

Comparative example 113

A mixture of 4'-fortetienne (4,00 g), N,N-dimethylformamide of dimethylacetal (4,48 g) and N,N-dimethyl who formamide (4 ml) was stirred at 110° C for 1 hour. The mixture is additionally stirred for 6 hours with removal of methanol at atmospheric pressure. After cooling to 25°C add ethyl acetate (48 ml) for dissolution. The solution prepared separately by dissolving monohydrate p-toluensulfonate acid (6,06 g) in water (7 ml) and added dropwise to acylhydrazone (1,91 g) is added at 25-30°C for about 5 min to an ethyl acetate solution discussed earlier. The mixture is stirred at room temperature for 5.5 hours and distribute by adding 5% aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and sequentially washed with water and 10% saturated solution of salt. The solvent is evaporated with quantitative obtain 1-ethyl-5-(4-forfinal)-1H-pyrazole in the form of oil.

NMR (CDCl3) δ: 1,38 was 1.43 (3H, m), 4.09 to to 4.17 (2H, m), 6,24 (1H, c), 7,14-7,17 (2H, m), 7,34-7,39 (2H, m), 7,53 (1H, c).

To a solution of the obtained oil in N,N-dimethylformamide (16 ml) at 70-80°C is added dropwise phosphorus oxychloride (of 7.55 g) for about 2 hours. The mixture was stirred at 80-85°C for 1 hour and at 90-95°C for 3 hours. At 40°C or lower is added dropwise water (16 ml) and 30°C or lower is added dropwise 4n. an aqueous solution of potassium hydroxide, to establish a pH of 7-8. The mixture is extracted with ethyl acetate and the organic layer is raybaut water. The solvent is evaporated and the residue is subjected to column chromatography on silica gel and elute with ethyl acetate-hexane (1:5, vol/vol) to obtain 1-ethyl-5-(4-forfinal)-1H-pyrazole-4-carbaldehyde (3,66 g, yield 58%) as oil.

NMR (CDCl3) δ: 1,39-of 1.45 (3H, m), 4,05-4,16 (2H, m), 7,26-7,29 (2H, m), 7,40-7,46 (2H, m), with 8.05 (1H, c), 9,58 (1H, c).

Comparative example 114

A mixture of 4'-fortetienne (3,95 g), N,N-dimethylformamide of dimethylacetal (4,43 g) and N,N-dimethylformamide (4 ml) was stirred at 110°C for 1 hour. The mixture is additionally stirred for 6 hours with removal of methanol at atmospheric pressure. After cooling to 25°C add ethyl acetate (48 ml) for dissolution. The solution prepared separately by dissolving benzoylhydrazone of monohydrochloride (4,99 g) in water (5 ml), added at 25-30°C for about 5 min to an ethyl acetate solution discussed earlier. The mixture is stirred at room temperature for 17 h and distribute by adding 5% aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and sequentially washed with water and 10% saturated solution of salt. The solvent is evaporated with quantitative obtain 1-benzyl-5-(4-forfinal)-1H-pyrazole in the form of oil.

NMR (CDCl3)δ: 5,32 (2H, c), 6,32 (1H, d,J=1,84 Hz), 7,02-7,10 (4H, m), 7.24 to 7,31 (5H, m), 7,60 (1H, d, J=1,82 Hz).

p> To a solution of the obtained oil in N,N-dimethylformamide (16 ml) at 70-80°C is added dropwise phosphorus oxychloride (7,45 g) for about 2 hours. The mixture was stirred at 80-85°C for 1 hour and at 90-95°C for 4 hours. At 40°C or lower is added dropwise water (16 ml) and 30°C or lower is added dropwise 4n. an aqueous solution of potassium hydroxide, to establish a pH of 7-8. The mixture is extracted with ethyl acetate and the organic layer washed with water. The solvent is evaporated and the residue is subjected to column chromatography on silica gel and elute with ethyl acetate-hexane (1:5, vol/vol) to obtain 1-benzyl-5-(4-forfinal)-1H-pyrazole-4-carbaldehyde (5,18 g, yield 65%) as oil.

NMR (CDCl3) δ: 5,24 (2H, c), 7,02-7,05 (2H, m), 7,15-7,21 (2H, m), 7,27-7,33 (5H, m), 8,10 (1H, c), a 9.60 (1H, c).

Comparative example 115

A mixture of p-methylacetophenone (of 5.00 g), N,N-dimethylformamide of dimethylacetal (6,66 g) and N,N-dimethylformamide (5 ml) was stirred at 110°C for 1 hour. The mixture is additionally stirred for 10 h with removal of methanol at atmospheric pressure. After cooling to 25°C ethyl acetate (60 ml) was added for dissolution. The solution prepared separately by dissolving in water monohydrate p-toluensulfonate acid (7,80 g) (7 ml) and added dropwise to methylhydrazine (1.89 g), added at 25-30°C for about 5 min to an ethyl acetate RA is Toru, discussed earlier. The mixture is stirred at room temperature for 5 hours and distribute by adding 5% aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and sequentially washed with water and 10% saturated solution of salt. The solvent is evaporated, with the quantitative obtain 1-methyl-5-(4-were)-1H-pyrazole in the form of oil.

NMR (CDCl3) δ: is 2.37 (3H, c), 3,86 (3H, c), of 6.26 (1H, d, J=1,88 Hz), 7.23 percent-7,33 (4H, m), 7,49 (1H, d, J=1,86 Hz).

To a solution of the obtained oil in N,N-dimethylformamide (20 ml) at 70-80°C is added dropwise phosphorus oxychloride (9,71 g) for about 2 hours. The mixture was stirred at 80-85°C for 1 hour and at 90-95°C for 3.5 hours. At 40°C or lower is added dropwise water (16 ml) and 30°C or lower is added dropwise 4n. an aqueous solution of potassium hydroxide, to establish a pH of 7-8. The mixture is extracted with ethyl acetate and the organic layer washed with water. The solvent is evaporated and the residue is subjected to column chromatography on silica gel and elute with ethyl acetate-hexane (1:7-1:5, vol/vol) to obtain 1-methyl-5-(4-were)-1H-pyrazole-4-carbaldehyde (4.52 g, yield 61%) as oil.

NMR (CDCl3) δ: 2,47 (3H, c), 3,82 (3H, c), 7,31-7,38 (4H, m), 8,03 (1H, c), being 9.61 (1H, c).

Comparative example 116

A mixture of p-methoxyacetophenone (of 5.00 g), N,N-dimethylformamide dimetilan the tal (5,95 g) and N,N-dimethylformamide (5 ml) was stirred at 110° C for 1 hour. The mixture is additionally stirred for 10 h with removal of methanol at atmospheric pressure. After cooling to 25°C to dissolve add ethyl acetate (60 ml). The solution prepared separately by dissolving monohydrate p-toluensulfonate acid (6,97 g) in water (7 ml) and added dropwise to methylhydrazine (1,69 g) is added at 25-30°C for about 5 min to an ethyl acetate solution discussed earlier. The mixture is stirred at room temperature for 18 h and distribute by adding 5% aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and sequentially washed with water and 10% saturated solution of salt. The solvent is evaporated, with quantitative getting 5-(4-methoxyphenyl)-1-methyl-1H-pyrazole in the form of oil.

NMR (CDCl3) δ: of 3.85 (3H, c), a 3.87 (3H, c), and 6.25 (1H, c), 6,97-7,00 (2H, m), 7,33 and 7.36 (2H, m), 7,49 (1H, c).

To a solution of the obtained oil in N,N-dimethylformamide (20 ml) at 70-80°C is added dropwise phosphorus oxychloride (8,55 g) for about 2 hours. The mixture was stirred at 80-85°C for 1 hour and at 90-95°C for 3 hours. At 40°C or lower is added dropwise water (20 ml) and 30°C or lower is added dropwise 4n. an aqueous solution of potassium hydroxide, to establish a pH of 7-8. The mixture is extracted with ethyl acetate and the organic is Loy washed with water. The solvent is evaporated and the residue is subjected to column chromatography on silica gel and elute with ethyl acetate-hexane (1:7-1:4, vol/vol) to obtain 5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (of 4.05 g, yield 56%) as oil.

NMR (CDCl3) δ: 3,81 (3H, c), with 3.89 (3H, c),? 7.04 baby mortality-was 7.08 (2H, m), 7,33-7,38 (2H, m), 8,02 (1H, c), being 9.61 (1H, c).

Comparative example 117

A mixture of 4'-fortetienne (10,00 g), N,N-dimethylformamide of dimethylacetal (11,21 g) and N,N-dimethylformamide (10 ml) was stirred at 110°C for 1 hour. The mixture is additionally stirred for 8 hours with removal of methanol at atmospheric pressure. After cooling to 25-30°C to dissolve add ethyl acetate (120 ml). The solution prepared separately by suspension monohydrate p-toluensulfonate acid (15.1 g) in water (3 ml) and added dropwise at 25°C or below 35% aqueous solution of methylhydrazine (10,48 g) added at an internal temperature of 25°C for about 10 min to an ethyl acetate solution discussed earlier. The mixture is stirred at room temperature for 4 hours, add 5% aqueous sodium bicarbonate solution and extracted with a mixture of ethyl acetate. The organic layer is successively washed with water and 5% saturated solution of salt. The solvent is evaporated, with quantitative getting 5-(4-forfinal)-1-methyl-1H-pyrazole in the form of oil.

NMR (CDCl 3) δ: 3,86 (3H, c), 6,27 (1H, c), 7,11-to 7.18 (2H,m), of 7.36-7,41 (2H, m)to 7.50 (1H, c).

To a solution of the obtained oil in dimethylformamide (40 ml) is added dropwise phosphorus oxychloride (18,87 g) at 70-80°C for about 3 hours. The mixture was stirred at 80°C for 1 hour and at 90°C for 4 hours. At 40°C or lower is added dropwise water (20 ml) and the internal temperature of 30°C or lower is added dropwise 4n. an aqueous solution of potassium hydroxide, to establish a pH of 7.5 to 8.0. Water (28 ml) is added dropwise and the mixture is stirred at 25°C for 1 hour. The precipitated crystals are collected by filtration and washed with 20% ethanol. The obtained crystals is recrystallized from ethanol-water to obtain 5-(4-forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde (br11.01 g, yield 74%).

NMR (CDCl3) δ: of 3.80 (3H, c), 7,22-7,28 (2H, m), 7,39-7,44 (2H, m), 8,03 (1H, c), being 9.61 (1H, c).

Comparative example 118

To a mixture of 5-(4-forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde (3.00 g), malonic acid (1,99 g) and simple bis(2-methoxyethanol) ether (9 ml) for about 10 min added dropwise piperidine (1.89 ml). The mixture was stirred at 90-95°C for 1 hour and, optionally, at 105-110°C for 4 hours. After cooling to 25°C add toluene (12 ml) and 1N. an aqueous solution of sodium hydroxide (15 ml) and the mixture is stirred. The aqueous layer was separated and the organic layer extracted with 1N. aqueous solution of hydro is sid sodium (6 ml). The aqueous layers are combined and washed with toluene. Layers was adjusted to pH 3.5 to 4.0 2n. hydrochloric acid at 20-30°C and added dropwise water (9 ml). After stirring at 25°C for 1 hour, the precipitated crystals are collected by filtration and washed with 20% ethanol to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (3,24 g, yield 90%).

NMR (DMSO-d6) δ: of 3.73 (3H, c), and 6.25 (1H, d, J=15,9 Hz), 7,14 (1H, d, J=15,9 Hz), 7,41-7,56 (4H, m), of 8.09 (1H, c), 12,11 (1H, usher.).

Comparative example 119

A mixture of ethyl 3-(3-furyl)-3-oxopropionate (7,8 g) and N,N-dimethylformamide of dimethylacetal (6,15 g) is stirred at reflux for 1 hour. The reaction mixture was concentrated and add methylhydrazine (of 5.92 g) and ethanol (50 ml). The mixture is stirred at reflux for 30 minutes, the Reaction mixture was concentrated, added to the residue water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain a pale red oil (of 7.55 g) from fractions, eluruumi hexane-ethyl acetate (4:1, volume/volume). This pale-red oil was dissolved in tetrahydrofuran (250 ml) and at 0°C carefully add lithium aluminum hydride (1.3 g) and the mixture was stirred at 0°C for 30 minutes In the enjoyment of the operating mixture gently add 1H. an aqueous solution of sodium hydroxide to until a solid product is no longer deposited and after stirring at room temperature for 30 min the mixture is filtered. The filtrate is concentrated to obtain a yellow oil (4,89 g). This yellow oil was dissolved in tetrahydrofuran (200 ml), to which is added activated manganese dioxide (10 g), and stirred while heating the mixture at room temperature for 14 hours. The reaction mixture is filtered. The filtrate is concentrated and the residue is subjected to column chromatography on silica gel to obtain 5-(3-furyl)-1-methyl-1H-pyrazole-4-carbaldehyde (4,25 g) as crystals from a fraction, eluruumi hexane-ethyl acetate (2:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 70-71°C.

From the faction, eluruumi after the above connections, receive 3-(3-furyl)-1-methyl-1H-pyrazole-4-carbaldehyde (0,60 g) as crystals. It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 77-78°C.

Comparative example 120

A mixture of 5-(3-furyl)-1-methyl-1H-pyrazole-4-carbaldehyde (900 mg), sodium hydride (60% in oil, 245 mg), ethyl diethylphosphonoacetate (1.26 g) and N,N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. The reaction is th mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives ethyl (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazole-4-yl]acrylate (866 mg, 69%) as colorless prismatic crystals. Melting point: 82-83°C.

Comparative example 121

To a mixture of ethyl (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazole-4-yl]acrylate (800 mg), tetrahydrofuran (10 ml) and ethanol (10 ml) is added 2n. an aqueous solution of sodium hydroxide (6.5 ml) and the mixture was stirred at 60°C for 1 hour. 1H. Hydrochloric acid was poured into the reaction mixture and the precipitated solids are collected by filtration, washed with water and dried in a stream of air to obtain (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazole-4-yl]acrylic acid (703 mg, 99%) as crystals. It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 218-219°C.

Comparative example 122

A mixture of ethyl 3-oxo-3-(2-thienyl)propionate (10.3 g) and N,N-dimethylformamide of dimethylacetal (7,28 g) is stirred at reflux for 30 minutes, the Reaction mixture was concentrated and add methylhydrazine (7,19 g) and ethanol (50 ml). The mixture is stirred at reflux for 30 minutes, the Reaction mixture was concentrated and the residue is poured onto water. A mixture of the former is reginout with ethyl acetate, and the organic layer washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain a pale red oil (9,37 g) from fractions, eluruumi hexane-ethyl acetate (4:1, volume/volume). This pale-red oil was dissolved in tetrahydrofuran (250 ml) and at 0°C carefully add lithium aluminum hydride (1.5 g) and the mixture was stirred at 0°C for 30 min In the reaction mixture is carefully added 1N. an aqueous solution of sodium hydroxide to until a solid product is no longer deposited and after stirring at room temperature for 30 minutes it is filtered. The filtrate is concentrated to obtain a yellow oil (6,53 g). This yellow oil was dissolved in tetrahydrofuran (250 ml). Added activated manganese dioxide (15 g) and the mixture is stirred at room temperature for 14 hours. The reaction mixture is filtered. The filtrate is concentrated, and the residue is subjected to column chromatography on silica gel to obtain 1-methyl-5-(2-thienyl)-1H-pyrazole-4-carbaldehyde (3,10 g) as a pale-yellow oil from a fraction, eluruumi hexane-ethyl acetate (2:1, volume/volume).

NMR (CDCl3) δ: to 3.92 (3H, c), 7,20-7,30 (2H, m), a 7.62 (1H, DD, J=5,1, 1.2 Hz), 8,03 (1H, c), 9,74 (1H, c).

From the faction, eluruumi after the above connections, receive 1-methyl-3-(2-thienyl)-1H-pyrazole-4-CT the aldehyde (1,81 g) as crystals. It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 71-72°C.

Comparative example 123

A mixture of 1-methyl-5-(2-thienyl)-1H-pyrazole-4-carbaldehyde (2.0 g), sodium hydride (60% in oil, 0.5 g), ethyl diethylphosphonoacetate (to 2.57 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives ethyl (2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazole-4-yl]acrylate (2,09 g, 77%) as pale yellow prismatic crystals. Melting point: 73-74°C.

Comparative example 124

To a mixture of ethyl (2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazole-4-yl]acrylate (2.0 g) and methanol (20 ml) is added 2n. an aqueous solution of sodium hydroxide (7,6 ml) and the mixture was stirred at 60°C for 30 min 1H. Hydrochloric acid was poured into the reaction mixture and the precipitated solids are collected by filtration, washed with water and dried in a stream of air to obtain (2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazole-4-yl]acrylic acid (1,69 g, 95%) as crystals. It recrystallization from methanol-simple isopropyl ether gives colorless prismatic crystals. The temperature of prawle the Oia: 210-212° C.

Comparative example 125

A mixture of ethyl 3-oxo-3-(3-pyridinyl)propionate (7,58 g) and N,N-dimethylformamide of dimethylacetal (6,07 g) is stirred at reflux for 30 minutes, the Reaction mixture was concentrated and add methylhydrazine (5,85 g) and methanol (50 ml). The mixture is stirred at reflux for 30 minutes, the Reaction mixture was concentrated and water was poured into the residue. The mixture is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain methyl 1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-carboxylate (1,15 g, 13%) as a pale-yellow oil from a fraction, eluruumi hexane-ethyl acetate (2:1, volume/volume).

NMR (CDCl3) δ: 3,71 (3H, c), of 3.78 (3H, c), 7,44 is 7.50 (1H, m), 7,76-of 7.82 (1H, m), 8,01 (1H, c)8,64 (1H, c), 8,72-8,76 (1H, m).

Comparative example 126

To a mixture of methyl 1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-carboxylate (1.1 g) and tetrahydrofuran (20 ml) at 0°C carefully add lithium aluminum hydride (192 mg) and the mixture is stirred at room temperature for 30 min. the reaction mixture was carefully added 1N. an aqueous solution of sodium hydroxide to until a solid product is no longer deposited and after stirring at room temperature for 30 min it has shown the comfort. The filtrate is concentrated to obtain a yellow oil (0.95 g). This yellow oil was dissolved in tetrahydrofuran (50 ml). Added activated manganese dioxide (3 g) and the mixture is stirred at room temperature for 14 hours. The reaction mixture is filtered and the filtrate concentrated. Recrystallization of the residue from ethyl acetate-hexane gives 1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-carbaldehyde (770 mg, 82%) as pale yellow prismatic crystals. Melting point: 118-119°C.

Comparative example 127

A mixture of 1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-carbaldehyde (750 mg), sodium hydride (60% in oil, 176 mg), ethyl diethylphosphonoacetate (1.08 g) and N,N-dimethylformamide (8 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives ethyl (2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-yl]acrylate (770 mg, 75%) as pale yellow prismatic crystals. Melting point: 159-160°C.

Comparative example 128

To a mixture of ethyl (2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-yl]acrylate (700 mg) and methanol (5 ml) is added 2n. aqueous sodium hydroxide solution (2.7 ml)and the mixture stirred at 40°C for 14 hours. In reaction the second mixture is poured a saturated aqueous solution of citric acid, to establish pH 5 and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The remainder will recrystallized from ethyl acetate-simple isopropyl ether to obtain (2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-yl]acrylic acid (296 mg, 47%) as pale yellow prismatic crystals. Melting point: 236-237°C.

Comparative example 129

A mixture of 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (400 mg), sodium hydride (60% in oil, 155 mg), ethyl diethylphosphonoacetate (795 mg) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives ethyl (2E)-3-(1,5-dimethyl-1H-pyrazole-4-yl)acrylate (304 mg, 49%) as colorless prismatic crystals. Melting point: 82-83°C.

Comparative example 130

To a mixture of ethyl (2E)-3-(1,5-dimethyl-1H-pyrazole-4-yl)acrylate (380 mg) and methanol (20 ml) is added 2n. an aqueous solution of sodium hydroxide (2.0 ml) and the mixture was stirred at 60°C for 14 hours. The reaction mixture was poured 1H. hydrochloric acid and extracted with a mixture of ethyl acetate. The organic layer was washed with water, dried the hell anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives (2E)-3-(1,5-dimethyl-1H-pyrazole-4-yl)acrylic acid (283 mg, 87%) as colorless prismatic crystals. Melting point: 217-219°C.

Comparative example 131

A mixture of 1-methyl-1H-pyrazole-4-carbaldehyde (2,59 g), sodium hydride (60% in oil, 1.13 g), ethyl diethylphosphonoacetate (5.8 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain ethyl (2E)-3-(1-methyl-1H-pyrazole-4-yl)acrylate (2,72 g, 64%) as crystals from a fraction, eluruumi hexane-ethyl acetate (1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 43-44°C.

Comparative example 132

To a mixture of ethyl (2E)-3-(1-methyl-1H-pyrazole-4-yl)acrylate (2.5 g), methanol (20 ml) and tetrahydrofuran (20 ml) is added 2n. an aqueous solution of sodium hydroxide (to 13.9 ml) and the mixture was stirred at 60°C for 3 hours. The reaction mixture was poured 1H. hydrochloric acid and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and to the center to obtain (2E)-3-(1-methyl-1H-pyrazole-4-yl)acrylic acid (1.75 g, 83%) as an amorphous form.

NMR (CDCl3) δ: 3,93 (3H, c), 6,16 (1H, d, J=15,8 Hz), EUR 7.57 (1H, c), the 7.65 (1H, d, J=15,8 Hz), 7,72 (1H, c).

Comparative example 133

A mixture of diethyl [3-(methyl bromide)benzyl]phosphonate (10 g), phthalimide potassium (5,77 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 14 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives diethyl {3-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]benzyl}phosphonate (9,40 g, 78%) as colorless prismatic crystals. Melting point: 100-101°C.

Comparative example 134

A mixture of diethyl [2-(methyl bromide)benzyl]phosphonate (11.2 g), phthalimide potassium (6,46 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 14 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives diethyl {2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]benzyl}phosphonate (11.3 g, 83%) as colorless prismatic crystals. Melting point: 91-92°C.

Comparative example 135

A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (7,06 g) 4-nitrobenzyl bromide (10 g), potassium carbonate (16.6 g) and N,N-dimethylformamide (60 ml) was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain methyl 1-(4-nitrobenzyl)-1H-1,2,4-triazole-5-carboxylate (1.50 g, 12%) as crystals from a fraction, eluruumi hexane-ethyl acetate (1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 126-130°C.

From the faction, eluruumi after the above connection, get methyl 1-(4-nitrobenzyl)-1H-1,2,4-triazole-3-carboxylate (1,49 g, 12%) as crystals. It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 175-177°C.

Comparative example 136

A mixture of methyl 1-(4-nitrobenzyl)-1H-1,2,4-triazole-5-carboxylate (1.3 g), 10% palladium on coal (130 mg) and ethanol (200 ml) is stirred under hydrogen atmosphere at room temperature for 2 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. The residue is subjected to column chromatography on silica gel to obtain methyl 1-(4-aminobenzyl)-1H-1,2,4-triazole-5-carboxylate (0.88 g, 76%) in whitecrystal from the faction, eluruumi hexane-ethyl acetate (1:2, vol/vol). It recrystallization from ethyl acetate-simple isopropyl ether gives colorless prismatic crystals. Melting point: 101-103°C.

Comparative example 137

A mixture of 1-(2-bromacil)-4-nitrobenzene (18.7 g), pyrazole (5.53 g) and potassium hydroxide (4,56 g) was stirred at 140°C for 8 min, the Reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 1-[2-(4-nitrophenyl)ethyl]-1H-pyrazole (1,37 g, 8%) as crystals from a fraction, eluruumi hexane-ethyl acetate (1:2, vol/vol). It recrystallization from ethyl acetate-hexane gives yellow prismatic crystals. Melting point:92-93°C.

Comparative example 138

A mixture of 1-[2-(4-nitrophenyl)ethyl]-1H-pyrazole (0.8 g), 10% palladium on coal (80 mg) and ethanol (200 ml) is stirred under hydrogen atmosphere at room temperature for 6 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. Recrystallization of the residue from ethyl acetate-hexane gives 1-[2-(4-AMINOPHENYL)ethyl]-1H-pyrazole (520 mg, 75%) as colorless prismatic crystals. Melting point: 73-74°C.

Comparative with the EP 139

A mixture of 4-nitrobenzylamine hydrochloride (8.0 g), ethyl 4-chloro-4-oxobutanoate (10,47 g), saturated aqueous sodium bicarbonate solution (100 ml) and ethyl acetate (100 ml) was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gives ethyl 4-[(4-nitrobenzyl)amino]-4-oxobutanoate (10.3 g, 87%) as colorless prismatic crystals. Melting point: 104-106°C.

Comparative example 140

A mixture of ethyl 4-[(4-nitrobenzyl)amino]-4-oxobutanoate (10 g), 10% palladium on coal (1 g) and ethanol (300 ml) is stirred under hydrogen atmosphere at room temperature for 14 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. Recrystallization of the residue from ethyl acetate-hexane gives ethyl 4-[(4-aminobenzyl)amino]-4-oxobutanoate (3.6 g, 40%) as colorless prismatic crystals. Melting point: 62-64°C.

Comparative example 141

A mixture of 2-(4-nitrobenzyl)-2H-tetrazole (5 g), 10% palladium on coal (500 mg), ethanol (100 ml) and tetrahydrofuran (100 ml) is stirred under hydrogen atmosphere at room temperature for 4 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrate is their. Recrystallization of the residue from ethyl acetate-hexane gives 2-(4-aminobenzyl)-2H-tetrazol (2.83 g, 66%) as yellow prismatic crystals. Melting point: 86-87°C.

Comparative example 142

A mixture of 1-(4-nitrobenzyl)-1H-tetrazole (5 g), 10% palladium on coal (500 mg), ethanol (100 ml) and tetrahydrofuran (100 ml) is stirred under hydrogen atmosphere at room temperature for 4 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. Recrystallization of the residue from ethyl acetate-hexane gives 1-(4-aminobenzyl)-1H-tetrazol (3.03 g, 71%) as yellow prismatic crystals. Melting point: 138-140°C.

Comparative example 143

A mixture of [1-(4-nitrobenzyl)-1H-imidazol-2-yl]methanol (3.6 g), 10% palladium on coal (400 mg) and ethanol (50 ml) is stirred under hydrogen atmosphere at room temperature for 4 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. Recrystallization of the residue from ethyl acetate-hexane gives [1-(4-aminobenzyl)-1H-imidazol-2-yl]methanol (2,53 g, 95%) as colorless prismatic crystals. Melting point: 125°C (decomposition)

Comparative example 144

A mixture of 4-methyl-1H-imidazole (25,5 g), 4-nitrobenzyl bromide (56 g), potassium carbonate (86 g) and N,N-dimethylformamide (500 ml) was stirred at room temperature T. the value of 14 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 5-methyl-1-(4-nitrobenzyl)-1H-imidazole (1.6 g, 3%) as crystals from a fraction, eluruumi methanol-ethyl acetate (1:20, vol/vol). It recrystallization from ethyl acetate-simple isopropyl ether gives colorless prismatic crystals. Melting point: 120-121°C.

From the faction, eluruumi prior to the above mentioned connection, get the mixture (25 g, containing 4-methyl-1-(4-nitrobenzyl)-1H-imidazole, approximately 75%) of 4-methyl-1-(4-nitrobenzyl)-1H-imidazole and 5-methyl-1-(4-nitrobenzyl)-1H-imidazole.

Comparative example 145

The mixture of the mixture (25 g, containing 4-methyl-1-(4-nitrobenzyl)-1H-imidazole, approximately 75%) of 4-methyl-1-(4-nitrobenzyl)-1H-imidazole and 5-methyl-1-(4-nitrobenzyl)-1H-imidazole obtained in the above comparative example 144, 10% palladium on coal (3 g) and ethanol (500 ml) is stirred under hydrogen atmosphere at room temperature for 14 hours. Palladium on coal is removed from the reaction mixture by filtration, and the filtrate concentrated. The remainder will recrystallized from ethyl acetate to obtain 1-(4-aminobenzyl)-4-methyl-1H-imidazole (3,91 g) as colorless prismatic crystals. The rate is temperature melting point: 141-142° C.

Comparative example 146

A mixture of 5-methyl-1-(4-nitrobenzyl)-1H-imidazole (1.4 g), 10% palladium on coal (200 mg) and ethanol (20 ml) at room temperature was stirred in hydrogen atmosphere for 4 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. Recrystallization of the residue from ethyl acetate-hexane gives 1-(4-aminobenzyl)-5-methyl-1H-imidazole (1,17 g, 97%) as colorless prismatic crystals. Melting point: 124-125°C.

Comparative example 147

A mixture of 4-ethyl-1H-imidazole (2,46 g), 4-nitrobenzyl bromide (between 6.08 g), potassium carbonate (7,08 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 14 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 4-ethyl-1-(4-nitrobenzyl)-1H-imidazole (1,95 g) as a yellow oil from a fraction, eluruumi with ethyl acetate-hexane (1:1, volume/volume). A mixture of 4-ethyl-1-(4-nitrobenzyl)-1H-imidazole (1,95 g), 10% palladium on coal (200 mg) and ethanol (50 ml) at room temperature was stirred in hydrogen atmosphere for 4 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. Recrystallization of the residue from utilize the ATA-hexane gives 1-(4-aminobenzyl)-5-methyl-1H-imidazole (1.44 g) as colorless prismatic crystals. Melting point: 137-138°C.

Comparative example 148

A mixture of 5,6-dimethyl-1H-benzimidazole (5.0 g), 4-nitrobenzyl bromide (6,16 g), potassium carbonate (7,88 g) and N,N-dimethylformamide (60 ml) at 60°C is stirred for 14 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain 5,6-dimethyl-1-(4-nitrobenzyl)-1H-benzimidazole (2.6 g, 32%) as crystals from a fraction, eluruumi methanol-ethyl acetate (1:20, vol/vol). It recrystallization from ethyl acetate-hexane gives a pale-red prismatic crystals. Melting point: 175-177°C.

Comparative example 149

A mixture of 5,6-dimethyl-1-(4-nitrobenzyl)-1H-benzimidazole (2.5 g), 10% palladium on coal (300 mg), ethanol (150 ml) and tetrahydrofuran (150 ml) is stirred under hydrogen atmosphere at room temperature for 4 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. Recrystallization of the residue from ethyl acetate-methanol to give 1-(4-aminobenzyl)-5,6-dimethyl-1H-benzimidazole (1.88 g, 84%) as colorless prismatic crystals. Melting point: 238-239°C.

Comparative example 150

A mixture of 1-(4-nitrobenzyl)-1H-indazole (9,25 g), 10% pall is palladium on coal (1 g), ethanol (100 ml) and tetrahydrofuran (100 ml) at room temperature was stirred in an atmosphere of hydrogen for 4 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. Recrystallization of the residue from acetone-hexane gives 4-(1H-indazol-1-ylmethyl)aniline (6,77 g, 83%) as colorless prismatic crystals. Melting point: 110-111°C.

Comparative example 151

A mixture of 2-(4-nitrobenzyl)-2H-1,2,3-benzotriazole (1.0 g), 10% palladium on coal (100 mg) and ethanol (20 ml) at room temperature was stirred in hydrogen atmosphere for 4 hours. Palladium on coal is removed from the reaction mixture by filtration and the filtrate concentrated. The residue is subjected to column chromatography on silica gel to obtain 4-(2H-1,2,3-benzotriazol-2-ylmethyl)aniline (313 mg, 35%) as crystals from a fraction, eluruumi with ethyl acetate-hexane (1:1, volume/volume). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 229-230°C.

Comparative example 152

To a mixture of 5-(4-forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde (4,50 g) and tetrahydrofuran (50 ml) at 0°C is added dropwise methyl magnesium bromide (1 mol/l solution in tetrahydrofuran, 25 ml) and the mixture was stirred at 0°C for 30 minutes, the Reaction mixture was poured into a saturated aqueous solution of chloride of am is one and extracted with a mixture of ethyl acetate. An ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated and the residue is dissolved in acetone (60 ml). This solution is cooled to 0°C and added dropwise Jones reagent (obtained using the method described inNew Courses in Chemistry ExperimentVol. 15, p. 151, published by Maruzen Company, Limited) dropwise until then, until the red color of the reagent will no longer disappear. The reaction mixture was added isopropyl alcohol and water and extracted with a mixture of ethyl acetate. An ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in N,N-dimethylformamide (50 ml). To this solution was added ethyl diethylphosphonoacetate (6.0 g) and sodium hydride (60% in oil, 1.0 g) and the mixture was stirred at 80°C for 12 hours. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. An ethyl acetate layer is dried over anhydrous magnesium sulfate, concentrated and the residue purified by column chromatography on silica gel to obtain a yellow oil from a fraction, eluruumi with ethyl acetate-hexane (1:1, volume/volume). This yellow oil was dissolved in a mixture of acetic acid 37% hydrochloric acid (20-20 ml) and the mixture was stirred at 120°C for 3 hours. The reaction mixture was concentrated and poured into water. The precipitated crystals are collected by filtration, washed with water and dried to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]but-2-e the OIC acid (4,60 g, 80%) as colorless crystals. It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 123-124°C.

Comparative example 153

In accordance with the method described in comparative example 44, 3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]butane acid is obtained from (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]but-2-ene acid, with a yield of 85%. Colorless prismatic crystals. Melting point: 90-91°C (recrystallized from ethyl acetate-hexane).

Comparative example 154

To a mixture of ethyl 1,5-diphenyl-1H-pyrazole-4-carboxylate (14.9 g) and tetrahydrofuran (250 ml) added dropwise diisobutylaluminium hydride (1 mol/l toluene solution, 120 ml)while cooling on ice. The reaction mixture was stirred at room temperature for 1 hour and poured into 1N. an aqueous solution of hydrochloric acid. The mixture is extracted with ethyl acetate. An ethyl acetate layer is washed subsequently with 1N. aqueous solution of hydrochloric acid and a saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain (1,5-diphenyl-1H-pyrazole-4-yl)methanol (12,6 g, 99%) as colorless crystals. It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 147-148°C.

Comparative the example 155

To a mixture of (1,5-diphenyl-1H-pyrazole-4-yl)methanol (11,78 g), triethylamine (10 ml) and ethyl acetate (300 ml) at 0°C added dropwise methanesulfonyl chloride (4.5 ml). The mixture is stirred at room temperature for 1 hour and an ethyl acetate layer washed sequentially with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain oil. This oil is dissolved in N,N-dimethylformamide (100 ml) and the resulting solution is added dropwise to a solution of sodium diethylmalonate in N,N-dimethylformamide (obtained using diethylmalonate, 20,33 g of sodium hydride (60% in oil, 4,88 g) and N,N-dimethylformamide, 200 ml) at 0°C. the Mixture is stirred at room temperature for 5 hours and poured into 1N. an aqueous solution of hydrochloric acid. The mixture is extracted with ethyl acetate. An ethyl acetate layer is washed subsequently with 1N. aqueous solution of hydrochloric acid and a saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain oil. A mixture of this oil, 6N. aqueous hydrochloric acid (100 ml) and acetic acid (50 ml) is heated under reflux for 5 hours. The reaction mixture is cooled, concentrated and poured into water. The precipitated crystals are collected by filtration, washed with water and dried to obtain 3-(1,5-diphenyl-1H-pyrazole-4-yl)impregnated the new acid.

Yield: 68%. Colorless needle-like crystals. Melting point: 159-160°C (recrystallized from acetone-hexane).

Comparative example 156

A mixture of 5-(4-chlorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (of 6.68 g), ethyl diethylphosphonoacetate (7.47 g), sodium hydride (60% in oil, of 1.30 g) and N,N-dimethylformamide (100 ml) at room temperature and stirred for 1 hour. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain colorless crystals (of 8.37 g). The mixture of crystals (4,55 g), platinum dioxide (228 mg) and ethanol (50 ml) at room temperature was stirred in hydrogen atmosphere at atmospheric pressure for 2 hours. The catalyst was removed by filtration and the filtrate is concentrated and purified by column chromatography to obtain ethyl 3-[5-(4-chlorophenyl)-1-methyl-1H-pyrazole-4-yl]propionate (4,70 g) as a colorless oil from a fraction, eluruumi hexane-ethyl acetate (1:2, vol/vol).

Elemental analysis: Calculated (C15H17ClN2O2C, 61,54; H, OF 5.85; N, TO 9.57. Found C, 61,28; H, 5,95; N, Of 9.21.

Comparative example 157

A mixture of ethyl 3-[5-(4-chlorophenyl)-1-methyl-1H-pyrazole-4-yl]propionate (2.35 g), 1H. an aqueous solution of sodium hydroxide (16 ml), tetrahydrofur is on (30 ml) and ethanol (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into an aqueous solution of potassium hydrosulfate and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 3-[5-(4-chlorophenyl)-1-methyl-1H-pyrazole-4-yl]propionic acid (1,46 g, 69%) as a colorless powder. Melting point: 138-140°C (recrystallized from acetone-hexane).

Comparative example 158

Potassium bis(trimethylsilyl)amide (20% toluene solution of 3.05 g) are added to a mixture of bis(2,2,2-triptorelin) (methoxycarbonylmethyl)phosphonate (973 mg), 18-crown-6 (Android 4.04 g) and tetrahydrofuran (50 ml) at -78°C. in Addition, add 5-(4-forfinal)-1-methyl-1H-pyrazole-4-carbaldehyde (312 mg) and the mixture is stirred overnight while allowing to warm from -78°C to room temperature. The reaction mixture was added saturated aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The organic layer is successively washed with 1N. hydrochloric acid, water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain methyl (2Z)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylate in the form of crystals (0.35 g, yield 95%) of the fraction, eluruumi hexane-ethyl acetate (4:1-1:1, volume/volume) (perakis allsouth from ethyl acetate-hexane). Melting point: 108-109°C.

Comparative example 159

A mixture of 1-(4-forfinal)-2-propanone (10.0 g) and N,N-dimethylformamide of dimethylacetal (8.00 g) was stirred at 120°C for 2 hours. The reaction mixture is cooled, and precipitated solid product, which is collected by filtration, add hexane to obtain 4-(dimethylamino)-3-(4-forfinal)but-3-EN-2-she (11.3 g, yield 83%) as a pale-yellow solid product.

NMR (CDCl3) δ: of 1.94 (3H, c), 2,70 (6H, users), 6,95-7,05 (2H, m), 7,1-7,2 (2H, m), 7,58 (1H, c).

Comparative example 160

A mixture of 4-(dimethylamino)-3-(4-forfinal)but-3-EN-2-he (10,36 g), methylhydrazine (2,31 g) and ethanol (50 ml) is stirred for 1 hour. while heating under reflux. The reaction mixture is concentrated, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain a yellow oil. This yellow oil was dissolved in carbon tetrachloride (100 ml)and add N-bromosuccinimide (9,79 g) and 2,2'-azobis(isobutyronitrile) (50 mg). The mixture is stirred for 5 hours while heating under reflux. The reaction mixture is concentrated, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrate to obtain altago oil. This yellow oil was dissolved in methanol (100 ml) and add sodium formate (10.0 g). The mixture is stirred for 16 hours under reflux. The reaction mixture is concentrated, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by column chromatography and elute with hexane-ethyl acetate (100:0-0:100, vol/vol), to separate the following two types of connections.

[4-(4-Forfinal)-1-methyl-1H-pyrazole-5-yl]methanol: (311 mg). Pale yellow solid product.

NMR (CDCl3) δ: 3,99 (3H, c), 4,74 (2H, c), 7,05-to 7.15 (2H, m), 7.3 to 7.4 (2H, m), 7,53 (1H, c).

[4-(4-Forfinal)-1-methyl-1H-pyrazole-3-yl]methanol: (60 mg). pale yellow solid product.

NMR (CDCl3) δ: to 3.92 (3H, c), 4,72 (2H, c), of 7.0, and 7.1 (2H, m), between 7.4 to 7.5 (2H, m), 7,45 (1H, c).

Comparative example 161

A mixture of [4-(4-forfinal)-1-methyl-1H-pyrazole-5-yl]methanol (250 mg), activated manganese dioxide (1.0 g) and tetrahydrofuran (10 ml) was stirred at room temperature for 3 hours. The reaction mixture is filtered and the organic layer concentrated to obtain 4-(4-forfinal)-1-methyl-1H-pyrazole-5-carbaldehyde (172 mg, yield 70%) as pale yellow crystals.

NMR (CDCl3) δ: to 4.23 (3H, c), and 7.1 to 7.2 (2H, m), 7,35-7,45 (2H, m), to 7.59 (1H, c), 9,84 (1H, c).

Comparative example 162

4-(4-forfinal)-1-methyl-H-pyrazole-3-carbaldehyde

In accordance with the method presented in the comparative example 161, specified in the title compound synthesized from [4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]methanol.

Yield: 80%. Pale yellow solid product.

NMR (CDCl3) δ: of 4.05 (3H, c), 7,05-to 7.15 (2H, m), 7,52 (1H, c), 7,55 and 7.6 (2H, m), 10,04 (1H, c).

Comparative example 163

A mixture of 4-(4-forfinal)-1,2,3-thiadiazole-5-carbaldehyde (180 mg), ethyl diethylphosphonoacetate (450 mg), sodium hydride (60% in oil, 40 mg) and N,N-dimethylformamide (3 ml) at room temperature and stirred for 2 hours. The reaction mixture was poured into 1N. an aqueous solution of hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer is concentrated and to the residue add 6N. an aqueous solution of hydrochloric acid (3 ml) and acetic acid (3 ml). The mixture is stirred for 3 hours while heating under reflux. The reaction mixture was concentrated and poured into water. Precipitated solids are collected by filtration, washed with water and dried to obtain (2E)-3-[4-(4-forfinal)-1,2,3-thiadiazole-5-yl]acrylic acid (130 mg, yield 60%) as a pale-yellow solid product.

NMR (DMSO-d6) δ: 6,69 (1H, d, J=15,5 Hz), 7,45 and 7.6 (3H, m), 7,75-a 7.85 (2H, m).

Example 1

A mixture of dimethyl 4-aminomethylphosphonate (0,86 g), (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (0.74 g), 1-hydroxy-1H-1,2,3-benzotri the ol hydrate (0,61 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0,77 g) and N,N-dimethylformamide (8 ml) at room temperature and stirred over night. The reaction mixture was poured into 0,5h. an aqueous solution of hydrochloric acid and extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, and then with a saturated solution of salt, dried (MgSO4) and concentrate. The obtained solid product is recrystallized from acetone-water to obtain (2E)-N-[4-(diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide (0,86 g, yield 65%) as colorless prismatic crystals. Melting point: 209-210°C.

In the same way as in example 1, to obtain compounds described in the examples 2-33, 36-50, 54-62, 65, 66, 69-77 and 80-82.

Example 2

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 68%. Colorless prismatic crystals. Melting point: 208-209°C (recrystallized from acetone-simple isopropyl ether).

Example 3

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}acrylamide

Yield: 25%. Colorless prismatic crystals. Melting point: 223-227°C (recrystallized from acetone-simple isopropyl ether).

Example 4

(2E)-N-[4-(Dimethyl shall osteometer)phenyl]-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 55%. Colorless prismatic crystals. Melting point: 199-200°C (recrystallized from ethyl acetate-hexane).

Example 5

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 57%. Colorless prismatic crystals. Melting point: 199-200°C (recrystallized from ethyl acetate-hexane).

Example 6

(2E)-3-[5-(3-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 39%. Colorless prismatic crystals. Melting point: 248-249°C (recrystallized from ethyl acetate-hexane).

Example 7

(2E)-3-[5-(3-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 51%. Colorless prismatic crystals. Melting point: 214-216°C (recrystallized from ethyl acetate-hexane).

Example 8

(2E)-3-[5-(4-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 61%. Colorless prismatic crystals. Melting point: 209-210°C (recrystallized from ethyl acetate-hexane).

Example 9

(2E)-3-[5-(4-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 45%. Colorless prismatic crystals. Melting point: 217-218°C (recrystallized from ethyl acetate-hexane).

Example 10

(2E)--[4-(Diethylphosphonate)phenyl]-3-(1-methyl-5-phenyl-1H-pyrazole-4-yl)acrylamide

Yield: 20%. Colorless prismatic crystals. Melting point: 219-220°C (recrystallized from ethyl acetate-hexane).

Example 11

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-(1-methyl-5-phenyl-1H-pyrazole-4-yl)acrylamide

Yield: 61%. Colorless prismatic crystals. Melting point: 239-240°C (recrystallized from ethyl acetate-hexane).

Example 12

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl}acrylamide

Yield: 49%. Colorless prismatic crystals. Melting point: 212-213°C (recrystallized from ethyl acetate-hexane).

Example 13

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl}acrylamide

Yield: 58%. Colorless prismatic crystals. Melting point: 200-201°C (recrystallized from ethyl acetate-hexane).

Example 14

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(2-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 67%. Colorless prismatic crystals. Melting point: 220-221°C (recrystallized from ethyl acetate-hexane).

Example 15

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(2-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 43%. Colorless prismatic crystals. Melting point: 238-240°C (recrystallized from ethyl acetate-hexane).

The use of the 16

(2E)-3-[5-(4-Bromophenyl)-1-methyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 57%. Colorless prismatic crystals. Melting point: 212-214°C (recrystallized from ethyl acetate-hexane).

Example 17

(2E)-3-[5-(4-Bromophenyl)-1-methyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 52%. Colorless prismatic crystals. Melting point: 229-231°C (recrystallized from ethyl acetate-hexane).

Example 18

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[1-methyl-5-(1-naphthyl)-1H-pyrazole-4-yl]acrylamide

Yield: 30%. Colorless prismatic crystals. Melting point: 207-209°C (recrystallized from ethyl acetate-hexane).

Example 19

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[1-methyl-5-(1-naphthyl)-1H-pyrazole-4-yl]acrylamide

Yield: 33%. Colorless prismatic crystals. Melting point: 229-231°C (recrystallized from ethyl acetate-hexane).

Example 20

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(3-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 35%. Colorless prismatic crystals. Melting point: 224-226°C (recrystallized from ethyl acetate-hexane).

Example 21

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(3-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 56%. Colorless prismatic crystals. Melting point:205-206° C (recrystallized from ethyl acetate-hexane).

Example 22

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[1-methyl-5-(4-were)-1H-pyrazole-4-yl]acrylamide

Yield: 58%. Colorless prismatic crystals. Melting point: 207-209°C (recrystallized from ethyl acetate-hexane).

Example 23

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[1-methyl-5-(4-were)-1H-pyrazole-4-yl]acrylamide

Yield: 57%. Colorless prismatic crystals. Melting point: 243-245°C (recrystallized from ethyl acetate-hexane).

Example 24

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(5-methyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}acrylamide

Yield: 36%. Colorless prismatic crystals. Melting point: 253-254°C (recrystallized from ethyl acetate-hexane).

Example 25

(2E)-N-{4-[(5,5-Dimethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 69%. Colorless prismatic crystals. Melting point: 271-273°C (recrystallized from ethyl acetate-hexane).

Example 26

(2E)-N-{4-[(4,6-Dimethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 62%. Colorless prismatic crystals. Melting point: 250-252°C (recrystallized from ethyl acetate-hexane).

Example 27

(2E)-N-{4-[(5-what util-5-ethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 53%. Colorless prismatic crystals. Melting point: 220-222°C (recrystallized from ethyl acetate-hexane).

Example 28

(2E)-N-[3-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 76%. Colorless prismatic crystals. Melting point: 170-172°C (recrystallized from ethyl acetate-hexane).

Example 29

(2E)-N-[2-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 65%. Colorless prismatic crystals. Melting point: 168-169°C (recrystallized from ethyl acetate-hexane).

Example 30

(2E)-N-[4-(Dibutylphthalate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 50%. The colorless solid product.

NMR (CDCl3) δ: to 0.89 (6H, t, J=7 Hz), to 1.3-1.4 (4H, m), 1,5-of 1.65 (4H, m), 3,11 (2H, d, J=21.5 in Hz)of 3.78 (3H, c), 3,9-4,00 (4H, m), 6.35mm (1H, d, J=15 Hz), 7.18 in-7,38 (6H, m), 7,40 (1H, d, J=15 Hz), 7,51 (2H,, d, J=8 Hz), 7,66 (1H, c), of 7.82 (1H, c).

Example 31

(2E)-N-[4-(Diethylphosphino)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 6%. Colorless prismatic crystals. Melting point: 174-176°C (recrystallized from ethyl acetate-hexane).

Example 32

(2E)-N-{4-[2-(Diethylphosphino)ethyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 19%. Colorless prismatic crystals. Melting point: 157-158°C (p will recrystallized from ethyl acetate-hexane).

Example 33

(2E)-N-[4-(Diethylphosphonate)-2-were]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 50%. Colorless prismatic crystals. Melting point: 154-155°C (recrystallized from ethyl acetate-hexane).

Example 34

The mixture of the mixture (250 mg), (2E)-3-[1-benzyl-5-(4-forfinal)-1H-pyrazole-4-yl]acrylic acid and (2E)-3-[1-benzyl-3-(4-forfinal)-1H-pyrazole-4-yl]acrylic acid obtained in comparative example 36, 1-hydroxy-1H-1,2,3-benzotriazole hydrate (142 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg), diethyl 4-aminomethylphosphonate (283 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 14 hours. The reaction mixture was poured into 1N. an aqueous solution of hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, and then with a saturated solution of salt, dried (MgSO4) and concentrate. The residue is subjected to column chromatography on silica gel to obtain (2E)-3-[1-benzyl-5-(4-forfinal)-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]-acrylamide (106 mg) as colorless powder from the faction, eluruumi with ethyl acetate. It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 207-208°C.

Example 35

(2E)-3-[1-Benzyl-3-4-forfinal)-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide (242 mg) was obtained as colorless powder from the fraction, eluruumi after (2E)-3-[1-benzyl-5-(4-forfinal)-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide obtained in example 34. It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 199-200°C.

Example 36

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[1-ethyl-5-(4-forfinal)-1H-pyrazole-4-yl]acrylamide

Yield: 73%. Pale yellow prismatic crystals. Melting point: 187-189°C (recrystallized from ethyl acetate-hexane).

Example 37

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[1-ethyl-5-(4-forfinal)-1H-pyrazole-4-yl]acrylamide

Yield: 74%. Pale yellow prismatic crystals. Melting point: 226-227 of the°C (recrystallized from ethyl acetate-hexane).

Example 38

(2E)-3-[5-(4-Forfinal)-1,3-dimethyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 70%. Pale yellow prismatic crystals. Melting point: 195-198°C (recrystallized from ethyl acetate-hexane).

Example 39

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1,3-dimethyl-1H-pyrazole-4-yl]acrylamide

Yield: 16%. Pale yellow prismatic crystals. Melting point: 159-160°C (recrystallized from ethyl acetate-hexane).

Example 40

(2E)-3-(5-Cyclohexyl-1-methyl-1H-pyrazole-4-yl)-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 19%. Bled what about the yellow solid product.

NMR (CDCl3) δ: 1,2-1,85 (10H, m), of 2.7-3.0 (1H, m)and 3.15 (2H, d, J=a 21.5 Hz), the 3.65 (3H, c), of 3.69 (3H, c), a 3.87 (3H, c), x 6.15 (1H, d,J=15,9 Hz), a 7.1 to 7.8 (7H, m).

Example 41

(2E)-3-(5-Cyclohexyl-1-methyl-1H-pyrazole-4-yl)-N-[4-(diethylphosphonate)phenyl]acrylamide

Yield: 13%. Pale yellow solid product.

NMR (CDCl3) δ: 1,2-of 1.85 (16H, m), 2.70 height is 3.00 (1H, m), 3,13 (2H, d, J=a 21.5 Hz), the 3.65 (3H, c), 3,95 of 4.1 (4H, m), x 6.15 (1H, d, J=16 Hz), a 7.1 to 7.8 (7H, m).

Example 42

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(2-furyl)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 72%. Colorless prismatic crystals. Melting point: 201-202°C (recrystallized from ethyl acetate-hexane).

Example 43

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(2-furyl)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 84%. Colorless prismatic crystals. Melting point: 195-196°C (recrystallized from ethyl acetate-hexane).

Example 44

(2E)-N-{4-[(5-Butyl-5-ethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(2-furyl)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 88%. Colorless prismatic crystals. Melting point: 201-202°C (recrystallized from ethyl acetate-hexane).

Example 45

(2E)-N-{4-[(Diethylphosphino)(methoxy)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 60%. Colorless prismatic crystals. Melting point: 200-201°C (recrystallized from ethyl acetate-hexane).

Example 46

(2E)-N-{4-[(Diethylphosphino)(hydroxy)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 15%. Colorless prismatic crystals. Melting point: 194-195°C (recrystallized from ethyl acetate-hexane).

Example 47

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(2-oxide-4,7-dihydro-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}acrylamide

Yield: 65%. Colorless prismatic crystals. Melting point: 169-171°C (recrystallized from ethyl acetate-hexane).

Example 48

(2E)-N-{4-[(Benzyloxycarbonyl)sulfanyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 36%. The colorless solid product.

NMR (CDCl3) δ: of 3.78 (3H, c), of 5.24 (2H, c), 6,27 (1H, d, J=15,5 Hz), 7,15-of 7.3 (4H, m), 7.3 to 7.4 (6H, m), and 7.5 and 7.6 (2H, m), to 7.61 (2H, d, J=8.5 Hz), 7,83 (1H, c).

Example 49

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[hydroxy(2-pyridinyl)methyl]phenyl}acrylamide

Yield: 23%. Pale-yellow crystals.

NMR (CDCl3) δ: of 3.75 (3H, c), and 5.30 (1H, users), 5,72 (1H, c), 6,27 (1H, d, J=15,5 Hz), and 7.1 to 7.4 (9H, m), 7,40 (1H, d, J=15,5 Hz), 7.5 to the 7.65 (3H, m), 7,80 (1H, c), 8,56 (1H, d, J=5 Hz).

Example 50

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[hydroxy(6-methyl-2-pyridinyl)methyl]phenyl}acrylamide

Yield: 68%. Colorless crystals.

NMR (DMSO-d6) δ: 2,59 (3H, c), 3,74 (3H, c), of 5.81 (1H, c), of 6.52 (1H, d, J=15,5 Hz), 7,14 (1H, d, J=15,5 Hz), 7.3 to the 7.65 (11H, m), 7,89 (1H, c), 8,03 (1H, users), 10,06 (1H, c).

Note the p 51

A mixture of (2E)-N-{4-[(benzyloxycarbonyl)sulfanyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide (488 mg), 3-(chloromethyl)-4-propyl-4H-1,2,4-triazole (240 mg), 1H. an aqueous solution of sodium hydroxide (3 ml) and ethanol (30 ml) at room temperature and stirred for 3 hours. The reaction mixture is concentrated, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazole-3-yl)methyl]thio}phenyl)acrylamide (310 mg, 65%) as pale yellow crystals.

NMR (CDCl3) δ: of 1.00 (3H, t, J=7 Hz), 1,8-of 1.95 (2H, m), of 3.77 (3H, c), of 3.97 (2H, t, J=7 Hz), 4,19 (2H, c), 6,34 (1H, d, J=15,5 Hz), 7,15 to 7.4 (8H, m), 7,51 (1H, d, J=8.5 Hz), 7,78 (1H, c), 8,02 (1H, users), 8,08 (1H, c).

Example 52

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazole-3-yl)methyl]thio}phenyl)acrylamide (96 mg), m-chloroperbenzoic acid (40 mg) and tetrahydrofuran (3 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by HPLC to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazole-3-yl)methyl]sulfinil}phenyl)-acrylamide (36 mg, 37%) as pale yellow crystals.

NMR (CDCl3) δas 0.96 (3H, t, J=7 Hz), 1.7 to 1.9 (2H, m), with 3.79 (3H, c), 3,98 (2H, t, J=7.5 Hz), is 4.21 (1H, d, J=9 Hz), 4,32 (1H, d, J=9 Hz), 6,34 (1H, d, J=15,5 Hz), 7,2-7,5 (8H, m), 7,73 (1H, d, J=8.5 Hz), 7,82 (1H, c), 8,01 (1H, users), 8,14 (1H, c).

Example 53

In the same way as in example 52, except that the used amount of m-chloroperbenzoic acid 60 mg, synthesize (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazole-3-yl)methyl]sulfonyl}phenyl)acrylamide.

Yield: 30%. Pale-yellow crystals.

NMR (CDCl3) δ: of 1.05 (3H, t, J=7 Hz), 1,9-2,0 (2H, m), with 3.79 (3H, c), 4,18 (2H, t, J=7.5 Hz), with 4.64 (2H, c), 6,37 (1H, d, J=15,5 Hz), 7,2 was 7.45 (6H, m), and 7.5 and 7.6 (2H, m), 7,7-7,8 (3H, m), 8,24 (1H, c).

Example 54

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[3-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 60%. Pale yellow prismatic crystals. Melting point: 197-198°C (recrystallized from ethyl acetate-hexane).

Example 55

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[4-(4-forfinal)-1-methyl-1H-pyrazole-5-yl]acrylamide

Yield: 74%. Pale yellow prismatic crystals. Melting point: 138-139°C (recrystallized from acetone-hexane).

Example 56

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]acrylamide

Yield: 62%. Pale yellow prismatic crystals. Melting point: 203-204°C (recrystallized from acetone-hexane).

Example 57

N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]propionamide

Yield: 53%. Colorless prismat the ical crystals. Melting point: 143-144°C (recrystallized from acetone-hexane).

Example 58

N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]propionamide

Yield: 47%. Colorless prismatic crystals. Melting point: 142-143°C (recrystallized from acetone-hexane).

Example 59

3-[5-(4-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]propionamide

Yield: 53%. Colorless crystals.

NMR (CDCl3) δ: of 1.24 (6H, t, J=7 Hz), 2,53 (2H, t, J=7 Hz), 2,82 (2H, t, J=7 Hz), 3,10 (2H, d, J=a 21.5 Hz), to 3.73 (3H, c), 3,95 of 4.1 (4H, m), 7,17 (1H, DD, J=1,5/8,5 Hz), 7,2-7,3 (2H, m), 7,37 (2H, d, J=8,5 Hz), to 7.4 and 7.5 (4H, m), 7,72 (1H, users).

Example 60

(2E)-N-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 53%. Colorless prismatic crystals. Melting point: 149-150°C (recrystallized from acetone-hexane).

Example 61

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[1-(4-forfinal)-1H-imidazol-5-yl]acrylamide

Yield: 68%. Colorless prismatic crystals. Melting point: 165-166°C (recrystallized from acetone-simple isopropyl ether).

Example 62

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[1-(4-forfinal)-1H-imidazol-5-yl]acrylamide

Yield: 62%. Colorless prismatic crystals. Melting point: 108-109°C (recrystallized from methanol-water).

A mixture of (2E)-N-[4-(diethylphosphonate)phenyl]-3-[1-(4-forfinal)-1H-imidazol-5-yl]acrylamide (92 mg), 5% palladium on coal (100 mg) and ethanol (10 ml) at room temperature was stirred in an atmosphere of hydrogen at atmospheric pressure for 3 hours. The reaction mixture was filtered, and the organic layer concentrated to obtain N-[4-(diethylphosphonate)phenyl]-3-[1-(4-forfinal)-1H-imidazol-5-yl]propionamide (60 mg, 65%) as a colorless solid product.

NMR (CDCl3) δ: of 1.24 (6H, t, J=7 Hz), 2.63 in (2H, t, J=7 Hz), of 2.92 (2H, t, J=7 Hz), 3,10 (2H, d, J=a 21.5 Hz), 3,9-4,1 (4H, m)6,94 (1H, c), 7,15-of 7.25 (4H, m), 7,25-to 7.35 (2H, m), 7,39 (2H, d, J=8 Hz), 7,53 (1H, c), 7,86 (1H, users).

In the same way as in example 63, synthesize compounds of examples 64, 67 and 68.

Example 64

N-[4-(Diethylphosphonate)phenyl]-3-[1-(4-forfinal)-1H-imidazol-5-yl]propionamide

Yield: 63%. The colorless solid product.

NMR (CDCl3) δ: of 2.64 (2H, t, J=7 Hz), only 2.91 (2H, t, J=7 Hz), 3,12 (2H, d, J=21,5 Hz)to 3.64 (3H, c), 3,68 (3H, c)6,94 (1H, c), 7,15-of 7.25 (4H, m), 7,25-to 7.35 (2H, m), 7,41 (2H, d, J=8 Hz), 7,53 (1H, c), 8,11 (1H, users).

Example 65

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]acrylamide

Yield: 64%. Colorless prismatic crystals. Melting point: 217-218°C (recrystallized from acetone-simple isopropyl ether).

Example 66

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]acrylamide

Output is: 81%. Colorless prismatic crystals. Melting point: decomposition at 250°C or above (recrystallized from methanol-acetone).

NMR (DMSO-d6) δ: 3,21 (2H, d, J=a 21.5 Hz), 3,57 (3H, c), 3,62 (3H, c), was 7.08 (1H, d, J=15,5 Hz), 7,2-7,4 (3H, m), of 7.4 to 7.7 (6H, m), of 8.90 (1H, c), 10,46 (1H, users).

Example 67

N-[4-(Diethylphosphonate)phenyl]-3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]propionamide

Yield: 77%. Pale yellow solid product.

NMR (CDCl3) δ: of 1.24 (6H, t, J=7 Hz), 3,0-3,1 (4H, m), 3,10 (2H, d, J=21 Hz), 3,9-4,1 (4H, m), 7,15-of 7.3 (4H, m), 7.3 to 7.4 (2H, m), of 7.48 (2H, d, J=8.5 Hz), 8,21 (1H, c), 8,8-9,0 (1H, m).

Example 68

N-[4-(Diethylphosphonate)phenyl]-3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]propionamide

Yield: 54%. Pale yellow solid product.

NMR (DMSO-d6) δ: 3,0-3,1 (4H, m), 3,11 (2H, d, J=21,5 Hz)to 3.64 (3H, c)to 3.67 (3H, c), 7,15-of 7.3 (4H, m), 7.3 to 7.4 (2H, m), of 7.48 (2H, d, J=8.5 Hz), to 8.20 (1H, c), which 9.22 (1H, users).

Example 69

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1,2,3-thiadiazole-4-yl]acrylamide

Yield: 45%. Pale yellow solid product.

NMR (CDCl3) δ: of 1.30 (6H, t, J=7 Hz)and 3.15 (2H, d, J=a 21.5 Hz), 4,05 to 4.2 (4H, m), 7,15-of 7.3 (4H, m), between 7.4 to 7.5 (2H, m), and 7.5 and 7.6 (2H, m), the 7.65 to 7.75 (2H, m), 9,29 (1H, users).

Example 70

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1,2,3-thiadiazole-4-yl]acrylamide

Yield: 54%. Pale-yellow crystals.

NMR (CDCl3) δ: 3,20 (2H, d, J=22 Hz), 3,71 (3H, c in), 3.75 (3H, c), 7,2-7,3 (4H, m), between 7.4 to 7.5 (3H, m), 7,58 (2H, d, J=8.5 Hz), 7,73 (1H, d, J=15 Hz), of 8.06 (1H, users).

When the EP 71

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[4-(4-forfinal)-1,2,3-thiadiazole-5-yl]acrylamide

Yield: 37%. Pale yellow prismatic crystals. Melting point: 173-175°C (recrystallized from acetone-hexane).

Example 72

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[4-(4-forfinal)-1,2,3-thiadiazole-5-yl]acrylamide

Yield: 53%. Pale yellow prismatic crystals. Melting point: 196-197°C (recrystallized from acetone-hexane).

Example 73

(2E)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]but-2-ename

Yield: 65%. Pale-yellow crystals.

NMR (CDCl3) δ: of 1.23 (6H, t, J=7 Hz), to 2.29 (3H, c), 3,10 (2H, d, J=a 21.5 Hz), 3,70 (3H, c), 3.95 to to 4.15 (4H, m), 5,78 (1H, c), and 7.1 to 7.4 (7H, m), between 7.4 to 7.5 (2H, m), of 7.64 (1H, c).

Example 74

N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]butanamide

Yield: 68%. Colorless crystals.

NMR (CDCl3) δ: 1,2-1,3 (9H, m), 2,4-2,6 (2H, m), 3,10 (2H, d, J=a 21.5 Hz), 3.15 and is 3.25 (1H, m), 3,68 (3H, c), 3,95 of 4.1 (4H, m)and 7.1 to 7.2 (4H, m), 7,2-7,3 (2H, m), 7,34 (2H, d, J=8.5 Hz), of 7.48 (1H, c), 7.5 to of 7.6 (1H, m).

Example 75

(2Z)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 76%. Colorless prismatic crystals. Melting point: 187-188°C (recrystallized from ethyl acetate-hexane).

Example 76

(2Z)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 76%. Colorless prismatic crystals. Melting point: 172-173°C (recrystallized from ethyl acetate-hexane).

Example 77

(2Z)-N-[4-(Diethylphosphonate)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 68%. Colorless prismatic crystals. Melting point: 208-209°C (recrystallized from ethyl acetate-hexane).

Example 78

In the same way as in example 51, obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(1-propyl-1H-imidazol-5-yl)methyl]thio}phenyl)acrylamide.

Yield: 65%. Pale-yellow amorphous form.

NMR (CDCl3) δ: of 0.97 (3H, t, J=7 Hz), 1,8-1,9 (2H, m), of 3.77 (3H, c)to 3.92 (2H, t, J=7 Hz), of 3.97 (2H, c), 6,33 (1H, d, J=15,5 Hz), to 6.67 (1H, c), 7,15 to 7.4 (7H, m), 7,4 was 7.45 (2H, m), 7,51 (1H, d, J=8,5 Hz), 7,78 (1H, c), 7,95-with 8.05 (1H, m).

Example 79

A mixture of 2-(ethoxycarbonyl)-3-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-2-propenyl}amino)phenyl]propionamide (420 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (266 mg) and acetonitrile (10 ml) at room temperature and stirred for 1 hour. The reaction mixture was concentrated and diluted with ethyl acetate. The mixture was sequentially washed with 1N. aqueous solution of hydrochloric acid, water and saturated salt solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated to obtain (2E)-N-{4-[(2,4-dioxo-1,3-oxazolidin-5-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-feast of the ol-4-yl]acrylamide (293 mg, 77%) as colorless crystals.

NMR (CDCl3) δ: 2,95-3,2 (2H, m), 3,74 (3H, c), 5,15-5,25 (1H, m), of 6.52 (1H, d, J=15,5 Hz), 7,05 to 7.2 (3H, m), 7,35 and 7.6 (6H, m), 7,89 (1H, c), 10,04 (1H, c), 11,70 (1H, users).

Example 80

N-[4-(Diethylphosphonate)phenyl]-3-(1,5-diphenyl-1H-pyrazole-4-yl)propionamide

Yield: 92%. Colorless prismatic crystals. Melting point: 157-159°C (recrystallized from ethyl acetate-hexane).

Example 81

N-[4-(Ethoxycarbonylmethyl)phenyl]-3-(1,5-diphenyl-1H-pyrazole-4-yl)propionamide

Yield: 92%. Colorless prismatic crystals. Melting point: 143-144°C (recrystallized from ethyl acetate-hexane).

Example 82

N-[4-(Methoxycarbonyl)phenyl]-3-(1,5-diphenyl-1H-pyrazole-4-yl)propionamide

Yield: 97%. Colorless prismatic crystals. Melting point: 196-197°C (recrystallized from ethyl acetate-hexane).

Example 83

A mixture of N-[4-(ethoxycarbonylmethyl)phenyl]-3-(1,5-diphenyl-1H-pyrazole-4-yl)propionamide (0,76 g), 1H. an aqueous solution of sodium hydroxide (5 ml) and ethanol (5 ml) was stirred at 50°C for 3 hours. The reaction mixture was poured into 1N. an aqueous solution of hydrochloric acid and the precipitated crystals are collected by filtration, washed with water and dried to obtain (4-{[3-(1,5-diphenyl-1H-pyrazole-4-yl)propanol]amino}phenyl)acetic acid.

Yield: 94%. Colorless prismatic crystals. The temperature of prawle the Oia: 199-201° C (recrystallized from ethyl acetate-hexane).

Example 84

In the same way as in example 83, receive 4-{[3-(1,5-diphenyl-1H-pyrazole-4-yl)propanol]amino}benzoic acid.

Yield: 93%. Colorless prismatic crystals. Melting point: 254-256°C(recrystallized from acetone-hexane).

Example 85

To a mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (0.50 g), N,N-dimethylformamide (0.05 ml) and tetrahydrofuran (15 ml) at room temperature is added dropwise, oxalyl chloride (0,30 g). The reaction mixture was stirred at room temperature for 30 min and concentrated. A mixture of the obtained residue 4-[(5-propyl-1,3,4-oxadiazol-2-yl)methyl]aniline (0,48 g) and N,N-dimethylacetamide (20 ml) was stirred at room temperature for 2 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(5-propyl-1,3,4-oxadiazol-2-yl)methyl]phenyl}acrylamide in the form of colorless crystals (0,81 g, yield 91%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 154-15° C.

In the same way as in example 85, get compounds described in the examples 86-108.

Example 86

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]phenyl}acrylamide obtained as colorless crystals (yield 83%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 262-263°C.

Example 87

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]acrylamide obtained as pale-yellow crystals (yield 84%). It recrystallization from acetone-methanol to give pale yellow prismatic crystals. Melting point: 252-253°C.

Example 88

(2E)-N-{4-[2-(5-Ethyl-1,3,4-oxadiazol-2-yl)ethyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 93%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 167-168°C.

Example 89

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[2-(1,3,4-oxadiazol-2-yl)ethyl]phenyl}acrylamide obtained as colorless crystals (yield 87%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 177-178°C.

Example 90

(2E)-N-{4-[2-(2-Ethyl-1,3-thiazol-4-yl)ethyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-shall irsol-4-yl]acrylamide obtained as colorless crystals (yield 74%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 190-191°C.

Example 91

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[2-(1,3-thiazol-4-yl)ethyl]phenyl}acrylamide obtained as colorless crystals (yield 65%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 211-212°C.

Example 92

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1,3-thiazol-4-ylethoxy)phenyl]acrylamide obtained as pale-yellow crystals (yield 91%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 171-172°C.

Example 93

(2E)-N-{4-[(2-Ethyl-1,3-thiazol-4-yl)methoxy]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 97%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 98-99°C.

Example 94

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1,3,4-oxadiazol-2-ylethoxy)phenyl]acrylamide obtained as colorless crystals (yield 76%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 154-155°C.

Example 95

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(4-methyl-1,3-about Sasol-2-yl)methyl]phenyl}acrylamide obtained as colorless crystals (yield 68%). It recrystallization from ethyl acetate-simple diisopropyl ether gives colorless prismatic crystals. Melting point: 220-221°C.

Example 96

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(pyridine-2-ylmethyl)phenyl]acrylamide obtained as colorless crystals (yield 87%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 215-216°C.

Example 97

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(5-methyl-1,3,4-oxadiazol-2-yl)methoxy]phenyl}acrylamide obtained as colorless crystals (yield 74%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 117-118°C.

Example 98

(2E)-N-{4-[(4-Ethyl-1,3-oxazol-2-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 88%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 174-175°C.

Example 99

(2E)-N-{4-[(2-Ethyl-1,3-thiazol-4-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 35%).

It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 178-179°C.

Example 100

(2E)-3-[5-(4-Forfinal)-1-m is Teal-1H-pyrazole-4-yl]-N-{4-[(2-methyl-1,3-thiazol-4-yl)methyl]phenyl}acrylamide obtained as colorless crystals (yield 63%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 192-193°C.

Example 101

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(1-methyl-1H-tetrazol-5-yl)methyl]phenyl}acrylamide obtained as colorless crystals (yield 32%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 243-244°C.

Example 102

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(2-methyl-2H-tetrazol-5-yl)methyl]phenyl}acrylamide obtained as colorless crystals (yield 96%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 159-161°C.

Example 103

(2E)-N-{4-[(1-Ethyl-1H-tetrazol-5-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 87%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 206-207°C.

Example 104

(2E)-N-{4-[(2-Ethyl-2H-tetrazol-5-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 61%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 187-188°C.

Example 105

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-neopentyl the Nile)acrylamide obtained as colorless crystals (yield 27%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 150-151°C.

Example 106

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)acrylamide obtained as colorless crystals (yield 70%). It recrystallization from tetrahydrofuran-hexane gives colorless prismatic crystals. Melting point: >300°C.

Example 107

(2E)-N-[4-(1,3-Benzoxazol-2-ylmethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 50%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 195-196°C.

Example 108

(2E)-N-[4-(1H-Benzimidazole-2-ylmethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 56%). It recrystallization from N,N-dimethylformamide-water gives colorless prismatic crystals. Melting point: >300°C.

Example 109

A mixture of ethyl (4-AMINOPHENYL)acetate (0.88 g), (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (1.0 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0,81 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1,02 g) and N,N-dimethylformamide (30 ml) at room temperature and stirred for 15 hours. In the reaction mixture by pouring the Ute water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain ethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]acetate as colorless crystals (1,49 g, yield 89%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 177-178°C.

In the same way as in example 109, receive compounds described in the examples 110-124.

Example 110

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(3-methyl-2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}acrylamide obtained as colorless crystals (yield 65%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 228-229°C.

Example 111

(2E)-N-{4-[(3-Ethyl-2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 40%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 214-215°C.

Example 112

Diethyl 4-({(2E)-3-[5-(4-forfinal)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzylphosphonate obtained as colorless crystals (yield 50%). His paracrystalline the Oia from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 181-182°C.

Example 113

(2E)-N-{4-[2-(4-Ethyl-1,3-thiazol-2-yl)ethyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 38%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 200-201°C.

Example 114

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(2-hydroxy-2-methylpropyl " phenyl]acrylamide obtained as colorless crystals (yield 89%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 188-189°C.

Example 115

(2E)-N-[4-(2-Ethyl-2-hydroxybutyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 55%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 150-151°C.

Example 116

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]phenyl}acrylamide obtained as pale-yellow crystals (yield 57%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 183-184°C.

Example 117

(2E)-N-(4-{[Acetyl(methyl)amino]methyl}phenyl)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 58%). It is recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 192-193°C.

Example 118

(2E)-N-{4-[(5-Ethyl-1,2,4-oxadiazol-3-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 51%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 150-152°C.

Example 119

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]phenyl}-acrylamide obtained as colorless crystals (yield 54%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 200-201°C.

Example 120

(2E)-N-{4-[(4-Ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals (yield 73%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 149-150°C.

Example 121

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(2-oxopropyl)phenyl]acrylamide obtained as colorless crystals (yield 17%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 186-187°C.

Example 122

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)acrylamide receive in the form of b is tcvetnyh crystals (yield 56%). It recrystallization from tetrahydrofuran-hexane gives colorless prismatic crystals. Melting point: 265-266°C.

Example 123

(2E)-N-{4-[(4,5-Dimethyl-1,3-thiazol-2-yl)methyl]phenyl}-3-{5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl}acrylamide obtained as colorless crystals (yield 56%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 210-211°C.

Example 124

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-ylmethyl)phenyl]acrylamide obtained as colorless crystals (yield 73%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 205-206°C.

Example 125

4-Ethyl-2-(4-nitrobenzyl)-1,3-thiazole (0.50 g), 5% palladium on coal (0.50 g) and tetrahydrofuran (30 ml) is subjected to catalytic recovery in the atmosphere of hydrogen at atmospheric pressure. The catalyst was removed by filtration and the filtrate concentrated. A mixture of the obtained residue, (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (0,49 g), 1-hydroxy-1H-1,2,3-benzothiazole hydrate (0,46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0,58 g) and N,N-dimethylformamide (10 ml) at room temperature and stirred for 15 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate is m The organic layer is successively washed with 0,1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain (2E)-N-{4-[(4-ethyl-1,3-thiazol-2-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide in the form of colorless crystals (0.35 g, yield 39%) of the fraction, eluruumi hexane-ethyl acetate (1:5, vol/vol). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 211-212°C.

In the same way as in example 125, receive compounds described in the examples 126-130.

Example 126

Ethyl 2-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxylate obtained as colorless crystals (yield 23%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 189-190°C.

Example 127

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(4-methyl-1,3-thiazol-2-yl)methyl]phenyl}acrylamide obtained as colorless crystals (yield 31%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 217-218°C.

Example 128

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pee the azole-4-yl]-N-{4-[(1,3-thiazol-2-yl)methyl]phenyl}acrylamide obtained as colorless crystals (yield 22%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 209-210°C.

Example 129

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1,3,4-oxadiazol-2-ylmethyl)phenyl]acrylamide obtained as colorless crystals (yield 63%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: p.223-224°C.

Example 130

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[2-(1,3-thiazol-2-yl)ethyl]phenyl}acrylamide obtained as colorless crystals (yield 24%). It recrystallization from ethyl acetate-hexane gives colorless prismatic crystals. Melting point: 201-202°C.

Example 131

A mixture of ethyl 2-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxylate (0.52 g), 1H. an aqueous solution of sodium hydroxide (2 ml), tetrahydrofuran (2 ml) and ethanol (2 ml) at 50°C is stirred for 30 min. the reaction mixture was added 1N hydrochloric acid (2 ml) and water, and the precipitated crystals are collected by filtration to obtain 2-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxylic acid as colorless crystals (0,41 g, yield 80%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 226-227 of the° C.

Example 132

A mixture of 2-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxylic acid (0.24 g), ammonium and 1-hydroxy-1H-1,2,3-benzotriazol (0.12 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 3 days. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with 0,1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 2-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxamide as colorless crystals (0.21 g, yield 88%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 159-160°C.

Example 133

A mixture of ethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]acetate (1,33 g), 1H. an aqueous solution of sodium hydroxide (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was added 1N. hydrochloric acid (5 ml) and water, and the precipitated crystals are collected by filtration to obtain [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]the p-2-enoyl]amino}phenyl]acetic acid as colorless crystals (1,14 g, yield 91%). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 245-246°C.

Example 134

To a mixture of [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0.40 g), 4-methylmorpholine (0.14 g) and tetrahydrofuran (10 ml) at 0°C is added dropwise a solution (5 ml) of isobutyl chlorocarbonate (0.20 g) in tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 hour and the insoluble material collected by filtration. The filtrate is added to a mixture of hydrazine hydrate (0.28 g) and tetrahydrofuran (10 ml) at 0°C. the Reaction mixture was stirred at 0°C for 1 hour and the reaction mixture was added saturated aqueous solution of ammonium chloride. The precipitated crystals are collected by filtration to obtain colorless crystals. A mixture of the obtained crystals, triethyl of orthopropionate (0,58 g), methanesulfonic acid (0.02 g) and tetrahydrofuran (10 ml) is heated under reflux for 1 hour. The reaction mixture was diluted with ethyl acetate, and the organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to column chromatography on silica gel to obtain (2E)-N-{4-[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]FeNi is}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide in the form of colorless crystals (0.24 g, yield 51%) of the fraction, eluruumi with ethyl acetate-methanol (20:1, vol/vol). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 164-165°C.

Example 135

To a mixture of [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (5.5 g), 4-methylmorpholine (1,91 g) and tetrahydrofuran (100 ml) at 0°C is added dropwise a solution (10 ml) of isobutyl chlorocarbonate (2,98 g) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 hour and the insoluble material collected by filtration. The filtrate is added dropwise to a mixture of hydrazine monohydrate (3,63 g) and tetrahydrofuran (30 ml), at 0°C. the Reaction mixture was stirred at 0°C for 2 hours and add saturated aqueous sodium bicarbonate solution. The precipitated crystals are collected by filtration to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(2-hydrazino-2-oxoethyl)phenyl]acrylamide in the form of pale yellow crystals (equal to 4.97 g, yield 87%). It recrystallization from N,N-dimethylformamide-water gives colorless prismatic crystals. Melting point: 273-274°C.

Example 136

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(2-hydrazino-2-oxoethyl)phenyl]acrylamide (0.50 g), triethyl of orthoacetate (0,63 g), methanesulfonic acid (0.025 g) and tetrahydrofuran (10 ml) nag is ewout under reflux for 1 hour. The reaction mixture was diluted with ethyl acetate, sequentially washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]phenyl}acrylamide in the form of pale yellow crystals (0.25 g, yield 46%) of the fraction, eluruumi with ethyl acetate-methanol (100:0 to 20:1, vol/vol). It recrystallization from ethyl acetate-hexane gives pale yellow prismatic crystals. Melting point: 151-152°C.

Example 137

A mixture of tert-butyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]carbamate (2.0 g) and 4n. hydrogen chloride in ethyl acetate (80 ml) at 70°C is stirred for 15 hours. The precipitated crystals are collected by filtration and washed with ethyl acetate. To the obtained crystals (0,30 g) is added 1N. an aqueous solution of sodium hydroxide (50 ml) and extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain (2E)-N-[4-(aminomethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide in the form of colorless crystals (0.18 g). It recrystallization from ethyl acetate-hexane gives bestv the fair prismatic crystals. Melting point: 201-202°C.

Example 138

A mixture of tert-butyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]carbamate (2.0 g) and 4n. hydrogen chloride in ethyl acetate (80 ml) at 70°C is stirred for 15 hours. The precipitated crystals are collected by filtration and washed with ethyl acetate. To a solution (10 ml) of the obtained crystals (of 1.00 g) in N,N-dimethylacetamide at room temperature is added triethylamine (0.39 g). The reaction mixture was stirred at room temperature for 30 min and add propionate (0.27 g). The reaction mixture is additionally stirred at room temperature for 2.5 days. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer is successively washed with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(propionamido)methyl]phenyl}acrylamide in the form of colorless crystals (0.51 g). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 271-272°C.

In the same way as in example 138, receive connections described in the examples 139-142.

Example 139

(2E)-3-[5-(4-Perfe who yl)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(isobutylamino)methyl]phenyl}acrylamide obtained as colorless crystals. It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 258-259°C.

Example 140

(2E)-N-{4-[(Butylimino)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide obtained as colorless crystals. It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 259-260°C.

Example 141

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(3-methylbutanoyl)amino]methyl}phenyl)acrylamide obtained as colorless crystals. It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 226-227 of the°C.

Example 142

N-[4-({(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]benzamide obtained as colorless crystals. It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 250-251°C.

Example 143

A mixture of dimethylamine (2M solution in tetrahydrofuran (THF, 1.7 ml), [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0,70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0,44 g) and N,N-dimethylformamide (20 ml) at room temperature and stirred for 15 hours. In the reaction mixture is poured onto water and the extras is giraut a mixture of ethyl acetate. The organic layer is successively washed with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain (2E)-N-{4-[2-(dimethylamino)-2-oxoethyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide in the form of colorless crystals (0.36 g, yield 49%) of the fraction, eluruumi with ethyl acetate-methanol (20:1, vol/vol). It recrystallization from acetone-simple diisopropyl ether gives colorless prismatic crystals. Melting point: 209-210°C.

Example 144

A mixture of diethylamine (0.17 g), [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0,70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0,44 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 15 hours. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel to obtain ((2E)-N-{4-[2-(who ethylamino)-2-oxoethyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide in the form of colorless crystals (0,48 g, yield 62%) of the fraction, eluruumi with ethyl acetate-methanol (20:1, vol/vol). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 175-176°C.

Example 145

To a mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (35,0 g), acetonitrile (245 ml) and dimethylformamide (0,175 ml) at 40-45°C add thionyl chloride (11,4 ml) and the mixture is stirred for 1 hour. Then add diethyl-4-aminomethylphosphonate (36,3 g) at 5°C and additionally added dropwise diisopropylethylamine (61,9 ml). The mixture is stirred at room temperature for 1 hour. Add 1H. an aqueous solution of sodium hydroxide (140 ml)to neutralize the reaction mixture, and optionally adding water (472,5 ml). The mixture is stirred at room temperature for 1 hour. The precipitated crystals are collected by filtration and washed with 30% solution of acetonitrile to obtain diethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate (61,5 g, yield 92%).

The resulting crystals are dissolved in 90% ethanol by heating, add warm water at 60-65°C, add while stirring the seed crystals and the mixture is cooled to room temperature to obtain crystals. Melting point: 208-209°C.

Example 146

A mixture of dimethyl 4-aminomethylphosphonate (258 mg), (E)-3-[5-(3-furyl)-1-methyl-1H-pyrazole-4-yl]acrylic acid (218 mg), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg) and N,N-dimethylformamide (8 ml) at room temperature and stirred over night. The reaction mixture was poured into 0,5h. an aqueous solution of hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, and then with a saturated solution of salt, dried (MgSO4) and concentrate. The obtained solid product is recrystallized from ethyl acetate-hexane to obtain dimethyl 4-{[(2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl]amino}benzylphosphonate (123 mg, 30%yield) as colorless prismatic crystals. Melting point: 176-177°C.

In the same way as in example 146, receive connections described in the examples 147-155.

Example 147

Diethyl 4-[{(2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino]benzylphosphonate

Yield: 37%. Colorless prismatic crystals. Melting point: 208-210°C (recrystallized from ethyl acetate-hexane).

Example 148

Dimethyl 4-({(2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzylphosphonate

Yield: 24%. Colorless prismatic crystals. Melting point: 247-248°C (recrystallized from ethyl acetate-hexane).

Example 149

Diethyl [4-({(2E)-3-[1-methyl-5-(2-t is enyl)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Yield: 31%. Colorless prismatic crystals. Melting point: 262-263°C (recrystallized from ethyl acetate-hexane).

Example 150

Diethyl 4-({(2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzylphosphonate

Yield: 37%. Colorless prismatic crystals. Melting point: 211-214°C (recrystallized from ethanol-ethyl acetate).

Example 151

Diethyl 4-{[(2E)-3-(1,5-dimethyl-1H-pyrazole-4-yl)prop-2-enoyl]amino}benzylphosphonate

Yield: 29%. Colorless prismatic crystals. Melting point: 228-230°C (recrystallized from ethyl acetate-hexane).

Example 152

Diethyl 4-{[(2E)-3-(1-methyl-1H-pyrazole-4-yl)prop-2-enoyl]amino}benzylphosphonate

Yield: 34%. Colorless prismatic crystals. Melting point: 201-202°C (recrystallized from ethyl acetate-hexane).

Example 153

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(hydroxymethyl)phenyl]acrylamide

Yield: 74%. Colorless prismatic crystals. Melting point: 117-118°C (recrystallized from ethyl acetate-simple isopropyl ether).

Example 154

Diethyl 4-[({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)methyl]benzylphosphonate

Yield: 74%. Amorphous form.

NMR (CDCl3) δ: of 1.25 (6H, t, J=7.0 Hz), 3,11 (2H, d, J=21,6 Hz), 3,76 (3H, c), 3,93-4,08 (4H, m), 4,46-4,50 (2H, m), 5,96-of 6.02 (1H, m), x 6.15 (1H, d, J=15,4 Hz), 7,15-,36 (9H, m), 7,74 (1H, c).

Example 155

(2E)-N-{4-[(2,4-Dioxo-1,3-thiazolidin-3-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 75%. Colorless prismatic crystals. Melting point: 245-247°C (recrystallized from ethyl acetate-hexane).

Example 156

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(hydroxymethyl)phenyl]acrylamide (8,4 g), thionyl chloride (2,59 ml) and tetrahydrofuran (70 ml) is heated under reflux for 3 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with water and then a saturated solution of salt, dried (MgSO4) and concentrated to obtain a solid product (6,22 g). To a mixture of 1,3-oxazolidin-2,4-dione (123,3 mg) and N,N-dimethylformamide (5 ml) is added sodium hydride (60% in oil, and 48.8 mg) and stirred the mixture at room temperature for 30 minutes resulting solid product (300 mg) is added to the reaction mixture and the mixture is additionally at room temperature and stirred over night. The reaction mixture was added water and extracted with a mixture of ethyl acetate. The organic layer is successively washed with 0,1N. hydrochloric acid, water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The remainder will recrystallized from ethyl acetate, the-hexane to obtain (2E)-N-{4-[(2,4-dioxo-1,3-oxazolidin-3-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide as a yellow prismatic crystals (132 mg, yield 37%). Melting point: 239-240°C.

In the same way as in example 146, receive connections described in the examples 157-158.

Example 157

(2E)-N-{4-[(2,5-Dioxo-1-imidazolidinyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 53%. Yellow prismatic crystals. Melting point: 249-250°C (recrystallized from ethyl acetate-hexane).

Example 158

(2E)-N-{4-[(2,6-Dioxo-1-piperidinyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 65%. Colorless prismatic crystals. Melting point: 218-220°C (recrystallized from ethyl acetate-hexane).

Example 159

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (1.0 g), oxalyl chloride (618 mg), tetrahydrofuran (60 ml) and N,N-dimethylformamide (2 drops) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and diluted with N,N-dimethylacetamide (50 ml). Add 4-(1H-imidazol-1-ylmethyl)aniline (844 mg) and the mixture at room temperature and stirred over night. In the reaction mixture is poured onto water and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with water, dried (MgSO4) and concentrate. The obtained solid product is recrystallized from acetone-hexane to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-imidazol-1-ylmethyl)phenyl]is Grilamid as pale yellow prismatic crystals (1,41 g, yield 86%). Melting point: 213-214°C.

In the same way as in example 146, receive connections described in the examples 160-179.

Example 160

(2E)-N-[4-(2-Amino-2-oxoethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 46%. Colorless prismatic crystals. Melting point: 253-255°C (recrystallized from ethyl acetate-hexane).

Example 161

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-pyrazole-1-ylmethyl)phenyl]acrylamide

Yield: 86%. Colorless prismatic crystals. Melting point: 189-191°C (recrystallized from acetone-hexane).

Example 162

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(2-isopropyl-1H-imidazol-1-yl)methyl]phenyl}acrylamide

Yield: 74%. Colorless prismatic crystals. Melting point: 271-272°C (recrystallized from acetone-hexane).

Example 163

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-1,2,4-triazole-1-ylmethyl)phenyl]acrylamide

Yield: 90%. Colorless prismatic crystals. Melting point: 225-226°C (recrystallized from acetone-hexane).

Example 164

Methyl 1-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]-1H-1,2,4-triazole-5-carboxylate

Yield: 87%. Colorless prismatic crystals. Melting point: 203-205°C (recrystallized from acetone-hexane).

<> Example 165

(2E)-N-(4-Acetylphenyl)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 65%. Colorless prismatic crystals. Melting point: 204-205°C (recrystallized from acetone-hexane).

Example 166

(2E)-N-[4-(Acetylamino)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 87%. Colorless prismatic crystals. Melting point: 281-282°C (recrystallized from acetone-hexane).

Example 167

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(2-hydroxyethyl)phenyl]acrylamide

Yield: 85%. Colorless prismatic crystals. Melting point: 198-200°C (recrystallized from acetone-hexane).

Example 168

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-were)acrylamide

Yield: 85%. Colorless prismatic crystals. Melting point: 178-180°C (recrystallized from acetone-hexane).

Example 169

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[3-(hydroxymethyl)phenyl]acrylamide

Yield: 42%. Colorless prismatic crystals. Melting point: 130-132°C (recrystallized from acetone-hexane).

Example 170

tert-Butyl 4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzylcarbamoyl

Yield: 69%. Colorless prismatic crystals. Melting point: 222-223°C (recrystallized from acetone-ol is stage isopropyl ether).

Example 171

(2E)-N-{4-[(4-Ethyl-1H-imidazol-1-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 30%. Colorless prismatic crystals. Melting point: 224-226°C (recrystallized from acetone-hexane).

Example 172

(2E)-N-{4-[(5,6-Dimethyl-1H-benzimidazole-1-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 74%. Colorless prismatic crystals. Melting point: 279-280°C (recrystallized from acetone-methanol).

Example 173

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(2-methyl-1H-benzimidazole-1-yl)methyl]phenyl}acrylamide

Yield: 58%. Colorless prismatic crystals. Melting point: 263-264°C (recrystallized from acetone-methanol).

Example 174

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[hydroxy(phenyl)methyl]phenyl}acrylamide

Yield: 50%. Colorless prismatic crystals. Melting point: 192-195 (in Russian)°C (recrystallized from ethyl acetate).

Example 175

(2E)-N-(4-Benzoylphenyl)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 28%. Colorless prismatic crystals. Melting point: 226-227 of the°C (recrystallized from acetone-hexane).

Example 176

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-indazol-1-ylmethyl)phenyl]acrylamide

Yield: 71%. Colorless prismatic crystals. Those who temperature melting point: 146-148° C (recrystallized from acetone-hexane).

Example 177

(2E)-N-[4-(1H-1,2,3-Benzotriazol-1-ylmethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 41%. Colorless prismatic crystals. Melting point: 226-227 of the°C (recrystallized from acetone-hexane).

Example 178

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(2H-indazol-2-ylmethyl)phenyl]acrylamide

Yield: 53%. Colorless prismatic crystals. Melting point: 231-232°C (recrystallized from acetone-hexane).

Example 179

(2E)-N-[4-(2H-1,2,3-Benzotriazol-2-ylmethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 50%. Colorless prismatic crystals. Melting point: 222-223°C (recrystallized from acetone-hexane).

Example 180

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (600 mg), oxalyl chloride (260 ml), tetrahydrofuran (10 ml) and N,N-dimethylformamide (2 drops) at room temperature and stirred for 3 hours. The reaction mixture was concentrated and diluted with N,N-dimethylacetamide (10 ml). Add ethyl 4-aminobenzoate (482 mg) and the mixture at room temperature and stirred for 3 hours. The reaction mixture was poured into 0.1 n. an aqueous solution of hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated aqueous BIC is rbonate sodium, and then a saturated solution of salt, dried (MgSO4) and concentrate. The obtained solid product is recrystallized from acetone-hexane to obtain ethyl 4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzoate (810 mg, yield 84%) as colorless needle-like crystals. Melting point: 202-203°C.

In the same way as in example 180, get compounds described in the examples 181-206.

Example 181

(2E)-N-[4-(Aminosulfonyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 39%. Pale yellow prismatic crystals. Melting point: 300-305°C (decomposition) (recrystallized from acetone-simple isopropyl ether).

Example 182

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-hydroxyphenyl)acrylamide

Yield: 65%. Colorless prismatic crystals. Melting point: 259-260°C (recrystallized from ethyl acetate-hexane).

Example 183

4-({(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzamide

Yield: 76%. Colorless prismatic crystals. Melting point: 276-278°C (recrystallized from acetone-hexane).

Example 184

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[2-(hydroxymethyl)phenyl]acrylamide

Yield: 22%. Colorless prismatic crystals. Melting point: 119-120°C (recrystallized from ACE the she-hexane).

Example 185

(2E)-N-[4-(1H-Benzimidazole-1-ylmethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 79%. Pale yellow prismatic crystals. Melting point: 243-244°C (recrystallized from acetone-hexane).

Example 186

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[2-(1H-pyrazole-1-yl)ethyl]phenyl}acrylamide

Yield: 82%. Colorless prismatic crystals. Melting point: 205-206°C (recrystallized from ethyl acetate-hexane).

Example 187

(2E)-3-{5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl}-N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}acrylamide

Yield: 71%. Colorless prismatic crystals. Melting point: 160-162°C (recrystallized from ethyl acetate-hexane).

Example 188

Ethyl 4-{[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]amino}-4-oxobutanoate

Yield: 57%. Colorless prismatic crystals. Melting point: 195-197°C (recrystallized from acetone-hexane).

Example 189

(2E)-N-{4-[(Acetylamino)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 62%. Colorless prismatic crystals. Melting point: 233-234°C (recrystallized from acetone-hexane).

Example 190

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}acrylamide

Yield: 63%. Colourless prismatic the ski crystals. Melting point: 232-233°C (recrystallized from ethanol-hexane).

Example 191

(2E)-N-{4-[(2-Ethyl-1H-imidazol-1-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 56%. Colorless prismatic crystals. Melting point: 237-238°C (recrystallized from ethanol-hexane).

Example 192

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(4-morpholinylmethyl)phenyl]acrylamide

Yield: 75%. Colorless prismatic crystals. Melting point: 202-203°C (recrystallized from ethanol-hexane).

Example 193

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1-pyrrolidinyl)phenyl]acrylamide

Yield: 25%. Colorless prismatic crystals. Melting point: 192-193°C (recrystallized from ethanol-hexane).

Example 194

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-1,2,3-triazole-1-ylmethyl)phenyl]acrylamide

Yield: 50%. Colorless prismatic crystals. Melting point: 252-253°C (recrystallized from ethanol-hexane).

Example 195

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-imidazol-1-yl)phenyl]acrylamide

Yield: 10%. Colorless prismatic crystals. Melting point: 238-239°C (recrystallized from ethanol-ethyl acetate).

Example 196

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(2H-1,2,3-triazole-2-ylmethyl)phenyl]but Grilamid

Yield: 74%. Colorless prismatic crystals. Melting point: 178-179°C (recrystallized from ethyl acetate-hexane).

Example 197

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-pyrazole-1-yl)phenyl]acrylamide

Yield: 63%. Pale yellow prismatic crystals. Melting point: 200-201°C (recrystallized from ethyl acetate-hexane).

Example 198

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(2H-tetrazol-2-ylmethyl)phenyl]acrylamide

Yield: 83%. Pale yellow prismatic crystals. Melting point: 210-211°C (recrystallized from ethyl acetate-hexane).

Example 199

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-tetrazol-1-ylmethyl)phenyl]acrylamide

Yield: 78%. Colorless prismatic crystals. Melting point: 233-234°C (recrystallized from ethyl acetate-hexane).

Example 200

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}phenyl)acrylamide

Yield: 38%. Colorless prismatic crystals. Melting point: 229-230°C (recrystallized from acetone-hexane).

Example 201

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(5-methyl-1H-imidazol-1-yl)methyl]phenyl}acrylamide

Yield: 50%. Colorless prismatic crystals. Melting point: 260-261°C (recrystallized from acetone-hexane).

Por the measures 202

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(4-methyl-1H-imidazol-1-yl)methyl]phenyl}acrylamide

Yield: 57%. Colorless prismatic crystals. Melting point: 202-203°C (recrystallized from acetone-hexane).

Example 203

(2E)-N-{4-[(1,1-Dioxide-4-thiomorpholine)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 73%. Colorless prismatic crystals. Melting point: 237-238°C (recrystallized from acetone-hexane).

Example 204

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(methylthio)phenyl]acrylamide

Yield: 76%. Colorless prismatic crystals. Melting point: 164-165°C (recrystallized from ethyl acetate-hexane).

Example 205

(2E)-N-(4-Benzoylphenyl)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 82%. Colorless prismatic crystals. Melting point: 110-112°C (recrystallized from acetone-hexane).

Example 206

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(phenylsulfonyl)phenyl]acrylamide

Yield: 61%. Colorless prismatic crystals. Melting point: 169-172°C (recrystallized from acetone-hexane).

Example 207

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(hydroxymethyl)phenyl]acrylamide (8,4 g), thionyl chloride (2,59 ml) and tetrahydrofuran (70 ml) is heated under reflux in those who tell 3 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with water and then a saturated solution of salt, dried (MgSO4) and concentrated to obtain a solid product (6,22 g). A mixture of this solid (1.0 g), timelocked sodium (0,57 g) and N,N-dimethylformamide (10 ml) was stirred at 40°C for 14 hours. The reaction mixture was poured into 0.1 n. an aqueous solution of hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, and then with a saturated solution of salt, dried (MgSO4) and concentrate. The residue is subjected to column chromatography on silica gel to obtain (2E)-3-{1-methyl-5-[4-(methylthio)phenyl]-1H-pyrazole-4-yl}-N-{4-[(methylthio)methyl]phenyl}acrylamide in the form of crystals (650 mg) from fraction, eluruumi hexane-ethyl acetate (2:1-1:1, volume/volume). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 145-146°C.

Example 208

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(hydroxymethyl)phenyl]acrylamide (8,4 g), thionyl chloride (2,59 ml) and tetrahydrofuran (70 ml) is heated under reflux for 3 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with CME is ü with ethyl acetate. An ethyl acetate layer was washed with water and then a saturated solution of salt, dried (MgSO4) and concentrated to obtain a solid product (6,22 g). A mixture of this solid product (300 mg), timelocked sodium (56,9 mg) and N,N-dimethylformamide (10 ml) at room temperature, stirred for 30 minutes, the Reaction mixture was poured into 0.1 n. an aqueous solution of hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, and then with a saturated solution of salt, dried (MgSO4) and concentrate. The residue is subjected to column chromatography on silica gel to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(methylthio)methyl]phenyl}acrylamide in the form of crystals (125 mg) from fraction, eluruumi hexane-ethyl acetate (1:1-0:1, volume/volume). It recrystallization from acetone-hexane gives colorless prismatic crystals. Melting point: 165-168°C.

In the same manner as in example 208, receive compounds described in the examples 209-214.

Example 209

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(methoxymethyl)phenyl]acrylamide

Colorless prismatic crystals. Melting point: 170-171°C (recrystallized from acetone-hexane).

Example 210

(2E)-N-{4-[(Ethylthio)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Colorless prismatic crystals. Melting point: 157-158°C (recrystallized from ethyl acetate-hexane).

Example 211

(2E)-N-{4-[(tert-Butylthio)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Colorless prismatic crystals. Melting point: 166-168°C (recrystallized from acetone-hexane).

Example 212

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(phenylthio)methyl]phenyl}acrylamide

Colorless prismatic crystals. Melting point: 197-198°C (recrystallized from acetone-hexane).

Example 213

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(1H-1,2,3-triazole-4-ylthio)methyl]phenyl}acrylamide

Colorless prismatic crystals. Melting point: 182-183°C (recrystallized from acetone-hexane).

Example 214

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(1-methyl-1H-tetrazol-5-yl)thio]methyl}phenyl)acrylamide

Colorless prismatic crystals. Melting point: 150-152°C (recrystallized from acetone-hexane).

Example 215

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(methylthio)methyl]phenyl}acrylamide (600 mg), m-chloroperbenzoic acid (387 mg) and tetrahydrofuran (50 ml) at 0°C is stirred for 20 min. the reaction mixture was added saturated aqueous solution of sodium sulfite and extracted with a mixture of et is lacerata. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, and then with a saturated solution of salt, dried (MgSO4) and concentrate. The obtained solid product is recrystallized from acetone-hexane to obtain (2E)-3-(5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl)-N-(4-((methylsulfonyl)-methyl)phenyl)acrylamide (340 mg, yield 54%) as colorless prismatic crystals. Melting point: 240-241°C.

In the same way as in example 215, receive connections described in the examples 216-221.

Example 216

(2E)-N-{4-[(Ethylsulfinyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 66%. Colorless prismatic crystals. Melting point: 228-229°C (recrystallized from ethyl acetate-hexane).

Example 217

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(methylsulfinyl)phenyl]acrylamide

Yield: 62%. Colorless prismatic crystals. Melting point: 260-261°C (recrystallized from acetone-hexane).

Example 218

(2E)-N-{4-[(tert-Butylsulfonyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 33%. Colorless prismatic crystals. Melting point: 242-243°C (recrystallized from acetone-hexane).

Example 219

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(phenylsulfinyl)methyl]phenyl}acrylamide

Yield: 47%. Bestv the fair prismatic crystals. Melting point: 236-237°C (recrystallized from acetone-methanol).

Example 220

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(1-methyl-1H-tetrazol-5-yl)sulfinil]methyl}phenyl)acrylamide

Yield: 66%. Colorless prismatic crystals. Melting point: 179-183°C (recrystallized from acetone-hexane).

Example 221

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(1H-1,2,3-triazole-4-ylsulphonyl)methyl]phenyl}acrylamide

Yield: 54%. Colorless prismatic crystals. Melting point: 179-183°C (recrystallized from acetone-hexane).

Example 222

A mixture of (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(methylthio)methyl]phenyl}acrylamide (600 mg), m-chloroperbenzoic acid (780 mg) and tetrahydrofuran (50 ml) at 0°C is stirred for 20 min. the reaction mixture was added saturated aqueous solution of sodium sulfite and the mixture is additionally stirred for 10 min and extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, and then with a saturated solution of salt, dried (MgSO4) and concentrate. The obtained solid product is recrystallized from acetone-hexane to obtain (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(methylsulphonyl)methyl]phenyl}acrylamide (490 mg, yield 75%) as colorless prismatic crystals. Temperature p is Alenia: 251-252° C.

In the same way as in example 222, receive connections described in the examples 223-227.

Example 223

(2E)-N-{4-[(Ethylsulfonyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 64%. Colorless prismatic crystals. Melting point: 257-258°C (recrystallized from ethyl acetate-hexane).

Example 224

(2E)-N-{4-[(tert-Butylsulfonyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide

Yield: 71%. Colorless prismatic crystals. Melting point: 260-261°C (recrystallized from acetone-hexane).

Example 225

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(phenylsulfonyl)methyl]phenyl}acrylamide

Yield: 66%. Colorless prismatic crystals. Melting point: p.223-224°C (recrystallized from acetone-hexane).

Example 226

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-(4-{[(1-methyl-1H-tetrazol-5-yl)sulfonyl]methyl}phenyl)acrylamide

Yield: 21%. Colorless prismatic crystals. Melting point: 224-225°C (recrystallized from acetone-hexane).

Example 227

(2E)-3-[5-(4-Forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(1H-1,2,3-triazole-4-ylsulphonyl)methyl]phenyl}acrylamide

Yield: 45%. Colorless prismatic crystals. Melting point: 204-206°C (recrystallized from acetone-hexane).

Example 228

A mixture of dieti the {3-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]benzyl}phosphonate (8.0 g), hydrazine hydrate (4 ml) and methanol (100 ml) is heated under reflux for 14 hours. The reaction mixture is cooled and the precipitated crystals are removed by filtration. The filtrate is concentrated and to the residue add 1H. an aqueous solution of sodium hydroxide (50 ml). The mixture is extracted with ethyl acetate. An ethyl acetate layer was washed with water and then a saturated solution of salt, dried (MgSO4) and concentrated to obtain a colorless oil (2.0 g). A mixture of this oil (310 mg), (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylic acid (246 mg), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg) and N,N-dimethylformamide (8 ml) at room temperature and stirred over night. The reaction mixture was poured into 0,5h. an aqueous solution of hydrochloric acid and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, and then with a saturated solution of salt, dried (MgSO4) and concentrate. The residue is subjected to column chromatography on silica gel to obtain diethyl-3-[({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)methyl]-benzylphosphonate (391 mg) as amorphous forms of fractions, eluruumi hexane-ethyl acetate (4:1-1:1, volume/volume).

NMR (CDCl3) δ: of 1.24 (6H, t, J=7.0 Hz), 3,12 (2H, d, J=21,6 Hz), 3,76 (3H, c), 3,93-4,08 (4H, m), 4,27 (2H, d, J=5.8 Hz, 5,95-6,10 (1H, m), 6,16 (1H, d, J=15.6 Hz), 7,15-7,37 (9H, m), 7,76 (1H, c).

In the same way as in example 228, get the connection described in example 229.

Example 229

Diethyl 2-[({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)methyl]benzylphosphonate receive in the form of an amorphous form (357 mg).

NMR (CDCl3) δ: of 1.28 (6H, t, J=7.0 Hz), 3,23 (2H, d, J=21,6 Hz), 3,74 (3H, c), 3,91-4,11 (4H, m)to 4.52 (2H, d, J=5.4 Hz), to 6.22 (1H, d, J=15,4 Hz), 7,14-7,42 (9H, m), 7,79 (1H, c), 7,89 (1H, users).

In a similar way as in example 1, to obtain compounds described in the examples 230-231.

Example 230

3-[5-(4-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl]-N-[4-(diethylphosphonate)phenyl]propionamide

Yield: 97%. Colorless crystals.

Analysis HPLC: purity 99.6 percent (retention time: 3,389 min)

MS(ESI+):462(M+H)

Example 231

Methyl 3-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]-2-hydroxypropionate

Yield 97%. Colorless crystals.

Analysis HPLC: purity of 80% (retention time: 3,385 min)

MS(ESI+):424(M+H)

Example 232

A mixture of methyl 3-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]-2-hydroxypropionate (1,34 g), 2n. an aqueous solution of sodium hydroxide (10 ml) and methanol (20 ml) at room temperature and stirred for 1 hour. The reaction mixture was poured into 1N. an aqueous solution of hydrochloric acid (100 ml). Precipitated solids collect filtrat is her washed with water and dried to obtain 3-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]-2-hydroxypropionic acid (800 mg, 62%) as colorless crystals.

Analysis HPLC: purity 100% (retention time: 3,216 min)

MS(ESI+):410(M+H)

Example 233

A mixture of 3-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]-2-hydroxypropionic acid (409 mg), ethyl chlorocarbonate (324 mg), triethylamine (405 mg) and ethyl acetate (10 ml) stirred at 0°C for 1 hour. To the reaction mixture is added a concentrated aqueous solution of ammonia (10 ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture was concentrated and precipitated solids are collected by filtration, washed with water and dried to obtain 2-(ethoxycarbonyl)-3-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]propionamide (471 mg, 98%) as colorless crystals.

Analysis HPLC: purity 94.7 percent (retention time: 3,398 minutes)

MS(ESI+):481(M+H)

Example 234

A mixture of ethyl 4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzoate (510 mg), 2n aqueous sodium hydroxide solution (1,29 ml) and ethanol (20 ml) at 50°C is stirred for 14 hours. The reaction mixture was added 1N. hydrochloric acid (2.6 ml) and extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with nassen the m aqueous solution of sodium bicarbonate, and then a saturated solution of salt, dried (MgSO4) and concentrate. The obtained solid product is recrystallized from acetone-hexane to obtain 4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)-benzoic acid (390 mg, yield 82%) as colorless prismatic crystals. Melting point: 291-292°C.

Of the compounds obtained in the above examples, compounds having different names, are specified hereinafter under different names.

Example 1

Dimethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 2

Diethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 4

Dimethyl [4-({(2E)-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 5

Diethyl [4-({(2E)-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 6

Dimethyl [4-({(2E)-3-[5-(3-chlorophenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 7

Diethyl [4-({(2E)-3-[5-(3-chlorophenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 8

Dimethyl [4-({(2E)-3-[5-(4-chlorophenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 9

Diethyl [4-({(2E)-3-[5-(4-chlorophenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}AMI is about)benzyl]phosphonate

Example 10

Dimethyl (4-{[(2E)-3-(1-methyl-5-phenyl-1H-pyrazole-4-yl)prop-2-enoyl]amino}benzyl)phosphonate

Example 11

Diethyl (4-{[(2E)-3-(1-methyl-5-phenyl-1H-pyrazole-4-yl)prop-2-enoyl]amino}benzyl)phosphonate

Example 12

Dimethyl {4-[((2E)-3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl}prop-2-enoyl)amino]benzyl}phosphonate

Example 13

Diethyl {4-[((2E)-3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl}prop-2-enoyl)amino]benzyl}phosphonate

Example 14

Dimethyl [4-({(2E)-3-[5-(2-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 15

Diethyl [4-({(2E)-3-[5-(2-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 16

Dimethyl [4-({(2E)-3-[5-(4-bromophenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 17

Diethyl [4-({(2E)-3-[5-(4-bromophenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 18

Dimethyl [4-({(2E)-3-[1-methyl-5-(1-naphthyl)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 19

Diethyl [4-({(2E)-3-[1-methyl-5-(1-naphthyl)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 20

Dimethyl [4-({(2E)-3-[5-(3-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 21

Diethyl [4-({(2E)-3-[5-(3-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 22

Dimethyl [4-({(2E)-3-[1-IU the Il-5-(4-were)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 23

Diethyl [4-({(2E)-3-[1-methyl-5-(4-were)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 28

Diethyl [3-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 29

Diethyl [2-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 30

Dibutil [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 31

Diethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]phosphonate

Example 32

Diethyl {2-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]ethyl}phosphonate

Example 33

Diethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)-3-methylbenzyl]phosphonate

Example 34

Diethyl [4-({(2E)-3-[1-benzyl-5-(4-forfinal)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 35

Diethyl [4-({(2E)-3-[1-benzyl-3-(4-forfinal)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 36

Dimethyl [4-({(2E)-3-[1-ethyl-5-(4-forfinal)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 37

Diethyl [4-({(2E)-3-[1-ethyl-5-(4-forfinal)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 38

Dimethyl [4-({(2E)-3-[5-(4-forfinal)-1,3-dimethyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 39

Diety is [4-({(2E)-3-[5-(4-forfinal)-1,3-dimethyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 40

Dimethyl {4-{[(2E)-3-(5-cyclohexyl-1-methyl-1H-pyrazole-4-yl)prop-2-enoyl]amino}benzyl}phosphonate

Example 41

Diethyl (4-{[(2E)-3-(5-cyclohexyl-1-methyl-1H-pyrazole-4-yl)prop-2-enoyl]amino}benzyl)phosphonate

Example 42

Dimethyl [4-({(2E)-3-[5-(2-furyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 43

Diethyl [4-({(2E)-3-[5-(2-furyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 45

Diethyl - [{4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl}(methoxy)methyl]phosphonate

Example 46

Diethyl {[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl](hydroxy)methyl}phosphonate

Example 48

O-Benzyl S-[4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)phenyl]thiocarbonate

Example 54

Diethyl [4-({(2E)-3-[3-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 55

Diethyl [4-({(2E)-3-[4-(4-forfinal)-1-methyl-1H-pyrazole-5-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 56

Diethyl [4-({(2E)-3-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 57

Diethyl [4-({3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]propanoic}amino)benzyl]phosphonate

Example 58

Dimethyl [4-({3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]propanoic}amino)benzyl]phosphonate

Example 59

Diety is [4-({3-[5-(4-chlorophenyl)-1-methyl-1H-pyrazole-4-yl]propanoic}amino)benzyl]phosphonate

Example 61

Diethyl [4-({(2E)-3-[1-(4-forfinal)-1H-imidazol-5-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 62

Dimethyl [4-({(2E)-3-[1-(4-forfinal)-1H-imidazol-5-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 63

Diethyl [4-({3-[1-(4-forfinal)-1H-imidazol-5-yl]propanoic}amino)benzyl]phosphonate

Example 64

Dimethyl [4-({3-[1-(4-forfinal)-1H-imidazol-5-yl]propanoic}amino)benzyl]phosphonate

Example 65

Diethyl [4-({(2E)-3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 66

Dimethyl [4-({(2E)-3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 67

Diethyl [4-({3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]propanol}amino)benzyl]phosphonate

Example 68

Dimethyl [4-({3-[4-(4-forfinal)-4H-1,2,4-triazole-3-yl]propanol}amino)benzyl]phosphonate

Example 69

Diethyl [4-({(2E)-3-[5-(4-forfinal)-1,2,3-thiadiazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 70

Dimethyl [4-({(2E)-3-[5-(4-forfinal)-1,2,3-thiadiazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 71

Diethyl [4-({(2E)-3-[4-(4-forfinal)-1,2,3-thiadiazole-5-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 72

Dimethyl [4-({(2E)-3-[4-(4-forfinal)-1,2,3-thiadiazole-5-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 73

Diethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]but-2-enoyl}amino)benzyl]phosphonate

the example 74

Diethyl [4-({3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]butanoyl}amino)benzyl]phosphonate

Example 75

Diethyl [4-({(2Z)-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 76

Dimethyl [4-({(2Z)-3-[5-(4-methoxyphenyl)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 77

Diethyl [4-({(2Z)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate

Example 80

Diethyl [4-{[3-(1,5-diphenyl-1H-pyrazole-4-yl)propanol]amino}benzyl]phosphonate

Example 81

Ethyl (4-{[3-(1,5-diphenyl-1H-pyrazole-4-yl)propanol]amino}-phenyl)acetate

Example 82

Methyl 4-{[3-(1,5-diphenyl-1H-pyrazole-4-yl)propanol]-amino}benzoate

Experimental example 1

Using glioma rat C6 assess the effect of compounds of the present invention for strengthening produtsirovaniya GDNF.

Glioma rat C6 (ATCC) are grown in the environment of the Needle, the modified Dulbecco (DMEM)containing 10% FBS (fetal calf serum) in 75 cm2the flask cultures (SUMITOMO BAKELITE Co., Ltd.), almost completely covered with collagen type 1 disconnect by treatment with trypsin and washed once with DMEM containing 10% FBS.

Cells after washing, diluted with DMEM containing 10% FBS to a concentration of 5×104/ml and seeded at 0.3 ml/well into each well of a 48 hole Cup for crops (SUMITOMO BAKELITE Co., Ltd.), the open collagen type 1. After 3 days culture in a Cup for crops placed in DMEM containing 1% BSA (bovine serum albumin, Sigma), which added various concentrations of the studied compounds, and optionally culturious within 2 days. The culture supernatant was separated and stored at -80°C to measurements GDNF.

The content of GDNF in the culture supernatant was measured using the following ELISA method.

Antibodies anti-GDNF (MAB212, R&D) diluted with TBS (Tris physiological buffer saline: 25 mmol/l Tris-HCl (pH 8.0), 150 mmol/l NaCl) to a concentration of 2 μg/ml and distributed in 0.1 ml/well into each well of 96-well plate to enzyme immunoassay. 96-well plate for ELISA analysis incubated over night at 4°C and washed once with TBS containing Tween 20, at a concentration of 0.05% (hereinafter abbreviated as mentioned TBST). Blocking solution (TBS containing 1% BSA and 5% sucrose) was added 0.2 ml/well in each well after washing and incubated the plate at room temperature for 1 hour, after which each well twice washed with TBST. The supernatant (0.1 ml) of the culture above C6 cells added to each well after washing, and the plate is incubated at room temperature for 3 hours, after which the wells are washed 5 times with TBST. 500-fold diluted antibodies anti-GDNF (G2791, Promega) was added 0.1 ml in each well, the donkey rinse, incubated at room temperature for 2 hours and washed 5 times with TBST. 5000-fold diluted antibodies against chicken IgY, labeled with horseradish peroxidase (G1351, Promega), add 0.1 ml/well in each well after washing, incubated at room temperature for 2 hours and washed 5 times with TBST. The substrate solution (TMB, BIO-RAD) add 0.1 ml/well in each well after washing, and allow for a degree of color development at room temperature for 8 minutes To terminate the reaction, add 0.1 ml of 1 mol/l phosphoric acid to each well, the reaction of the degree of color development. Measure the absorbance of the reaction solution at a wavelength of 450 nm.

In the same way as above, except that the test compound is not used, perform the ELISA method, and this is used as the control group.

Using different concentrations of GDNF (Promega) carry out the ELISA method in the same manner as above, and prepare a standard sample line.

From the above absorption coefficient and standard line samples calculate the content of GDNF in the sample, and the concentration (EC50), which causes a 50% increase in GDNF compared with the control group, calculated by linear regression. The results are shown in table 1.

Table 1
Number exampleThe value of EC50(µmol/l)
10,2
20,4
51,0
92,5
110,9
270,5
491,6
500,4
600,8
610,4
711,7
910,49
1100,31
1210,18
1400,22
1470,46
1490,51
1590,12
1610,13
1630,19
1850,3
1900,59
1920,54
1930,16
1950,12
2220,12
223being 0.036

As shown in table 1, the compound of the present invention has an action of enhancing the production of GDNF.

Experimental example 2

With use the of PC12 cells evaluate the neuroprotective activity of the compounds of the present invention.

The PC12 cells pre-kulturraum in one day in a solution of DMEM cultures (medium Needle, modified, Dulbea)containing 10% FCS (fetal calf serum), in an incubator, at 37°C, 5% CO2and sow, 5×103/well in 24-well plate (Falcon), in the same environment. After the cells will stick to the bottom surface, the culture is replaced by the solution to the crop DMEM containing 0.5% FCS and 2 ng/ml NGF (Wako Pure Chemical Industries, Ltd.). After kulturarbeit during the night add the studied compound at a concentration of 0.3-3.0 µmol/l and cells culturious for two more days. To kulturarbeit cells add glutaraldehyde to a final concentration of 2%, and the cells are fixed within 1 hour., then stained using Diff-Quick (International Reagents Corporation). Cells are washed, air dried and observed under a microscope.

In the cells treated with the compounds of example 2, example 49, 60, 110, 149, 159, 161, 185, 192, 222 and example 223, demonstrate superior education naritai network, which demonstrates that these compounds have neuroprotective effect.

Example of preparation 1 (receiving capsules)

1) connection example 130 mg
2) chop aspersky powder cellulose 10 mg
3) lactose19 mg
4) magnesium stearate1 mg
Only60 mg

1), 2), 3) and 4) are mixed and filled into gelatin capsules.

Example of preparation 2 (getting the pill)

1) connection example 130 g
2) lactose50 g
3) corn starch15 g
4) calcium carboxymethylcellulose44 g
5) magnesium stearate1 g
1000 pills only140 g

The total number of 1), 2) and 3), and 30 g of 4) are kneaded with water and after drying in a vacuum granularit. The granules are mixed with 14 g of 4) and 1 g of 5) and pressed through the machine for tableting. So, get 1000 tablets containing 30 mg of compound of example 1 per pill.

Industrial application

The compound of the present invention has an excellent effect of enhancing the production or secretion of neurotrophic factor and can be used for prevention or treatment of neuropathy and the like.

This application is based on patent application No. 2002-320153 filed in Japan, the entire contents of which, thereby, on the but as a reference.

References cited here, including patents and patent applications incorporated herein in their entirety, as references, to the extent in which they are described here.

1. The compound represented by the formula

where ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents) selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, With1-6alkoxy and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or

With1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y is a bond or C1-8alkylen;

Y1is a bond or C1-8alkylen;

D represents a benzene ring, optionally having the e, in addition, the Deputy (deputies) selected from C1-6of alkyl;

R3represents a

(A) an acyl group selected from the

(a) a carboxyl group;

(b) C1-6alkoxy-carbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono - or di-C1-6allylcarbamate;

(f) sulfamoyl group;

(g)1-6alkylsulfonyl group optionally substituted by triazolyl, optionally substituted C1-6alkyl group (groups);

(h)1-6alkylsulfonyl group, optionally substituted by triazolyl, optionally substituted C1-6alkyl group (groups);

(i)1-6alkyl-carbonyl group;

(j) benzoyl;

(k) phenylsulfinyl;

(l) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) phenylsulfonyl; and

(n) 5 - and 6-membered aromatic heterocyclisation, selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups); or

(C) heterocyclic group selected from the

(o) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents), selected from C1-6of alkyl, hydroxy-C1-6of alkyl, carboxyl group, carbamoyl group and1-6alkoxy-carbonyl group;

(b) an aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(q) a 5 - or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(r) tetrahydroindazole;

or its salt.

2. The compound according to claim 1, in which a, is a pyrazol ring, optionally substituted by 1 or 2 substituents selected from C1-10 of alkyl, phenyl and benzyl.

3. The compound according to claim 1, which is a

(1) C6-10aryl group optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted by 1-3 halogen atoms, C1-6alkoxy and halogen atom, or

(2) a 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl.

4. The compound according to claim 1, in which Y is a bond or C1-4alkylen.

5. The compound according to claim 1, in which Y1is a bond or C1-4alkylen.

6. The connection, which is diethyl [4-({(2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate or its salt.

7. The connection, which is (2E)-N-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide or its salt.

8. The compound (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-imidazol-1-ylmethyl)phenyl]acrylamide or its salt.

9. The connection, which is (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(1H-pyrazole-1-ylmethyl)phenyl]acrylamide or its salt.

10. The connection, which is diethyl [4-({(2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazole-4-yl]prop-2-enoyl}amino)benzyl]phosphonate or its salt.

11. The connection that submitted the a (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(3-methyl-2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}acrylamide or its salt.

12. The connection, which is (2E)-N-[4-(1H-benzimidazole-1-ylmethyl)phenyl]-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide or its salt.

13. The connection, which is (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[(methylsulphonyl)methyl]phenyl}acrylamide or its salt.

14. The connection, which is (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-{4-[hydroxy(2-pyridinyl)methyl]phenyl}acrylamide or its salt.

15. The connection, which is (2E)-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]-N-[4-(4-morpholinylmethyl)phenyl]acrylamide or its salt.

16. The connection, which is (2E)-N-{4-[(ethylsulfonyl)methyl]phenyl}-3-[5-(4-forfinal)-1-methyl-1H-pyrazole-4-yl]acrylamide or its salt.

17. Pharmaceutical agent for the prevention and treatment of neuropathy, containing a compound according to claim 1 and a pharmaceutically acceptable carrier.

18. Pharmaceutical means 17 where neuropathy is selected from diabetic neuropathy.

19. Pharmaceutical means to enhance the production or secretion of neurotrophic factor, which contains a compound according to claim 1 and a pharmaceutically acceptable carrier.

20. A pharmaceutical remedy, which contains a compound according to claim 1 and a pharmaceutically acceptable carrier.

21. Pharmaceutical tool for protecting nerve, which contain what it the connection according to claim 1 and a pharmaceutically acceptable carrier.

22. Pharmaceutical agent for the prevention and treatment of neuropathic pain, containing a compound according to claim 1 and a pharmaceutically acceptable carrier.

23. The pharmaceutical agent according to item 22, where neuropathic pain is posthepatitic neuralgia.

24. Prophylaxis or treatment of neuropathy, which contains a compound represented by the formula

where ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, C1-6alkoxy, C1-6alkylthio and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y of t which provides a communication or 1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, optionally substituted by substituent (substituents), selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) a carboxyl group;

(b) C1-6alkoxycarbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono-or di-C1-6alkyl-carbamoyl group;

(f)1-6alkylsulfonyl group;

(g) C1-6alkylsulfonyl group;

(h)1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6alkyl groups, hydroxy-C1-6alkyl group, carboxyl group, carbamoyl group and1-6alkoxy-carbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(o) a 5-or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(R) tetrahydroindazole;

(q) hydroxy;

(r)1-6alkoxy group;

(s) C1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (not necessarily replace the military With 1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterocycly group selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x) C1-6alkoxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

(3) a carboxyl group;

(4) C1-6alkoxycarbonyl group;

(5) C1-6alkylcarboxylic group;

(6) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(7) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzoyl;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group selected from imidazolyl and pyrazolyl;

(13) benzyloxycarbonylation;

(14) C1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted by the 1-6alkyl group(groups));

(15) C1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and triazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(16) C1-6alkylcarboxylic group; and

(17)hydroxy;

and its salts.

25. The tool point 24, where neuropathy is a diabetic neuropathy.

26. The means to enhance the production or secretion of neurotrophic factor, which contains a compound of the formula

where ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, With1-6alkoxy, C1-6alkylthio and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y is a bond or C1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, optionally substituted by substituent (substituents), selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) a carboxyl group;

(b) (C1-6alkoxycarbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono - or di-C1-6alkyl-carbamoyl group;

(f)1-6alkylsulfonyl group;

(g)1-6alkylsulfonyl group;

(h)1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic heterocyclisation the La, selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6alkyl groups, hydroxy-C1-6alkyl group, carboxyl group, carbamoyl group and C1-6alkoxy-carbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(o) a 5 - or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(p) then it is carbonated is romanttisella;

(q) hydroxy;

(r)1-6alkoxy group;

(s)1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (optionally substituted C1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterocycly group selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x)1-6alkoxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

(3) a carboxyl group;

(4)1-6alkoxycarbonyl group;

(5)1-6alkylcarboxylic group;

(6) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(7)1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzoyl;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group, SEL is Anna from imidazolyl and pyrazolyl;

(13) benzyloxycarbonylation;

(14)1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(15)1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and triazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(16) C1-6alkylcarboxylic group; and

(17) hydroxy;

and its salts.

27. The remedy for the relief of pain containing compound according to claim 1, or its salt.

28. Neuroprotective agent containing the compound represented by the formula

where ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, With1-6alkoxy, C1-6alkisti is and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y is a bond or C1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, optionally substituted by substituent (substituents), selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) a carboxyl group;

(b) C1-6alkoxycarbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono - or di-C1-6alkyl-carbamoyl group;

(f)1-6alkylsulfonyl group is s;

(g)1-6alkylsulfonyl group;

(h)1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6alkyl groups, hydroxy-C1-6alkyl group, carboxyl group, carbamoyl group and1-6alkoxy-carbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(o) a 5 - or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxo is oxazolidinyl, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(R) tetrahydroindazole;

(q) hydroxy;

(r)1-6alkoxy group;

(s) C1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (optionally substituted C1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterocycly group selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x) C1-6alkoxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

(3) a carboxyl group;

(4) C1-6alkoxycarbonyl group;

(5) C1-6alkylcarboxylic group;

(6)1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(7)1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(GRU is the groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzoyl;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group selected from imidazolyl and pyrazolyl;

(13) benzyloxycarbonylation;

(14) C1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(15) C1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and triazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(16)1-6alkylcarboxylic group; and

(17) hydroxy;

and its salts.

29. The remedy for the prevention and treatment of neuropathic pain, which contains a compound according to claim 1 or its salt.

30. The means by clause 29, where neuropathic pain is a herpetic neuralgia.

31. A method of preventing or treating neuropathy in a mammal, which comprises introducing the compound represented by the formula

where ring a is an imidazole, pyrazole, thiadiazole elutriator, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, With1-6alkoxy, C1-6alkylthio and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or1-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y is a bond or C1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, optionally substituted by substituent (substituents), selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) a carboxyl group;

(b) C1-6alkoxycarbonyl group;

(c) (mono - or di-is 1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono - or di-C1-6alkyl-carbamoyl group;

(f) C1-6alkylsulfonyl group;

(g) C1-6alkylsulfonyl group;

(h) C1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6alkyl groups, hydroxy-C1-6alkyl groups, carboxyl groups, carb is Olney group and 1-6alkoxy-carbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(o) a 5-or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(R) tetrahydroindazole;

(q) hydroxy;

(r) C1-6alkoxy group;

(s)1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (optionally substituted C1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterocycly group selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x)1-6alkoxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

p num="2381"> (3) a carboxyl group;

(4)1-6alkoxycarbonyl group;

(5) C1-6alkylcarboxylic group;

(6)1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(7) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzoyl;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group selected from imidazolyl and pyrazolyl;

(13) benzyloxycarbonylation;

(14) C1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(15) C1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and triazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(16) C1-6alkylcarboxylic group; and

(17) hydroxy;

and its salts.

32. The method according to p, where PN represents the t of a diabetic neuropathy.

33. Method of strengthening the production or secretion of neurotrophic factor in a mammal, which comprises introducing the compound represented by the formula

where ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, C1-6alkoxy, C1-6alkylthio and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y is a bond or C1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, it is certainly substituted by the Deputy (deputies), the selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) a carboxyl group;

(b) (C1-6alkoxycarbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono - or di-C1-6alkyl-carbamoyl group;

(f) C1-6alkylsulfonyl group;

(g) C1-6alkylsulfonyl group;

(h) C1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imides is Lila, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6alkyl groups, hydroxy-C1-6alkyl group, carboxyl group, carbamoyl group and1-6alkoxy-carbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(o) a 5-or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(R) tetrahydroindazole;

(q)hydroxy;

(r) C1-6alkoxy group;

(s)1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (optionally substituted C1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterotic is otio group, selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x)1-6alkoxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

(3) a carboxyl group;

(4)1-6alkoxycarbonyl group;

(5)1-6alkylcarboxylic group;

(6) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(7)1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzoyl;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group selected from imidazolyl and pyrazolyl;

(13) benzyloxycarbonylation;

(14) C1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(15) C1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and three who were salila (heterocyclic group optionally substituted C 1-6alkyl group(groups));

(16) C1-6alkylcarboxylic group; and

(17) hydroxy;

and its salts.

34. Method of reducing pain in a mammal, which comprises introducing the compound according to claim 1 or its salt of said mammal.

35. The way to protect nerve in a mammal, which comprises introducing the compound represented by the formula

where ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, C1-6alkoxy, C1-6alkylthio and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y depict is to place a link or 1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, optionally substituted by substituent (substituents), selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) a carboxyl group;

(b) C1-6alkoxycarbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono-or di-C1-6alkyl-carbamoyl group;

(f)1-6alkylsulfonyl group;

(g)1-6alkylsulfonyl group;

(h)1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6alkyl groups, hydroxy-C1-6alkyl group, carboxyl group, carbamoyl group and1-6alkoxy-carbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(o) a 5 - or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(R) tetrahydroindazole;

(q) hydroxy;

(r) C1-6alkoxy group;

(s) C1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (not necessarily Thames is authorized To 1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterocycly group selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x)1-6alkoxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

(3) a carboxyl group;

(4)1-6alkoxycarbonyl group;

(5) C1-6alkylcarboxylic group;

(6)1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(7) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzoyl;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group selected from imidazolyl and pyrazolyl;

(13) benzyloxycarbonylation;

(14) C1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted by the 1-6alkyl group(groups));

(15)1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and triazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(16)1-6alkylcarboxylic group; and

(17) hydroxy;

and its salts.

36. Method of prevention and treatment of neuropathic pain in a mammal, which comprises introducing the compound according to claim 1 or its salt of said mammal.

37. The method according to 36, where neuropathic pain is a herpetic neuralgia.

38. The use of compounds represented by the formula

in which ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl; is a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, With1-6alkoxy, C1-6alkylthio and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group is selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y is a bond or C1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, optionally substituted by substituent (substituents), selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) a carboxyl group;

(b) (C1-6alkoxycarbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono - or di-C1-6alkyl-carbamoyl group;

(f) C1-6alkylsulfonyl group;

(g)1-6alkylsulfonyl group;

(h)1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6alkyl groups, hydroxy-C1-6alkyl group, carboxyl group, carbamoyl group and1-6alkoxy-carbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(o) a 5 - or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and diocletianopolis the sludge, optionally substituted C1-6alkyl group(groups);

(R) tetrahydroindazole;

(q) hydroxy;

(r)1-6alkoxy group;

(s)1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (optionally substituted C1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterocycly group selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x) C1-6alkoxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

(3) a carboxyl group;

(4)1-6alkoxycarbonyl group;

(5) C1-6alkylcarboxylic group;

(6) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(7) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzo is a;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group selected from imidazolyl and pyrazolyl;

(13)benzyloxycarbonylation;

(14) C1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(15)1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and triazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(16)1-6alkylcarboxylic group; and

(17)hydroxy;

and its salts to obtain funds for the prevention or treatment of neuropathy.

39. The application of § 38, where neuropathy is a diabetic neuropathy.

40. The use of compounds represented by the formula

in which ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10 aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, With1-6alkoxy, C1-6alkylthio and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y is a bond or C1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, optionally substituted by substituent (substituents), selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) a carboxyl group;

(b) C1-6alkoxycarbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen is a;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono-or di-C1-6alkyl-carbamoyl group;

(f) C1-6alkylsulfonyl group;

(g) C1-6alkylsulfonyl group;

(h) C1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6alkyl groups, hydroxy-C1-6alkyl group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, long is Ino substituted C 1-6alkyl group(groups);

(o) a 5-or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(R) tetrahydroindazole;

(q)hydroxy;

(r) C1-6alkoxy group;

(s) C1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (optionally substituted C1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterocycly group selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x)1-6alkoxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

(3) a carboxyl group;

(4) C1-6alkoxycarbonyl group;

(5) C1-6alkylcarboxylic group;

(6)1-6alkylsulfonyl, optionally substituted triazolium, long is correctly replaced With 1-6alkyl group(groups);

(7)1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzoyl;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group selected from imidazolyl and pyrazolyl;

(13) benzyloxycarbonylation;

(14) C1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(15) C1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and triazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(16) C1-6alkylcarboxylic group; and

(17) hydroxy;

and its salts to obtain funds to enhance the production or secretion of neurotrophic factor.

41. The use of compounds according to claim 1 or its salt to produce funds for the relief of pain.

42. The use of compounds represented by the formula

in which ring a is an imidazole, pyrazole, thiadiazole or triazole, which may also have 1 or 2 substituent selected from C1-10of alkyl, phenyl and benzyl;

Represents a

(1) C1-10alkyl,

(2)3-10cycloalkyl,

(3) (C6-10aryl, optionally substituted by substituent(substituents), selected from C1-6the alkyl, optionally substituted from 1 to 3 halogen atoms, With1-6alkoxy, C1-6alkylthio and halogen atom, or

(4) 5-6-membered monocyclic aromatic heterocyclic group selected from Furie, tanila and pyridyl;

X represents a C1-8alkylen or2-8albaniles;

Z is a-CONR2- (R2represents a hydrogen atom or a C1-6alkyl, and the carbon atom in-CONR2- associated with X and the nitrogen atom in-CONR2associated with Y);

Y is a bond or C1-8alkylen; and

R1represents a

(I) oxidehydrogenation, optionally substituted C1-6alkyl group (groups); or

(II) benzene, optionally substituted by substituent (substituents), selected(s)

(1) C1-6alkyl group optionally substituted by 1 or 2 substituents selected from

(a) carboxyl the th group;

(b) (C1-6alkoxycarbonyl group;

(c) (mono - or di-C1-6alkyl)phosphonic group, optionally forming a 6-7 membered cycle (optionally substituted C1-6alkyl group(or groups)together with the adjacent oxygen substituted phosphorus atom and two atoms of oxygen;

(d) carbamoyl group, optionally substituted amino group (or groups);

(e) mono - or di-C1-6alkyl-carbamoyl group;

(f) C1-6alkylsulfonyl group;

(g)1-6alkylsulfonyl group;

(h) C1-6alkylcarboxylic group;

(i) phenylsulfinyl;

(j) a 5 - or 6-membered aromatic geterotsiklicheskikh selected from triazolylmethyl and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(k) phenylsulfonyl;

(l) a 5 - or 6-membered aromatic heterocyclisation selected from triethylsulfonium and tetraallylsilane, optionally substituted C1-6alkyl group(groups);

(m) a 5 - or 6-membered aromatic heterocyclic group selected from thiazolyl, oxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl, optionally substituted by substituent (substituents) selected from C1-6Ala the school group, hydroxy-C1-6alkyl group, carboxyl group, carbamoyl group and1-6alkoxy-carbonyl group;

(n) aromatic condensed heterocyclic group selected from benzimidazolyl, inspiratie, benzoxazolyl and benzotriazolyl, optionally substituted C1-6alkyl group(groups);

(o) a 5-or 6-membered non-aromatic heterocyclic group selected from morpholinyl, pyrrolidinyl, dioxothiazolidine, dioxoimidazolidin, oxodegradable, dioxoimidazolidin, dioxopiperazinyl and dioxythiophene, optionally substituted C1-6alkyl group(groups);

(R) tetrahydroindazole;

(q)hydroxy;

(r)1-6alkoxy group;

(s) C1-6alkylthio group;

(t) amino, optionally mono - or disubstituted by 1 or 2 substituents selected from C1-6of alkyl, C1-6alkylcarboxylic group (optionally substituted C1-6alkoxycarbonyl group)1-6alkoxycarbonyl group and benzoyl;

(u) phenyl;

(v) phenylthio;

(w) a 5-membered aromatic heterocycly group selected from triazolyl group, tetrazolyl group, optionally substituted C1-6alkyl group(groups);

(x) C1-6al is oxycarbonyl group;

(2) (mono - or di-C1-6alkyl)phosphono group;

(3) a carboxyl group;

(4) C1-6alkoxycarbonyl group;

(5)1-6alkylcarboxylic group;

(6) C1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(7)1-6alkylsulfonyl, optionally substituted triazolyl, optionally substituted C1-6alkyl group(groups);

(8) carbamoyl group;

(9) sulfamoyl group;

(10) benzoyl;

(11) phenylsulfonyl;

(12) a 5-membered aromatic heterocyclic group selected from imidazolyl and pyrazolyl;

(13) benzyloxycarbonylation;

(14)1-6alkoxy group, optionally substituted 5-membered aromatic heterocyclic group selected from thiazolyl and oxadiazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(15) C1-6alkylthio group, optionally substituted 5-membered aromatic heterocyclic group selected from imidazolyl and triazolyl (heterocyclic group optionally substituted C1-6alkyl group(groups));

(16)1-6alkylcarboxylic group; and

(17) hydroxy;

and its salts to obtain neuroprotective agents.

43. The use of compounds according to claim 1 or its salts for the production of products for the prevention or treatment of neuropathic pain.

44. Use p.43, where neuropathic pain is a herpetic neuralgia.

45. The method of obtaining the compound represented by the formula

in which each symbol is defined as in claim 1, or its salt, which comprises the interaction of the compounds represented by the formula

in which each symbol is as defined above, or its salt, with a compound represented by the formula

in which each symbol is as defined above, or its salt.

46. The method of obtaining the compound represented by the formula

which is a6-14aryl group, optionally substituted by a halogen atom, and

ALK4represents a C1-6alkyl group or a C7-13aracelio group or its salt, which comprises the interaction of the compounds represented by the formula

in which W represents the FDS is th-HE-or-N(ALK 2)(ALK3), in which ALK2and ALK3are the same or different and each represents a C1-6alkyl group, and a is as defined above, or its salt, with1-6acylhydrazines or7-13acylhydrazines, in the presence of acid.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention can be used for separating rare-earth and coloured metals and pertains to new phosphorous-containing complex-forming phosphine oxides with general formula (I) and methods of obtaining them: , where R1 = H, R2 = Ph, R3 = R4 = Ph, Me, Et, Pr, CH2Ph, 2-MeO-C6H4, C8H17; R1 = 4-Me, R2 = Ph, R3 = R4 = Ph, CH2Ph, 2-MeO-C6H4; R1 = H, R2 = 1-naphthyl, R3 = R4 = Ph, CH2Ph, 2-MeO-C6H4; R1=H,R2 = Bu,R3 = R4 = Ph; R1 = H, R2 = Ph, R3 = cyclo-C6H11, R4 = Et, Ph. The method of obtaining phosphine oxides (I) involves reaction in a medium of an organic solvent of chlorophosphorinine oxides with formula (II) with corresponding Grignard reagents, hydrolysis of the reaction mixture and separation of target compounds.

EFFECT: obtaining new phosphorous-containing complex-forming compounds with formula (I).

18 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemical technology.

SUBSTANCE: invention describes a method for synthesis of pentaerythritol diphosphites with the high content of spiro-isomer. Pentaerythritol diphosphites are synthesized by a successive re-esterification method in the presence of monophosphite, and then in the presence of substituted phenol or other alcohol, and wherein indicated reactions of re-esterification are carried out under conditions of controlled temperature and pressure. The reaction conditions provide to synthesize intermediate derivative and final pentaerythritol diphosphite with the high content of spiro-isomer and the high total yield of diphosphites.

EFFECT: improved method of synthesis.

26 cl, 1 ex

-amino-1-hydroxyethylidene-1,1 - bisphosphonic acids" target="_blank">

The invention relates to cyclic phosphorus-containing compounds f-crystals of Z-R1(I) where Z is selected from the group consisting of: a) H2N-C2-5alkylen, b)pyridyl-3-C1-5alkylen, b) WITH a2-6alkyl (N-CH3)C2H4; R1selected from the structures (a) and (b), where X is HE, and Cl, which are intermediates for obtaining-amino-1-hydroxyethylidene-1,1-bisphosphonic acids of formulas IIIA, IIIB and IIIC, where Z has the above value, M is the cation of the base

The invention relates to organic chemistry, chemistry of physiologically active compounds and may find application in biomedical research

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

The invention relates to organic chemistry, specifically to methods of producing phosphoric esters of thiamine, which (namely fosfotiamina and cocarboxylase hydrochloride) is used in medicine as drugs

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry.

SUBSTANCE: invention refers to C-phosphorylated acetamidines containing reactionable CH-acid methylene group which can be used as parent compound for bromine derivative C-phosphorylated acetamidines for medicine and agriculture concerns as biologically active substances. C-phosphorylated acetamidines in this invention are characterised by general formula: where R1 is selected from group i-C3H7, i-C4H9, C4H9; R2 is selected from groups C(O)CH3, C(O)C3H7, C(O)C6H5, P(O)(OC4H9-i)2; R3 represents C1-C4-alkyl; R4 is selected from groupC1-C4-alkyl or phenyl provided that R4 represents phenyl if R2 represents group P(O)(OC4H9-i)2.

EFFECT: expansion of chemical compounds range, suitable for production of biologically active substances.

1 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to method of production of C-phosphorylated alkylamidines serving as parent compounds of biologically active compounds for medicine and agriculture, of formula: where R1=C3-C4alkyl or isoalkyl; R2=CH3, C6H5; R3=C2-C4-alkyl or isoalkyl; R4=H, CH3, C3H7, C6H5, COOC2H5. Method includes in production of sodium derivatives of C-phosphorylated alkylamidines resulted from reaction of C-phosphorylated acetamidine with sodium. Produced sodium derivative is alkylated with alkylhalogenide in dioxane medium at mole ratio sodium:C-phosphorylated acetamidine:alkylhalogenide (1:1:1÷1.1), respectvely at temperature 20÷50°C.

EFFECT: production of new C-phosphorylated alkylamidines with high yield exceeding 78%.

1 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to protection of metals from corrosion using lacquer coating. This engineering problem can be solved by using calcium hydroxyethylidenediphosphonate with formula CH3(OH)C(PO3)2Ca2 as an anti-corrosion pigment, with higher anti-corrosion activity as compared to the prototype - protonated zinc hydroxyethylidenediphosphonate and a control specimen - zinc tetraoxychromate.

EFFECT: low-toxic high performance anti-corrosion pigment.

1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention concerns process of production of diisopropyl {[1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate represented by the formula , which is the key intermediate compound in synthesis of antiviral nucleoside analogue. The invention also concerns new intermediate compounds of formulae and , and their production of compound (2) obtained under this invention, which is an antiviral nucleoside analogue (especially against hepatitis B virus) represented by the formula .

EFFECT: high purity grade and high output.

4 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention describes compound of the formula (I): wherein R1 means hydrogen atom (H); R2 means -SH, -S-C(O)-R8, -P(O)(OR5)2, -P(O)(OR5)R6, -P(O)(OR5)-R7-C(O)-R8, -P(O)(OR5)-R7-N(R5)-S(O)2-R9 or -P(O)(OR5)-R7-N(R5)-C(S)-N(R6)2; R3 means tetrazole, -C(O)OR6, -C(O)O-R7-OC(O)R5; R4 means optionally substituted aryl, or R4 means N-heterocyclyl. Also, invention describes compounds of the formula (II): and (III): wherein X means -CH2- or -O-, and pharmaceutical compositions comprising indicated compounds. Proposed compounds possess inhibitory effect on activity of plasma carboxypeptidase B and used as anti-thrombosis agents.

EFFECT: valuable medicinal and biochemical properties of compounds.

34 cl, 19 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to phosphonic acid compounds used as inhibitors of serine proteinase of the general formula (I): wherein R1 is chosen from group comprising piperidinyl, pyrrolidinyl and 1,3,8-triazaspiro[4,5]dec-8-yl (wherein heterocyclic ring as added to nitrogen atom in ring) and -N(R7R80 wherein this heterocyclic ring is substituted optionally with one or two substitutes chosen independently from group comprising the following compounds: (a) C1-C8)-alkyl substituted optionally at terminal carbon atom with a substitute chosen from group comprising aryl, heteroaryl; c) phenyl and naphthalenyl; i) benzothiazolyl; R7 is chosen from group comprising hydrogen atom and (C1-C8)-alkyl; R8 is chosen from group comprising: (aa) (C1-C8)-alkyl; (ab) cycloalkyl; (ac) cycloalkenyl, and (ad) heterocyclyl (wherein R8 is added to carbon atom in ring) wherein (ab) cycloalkyl; (ac) cycloalkenyl, and (ad) heterocyclyl (wherein heterocyclyl (ad) comprises at least one cyclic nitrogen atom) substitutes and cycloalkyl moiety (aa) of a substitute is substituted optionally with substitutes chosen independently from group comprising: (ba) (C1-C8)-alkyl substituted at terminal carbon atom with a substitute chosen from group comprising amino-group (with two substitutes chosen independently from group comprising hydrogen atom and (C1-C8)-alkyl); (bb) (C1-C8)-alkoxy-group substituted at terminal carbon atom with a substitute chosen from group comprising carboxyl; (bc) carbonyl substituted with a substitute chosen from group comprising (C1-C8)-alkyl, aryl, aryl-(C2-C8)-alkenyl; (bd) aryl; (be) heteroaryl; (bf) amino-group substituted with two substitutes chosen independently from group comprising hydrogen atom and (C1-C8)-alkyl; (bh) halogen atom; (bi) hydroxy-group; (bk) heterocyclyl wherein (bd) is aryl substitute, and heteroaryl moiety (bc) comprise a substitute (halogen atom)1-3; R4 is chosen from group comprising aryl and heteroaryl wherein heteroaryl comprises halogen atom as a substitute; R2 and R3 are bound with benzene ring and represent hydrogen atom, and R2 and R3 form in common optionally at least one ring condensed with benzene ring forming polycyclic system wherein this polycyclic system is chosen from group comprising (C9-C14)-benzocondensed cycloalkenyl, (C9-C14)-benzocondensed phenyl; R5 is chosen from group comprising hydrogen atom and (C1-C8)-alkyl; R6 is chosen from group comprising (C1-C8)-alkyl and hydroxy-group; Y is absent, and X represents a single substitute that is added by a double bond and represents oxygen atom (O), and Z is chosen from group comprising a bond, hydrogen atom, and its salts. Also, invention relates to a method for synthesis of these compounds, to their composition inhibiting serine proteinase and to a method for its preparing. Proposed invention describes a method for treatment of inflammatory or serine proteinase-mediated disorder.

EFFECT: valuable biochemical and medicinal properties of compounds.

64 cl, 5 tbl, 38 ex

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