Cyclic simple ether, methods of its production, pharmaceutical composition and method of modulating sodium channel

 

(57) Abstract:

Describes a new cyclic simple ester of the formula (I), where each R1and R2represents a hydrogen atom, lower alkyl or C1-6alkylaryl; R3, R4and R5each represents lower alkyl; R6is lower alkyl; Ar represents C6-14aryl which may be substituted with halogen, C1-6the alkyl, C1-6alkoxy or1-3alkylenedioxy; ring a represents a 5 - to 8-membered saturated nitrogen-containing heterocyclic ring; X represents a lower alkylene; Y represents a carbon atom or nitrogen; For represents a group of formula (a), (b), (C) or (d), where R7represents a hydrogen atom or a C6-14aryl which may be substituted with halogen or1-6alkoxy; R10represents a hydrogen atom or a C7-16aralkyl; Zb represents a bond or a divalent hydrocarbon group selected from the group comprising FROM1-8alkylen,2-8albaniles or a group of the formula: -(CH2)p-M-(CH2)q- where p and q each represents an integer from 0 to 8, and p + q is an integer from 1 to 8; M represents O or NR9where R9represents a hydrogen atom, when Eli its salt, which is suitable for the manufacture of pharmaceutical compositions for modulating sodium channel. Describes a method of producing ether, pharmaceutical composition and method of modulating sodium channel. 7 C. and 19 C.p. f-crystals, 5 PL.

The invention relates to new cyclic esters with very good modulatory activity against sodium channels, to their preparation and application.

Background of the invention

Substances that modulate sodium channel controlled by pulse potential difference, known as local anesthetics, antiarrhythmic funds or anti-convulsants. Recent studies have shown that modulators of sodium channels is also effective as a therapeutic drug for the treatment of diseases and disorders of the Central nervous system, such as ischemic disorder of the Central nervous system, brain injury, spinal cord injury, and so on (Trends in Pharmacological Science, 16, 309-316, 1995). Ischemic or traumatic nerve damage entails the retention of sodium ions in local neurons or nerve fibers (Stroke, 20, 1377-1382, 1989), and this retention of sodium causes the development of edema is), and encouraging the inflow of calcium ions under the influence of Na+/Ca2+the ion exchanger (Neuron, 12, 295-300, 1994), which leads to cell damage.

Known as modulators of sodium channels BW619C89, lifarizine, riluzole, and some other compounds (Trends in Pharmacological Science, 16, 309-316, 1995), but cyclic ethers having an amino group on a condensed ring systems, is not known.

As cyclic ethers, having an amino group on a condensed ring systems are known, among others, the following connections:

1) Aminocoumarin the following formula, having inhibitory activity against perechisleniya lipids (EP-A-483772 and his twin JP-A-5-140142):

< / BR>
where each of R1and R2is hydrogen, acyl, alkoxycarbonyl or aliphatic or aromatic group which may be substituted; each of R3, R4and R5is hydroxy, which can be allyawan, or amino-, alkoxy - or aliphatic group which may be substituted, or two of the radicals R3, R4and R5can form carbocycle; each of R6and R7represents an aliphatic group which may be zames the R9represent hydrogen or an aliphatic or aromatic group which may be substituted.

2) Aminocoumarin the following formula, having inhibitory activity against perechisleniya lipids (JP-A-641123).

< / BR>
where R1, R2, R3and R4may be the same or different and are each lower alkyl; ring A represents benzene ring, substituted by at least one Deputy, selected from lower alkyl, lower alkoxy and halogen.

3) Crystalline salt of the enantiomer of 5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidine)-2,3-dihydrobenzo[b] -furan having inhibitory activity against perechisleniya lipids (USP 5552552).

However, there are no reports that these compounds possess modulatory activity against sodium channels.

It is expected that all of modulating sodium channels substance possessing satisfactory, modulating activity against sodium channels associated with the appropriate kinetics intracranial migration and metabolic stability, will show good efficacy in the treatment of diseases and disorders of the Central nervous system (CIS is on the brain, spinal cord injury, injury from sharp movements of the limbs and so on), epilepsy, neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neuropathy etc), vascular dementia (for example, mnogoparnaya dementia, disease Binswanger and so on), menucalendarclock psychosis, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine and brain swelling. However, there is currently no satisfactory modulator and there is a need to create compounds with satisfactory modulating activity against sodium channels and is suitable for use as a medicine.

The creators of the present invention have conducted extensive studies of compounds with modulating activity against sodium channels, and succeeded in creating a new connection, which is structurally characterized in that the carbon atom in position 2 condensed cyclic simple ether was replaced at the same time lower alkyl group and a group of the formula:

< / BR>
where each of the symbols has a value that is the same as opredelennuju group, which may be substituted, or acyl; each R3, R4and R5represents lower alkyl which may be substituted, or lower alkoxy which may be substituted, or R4and R5taken together, represent a 5 - or 6-membered carbocyclic group;

R6is lower alkyl;

Ar represents an aromatic group which may be substituted;

ring A represents A 5-8-membered nitrogen-containing heterocyclic ring which may be substituted;

X represents a lower alkylene, which may be substituted;

Y represents a carbon atom or nitrogen;

Za represents a group of the formula:

< / BR>
< / BR>
where R7represents a hydrogen atom or an aromatic group which may be substituted; R10represents a hydrogen atom, a hydrocarbon group which may be substituted, or acyl;

Zb is a bond or a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur; and

m represents an integer from 1 to 3, or salts thereof [hereinafter referred to briefly as compound (I)]. They suddenly discovered that the compound of the following formula or its from the very basic to the sodium channel modulator, for example a good affinity to sodium channel and a high resistance, and as such is well suited for use as a drug. The present invention was created based on the above findings.

< / BR>
where Q represents a hydrogen atom, an aromatic group which may be substituted, or a group of the formula: -Zc-Ar, where Zc represents a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur; and Ar has the same meaning as defined above; ring Aa represents a 5-8-membered nitrogen-containing heterocyclic ring which may be substituted, or corresponding benzene system; other respective symbols have the same meanings as defined above.

Disclosure of the invention

The present invention is directed to

(1) compound (I),

(2) the compound according to item (1), in which each of R1and R2is

(i) a hydrogen atom,

(ii) C1-6alkyl which may be substituted by 1-5 substituents selected from the group consisting of halogen, C3-6cycloalkyl, C2-6the quinil, C2-6alkenyl, C6-10aryl, C7-11aralkyl, Cis lexi, C6-10arylcarboxylic, carboxy, C1-6alkoxycarbonyl, carbamoyl, amidino, imino, amino, mono-C1-6alkylamino, di-C1-6alkylamino, 3-6-membered cyclic amino, C1-3alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfine, phosphino, sulfamoyl, mono-C1-6alkylsulfonyl, di-C1-6alkylsulfonyl, C1-6alkylthio, C6-10aaltio, C1-6alkylsulfonyl, C6-10arylsulfonyl, C1-6alkylsulfonyl and C6-10arylsulfonyl, or

iii) acyl selected from the group consisting of formyl, C1-6alkylsulphonyl, C6-10arylcarbamoyl, C6-10aryl-C1-6alkylsulphonyl, C1-6alkoxycarbonyl, C6-10aryl-C1-6alkoxycarbonyl, C1-6alkylsulfonyl, C6-10arylsulfonyl, which can be substituted by 1-3 C1-6alkilani, and C6-10aryl-C1-6alkylsulfonyl;

each of the symbols R3, R4and R5is

(i) C1-6alkyl which may be substituted by 1-5 substituents selected from the group consisting of halogen, C3-6cycloalkyl, C2-6the quinil, C2-6alkenyl, C6-10aryl, C7-11aralkyl, C1-6alkoxy, C6-10aryloxy, C1-6SUB> alkoxycarbonyl, carbamoyl, amidino, imino, amino, mono-C1-6alkylamino, di-C1-6alkylamino, 3-6-membered cyclic amino, C1-3alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfine, phosphono, sulfamoyl, mono-C1-6alkylsulfonyl, di-C1-6alkylsulfonyl, C1-6alkylthio, C6-10aaltio, C1-6alkylsulfonyl, C6-10arylsulfonyl, C1-6alkylsulfonyl and C6-10arylsulfonyl, or

ii) C1-6alkoxy which may be substituted by 1-5 substituents selected from the group consisting of halogen, C3-6cycloalkyl, C2-6the quinil, C2-6alkenyl, C6-10aryl, C7-11aralkyl, C1-6alkoxy, C6-10aryloxy, C1-6alkylsulphonyl, C6-10arylcarbamoyl, C1-6alkylcarboxylic, C6-10arylcarboxylic, carboxy, C1-6alkoxycarbonyl, carbamoyl, amidino, imino, amino, mono-C1-6alkylamino, di-C1-6alkylamino, 3-6-membered cyclic amino, C1-3alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfine, phosphono, sulfamoyl, mono-C1-6alkylsulfonyl, di-C1-6alkylsulfonyl, C1-6alkylthio, C6-10aaltio, C1-6alkylsulfonyl, CAtie together with the respective adjacent carbon atoms, form a 5 - or 6-membered carbocyclic group selected from the group consisting of 6-membered aromatic hydrocarbon ring or 5 - or 6-membered of cycloalkene;

R6represents C1-6alkyl;

Ar is (i) C6-14aryl or (ii) 5-10-membered aromatic heterocyclic group containing, besides carbon, 1-4 heteroatoms, selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-5 substituents selected from the group consisting of halogen, C1-3alkylenedioxy, nitro, cyano, C1-6the alkyl which may be halogenated, a C3-6cycloalkyl, C1-6alkoxy which may be halogenated, a C1-6alkylthio, which may be halogenated, hydroxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino, C1-6alkylsulphonyl, carboxy, C1-6alkoxycarbonyl, carbamoyl, mono-C1-6allylcarbamate, di-C1-6allylcarbamate, C6-10arylcarbamoyl, sulfo, C1-6alkylsulfonyl, C6-10aryl and C6-10aryloxy;

ring A represents A 5-8-membered nitrogen-containing heterocyclic ring, optionally containing, in addition to the nitrogen and carbon atoms, 1-4 heteroatoms selected from nitrogen, sulfur and colorindex, nitro, cyano, C1-6the alkyl which may be halogenated, a C3-6cycloalkyl, C1-6alkoxy which may be halogenated, a C1-6alkylthio, which may be halogenated, hydroxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino, C1-6alkylsulphonyl, carboxy, C1-6alkoxycarbonyl, carbamoyl, mono-C1-6allylcarbamate, di-C1-6allylcarbamate, C6-10arylcarbamoyl, sulfo, C1-6alkylsulfonyl, C6-10aryl and C6-10aryloxy;

X represents C1-6alkylene, which can be substituted by 1-3 substituents selected from the group consisting of halogen, C1-6of alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6the quinil, C6-14aryl, nitro, cyano, hydroxy, C1-6alkoxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino, C1-6alkylsulphonyl, C6-10aryloxy and oxo;

Y represents (i) a nitrogen atom or ii) a group of the formula:

> C(R8)-,

where R8represents a hydrogen atom, halogen, nitro, cyano, C1-6alkyl which may be halogenated, a C3-6cycloalkyl, C1-6alkoxy which may be halogenated, a C1-6alkylthio, which can be the Nile, carboxy, C1-6alkoxycarbonyl, carbarnoyl, mono-C1-6allylcarbamate, di-C1-6allylcarbamate, C6-10arylcarbamoyl, sulfo, C1-6alkylsulfonyl, C6-10aryl or C6-10aryloxy;

R7represents a hydrogen atom or a (i) C6-14aryl or (ii) 5-10-membered aromatic heterocyclic group containing, besides carbon, 1-4 heteroatoms, selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-5 substituents selected from the group consisting of halogen, C1-3alkylenedioxy, nitro, cyano, C1-6the alkyl which may be halogenated, a C3-6cycloalkyl, C1-6alkoxy which may be halogenated, a C1-6alkylthio, which may be halogenated, hydroxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino, C1-6alkylsulphonyl, carboxy, C1-6alkoxycarbonyl, carbamoyl, mono-C1-6allylcarbamate, di-C1-6allylcarbamate, C6-10arylcarbamoyl, sulfo, C1-6alkylsulfonyl, C6-10aryl and C6-10aryloxy;

R10represents i) a hydrogen atom,

(ii) C1-6alkyl, C2-6alkenylphenol, C2-6alkylamino, C3-6cycloalkyl, C6-14the s, consisting of halogen,3-6cycloalkyl, C2-6the quinil, C2-6alkenyl, C6-10aryl, C7-11aralkyl, C1-6alkoxy, C6-10aryloxy, C1-6alkylsulphonyl, C6-10arylcarbamoyl, C1-6alkylcarboxylic, C6-10arylcarboxylic, carboxy, C1-6alkoxycarbonyl, carbamoyl, amidino, imino, amino, mono-C1-6alkylamino, di-C1-6alkylamino, 3-6-membered cyclic amino, C1-3alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfine, phosphono, sulfamoyl, mono-C1-6alkylsulfonyl, di-C1-6alkylsulfonyl, C1-6alkylthio, C6-10aaltio, C1-6alkylsulfonyl, C6-10arylsulfonyl, C1-6alkylsulfonyl and C6-10arylsulfonyl, or

iii) acyl selected from the group consisting of formyl, C1-6alkylsulphonyl, C6-10arylcarbamoyl, C6-10aryl-C1-6alkylsulphonyl, C1-6alkoxycarbonyl, C6-10aryl-C1-6alkoxycarbonyl, C1-6alkylsulfonyl, C6-10arylsulfonyl, which can be substituted by 1-3 C1-6alkilani, and C6-10aryl-C1-6alkylsulfonyl; and

Zb represents a divalent aliphatic hydrocarbon group selected from R>
(CH2)p-M-(CH2)q-,

where each of the symbols p and q represents an integer from 0 to 8, and p + q is an integer from 1 to 8; M is O, NR9, S, SO or SO2,

where R9represents a hydrogen atom, a C1-6alkyl, C3-6cycloalkyl, C6-14aryl, C7-11aralkyl or acyl selected from the group consisting of formyl, C1-6alkylsulphonyl, C6-10arylcarbamoyl, C6-10aryl-C1-6alkylsulphonyl, C1-6alkoxycarbonyl, C6-10aryl-C1-6alkoxycarbonyl, C1-6alkylsulfonyl, C6-10arylsulfonyl, which can be substituted by 1-3 C1-6alkilani, and C6-10aryl-C1-6alkylsulfonyl, each divalent group may be substituted by 1-5 substituents selected from the group consisting of halogen, nitro, cyano, C1-6the alkyl which may be halogenated, a C3-6cycloalkyl, C1-6alkoxy which may be halogenated, a C1-6alkylthio, which may be halogenated, hydroxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino, C6-14aryl, C7-11aralkyl, C6-10aryloxy, oxo, formyl, C1-6alkylsulphonyl, C6-10arylcarbamoyl, C6-10aryl-Csulfonyl, C6-10arylsulfonyl, which can be substituted by 1-3 C1-6alkilani, and C6-10aryl-C1-6alkylsulfonyl,

(3) the compound according to item (1), in which Za represents a group of the formula:

< / BR>
< / BR>
where R7has the same meaning as defined above,

(4) the compound according to item (1), in which each of the symbols1and R2represents a hydrogen atom,

(5) the compound according to item (1), in which each of the symbols3, R4and R5represents C1-6alkyl,

(6) the compound according to item (1) in which R6represents C1-6alkyl,

(7) the compound according to item (1), in which Ar represents a C6-14aryl which may be substituted by 1-3 substituents selected from the group consisting of halogen, C1-6the alkyl and C1-6alkoxy,

(8) the compound according to item (1), in which ring A represents A 6-membered nitrogen-containing heterocyclic ring which may be substituted,

(9) the compound according to item (1) in which X represents methylene,

(10) the compound according to item (1) in which Y represents CH,

(11) the compound according to item (1), in which Za represents a group of the formula:

< / BR>
where the respective symbols have the same meanings as defined is substituted,

(13) the compound according to item (1) in which R10represents a hydrogen atom,

(14) the compound according to item (1) where Zb is the link

(15) the compound according to item (1) in which m = 1,

(16) the compound according to item (1), in which each of R1and R2represents a hydrogen atom;

each of R3, R4, R5and R6represents C1-6alkyl;

Ar represents phenyl which may be substituted by 1-3 substituents selected from the group consisting of halogen,1-6the alkyl and C1-6alkoxy;

ring A represents A 6-membered nitrogen-containing heterocyclic ring;

X represents methylene;

Y represents CH or N;

Za represents a group of the formula:

< / BR>
where R7represents phenyl may be substituted by 1-3 substituents selected from the group consisting of halogen, C1-6the alkyl and C1-6alkoxy; and R10represents a hydrogen atom;

Zb is a bond or C1-6alkylene, which may be substituted C6-10by aryl; and

m = 1 or 2

(17) the compound according to item (1), in which each of R1and R2represents a hydrogen atom;

each of R3, R4, R5and R6represents C1-stafleet 6-membered nitrogen-containing heterocyclic ring;

X represents methylene;

Y represents CH or N;

Za represents a group of the formula

< / BR>
where R7arepresents a hydrogen atom or a C6-10aryl;

Zb is a bond or (i) C1-6alkylenes or (ii) C2-6alkenylamine group which may be substituted C6-10by aryl; and

m = 1,

(18) the compound according to item (1), in which each of R1and

R2represents hydrogen;

each of R3, R4, R5and R6represents C1-6alkyl;

Ar represents C6-10aryl which may be substituted by 1-3 substituents selected from the group consisting of halogen, methylenedioxy,1-6the alkyl and C1-6alkoxy;

ring A represents A 6-membered nitrogen-containing heterocyclic ring;

X represents methylene;

Y represents CH or N;

Za represents a group of the formula:

< / BR>
< / BR>
where R7brepresents a hydrogen atom or a C6-10aryl which may be substituted with halogen, and R10arepresents a hydrogen atom or a C7-11aralkyl;

Zb is a bond or a divalent group selected from the group consisting of (i) C1-6alkylene, (ii) C2-6Alcanena and (iii) groups of the formula:

-(CH2the th number from 1 to 6 and M' is O or NH, each of the divalent group may be substituted C6-10by aryl; and

m = 1 or 2

(19) the compound according to item (1), which is a

1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)- methyl] -N-(diphenylmethyl)-4-piperidylamine,

(-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine,

(+)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N- (diphenylmethyl)-4-piperidylamine,

1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl) methyl]-N-(diphenylmethyl)-4-piperidylamine,

(-)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl) methyl]-N-(diphenylmethyl)-4-piperidylamine,

(+)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl) methyl]-N-(diphenylmethyl)-4-piperidylamine or their salt,

(20) the method of obtaining the compounds according to paragraph (1), which includes

(i) the interaction of the compounds of formula:

< / BR>
where L represents a leaving group, and other symbols have the same meanings as defined above, or its salt with the compound of the formula:

< / BR>
where the respective symbols have the same meanings as defined above, or its salt;

(ii) the exposure of the compounds of formula:

< / BR>
where sootwetstwii (C) the acylation and subsequent reduction;

(iii) the interaction of the compounds of formula:

< / BR>
where n is an integer from 1 to 4, and other symbols have the same meanings as defined above, or its salt with the compound of the formula:

< / BR>
where R11represents a hydrogen atom or a hydrocarbon group which may be substituted;

Zd represents a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur;

Ar has the same meanings as defined above, or its salt;

(iv) coordination compounds of the formula:

< / BR>
where the symbols have the same meanings as defined above, or its salt with the compound of the formula:

< / BR>
where the symbols have the same meanings as defined above, or its salt, optionally followed by reduction; or

(v) the exposure of the compounds of formula:

< / BR>
where the symbols have the same meanings as defined above, or its salt (a) nitration and subsequent reduction or (b) reaction diazoacetate with subsequent recovery,

(21) a pharmaceutical composition which contains the compound according to item (1), if neobhodi modulation of sodium channel

(23) the composition according to item (22), which is intended for the prevention or treatment of ischemia of the Central nervous system, trauma of the Central nervous system, neurodegenerative diseases or brain edema,

(24) a method of modulating sodium channel in a mammal, in need thereof, which includes an introduction to such mammal an effective amount of the compound according to item (1) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable excipient, carrier or diluent,

(25) the use of the compounds according to paragraph (1) or salts thereof for the manufacture of pharmaceutical compositions for modulating sodium channel

(26) the pharmaceutical composition for modulating sodium channel, which contains the compound (1a), and

(27) the composition according to item (26), which contains (S)-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranyl,

2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)methyl]- 5-benzofuranyl,

(-)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranyl,

(+)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranyl,

7-tert-butyl-2,3-dihydro-2,4,6-the-piperidinyl)methyl]-5-benzofuranyl,

(+)-7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranyl or salt.

In the above formulas, the "lower alkyl" of the "lower alkyl which may be substituted", for R1, R2, R3, R4or R5includes, for example, C1-6alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

"The Deputy," which may be substituted "lower alkyl" includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), cycloalkyl (for example, C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on ), the lower quinil (for example, C2-6quinil, such as ethinyl, 1-PROPYNYL, propargyl and so on), lower alkenyl (for example, C2-6alkenyl, such as vinyl, allyl, Isopropenyl, butenyl, Isobutanol and so on), aryl (for example, C6-10aryl, such as phenyl, naphthyl and so on), aralkyl (for example, 7-11aralkyl, such as benzyl, -methylbenzyl, phenethyl, and so on), lower alkoxy (for example, C1-6alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and so on), aryloxy (for example, C6-10aryloxy, such as phenoxy and so on), the lower Alka is(for example, C6-10arylcarbamoyl, such as benzoyl, naphtol and so on), lower alkanoyloxy (for example, C1-6alkylcarboxylic, such as atomic charges, propionyloxy, butyryloxy, isobutyryloxy and so on), arylcarboxylic (for example, C6-10arylcarboxylic, such as benzoyloxy, naphthyloxy and so on), carboxy, lower alkoxycarbonyl (for example, C1-6alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, tert-butoxycarbonyl and so on), carbarnoyl, amidino, imino, amino, mono-lower alkylamino (for example, mono-C1-6alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino and so on ), di-lower alkylamino (for example, di-C1-6alkylamino, such as dimethylamino, diethylamino, methylethylamine, dipropylamine, Diisopropylamine, dibutylamine and so on), 3-6-membered cyclic amino, optionally containing in addition to carbon and one nitrogen atom, 1-3 heteroatom selected from oxygen, sulfur and nitrogen (for example, 3-6-membered cyclic amino such as aziridinyl, azetidin, pyrrolidinyl, pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino, morpholino, thiomorpholine, digit the si, such as methylenedioxy, Ethylenedioxy and so on), hydroxy, nitro, cyano, mercapto, sulfo, sulfine, phosphono, sulfamoyl, monoalkylphenol (for example, mono-C1-6alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylphenol, butylsulfonyl and so on), dialkylamino (for example, di-C1-6alkylsulfonyl, such as di-methylsulfanyl, diethylcarbamoyl, dipropylamino, dibutylamino and so on), lower alkylthio (for example, C1-6alkylthio, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and so on), arieti (for example, C6-10aaltio, such as phenylthio, naphthylthio and so on), low alkylsulfonyl (for example, C1-6alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and so on ), arylsulfonyl (for example, C6-10arylsulfonyl, such as phenylsulfinyl, naphthylmethyl and so on ), lower alkylsulfonyl (for example, C1-6alkylsulphonyl, such as methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and so on) and arylsulfonyl (for example, C6-10arylsulfonyl, such as phenylsulfonyl, naphthylmethyl and so on).

"Lower alkyl" lower alkyl, motorcitycasino 1-3, moreover, when the number of substituents is not less than 2, then the substituents may be the same or different.

"Acyl" for R1or R2includes, for example, acyl derived from carboxylic acids or sulfonic acids. Preferred acyl include formyl, lower alkylsulphonyl (for example, C1-6alkylsulphonyl, such as acetyl, propionyl, butyryl, isobutyryl and so on), arylcarbamoyl (for example, C6-10arylcarbamoyl, such as benzoyl, naphtol and so on), aralkylamines (for example, C6-10aryl-C1-6alkylsulphonyl, such as benzylcarbamoyl, ventilkappen, naphthylethylene and so on), low alkoxycarbonyl (for example, C1-6alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, tert-butoxycarbonyl and so on), Uralelectromed (for example, C6-10aryl-C1-6alkoxycarbonyl, such as benzyloxycarbonyl and so on), lower alkylsulfonyl (for example, C1-6alkylsulfonyl, such as mesyl, ethylsulfonyl, propylsulfonyl and so on ), C6-10arylsulfonyl, optional with C1-6alkyl (for example, phenylsulfonyl, naphthylmethyl, toil and so on) and aralkylamines (for example, Cthe.).

Preferably each of R1and R2represents a hydrogen atom, a C1-6alkyl or C1-6alkylsulphonyl. More preferred is a hydrogen atom or a C1-6alkyl. Especially preferred is a hydrogen atom.

"Lower alkoxy" lower alkoxy which may be substituted", for R3, R4or R5includes, for example, C1-6alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy. "The Deputy," which may be substituted "lower alkoxy" includes the same substituents as mentioned above for "lower alkyl" and the number of substituents may be the same as specified for "lower alkyl".

"5 - or 6-membered carbocyclic group, which may be formed by the radicals R4and R5taken together with the respective adjacent carbon atoms, includes, for example, 6-membered aromatic hydrocarbon ring (e.g. benzene ring, and so on) and 5 - or 6-membered cycloalkane (for example, cyclopentene, cyclopentadiene, cyclohexene and so on).

Preferably each of R3, R4and R5represents C1-6alkyl. More preferably each of R1, R2, R3, R4or R5.

Preferably R6represents C1-6alkyl. More preferred is methyl.

"Aromatic group" of the "aromatic group which may be substituted" for Ar includes, for example, an aromatic hydrocarbon group and aromatic heterocyclic group.

"Aromatic hydrocarbon group" includes, for example, C6-14monocyclic or condensed polycyclic aromatic hydrocarbon group. For example, you can call C6-14aryl, such as phenyl, 1-naphthyl, 2-naphthyl, antrel etc. Preferred is C6-10aryl, such as phenyl, 1-naphthyl, 2-naphthyl etc., Particularly preferred is phenyl.

The above-mentioned "aromatic heterocyclic group" includes, for example, 5-10-membered monocyclic or condensed heteroaromatic group containing, besides carbon, one or more, for example 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen. In particular, it includes a monovalent group formed by removal of any one of a hydrogen atom, respectively, of the aromatic GE the ring (preferably 5 - or 6-membered monocyclic ring) and one or more (preferably 1 or 2, more preferably 1) aromatic rings (e.g. benzene or pyridine ring, and so on), such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, oil [2,3-b] thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, isoquinoline, quinoline, carbazole, isothiazol, isoxazol, etc. Preferred "aromatic heterocyclic group" include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chinolin, 3-chinolin, 4-chinolin, 2-chinolin, 8-chinolin, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzothiazyl, benzofuranyl, 2-thienyl, 3-thienyl, 2-benzoxazolyl, 2-benzimidazolyl and 2-peridotites. Especially preferred are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chinolin, 3-chinolin, 4-chinolin, 2-indolyl and 3-indolyl.

"Deputy" of the "aromatic group which may be substituted" for Ar includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), C1-3alkylenedioxy (for example, methylenedioxy, Ethylenedioxy and so on), nitro, cyano, C1-6alkyl which may be halogenated, a C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, College generowanym, hydroxy, amino, mono-C1-6alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino and so on), di-C1-6alkylamino (for example, dimethylamino, diethylamino, methylethylamine, dipropylamine, dibutylamine and so on), C1-6alkylsulphonyl (for example, acetyl, propionyl and so on), carboxy, C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl and so on), carbarnoyl, mono-C1-6allylcarbamate (for example, methylcarbamoyl, ethylcarbitol and so on), di-C1-6allylcarbamate (for example, dimethylcarbamoyl, di-ethylcarbamate and so on ), C6-10arylcarbamoyl (for example, phenylcarbamoyl, afterburner and so on), sulfo, C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl and so on ), C6-10aryl (e.g. phenyl, naphthyl and so on) and C6-10aryloxy (for example, phenyloxy, naphthyloxy and so on). When the Deputy represents a C1-3alkylenedioxy, it preferably forms a ring with two adjacent carbon atoms.

"C1-6alkyl which may be halogenated" includes, for example, C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and so on), NeoMaster, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, propyl, 3,3,3-cryptochromes, isopropyl, butyl, 4,4,4-tripcomputer, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tryptophanyl, hexyl, 6,6,6-triptorelin etc.

"C1-6alkoxy which may be halogenated" includes, for example, C1-6alkoxy, optionally having 1-3 halogen atom (e.g. fluorine, chlorine, bromine, iodine and so on). For example, you can call methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-triptoreline, propoxy, isopropoxy, butoxy, 4,4,4-triptoreline, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.

"C1-6alkylthio, which may be halogenated" includes, for example, C1-6alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and so on), optionally having 1-3 halogen atom (e.g. fluorine, chlorine, bromine, iodine and so on). So, for example, can be called methylthio, deformality, triptoreline, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-cryptosporidia, pentylthio, hexylthio, etc.

"Aromatic group" of the "aromatic group which may be substituted" may have 1 to 5, predpochtitel, include those described above. With the introduction of two or more substituents they may be the same or different.

Preferably Ar represents C6-14aryl (preferably phenyl), 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, 2-indolenine or 3-indolering group which may be substituted. More preferably Ar represents C6-10aryl which may be substituted. Preferred "Deputy" in this case includes halogen, C1-6alkoxy and C1-6alkyl. More preferably Ar represents C6-14aryl (preferably phenyl), which may be substituted by 1-3 substituents selected from halogen, C1-6alkoxy and C1-6the alkyl.

"5-8-membered nitrogen-containing heterocyclic ring" "5-8-membered nitrogen-containing heterocyclic ring which may be substituted" for ring A includes, for example, 5-8-membered saturated or unsaturated heterocyclic ring, each of which contains, in addition to carbon, at least one nitrogen atom. The list of such heterocyclic rings include piperidine, piperazine, 1,2,5,6-tetrahydropyridine, pyrrolidin, 1H-azepin, 1H-2,3-dehydroacetic, 1H-2,3,4,5-tetrahydroazepine, 1H-2,3,6,7 - tetrahydro is tetrahydro-1,4-diazepin, 1H-2,3,4,5,6,7-hexahydro-1,4-diazepin, 1,2-digiraatii, 2,3,4,5-tetrahydrothieno, 1,2,3,4,5,6-hexahydroazepin, 1,2,3,4,5,6,7,8-octahydrate, 1,2-dihydro-1,5-diasorin, 1,2,3,4,5,6-hexahydro-1,5-diasorin, 1,2,3,4,5,6,7,8-octahydro-1,5-diasorin, etc. is Preferred 6-membered nitrogen-containing heterocyclic ring. More preferred are piperidine and piperazine.

"Deputy", which can, optionally, be on "5-8-membered nitrogen-containing heterocyclic ring" includes the same groups as listed above for the "aromatic group which may be substituted" in connection with Ar. The number of substituents may be from 1 to 3, with the introduction of two or more substituents they may be the same or different.

Preferably, the ring A represents A 6-membered nitrogen-containing heterocyclic ring which may be substituted. More preferably ring a is piperidine or piperazine.

"Lower alkylene" lower alkylene, which may be substituted" for X includes, for example, a divalent group formed by removal of two hydrogen atoms respectively from C1-6alkanes. "Lower alkylene" includes, for example, nerazvit and so on, preferred are methylene and ethylene. Especially preferred is methylene.

"Deputy", not necessarily present in the above-mentioned "lower alkylene, which may be substituted" includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and so on), C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl and so on ), C2-6alkenyl (for example, vinyl, allyl, 1-propenyl, 2-butenyl and so on ), C2-6quinil (for example, ethinyl, 2-PROPYNYL, 2-butynyl and so on), C6-14aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, diphenylol and so on), nitro, cyano, hydroxy, C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy and so on), amino, mono-C1-6alkylamino (for example, methylamino, ethylamino and so on), di-C1-6alkylamino (for example, dimethylamino, diethylamino, methylethylamine and so on), C1-6alkylsulphonyl, (for example, acetyl, propionyl and so on), C6-10aryloxy (for example, phenyloxy, naphthyloxy and so on) and oxo.

"Lower alkylene" lower alkylene, which may be substituted" may have 1 to 3, preferably 1 or 2, such replacement shall be the same or different.

Preferable example of X is methylene.

When Y is carbon, can usually be defined as a group of the formula: > C(R8)-.

In the above formula, R8is, for example, a hydrogen atom, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), nitro, cyano, C1-6alkyl which may be halogenated, a C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on), C1-6alkoxy which may be halogenated, a C1-6alkylthio, which may be halogenated, hydroxy, amino, mono-C1-6alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino and so on), di-C1-6alkylamino (for example, timemillis, diethylamino, methylethylamine, dipropylamine, dibutylamine and so on), C1-6alkylsulphonyl, (for example, acetyl, propionyl and so on), carboxy, C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl and so on), carbarnoyl, mono-C1-6allylcarbamate (for example, methylcarbamoyl, ethylcarbitol and so on), di-C1-6allylcarbamate (for example, dimethylcarbamoyl, diethylcarbamoyl and so on), C6-10arylcarbamoyl (for example, phenylcarbamoyl, naftilan the example, phenyl, naphthyl and so on) and C6-10aryloxy (for example, phenyloxy, naphthyloxy and so on). Preferably R8represents hydrogen, cyano, C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and so on), C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy and so on), hydroxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino or C1-6alkylsulphonyl.

When Y is nitrogen, Za preferably represents a group of the formula

< / BR>
where R7such as defined above.

Preferably Y represents CH or N. More preferably, Y represents CH.

"Aromatic group which may be substituted",7include groups similar to those specified for the "aromatic group which may be substituted", when it spoke of Ar.

Preferably R7represents hydrogen or C6-10aryl which may be substituted. More preferred is C6-10aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl etc., preferably phenyl), which may be substituted with halogen.

"Hydrocarbon group" of the "hydrocarbon group odorata from hydrocarbon compounds, and includes both acyclic and cyclic hydrocarbon groups (e.g. alkyl, alkenyl, quinil, cycloalkyl, aryl, aralkyl and so on ). Preferred is the following acyclic or cyclic C1-16hydrocarbon group:

(i) C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and so on),

(ii) C2-6alkenyl (for example, vinyl, allyl, Isopropenyl, butenyl, Isobutanol, second-butenyl and so on),

(iii) C2-6quinil (for example, ethinyl, propargyl, butynyl, 1-hexenyl and so on),

(iv) C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on),

(v) C6-14aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, diphenyl, 2-antrel etc., preferably phenyl),

(vi) C7-16aralkyl (for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylether, 3-phenylpropyl, 4-phenylbutyl, 5-fenilpentil and so on, preferably benzyl).

"Deputy", not necessarily present in the "hydrocarbon group which may be substituted" includes 1-5, preferably 1-3, substituents similar to the "Deputy" lower alkyl which may be substituted", for R1, R2, R3 or R2.

Preferably R10represents hydrogen or C7-11aralkyl. Especially preferred is hydrogen.

Za preferably represents a group of the formula:

< / BR>
where the symbols have the same meanings as defined above. More preferred is a group of the formula:

< / BR>
where R7has the same meaning as defined above.

"Divalent aliphatic hydrocarbon group which may contain oxygen, nitrogen or sulfur", "divalent hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur, for Zb includes, for example, (i) methylene or (ii) a divalent group formed by removal of one hydrogen atom from each of two carbon atoms saturated or unsaturated aliphatic hydrocarbon, and optionally having 1 or 2 (preferably 1) heteroatoms selected from oxygen, nitrogen and sulfur, between carbon atoms or end(s) position(s). Preferred is a group having 1-8 carbon atoms. Examples of groups include:

(i) C1-8alkylene (for example, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2
-CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=CH-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH=CH -, and so on),

(iii) C2-8akinyan (for example, -CC-, -CH2-CC-, -CH2-CC-CH2-CH2- etc),

(iv) a group of the formula: -(CH2)p-M-(CH2)q- where M is O, NR9, S, SO or SO2; each of p and q represent an integer from 0 to 8, and p+q is an integer from 1 to 8. In the above formula, R9represents a hydrogen atom, a C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and so on), C3-6cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl and so on), C6-14aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, diphenylol and so on), C7-11aralkyl (for example, benzyl, phenethyl, and so on) or acyl. Just the above-mentioned "acyl" includes the same groups as mentioned for the "acyl" represented by the symbol R1or R2.

M preferably represents O or NR9where R9preferably represents hydrogen.

Each of p and q preferably represents an integer from 0 to 5, more preferably an integer from 0 to 4.

"Deputy", not necessarily the presence of the ru, includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), nitro, cyano, C1-6alkyl which may be halogenated, a C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on), C1-6alcokey, which may be halogenated, a C1-6alkylthio, which may be halogenated, hydroxy, amino, mono-C1-6alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino and so on ), di-C1-6alkylamino (for example, dimethylamino, diethylamino, methylethylamine, dipropylamine, dibutylamine and so on), C6-14aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, diphenylol and so on), C7-11aralkyl (for example, benzyl, phenethyl, and so on), C6-10aryloxy (for example, phenyloxy, naphthyloxy and so on), oxo, and acyl. The above-mentioned "C1-6alkyl which may be halogenated", "C1-6alkoxy which may be halogenated", and "C1-6alkylthio, which may be halogenated", can be the same as above as the substituents in the aromatic group Ar. The above "acyl" includes the same groups as mentioned for the "acyl" represented by the symbol R1or R2.

These replace estately may be the same or different.

Zb preferably represents a bond or C1-8alkylen. More preferably Zb represents the relationship.

"Aromatic group which may be substituted", for Q may be the same as the "aromatic group which may be substituted" for Ar.

"Divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur, for Zc can be the same as the "divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur, for Zb.

Q preferably represents an aromatic group which may be substituted.

"5-8-membered nitrogen-containing heterocyclic ring which may be substituted", "5-8-membered nitrogen-containing heterocyclic ring which may be substituted, or corresponding condensed benzene ring system" for ring Aa may be the same as "5-8-membered nitrogen-containing heterocyclic ring which may be substituted" for ring A. "Condensed benzene ring system corresponding to 5-8-membered nitrogen-containing heterocyclic ring which may be substituted" may predstavitelskogo ring, which may be substituted" for ring A "benzene ring which may be substituted" in the plane of condensation.

"Deputy", not necessarily present in the "benzene ring which may be substituted" may be similar to the Deputy, it is not necessarily present in the "aromatic group which may be substituted" for Ar. The number of substituents may be from 1 to 4.

Preferably the ring Aa represents a 6-membered nitrogen-containing heterocyclic ring. More preferably ring Aa represents piperidine.

The preferred compound (I is a compound in which each of R1and R2represents a hydrogen atom;

each of R3, R4, R5and R6represents C1-6alkyl;

Ar represents phenyl which may be substituted by 1-3 substituents selected from the group consisting of halogen,1-6the alkyl and C1-6alkoxy;

ring A represents A 6-membered nitrogen-containing heterocyclic ring;

X represents methylene;

Y represents CH or N;

Za represents a group of the formula:

< / BR>
where R7'represents phenyl which may be substituted by 1-3 will replace the em hydrogen atom;

Zb is a bond or C1-6alkylene, which may be substituted C6-10by aryl; and

m = 1 or 2.

Preferred are compounds (including their salts) of formula (I), where

each of R1and R2represents hydrogen;

each of R3, R4, R5and R6represents C1-6alkyl;

Ar is (i) C6-10aryl, (ii) 2-pyridyl, (iii) 3-pyridyl, (iv) 4-pyridyl, (v) 2-indolyl or (vi), 3-indolyl, each of which may be substituted by 1-3 substituents selected from the group consisting of halogen, C1-3alkylenedioxy, nitro, cyano, C1-6the alkyl which may be halogenated, a C3-6cycloalkyl, C1-6alkoxy which may be halogenated, a C1-6alkylthio, which may be halogenated, hydroxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino, C1-6alkylsulphonyl, carboxy, C1-6alkoxycarbonyl, carbamoyl, mono-C1-6allylcarbamate, di-C1-6allylcarbamate, C6-10arylcarbamoyl, sulfo, C1-6alkylsulfonyl, C6-10aryl and C6-10aryloxy;

ring A represents A 6-membered nitrogen-containing heterocyclic ring;

X represents methylene;

Y, not only the 6-10
aryl which may be substituted with halogen;

R10arepresents a hydrogen atom or a C7-11aralkyl;

Zb is a bond or (i) C1-6alkylene, (ii) C2-6albaniles or (iii) groups of the formula

-(CH2)p-M-(CH2)q-,

where each of p' and q' represents an integer from 0 to 5, p' + q' represents an integer from 1 to 6 and M' is O or NH, and each group may be substituted C6-10by aryl; and

m = 1 or 2.

Especially preferred are compounds in which R10arepresents a hydrogen atom, Zb is a bond and m = 1, and their salts.

Also preferred are compounds (including their salts) of formula (I), where

each of R1and R2represents a hydrogen atom;

each of R3, R4, R5and R6represents C1-7alkyl;

Ar represents C6-10aryl which may be substituted on methylendioxy;

ring A represents A 6-membered nitrogen-containing heterocyclic ring;

X represents methylene;

Y represents CH or N;

Za represents a group of the formula:

< / BR>
R7arepresents a hydrogen atom or a C6-10aryl;

Zb represents (i) a bond or (ii) C1-6

Preferred are also compounds (including their salts) of formula (I), where

each of R1and R2represents a hydrogen atom;

each of R3, R4, R5and R6represents C1-6alkyl;

Ar represents C6-10aryl which may be substituted by 1-3 substituents selected from the group consisting of halogen, methylenedioxy,1-6the alkyl and C1-6alkoxy;

ring A represents A 6-membered nitrogen-containing heterocyclic ring;

X represents methylene;

Y represents CH or N;

Za represents a group of the formula:

< / BR>
< / BR>
R7brepresents a hydrogen atom or a C6-10aryl which may be substituted with halogen;

R10arepresents a hydrogen atom or a C7-11aralkyl;

Zb is a bond or (i) C1-6alkylene, (ii) C2-6albaniles or (iii) a group of the formula

-(CH2)p-M-(CH2)q-,

where each of p' and q' each represents an integer from 0 to 5, p' + q' represents an integer from 1 to 6 and M' is O or NH, and each group may be substituted C6-10by aryl; and

m = 1 or 2.

Preferred species of compound (I) of the present invention include:

2-[(4-eventform-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine,

(-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine,

(+)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine,

1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine,

(-)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl)methyl]-N-(diphenylmethyl)-4 - piperidylamine,

(+)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl)methyl]-N-(diphenylmethyl)-4-piperidylamine,

2-[[4-(diphenylmethoxy)-1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl,

1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(3,3-diphenylpropyl)-4-piperidinedione,

2,3-dihydro-2,4,6,7-tetramethyl-2-[[4-(2-phenylethyl)-1-piperazinil] methyl] -5-benzofuranyl and their salts.

More preferred is

1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine,

(-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine,

(+)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin--yl)methyl] - N-(diphenylmethyl)-4-piperidylamine,

1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl)ml]-N-(diphenylmethyl)-4-piperidylamine,

(+)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-relativesource-2-yl) methyl]-N-(diphenylmethyl)-4-piperidine or salt.

Preferred compounds of formula (Ia), including their salts, are compounds in which each of R1and R2represents a hydrogen atom, a C1-6alkyl or C1-6alkylsulphonyl;

each of R3, R4, R5and R6represents C1-6alkyl;

ring A represents A 6 - or 7-membered nitrogen-containing heterocyclic ring which may be condensed with a benzene ring;

X represents methylene;

Y represents (i) a group of the formula >C(R8a) - (where R8arepresents a hydrogen atom or hydroxy) or (ii) N;

Q represents (i) hydrogen atom, (ii) C6-10aryl or 6-membered nitrogen-containing aromatic group which may be substituted with halogen or C1-6alkoxy, or (iii) a group of the formula Zc'-Ar' (where Zc' represents C1-6alkylenes or C2-6alkenylamine group which may be substituted C6-10the aryl or oxo, and may contain oxygen; and Ar' represents a C6-10aryl); and

m = 1.

Preferred species of the compound (Ia) include the

(S)-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperalin,

(-)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl]-5-benzofuranyl,

(+)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl]-5-benzofuranyl,

7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl]-5-benzofuranyl,

(-)-7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl]-5-benzofuranyl,

(+)-7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl]-5-benzofuranyl or salt.

More preferred are (S)-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl] -5-benzofuranyl and its salt.

The compound (I) and compound (Ia) include stereoisomers, but the scope of the present invention also includes the corresponding isomers and mixtures thereof.

The salt of compound (I) of the present invention or compound (Ia) is usually pharmacologically acceptable salt, such as salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic and acidic amino acids. The preferred salts with inorganic bases are salts with alkali metals such as sodium, potassium and so on, salts with organic bases are salts with trimethylamine, the triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and N,N'-dibenziletilendiaminom etc., the Preferred salts with inorganic acids are salts with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. are Preferable salts with organic acids are salts with formic acid, acetic acid, triperoxonane acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid, etc. are Preferable salts with basic amino acids are salts with arginine, lysine, ornithine etc., the Preferred salts with acidic amino acids are salts with aspartic acid, glutamic acid, etc.

Especially preferred salts are pharmacologically acceptable salts. When the compound (I) or compound (Ia) contains a basic functional group, preferred salt includes corresponding salt of the slot, sulfuric acid, phosphoric acid, etc. and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonate acid, p-toluensulfonate acid, etc. When there is an acid functional group, preferred salt includes corresponding salts with alkaline metals such as sodium, potassium etc., salts with alkaline earth metals such as calcium, magnesium and so on, and ammonium salts.

Next described is a method of obtaining the compound (I) of the present invention.

The compound (I) of the present invention can be obtained known as such ways or their analogues, or by the methods shown in the following schemes reactions. The compound (Ia) can be obtained known as such (for example, by methods disclosed in EP-A-483772, JP-A-5140142, JP-A-641123, USP 5552552 and so on) or their analogues, or by the methods shown in the following schemes reactions.

On the schemes of reactions 1-6 (see at the end of the description) corresponding symbols have the same meanings as previously defined. Compounds (II)-(XXVIII) diagrams Vliet to be obtained in known per se manner, for example any of the methods disclosed in JP-A-6287585, JP-A-5140142, J. Am. Oil Chem. Soc., 51, 200-203, 1974, and so on, or in any way resembles the well-known methods.

The compound (V) may be obtained in known per se manner, for example by the method disclosed in JP-A-5140142, or any similar method.

The compound (VII) can be purchased on the market, if there is, or can be obtained in a known manner, for example by the method disclosed in Eur. J. Med. Chem. 15, 363-370, 1980, JP-A-249726, and so on, or any similar method.

The compound (III) (where L represents a leaving group) can be obtained by a method that includes the restoration of the carboxyl group of compound (II), either directly or after esterification to obtain the corresponding alcohol, which is subjected sulfonic esterification or galogenirovannyie.

"Leaving group" for L includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), C1-5alkylsulfonate, which may be halogenated (for example, methanesulfonate, econsultancy, trichlorocarbanilide and so on), and arylsulfonate (for example, benzosulfimide, which may be substituted, typically p-toluensulfonate and is, for example, metal hydrides such as aluminum hydride, the hydride diisobutylaluminum etc., hydrogen-metal complexes, such as sociallyengaged, borohydride sodium and so on, boranova complexes, such as balancerationality complex, porandamaterjalides complex and so on, alkylborane, such as axillary, dissimilar and so on, and DIBORANE. The relative content of the reducing agent, if we take as an example a metal hydride, is about 0.5-10 mol, preferably about 0.5 to 3.0 mol, per mole of compound (II), and in the case of hydrogen-metal complex is about 0.5-10 mol, preferably about 0.5-5.0 mol, per mole of compound (II). Share boranova complex, alkylborane or DIBORANE is about 1.0-10.0 mol, preferably 1.0 to 5.0 mol, per mole of compound (II). This reaction it is advisable to carry out in the presence of an inert solvent. No other relations special restrictions on the type of solvent, if only it does not interfere with the course of the reaction. It is preferred to use alcohols such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, CEC is formic acid, acetic acid, etc. and mixtures of such solvents. The reaction time is usually 1-100 hours, preferably about 1-50 hours. The reaction temperature is usually 0-120oC, preferably 20-80oC. Upon completion of the reaction, the reaction mixture may be subjected to the next reaction either as it is or after partial purification, and the resulting connection can be easily selected known per se method and purified by usual method such as recrystallization, distillation, chromatography, etc.

The reducing agent for use in the process containing tarifitsirovana of compound (II) in the usual method of organic chemistry and restoring the received complex ester includes, for example, metal hydrides such as aluminum hydride, the hydride diisobutylaluminum etc., hydrogen-metal complexes, such as sociallyengaged, borohydride sodium and so on, boranova complexes, such as balancerationality complex, porandamaterjalides complex and so on, alkylborane, such as axillary, dissimilar and so on, DIBORANE and the hydrogenation catalysts such as Raney Nickel, the Raney cobalt, etc. Relative concentration of reducing agent, if you take in chacago ester compounds (II), and in the case of hydrogen-metal complex is about 1.0-10 mol, preferably about 1.0 to 3.0 mol, per mole of ester of compound (II). If boranova complex, alkylborane or DIBORANE their relative content per mole of ester of compound (II) is about 1.0-5.0 mol. In the case of hydrogenation, the hydrogenation catalyst is used in a proportion of about 10-1000 wt.%, preferably approximately 80-300 wt.%, by weight of ester of compound (II). This reaction it is advisable to carry out in the presence of an inert solvent. No other relations special restrictions on the type of solvent, if only it does not interfere with the course of the reaction. Examples of the solvent include alcohols such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on , hydrocarbons, such as benzene, toluene, cyclohexane, etc., amides such as N, N-dimethylformamide, N, N-dimethylacetamide, etc. and organic acids such as formic acid, acetic acid, etc. and mixtures of such solvents. Depending on the activity and amount of the used catalyst, the reaction time is usually 1-100 hours, preferably about 1-50 hours. Temperature pressure of hydrogen is usually set in the range of 1-100 atmospheres. Upon completion of the reaction, the reaction mixture may be subjected to the next reaction either as it is or after partial purification, and the resulting connection can be easily selected known per se method and purified by usual method such as recrystallization, distillation, chromatography, etc.

For the conversion obtained in the manner described alcohol ester sulfonic acid is used sulfonyloxy agent, such as methanesulfonate or p-toluensulfonate, optionally in combination with a base, if necessary. Sulfonyloxy agent is used with the relative content of about 1.0-5.0 mol, preferably about 1.0 to 2.0 mol, per mole of alcohol. This reaction is preferably carried out in an inert solvent. There are no particular restrictions on the type of solvent that can be used, but it is reasonable to use ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, hexane, etc., amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-DD, and so on, nitrogen-containing aromatic hydrocarbon compounds, such as pyridine, lutidine, quinoline, etc. and mixtures of such solvents. The base, which can be optionally used includes, for example, triethylamine and pyridine. The reaction temperature is in the range of 20-150oC, preferably 0-100oC. the reaction Time ranges usually from 5 minutes to 24 hours, preferably from 10 minutes to 5 hours.

Halogenation agent includes, for example, thionylchloride, such as thionyl chloride, thienylboronic and so on, phosphorylchloride, such as phosphorylchloride, phosphorylated and so on, the phosphorus halides such as pentachloride phosphorus, trichloride phosphorus, pentabromide phosphorus, tribromide phosphorus and so on, oxaliplatin, such as oxacillin and so on, and phosgene. Halogenation agent is used in proportions of about 1.0 to 30 mol, preferably about 1.0 to 10 mol, per mole of alcohol. This reaction is preferably carried out in the absence of solvent or in an inert solvent. The type of solvent is not critical, but is advisable to use aromatic hydrocarbons such as benzene, toluene, etc., saturated hydrocarbons such as cyclohexane, hexane and so on, simple aracetamol and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. and mixtures of such solvents. The reaction time ranges usually from 10 minutes to 12 hours, preferably from 10 minutes to 5 hours. The reaction temperature is in the range of usually 10 to 200oC, preferably 10 to 120oC. Obtained in the manner described compound (III) may be subjected to the next reaction either as the reaction mixture or after partial purification, and can be easily selected known per se method and purified by usual method such as recrystallization, distillation, chromatography, etc.

The compound (IV) can be obtained by nitration of the compound (III). Nitrouse agent, which can be used includes, for example, mixed acid, acetylated, fuming nitric acid, tetrafluoroborate nitronium (NO2+BF4-and triftorbyenzola nitronium (NO2+CF3SO3-). Nitrouse agent is used in proportions of about 1.0 to 50 mol, preferably about 1.0 to 10 mol, per mol of compound (III). This reaction should be carried out in the absence of solvent or in an inert solvent. Type ispolzovat, the acid anhydrides such as acetic anhydride, mineral acids such as sulfuric acid, nitric acid etc., saturated hydrocarbons such as cyclohexane and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. and mixtures of such solvents. The reaction time ranges usually from 10 minutes to 12 hours, preferably from 10 minutes to 5 hours. The reaction temperature is in the range of usually 10 to 200oC, preferably 10-120oC. Obtained in the manner described compound (IV) can be subjected to the next reaction either as the reaction mixture or after partial purification, and can be easily selected known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

The compound (VI) can be obtained by recovery of the compound (IV) and, optionally, its exposure to the alkylation and/or acylation. The reducing agent which can be used for this repair includes, for example, metal hydrides such as aluminum hydride, the hydride diisobutylaluminum etc., hydrogen-metal complexes, such as socialogically complex and so on, alkylborane, such as axillary, dissimilar and so on, DIBORANE, some metals, such as zinc, aluminum, tin, iron, etc. and alkali metal (e.g. sodium, lithium, and so on) in liquid ammonia (recovery Birch). In addition to these reducing agents can be used in a variety of catalysts such as palladium on carbon, platinum oxide, Raney Nickel, Raney cobalt, etc. as hydrogenation catalysts. The relative content of the reducing agent, if we take as an example the metal hydride is about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per mole of the compound (IV), and in the case of hydrogen-metal complex is about 1.0-10 mol, preferably about 1.0 to 3.0 mol, per mole of the compound (IV). If boranova complex, alkylborane or DIBORANE their relative content per mole of the compound (IV) is about 1.0-5.0 mol. In the case of metal it is used in a proportion of about 1.0 to 20 equivalents, preferably about 1-5 equivalents. In the case of using the alkali metal its share is about 1-20 equivalents, preferably about 1-5 equivalents. In the case of a hydrogenation catalyst such as palladium on carbon, platinum oxide, Nickel R is unity (IV). This reaction it is advisable to carry out in an inert solvent. The type of solvent is not critical, if only it does not interfere with the course of the reaction. Preferred are alcohols, such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc. and organic acids such as formic acid, acetic acid, etc. and mixtures of such solvents. When using Raney Nickel or Raney cobalt can be added amine, such as ammonia, to suppress side reactions. Depending on the type and amount used of the catalyst, the reaction time is usually 1-100 hours, preferably about 1-50 hours. The reaction temperature is usually 0-120oC, preferably 20-80oC. using a catalyst hydrogenation pressure of hydrogen is usually set in the range of 1-100 atmospheres. Upon completion of the reaction, the reaction mixture may be subjected to the next reaction either as it is or after partial purification, and the resulting compound can be easily separated famous ASS="ptx2">

The obtained amine optionally alkylate.

Thus, the compound (VI) (in which at least one of R1and R2represents a hydrogen atom) is subjected to interaction with the appropriate alkylating agent (for example, corresponding alkylhalogenide or appropriate alkylsulfonates and so on), optionally in the presence of a base. An alkylating agent is used in proportions of about 1.0-5.0 mol, preferably about 1.0 to 2.0 mol, per mol of compound (VI). The base, which can be used includes, for example, inorganic bases such as sodium carbonate, carbonita potassium, cesium carbonate, sodium bicarbonate, etc., aromatic amines such as pyridine, lutidine, etc. , tertiary amines, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and so on, hydrides of alkali metals, such as sodium hydride, potassium hydride, etc., amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium, and so on , and alkoxides of metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and so on, the Basis used to prop the ü in an inert solvent. There are no particular restrictions on the type of solvent. Preferred are alcohols, such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, hexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., NITRILES, such as acetonitrile, propionitrile and so on, sulfoxidov, such as dimethyl sulfoxide, etc. and mixtures of such solvents. The reaction time ranges usually from 30 minutes to 48 hours, preferably 1-24 hours. The reaction temperature is in the range of usually 20 to 200oC, preferably 0-150oC.

The obtained amine optionally acelerou.

Thus, the compound (VI) (in which at least one of R1and R2represents a hydrogen atom) is subjected to interaction with allermuir agent, optionally in the presence of base or acid. Allermuir agent can be, for example, the corresponding carboxylic acid or its reactive derivative, for example, halogenmethyl, acid anhydride, 0-2,0 mol, per mole of compound (VI). This reaction should be carried out in the absence of solvent or in an inert solvent. There are no particular restrictions on the type of solvent that can be used. Preferred are ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, hexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., NITRILES, such as acetonitrile, propionitrile and so on, sulfoxidov, such as dimethyl sulfoxide and so on, nitrogen-containing aromatic hydrocarbon compounds, such as pyridine, lutidine, quinoline, etc. and mixtures of such solvents. The base, which may be, although not necessarily, used, include, for example, triethylamine and pyridine. Acid, which may be, although not necessarily, used, include, for example, methanesulfonate acid, p-toluensulfonate acid and camphorsulfonic acid. The reaction temperature is in the range of usually about 20 to 150oC, preferably 0-100oC. the reaction Time ranges usually is t to be subjected to the next reaction either in the form of a reaction mixture, or after partial purification, and can be easily selected known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

If required, the reaction described above alkylation and acylation can be carried out in combination or several times.

The compound (VI) can also be obtained by treating compound (V) halogenation reagent. This reaction can be carried out, when necessary, using bases, basic salts, or a radical initiator or under the influence of light. Halogenation reagent includes, for example, halogen, such as bromine, chlorine or iodine, imide, such

as N-bromosuccinimide, adduct of halogen, such as benzyltrimethylammonium, benzyltriethylammonium, Tetramethylammonium, bromine adduct, perbromic of pyridinylamino, dioxane dibromide. Halogenation agent is used in proportions of about 1.0-5.0 mol, preferably about 1.0 to 2.0 mol, per mol of compound (V). This reaction is preferably carried out in the absence of solvent or in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Prefer irty, such as methanol, ethanol, propanol, etc., hydrocarbons, such as benzene, toluene, cyclohexane, hexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., NITRILES, such as acetonitrile, propionitrile and so on, sulfoxidov, such as dimethyl sulfoxide, etc. and organic acids such as acetic acid, propionic acid and so on, nitroalkanes, such as nitromethane, etc., aromatic amines such as pyridine, lutidine, quinoline, etc. and mixtures of such solvents. The base, which may be, although not necessarily, used, include, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, etc., aromatic amines such as pyridine, lutidine and so on, and tertiary amines, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine etc. Basic salt, which can be though not necessarily, used, include, for example, sodium acetate, potassium acetate, etc. Radical initiator, which may be the case of exposure light can be used a halogen lamp. The reaction temperature is in the range of generally about 50-150oC, preferably 0-100oC. the reaction Time ranges usually from 5 minutes to 24 hours, preferably from 10 minutes to 5 hours.

The compound (VI) can be also obtained by a method comprising the cyclization of compound (V) organic percolate, optionally in the presence of a base, and exposure of the resulting alcohol sulfonic esterification. Organic percolate, which can be used includes, for example, m-chloroperbenzoic acid and peracetic acid. Organic percolate used in a proportion of about 1.0-5.0 mol, preferably about 1.0 to 2.0 mol, per mol of compound (V). This reaction is preferably carried out in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Preferred are water, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on; hydrocarbons, such as benzene, toluene, cyclohexane, hexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., NITRILES, t is you, such as acetic acid, propionic acid, etc., nitrogen-containing aromatic hydrocarbon compounds, such as pyridine, lutidine, quinoline, etc. and mixtures of such solvents. The base, which may be, although not necessarily, used, include, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, etc., aromatic amines such as pyridine, lutidine and so on , and tertiary amines, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylamino-pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholin and so on, the reaction Temperature is in the range of usually about 20 to 150oC, preferably 0-100oC. the reaction Time ranges usually from 5 minutes to 24 hours and preferably from 10 minutes to 5 hours. Subsequent reaction of the sulfonic esterification can be carried out under the same conditions described for obtaining the compound (III) from compound (II). Collected in this way the compound (VI) can be subjected to the next reaction either as the reaction mixture or after partial purification, and can be easily selected known in itself by the way and the unity (I) can be obtained by exposure of the compound (VI) is condensed with compound (VII).

This condensation of the compound (VI) with compound (VII) can be carried out optionally in the presence of a base. The base includes, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, etc., aromatic amines such as pyridine, lutidine, etc., tertiary amines, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and so on, hydrides of alkali metals, such as sodium hydride, potassium hydride, etc., amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium, and so on, and alkoxides of metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and so on, the Base is used in a proportion of about 1.0 to 30 mol, preferably about 1.0 to 10 mol, per mol of compound (VI). This reaction should be carried out in the absence of solvent or in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Preferred are halogenated hydrocarbons such as dichloroethane, chloroform and so on, aliphatic hydrocarbons, such as ediately ether, diisopropyl ether and so on, amides, such as dimethylformamide, dimethylacetamide, etc., alcohols, such as methanol, ethanol, etc. and mixtures of such solvents. The proportion of solvent is usually from 0.2 to 50 ml, preferably 2 to 20 ml per gram of compound (VI). This reaction is carried out usually at 5-200oC, preferably 5-180oC. the reaction Time ranges usually from about 5 to 72 hours, preferably about 0.5 to 30 hours. When using high temperature, the reaction is usually carried out in an autoclave or the like.

With regard to the compound (IX) (where L has the same meaning as defined above, r represents 1 or 2), the compound (IX) in which r = 1, can be obtained by interaction of the compound (VI) in which m = 1, that is, compounds (VIII) (where r has the meaning indicated above), in which r = 1, cenocoeliinae. Cenocoeliinae includes, for example, sodium cyanide, potassium cyanide, and their mixture. You can also use cenocoeliinae obtained through the implementation of in situ (in place) interaction of cyanide salt of an alkali metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or the like. Cenocoeliinae used in proporti is led in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. The preferred solvent includes alcohols such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, hexane, etc. , amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, o-dichlorobenzene and so on, sulfoxidov, such as dimethylsulfoxide, etc., water and mixtures of such solvents. The reaction can be carried out using water and insoluble or poorly water-soluble solvent selected from the above solvents, in the presence of a phase transfer catalyst. Interphase catalyst, which can be used includes, for example, salts of Quaternary ammonium compounds, such as tetrabutylammonium, benzyltrimethylammonium, etc. and salts of Quaternary foine. Interphase catalyst is used in a proportion of about 0.001 to 10 mol, preferably about 0.005 to 0.5 mol, per mol of compound (VIII). The reaction time ranges usually from 1oC, preferably 20-150oC. Obtained in the manner described compound (IX) can be subjected to the next reaction either as the reaction mixture or after partial purification, and can be easily selected known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

With regard to the compound (X) (where r has the same meaning as defined above), the compound (X), where r = 1, can be obtained by hydrolysis of compound (IX) in which r = 1, with an acid or a base. Acid hydrolysis may be effected with a mineral acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid, etc., Lewis acid, such as trichloride boron, tribromide boron, etc. alone or in combination with thiol or sulfide, or organic acid, such as triperoxonane acid, p-toluensulfonate acid, etc. Basically the hydrolysis can be carried out using a metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc., metal carbonate such as sodium carbonate, potassium carbonate and so on, metal alkoxide such as sodium methoxide, ethoxide sodium, Troth or base used in the ratio of about 0.1-20 mol, preferably 0.5 to 12 mol, per mol of compound (IX). This reaction should be carried out in the absence of solvent or in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. The preferred solvent includes alcohols such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, hexane and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, o-dichlorobenzene and so on, sulfoxidov, such as dimethylsulfoxide, etc., water and mixtures of such solvents. The reaction time ranges usually from 10 minutes to 50 hours, preferably from 30 minutes to 40 hours. The reaction temperature is in the range of usually 0 to 200oC, preferably 20-150oC. Obtained in the manner described compound (X) can be used either as the reaction mixture or after partial purification, and can be easily selected known per se method and purified by usual method such as recrystallization, distillation, chromatography, etc.

The compound (VIII), I compound (III) from compound (II).

The compound (IX) in which r = 2, can be obtained from compound (VIII) in which r = 1, as described above with regard to obtain compound (IX) in which r = 1, from compound (VIII) in which r = 2.

The compound (X) in which r = 2, can be obtained from compound (IX) in which r = 2, as described above with regard to obtain compound (X), where r = 1, from compound (IX) in which r = 1.

The compound (XI) in which r has the same meaning as defined above) can be obtained by condensation of compound (VII) with compound (X), a reactive derivative of compound (X) or a salt of the compound (X). The reactive derivative of compound (X) include the corresponding halides (e.g. acid chloride, bromohydrin and so on), acid amides (for example, the appropriate acid amides with pyrazole, imidazole, benzotriazole and so on ), mixed acid anhydrides (for example, mixed anhydrides of the acids with mono-C1-4alkylphenyl acids such as monomethylamine acid, monoethylamine acid, monoisopropylamine acid, mono-tert-butylurea acid and so on; mixed anhydrides of the acids with mono-C7-10aralkylamines acids, such as monobenzone carboxylic acids, such as acetic acid, tsianuksusnym acid, propionic acid, butyric acid, somalina acid, Pavlova acid, triperoxonane acid, trichloroacetic acid, acetoacetic acid and so on; mixed acid anhydrides with7-11aromatic carboxylic acids such as benzoic acid, p-tolarova acid, p-chlorbenzoyl acid and so on; mixed acid anhydrides with organic sulfonic acids, such as methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid and so on; and mixed acid anhydrides with monoalkylphenol acid and so on ), azides acids, active esters (e.g., ether diethoxyphosphoryl acid, ether diphenoxyethane acid, p-nitrophenyloctyl ether, 2,4-dinitrophenoxy ether, tiometry ether, pentachlorphenol ether, ester with N-hydroxysuccinimide, ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, ester with 6-chloro-1-hydroxybenzotriazole, ester with 1-hydroxy-1H-2 - pyridone, and so on), and the active complex thioethers (for example, 2-pyridylthio, 2-benzothiazolylthio and so on).

Alternatively, the use of a reactive derivative of compound (X) is inanam (VII) in the presence of a suitable condensing agent. Used condensing agent includes, for example, N,N,-disubstituted carbodiimide, such as N,N'-dicyclohexylcarbodiimide, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), and so on, azalide, such as N,N'-carbonyldiimidazole and so on, dehydrating agents such as N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxystyrene and so on, and salts of 2-halogenopyrimidines, such as 2-chloromethyl-pyridiniumyl, 2-fluoro-1-methylpyridinium etc., the Compound (VII) is used in a proportion of generally about 1.0-5.0 mol, preferably about 1.0 to 2.0 mol, per mol of compound (X), a reactive derivative of compound (X) or salts of the compound (X). This reaction should be carried out in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Preferred are ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., NITRILES, such as acetonitrile, are impregnated is as a reactive derivative of compound (X) used gelegenheid, cream acid anhydride or a reactive ester, the reaction can be carried out in the presence of acid acceptor to remove released from the reaction system acid. The acid acceptor, which can be used for this purpose include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, etc., aromatic amines such as pyridine, lutidine and so on, and tertiary amines, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc. depending on the type of reagent and solvent used, the reaction time ranges usually from 30 minutes to 48 hours, preferably from 30 minutes to 24 hours. The reaction temperature is in the range of usually 0 to 100oC, preferably 0-70oC.

Collected in this way the compound (XI) can be subjected to the next reaction either as the reaction mixture or after partial purification, and can be easily selected known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

Camping used for this recovery includes, for example, metal hydrides such as aluminum hydride, the hydride diisobutylaluminum etc., hydrogen-metal complexes, such as sociallyengaged, borohydride sodium and so on, boranova complexes, such as balancerationality complex, porandamaterjalides complex and so on, alkylborane, such as axillary, dissimilar and so on, and DIBORANE. For each mol of compound (XI) the reducing agent is used in proportions of about 1.0-10 mol, preferably about 1.0 to 3.0 mol, in the case of metal hydride, about 1.0-10 mol, preferably about 1.0-5.0 mol, in the case of hydrogen-metal complex and about 1.0-10.0 mol, preferably about 1.0-7.0 mol, in case boranova complex, alkylborane or DIBORANE. This reaction should be carried out in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Preferred are ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, etc. and mixtures of such solvents. The reaction time ranges usually from 15 minutes to 100 hours, preferably from 20 minutes to 50 hours. Tempaction the mixture can be subjected to the next reaction either in the form as it is, or after partial purification, and the compound obtained in the reaction mixture can be easily separated known per se method and purified by usual separation method such as recrystallization, distillation, chromatography, etc.

The compound (XII) can be obtained by removing groups of the formula: -Za-Zb-Ar (where the respective symbols have the meanings as defined above) of the compound (I) where Y = N. This is the removal of the protection can be carried out by treating the above compound (I) with a suitable reagent such as acid, base, ultraviolet light, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium and palladium acetate, or through the implementation of reduction reaction. These reactions can be carried out in accordance with known as such ways, for example by the methods described in Protective Groups in Organic Synthesis, second edition, John Wiley & Sons, Inc. , 1991. Collected in this way the compound (XII) can be subjected to the next reaction either as the reaction mixture or after partial purification, and can be easily selected known per se method and purified by usual method of purification such as recrystallization, distillation, chrome is the exposure of the latter (i) the alkylation, (ii) acylation or (iii) the acylation and subsequent reduction of the obtained amide.

The acylation can be carried out as described above for obtaining the compound (I) from compound (VI).

The acylation can be carried out as described above with respect to obtaining the compound (XI) from the compound (X). The stage at which restores the amide obtained by acylation may be carried out as described above with respect to obtaining the compound (I) from compound (XI).

The compound (XIV) (where n is an integer from 1 to 4) can be obtained by subjecting compound (VI) and the compound (XIII) (where n has the same meaning as defined above) condensation, similar to the above condensation of compounds (VI) and compound (VII).

The compound (XIII) can be bought on the market, when it's there, or you can get a known per se manner, for example, described in J. Med. Chem. , 34, 1073, 1991, etc.

The compound (XV) (where n has the same meaning as defined above) can be obtained by subjecting compound (XIV) is known in itself oxidation reactions. Oxidant that can be used for this reaction include compounds chromic acid, p-periodic acid, m-period acid, m-periodate sodium and so on, metal oxides such as manganese dioxide, silver oxide, lead oxide, and so forth, the combination of a sulfoxide such as dimethylsulfoxide, with a dehydrating agent such as oxacillin or N,N'-dicyclohexylcarbodiimide. The oxidizing agent is used in proportions of about 1-30 mol, preferably about 1-10 mol, per mol of compound (XIV). There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Preferred are ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., ketones, such as acetone, methyl ethyl ketone, and so on , NITRILES, such as acetonitrile, propionitrile and so on, the sulfoxidov, such as dimethylsulfoxide, etc., water and mixtures of such solvents. The reaction time ranges usually from 5 minutes to 48 hours, preferably from 5 minutes to 16 hours. The reaction temperature is in the range of usually 90-200oC, preferably 80 to 150oC. On the Windows of the donkey partial purification, and the target compound obtained in the reaction system can be easily selected known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

The compound (I) can also be obtained by reductive condensation of compounds (XV) and compound (XVI) (where R11represents a hydrogen atom or a hydrocarbon group which may be substituted; Zd represents a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur).

"Hydrocarbon group which may be substituted", for R11may be the same as the "hydrocarbon group which may be substituted", for R10as specified above.

"Divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur, for Zd may be the same as the "divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur" specified for Zb. When the above divalent aliphatic "hydrocarbon group which may be substituted", contains sour is when it is commercially available, or can be obtained in known per se manner.

The compound (XVI) is used in proportions of about 0.5 to 2 mol, preferably 0.8 to 1.5 mol, per mol of compound (XV). Used the reducing agent includes, for example, metal hydrides such as aluminum hydride, the hydride diisobutylaluminum etc., hydrogen-metal complexes, such as sociallyengaged, borohydride sodium, lambrogini sodium and so on, boranova complexes, such as balancerationality complex, porandamaterjalides complex and so on, alkylborane, such as axillary, dissimilar and so on , and DIBORANE. When carrying out this reaction it is possible, though not necessary to use an acid (e.g. hydrogen chloride, sulfuric acid, acetic acid, triperoxonane acid and so on). For each mol of compound (XV) the reducing agent is used in proportions of about 0.3 to 10 mol, preferably about 0.3 to 3.0 mol, in the case of metal hydride, about 0.3 to 10 mol, preferably about 0.5-5.0 mol, in the case of hydrogen-metal complex and about 1.0-10.0 mol, preferably about 1.0 to 3.0 mol, in case boranova complex, alkylborane or DIBORANE. This reaction it is advisable to carry out in an inert solvent. No esotericism are alcohols, such as methanol, ethanol, propanol and so on , ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc., water and mixtures of such solvents.

The reaction time ranges usually from 10 minutes to 10 hours, preferably from 10 minutes to 2 hours. The reaction temperature is usually 20-120oC, preferably 10 to 80oC. Upon completion of the reaction, the reaction mixture may be subjected to the next reaction either as it is or after partial purification, and the target compound can be easily separated known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

The compound (I) can also be obtained by subjecting compound (XV) and compound (XVI) reductive condensation using hydrogen and a hydrogenation catalyst such as platinum oxide, palladium on carbon, Raney Nickel, Raney cobalt or the like. The content of the hydrogenation catalyst relative to the compound (XV) is in the range of about 0.1-1000 wt.%, preferably and the type of solvent, if it does not interfere with the course of the reaction, but the preferred solvents are alcohols, such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc. and organic acids such as formic acid, acetic acid, etc. and mixtures of such solvents. Depending on the activity and amount of the used catalyst, the reaction time ranges usually from 10 minutes to 100 hours, preferably from 10 minutes to 10 hours. The reaction temperature is usually 0-120oC, preferably 20-80oC. When using a hydrogenation catalyst, the hydrogen pressure is usually 1-100 atmospheres. Upon completion of the reaction, the reaction mixture may be subjected to the next reaction either as it is or after partial purification, and the target compound obtained in the reaction mixture can be easily separated known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

The compound (XVIII) (where R12is airglow compound (VI) and compound (XVII) (where the respective symbols have the same meanings, as defined above) condensation, similar to that used for obtaining the compound (I) from compound (VI).

"Hydrocarbon group" for R12may be the same as the "hydrocarbon group" of the "hydrocarbon group which may be substituted" defined for R10.

The compound (XVII) can be purchased when it is commercially available, or can be obtained in known per se manner, for example by the method described in Am. Chem. Soc., 75, 6249, 1953, etc.

The compound (XIX) (where n has the same meaning as defined above) can be obtained by exposure of the compound (XVIII), acid or alkaline hydrolysis. Acid hydrolysis can be carried out using, for example, mineral acids such as chloromethane acid, sulfuric acid, etc., a Lewis acid such as trichloride boron, tribromide boron, and so forth, the combination of a Lewis acid with a thiol or sulfide, or organic acids, such as triperoxonane acid, p-toluensulfonate acid etc., Alkaline hydrolysis can be carried out using a metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc., metal carbonate, such as the carbonate is Leah, and so on, or organic bases such as triethylamine, imidazole, formamidine etc.. Acid or base used in the ratio of about 0.5-20 mol, preferably about 0.5-10 mol, per mol of compound (XVIII). This reaction should be carried out in the absence of solvent or in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Preferred solvents are alcohols, such as methanol, ethanol, propanol, etc., aromatic hydrocarbons such as benzene, toluene, etc., saturated hydrocarbons such as cyclohexane, hexane, etc. and organic acids such as formic acid, acetic acid and so on, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. , NITRILES, such as acetonitrile, propionitrile etc., ketones, such as acetone, methyl ethyl ketone, and so on, sulfoxidov, such as dimethylsulfoxide etc., water and mixtures of such solvents. The reaction time ranges usually from 10 minutes to 60 hours, preferably from 10 Miocene described, the compound (XIX) can be subjected to the next reaction either in the form of a reaction mixture, or after partial purification, and can be easily selected known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

The compound (XX) (where n and Zd have the same meanings as respectively defined above) can be obtained by subjecting compound (XVI) condensation with compound (XIX), a reactive derivative of compound (XIX) or a salt of the compound (XIX) as described in obtaining the compound (XI) from the compound (X). The compound (I) can also be obtained by subjecting the compound (XX) recovery as described in obtaining the compound (I) from compound (XI).

The compound (XXI) (where M is a metal and R13represents a hydrocarbon group which may be substituted, or silyl) can be obtained in known per se manner, for example by the method described in JP-A-5-140142, or any similar method.

"Metal" M includes, for example, alkali metals such as lithium, sodium, etc. , alkaline earth metals such as magnesium, etc., copper, zinc, boron, aluminum, cerium and titanium.

"Hydrocarbon group which may be substituted", for R13includes 13 includes, for example, three-C1-6-alkylsilane (e.g., trimethylsilyl, tert-butyldimethylsilyl).

The compound (XXII) (where the symbols have the meanings as defined above) can be obtained in known per se manner, for example by the methods described in Journal of The American Chemical Society, 109, 5765-5780, 1987, or any equivalent method.

The compound (XXV) can be obtained in known per se manner, for example by the methods described in JP-A-5140142 or other literature, or any equivalent method.

From the compound (XXIII) (where the respective symbols have the meanings as defined above), the compound in which m = 1 and X represents methylene, can be obtained by exposure of the compound (XXI) (XXII), in which m = 1 and X represents a methylene condensation. The compound (XXI) is used in a proportion of about 0.8 to 10 mol, preferably about 1.0-5.0 mol, per mol of compound (XXII). This reaction it is advisable to carry out in an inert solvent (i.e. a solvent, indifferent to the reaction; this also applies to the further description). There are no particular restrictions on the type of solvent. But the preferred solvents are ethers, such as diethyl so on, and mixtures of such solvents. The reaction time ranges usually from 10 minutes to 100 hours, preferably from 10 minutes to 10 hours. The reaction temperature is usually 100-30oC, preferably 80 to 20oC. This reaction can be, although not necessarily, carried out in the presence of additives. This additive includes complexes of boron TRIFLUORIDE such as boron TRIFLUORIDE-diethyl ether, boron TRIFLUORIDE-dimethyl sulfide, etc. and salts of copper, such as copper iodide (I). Additive used in proportions of about 0.1 to 3.0 mol, preferably about 0.5 to 1.5 mol, per mol of compound (XXII). Collected in this way the reaction mixture can be used for the next reaction either as it is or in a partially purified form, and the target compound can be easily isolated from the reaction mixture and optionally purified by such methods of separation as recrystallization, distillation, chromatography, etc.

Of the compounds (XXIV) (where the respective symbols have the meanings as defined above), the compound in which m = 1 and X represents methylene, can be obtained by exposure of the compound (XXIII) in which m = 1 and X represents methylene, cyclization with base. The basis of that model, the potassium hydroxide and so on, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, etc., aromatic amines such as pyridine, lutidine, etc., tertiary amines, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and so on, hydrides of alkali metals, such as sodium hydride, potassium hydride, etc., amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium, and so on, and alkoxides of metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and so on, the Base is used in a proportion of about 1.0-5.0 mol, preferably about 1.0 to 2.0 mol, per mol of compound (XXIII). This reaction should be carried out in an inert solvent. There are no particular restrictions on the type of solvent. Preferred are alcohols, such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-di-methoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, hexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons, such is ITIL and so on, the sulfoxidov, such as dimethylsulfoxide, etc., water and mixtures of such solvents. The reaction time ranges usually from 5 minutes to 3 hours, preferably from 5 minutes to 2 hours. The reaction temperature is in the range of usually 20 to 200oC, preferably 10 to 120oC.

Of the compounds (III) (where the respective symbols have the meanings as defined above), the compound in which m = 1 and X represents methylene, can be obtained by exposure of the compound (XXIV) in which m = 1 and X represents methylene, reactions to unprotect R13using acid or base as catalyst and subsequent cyclization. The catalyst which can be used for this purpose include mineral acid, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc. and organic acid such as acetic acid, triperoxonane acid and so on, boron TRIFLUORIDE-diethyl ether, a Lewis acid such as zinc chloride, tin chloride, and so on, sulfonic acid such as p-toluensulfonate acid, methanesulfonate acid, etc., inorganic base such as sodium hydroxide, potassium hydroxide and so on, the basic salt, such as sodium carbonate etc., tertiary amine, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and so on, the alkali metal hydride such as sodium hydride, potassium hydride, etc., metal amide such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium, etc. or a metal alkoxide such as sodium methoxide, ethoxide sodium, tert-piperonyl potassium etc., Acid or base used in the ratio of about 0.1-30 mol, preferably about 0.5-10 mol, per mol of compound (XXIV). This reaction should be carried out in an inert solvent. There are no particular restrictions on the type of solvent. Preferred are alcohols, such as methanol, ethanol, propanol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, such as benzene, toluene, cyclohexane, etc., amides such as N,N-dimethylformamide, N,N-di-methylacetamide and so on, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and so on, NITRILES, such as acetonitrile, propionitrile etc., ketones, such as acetone, methyl ethyl ketone, etc., water and compounds>from 5 minutes to 3 hours. The reaction temperature is in the range of usually 20 to 120oC, preferably 0-80oC. Obtained in the manner described, the reaction mixture can be used for the next reaction either as it is or in a partially purified form, and the target compound can be easily isolated from the reaction mixture and optionally purified by such methods of separation as recrystallization, distillation, chromatography, etc.

Of the compounds (III) (where the respective symbols have the meanings as defined above), the compound in which m = 1 and X represents methylene, can also be obtained from compound (XXV) in which X represents methylene, as well as the compound (VI) from compound (V).

The compound (XXVI) can be obtained by exposure to compounds (III) and compound (VII) condensation as in the case of obtaining compound (I) from compound (VI).

The compound (I) can be obtained by nitration of the compound (XXVI) as well as in the process of obtaining the compound (IV) from compound (III), with subsequent reduction of the nitro group as well as in the process of obtaining compound (VI) from compound (IV). In addition, can be made optional reaction Alki the ect can be used for the next reaction either in the form as it is, or in a partially purified form, and the target compound can be easily isolated from the reaction mixture by known methods, and optionally purified, such partitioning methods as recrystallization, distillation, chromatography, etc.

The compound (I) can be obtained by subjecting the compound (XXVI) azocoupling reaction with the salt of the page, followed by reduction of the obtained azo compounds. Salt the page, which can be used include salts of aryldiazonium, such as benzodiazepined, 4-nitrobenzaldehyde, 2,4-dinitrobenzaldehyde, 4-sulfobenzoate and so on Salt page can be obtained in a known per se method, for example by the methods described in JP-A-5140142 and other literature, or any similar means to them. This link page is used in a proportion of about 0.8 to 3 mol per mol of compound (XXVI). This reaction result, it is advisable to carry out in an inert solvent. There are no particular restrictions on the type of inert solvent, if only it could proceed the reaction. But preferred are ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on, hydrocarbons, so onirovanie hydrocarbons, such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and so on, NITRILES, such as acetonitrile, propionitrile etc., ketones, such as acetone, methyl ethyl ketone, etc. and organic acids such as acetic acid, propionic acid, etc., water and mixtures of such solvents. The reaction time ranges usually from 10 minutes to 100 hours, preferably from 20 minutes to 30 hours. The reaction temperature is in the range of usually 20 to 80oC, preferably 0-50oC. Obtained in the manner described, the reaction mixture can be used for the next reaction either as it is or in a partially purified form, and the target compound can be easily isolated from the reaction mixture by known methods, and optionally purified by such methods of separation as recrystallization, distillation, chromatography etc., Subsequent recovery of the azo compounds can be carried out under the same conditions as those described for obtaining the compound (VI) from compound (IV). The reaction of alkylation and acylation, which is not necessarily subjected to the compound (VI) may not necessarily apply also to the compound (I) in a suitable combination, or one after the other. Retrieved described obsticle purified form, and the target compound can be easily isolated from the reaction mixture by known methods, and optionally purified by such methods of separation as recrystallization, distillation, chromatography, etc.

In addition, using as starting material an optically active species of the compound (XXII) can be easily synthesize optically active species of compound (I).

The compound (XXVII) can be obtained in a known per se method, for example by the methods disclosed in JP-A-5140142, or any equivalent method.

The compound (XXVIII) (where L has the same meaning as defined above; m is 1) can also be obtained by treating compound (V) halogenation reagent. This reaction can be carried out using bases, basic salts, or a radical initiator or under the influence of light when you need it. Halogenation reagent includes, for example, halogen, such as bromine, chlorine or iodine, imide such as N-bromosuccinimide, adduct of halogen, such as benzyltrimethylammonium, benzyltriethylammonium, bromine adduct, Tetramethylammonium, perbromic of pyridinylamino, dioxane dibromide. The halogenation Ajaccio preferably carried out in the absence of solvent or in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Preferred are ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and so on , alcohols, such as methanol, ethanol, propanol, etc., hydrocarbons, such as benzene, toluene, cyclohexane, hexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., NITRILES, such as acetonitrile, propionitrile and so on, sulfoxidov, such as dimethyl sulfoxide, etc. and organic acids such as acetic acid, propionic acid, etc., nitroalkanes, such as nitromethane, etc., aromatic amines such as pyridine, lutidine, quinoline, etc. and mixtures of such solvents. The base, which may be, although not necessarily, used, include, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, etc., aromatic amines such as pyridine, lutidine and so on , and tertiary amines, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperid the van, includes, for example, sodium acetate, potassium acetate, etc. Radical initiator, which may be, although not necessarily, used, include, for example, benzoyl peroxide, azobisisobutyronitrile, etc. In case of exposure light can be used a halogen lamp. The reaction temperature is in the range of usually about 50-150oC, preferably 0-100oC. the reaction Time ranges usually from 5 minutes to 24 hours, preferably from 10 minutes to 5 hours.

The compound (XXVIII) can be also obtained by a method comprising the cyclization of compound (XXVII) organic percolate, optionally in the presence of a base, and exposure of the resulting alcohol sulfonic esterification. Organic percolate, which can be used includes, for example, m-chloroperbenzoic acid and peracetic acid. Organic percolate used in a proportion of about 1.0-5.0 mol, preferably about 1.0 to 2.0 mol, per mol of compound (XXVII). This reaction is preferably carried out in an inert solvent. There are no particular restrictions on the type of solvent, if it does not interfere with the course of the reaction. Preferred are water, ethers such as diethyl ether, tetrahed the IDA, such as N,N-dimethylformamide, N,N-dimethylacetamide, and so on , halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., NITRILES, such as acetonitrile, propionitrile and so on, sulfoxidov, such as dimethyl sulfoxide, etc. and organic acids such as acetic acid, propionic acid, etc., aromatic amines such as pyridine, lutidine, quinoline, etc. and mixtures of such solvents. The base, which may be, although not necessarily, used, include, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, etc. , aromatic amines such as pyridine, lutidine and so on, and tertiary amines, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholin and so on, the reaction Temperature is in the range of usually about 20 to 150oC, preferably 0-100oC. the reaction Time ranges usually from 5 minutes to 24 hours, preferably from 10 minutes to 5 hours. Subsequent reaction of the sulfonic esterification can be carried out under the same conditions as described for the floor is etousa reaction either in the form of a reaction mixture, or after partial purification, and can be easily selected known per se method and purified by usual method of purification such as recrystallization, distillation, chromatography, etc.

The compound (VI) can be obtained by subjecting the compound (XXVIII) the alkylation, in the presence of a proton acid or a Lewis acid. The alkylating agent includes, for example, alcohols, such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, and so on, halogenated hydrocarbons, such as isopropylchloride, tert-butyl chloride and so on, alkenes, such as isobutene and so on, esters such as ISO-propyl, tert-butyl acetate, diisopropylamide, p-toluensulfonate, isopropylphenyl and so on, ethers such as tert-butyl methyl ether etc., an Alkylating agent is used in proportions of about 1.0 to 30 mol, preferably about 1.0 to 15 mol, per mol of compound (XXVIII). Proton acid, which can be used includes, for example, concentrated sulfuric acid, triperoxonane acid, etc. Used by the Lewis acid includes, for example, such as aluminum chloride, aluminum bromide, iron chloride (III) chloride tin (IV) chloride titanium, zinc chloride, etc. Proton acid and a Lewis acid of approximately 1.0 to 200 mol, preferably about 1.0 to 100 mol, per mol of compound (XXVIII). The Lewis acid is used in a proportion of about 1.0-5.0 mol, preferably about 1.0 to 2.0 mol, per mol of compound (XXVIII). This reaction it is advisable to carry out in an inert solvent. There are no particular restrictions on the type of solvent. Preferred are hydrocarbons, such as benzene, toluene, xylene, cyclohexane, hexane and so on, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachlorethane and so on , NITRILES, such as acetonitrile, propionitrile and so on, nitroalkanes, such as nitromethane, etc. and mixtures of such solvents. The reaction temperature is in the range of usually 20 to 200oC, preferably 0-150oC. the reaction Time ranges usually from 5 minutes to 24 hours, preferably from 10 minutes to 5 hours. Collected in this way the compound (VI) can be subjected to the next reaction either as the reaction mixture or after partial purification, and can be easily selected known per se method and purified by conventional methods of purification such as recrystallization, distillation, chromatography, etc.

When in the above reactions and PPy compounds can be introduced protective group, commonly used in the chemistry of peptides, and the target compound can be obtained by removal of the protective groups when necessary.

The protective group for the functional amino group includes, for example, formyl and C1-6alkylcarboxylic (for example, acetyl, propionyl and so on), phenylcarbonylamino, C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl and so on ), vinyloxycarbonyloxy,7-10aracelikarsaalyna (for example, benzyloxycarbonyl and so on ), trailing and palolo groups, each of which may be substituted. Deputy here may be, for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on),1-6alkylsulphonyl (for example, acetyl, propionyl, valeryl and so on), nitro and so on, the Number of possible substituents is 1 to 3.

The protective group for carboxyl functional group includes, for example, C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and so on ), phenyl, trailing and silyl groups, each of which may be substituted. Deputy here may be, for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), formyl, C1-6alkylsulphonyl (for example, acetyl, propionyl, butylcarbamoyl and so on) and so on The number of possible substituents is 1 to 3.

The protective group for the functional hydroxy-group includes, for example, C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and so on), phenyl, C7-11Uralkaliy (e.g., benzyl etc), formyl, C1-6alkylcarboxylic (for example, acetyl, propionyl and so on), vinyloxycarbonyloxy, C7-11aracelikarsaalyna (for example, benzyloxycarbonyl and so on ), tetrahydropyranyloxy, tetrahydrofuranyl and silyl groups, each of which may be substituted. The Deputy may be, for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), C1-6alkyl (e.g. methyl, ethyl, tert-butyl, and so on), C7-11aralkyl (e.g., benzyl etc.,), C6-10aryl (e.g. phenyl, naphthyl and so on), nitro and so on, the Number of possible substituents is 1-4.

The protective group can be removed by known methods or similar methods. You can, for example, to call the treatment with acid, base, ultraviolet light, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium, palladium acetate or the like or recovery.

Anyway, if sinekli removal of the protective groups, acylation, alkylation, hydrogenation, oxidation, reduction, lengthening the carbon chain and the exchange of substituents. These reactions may be carried out by methods such as described in Shin Jikken Called Koza (New Series in Experimental Chemistry) 14 and 15, 1977 (Maruzen Publishing Co.), and so on

When the target connection get in free form can be converted to a salt by conventional methods. When the target connection receive in the form of a salt, it can be converted into the free compound or another type of salt. Thus obtained compound (I) can be isolated from the reaction mixture and purified known as such methods, such as disproportionation, concentration, solvent extraction, fractional distillation, crystallization, recrystallization and chromatography.

When the compound (I) exists in the form of configurational isomers (isomers provisions), diastereomers, conformers, the respective isomers can be isolated by the methods described above for fractionation and purification. When the compound (I) is a racemic compound, it can be divided into (S) and (R) forms by any conventional method of optical separation. The compound (I) may be in the form of Hydra is a high affinity for sodium channel, especially section 2, with low toxicity and low risk for harmful effects, so they are useful as safe medicines.

The compound (I) and (Ia) act as modulators of sodium channels in mammals (e.g. mouse, rat, hamster, rabbit, cat, dog, pig, cattle, sheep, monkey, human etc) and can be used as a prophylactic and/or therapeutic agents for various diseases and disorders of the Central nervous system, such as ischemia of the Central nervous system, trauma of the Central nervous system (e.g. brain injury, spinal cord injury, injury from sharp movements of the limbs and so on ), epilepsy, neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neuropathy etc), vascular dementia (for example, mnogoparnaya dementia, disease Binswanger and so on ), manic-depressive psychosis, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine, brain swelling, and so forth. In addition, compound (I) and (Ia) have high anti-oxidant activity and modalist for the above diseases and ischemic cardiovascular diseases (for example, myocardial infarction, angina, and so on), atherosclerosis and other diseases. Including as a preventive and/or therapeutic agent for ischemic Central nervous system injury of the Central nervous system, neurodegenerative diseases and cerebral edema.

Each of the compounds (I) and (Ia) is only slightly toxic and can be safely administered separately or in the form of a pharmaceutical composition prepared by mixing with a pharmacologically acceptable carrier in accordance with the existing pharmaceutical practice in such dosage forms as tablets (including pills and tablets, film-coated), powders, granules, capsules (including soft capsules), solutions, injections, suppositories and dosage forms with controlled release, oral or other routes of administration (e.g., topically, rectally, intravenously, and so on ). The relative content of compound (I) or (Ia) in the pharmaceutical compositions of the present invention may be in the range from about 0.01% to about 100% by weight. The dose depends on the patient or recipient, the route of administration, the condition to be treated, and other factors. Vamsha recommended dose of the active ingredient [compound (I) or compound (Ia)] is approximately 0.05-30 mg/kg of body weight, preferably about 0.1-20 mg/kg body weight, more preferably about 0.1-5 mg/kg of body weight and even more preferably about 0.1-2 mg/kg body weight per day as a single dose or several separate doses. The compound (I) or (Ia) may be used in combination with other active substances (e.g., an antithrombotic agent, such as argatroban and so on, thrombolytic agent such as urokinase, tissue plasminogen activator, and so on, inhibitor of platelet aggregation, such as ozagrel and so on, anticoagulant, such as heparin, etc., an antagonist of histamine receptors, such as cimetidine, famotidine, and so on, the cure for Parkinson's disease, such as dopamine, levodopa, and so on, anticonvulsive agent groups as such as phenytoin, mephenytoin, ethotoin and so on, anticonvulsive or analgesic means group barbitala, such as phenobarbital, mephobarbital, metharbital etc., calcium channel blockers, such as diltiazem and so on, imipenem-cilastatin sodium, glycerin and so on). So, any of these other active substances can be traditionally cooked in combination with compound (I) or (Ia) to obtain pharmacienne solutions suppositories, dosage forms with controlled release and so on).

Pharmacologically acceptable carrier, which can be used for the manufacture of pharmaceutical compositions of the present invention includes various kinds of organic or inorganic carriers which are commonly used in pharmaceutical practice, such as a filler, a lubricating substance, binder and loosening the material for solid preparations, or solvent, solubilizer, suspendisse substance, isotonic agent, buffer and local anaesthetic or a soothing agent for liquid preparations. If necessary, can also be included such common additives, as an antiseptic, antioxidant, dye, podslushivaet, adsorbent, wetting agent, etc.

The filler include lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride, etc.

Grease include magnesium stearate, calcium stearate, talc, colloidal silicon dioxide, etc.

Binder includes, for example, crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxymethylcellulose etc.

Loosening the substance includes, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium-croscarmellose, sodium carboximetilkrahmal, L-hydroxypropylcellulose etc.

The solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc.

The solubilizer includes polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.

Suspendisse substance includes a variety of surface-active substances, such as steartrimonium, sodium lauryl sulfate, lauramidopropyl acid, lecithin, benzylaniline, benzathine, glicerina-stearate, etc. and hydrophilic macromolecular substances such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose etc.,

Isotonic substance includes glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.

The buffer include phosphate, acetate, carbonate, citrate, etc.

Local benzoine acid, chlorbutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid, etc.

The antioxidant include sulfites, ascorbic acid, -tocopherol, etc.

The best way of carrying out the invention

The following reference examples, examples, examples of drug production and experimental examples are intended for a more detailed description of the present invention and in no way should be construed as limiting the scope of invention.

When used in the following reference and working examples, the term "room temperature" generally means about 10-35oC. the Symbol % means percent by weight unless otherwise stated, but all the output values are represented in mol/mol%.

Used silica gel was mostly NH-DM1020 production Fuji Silysia Chemical Ltd.

Other abbreviations used in the text have the following meanings:

s): singlet

d (l): doublet

t (t): triplet

q (kW): Quartet

m (m): multiplet

dd (DD: double doublet

dt (dt): double triplet

quintet: quintet

br (W): wide

J: constant interaction

Hz (Hz): Hertz

CDCl3: Tatarinov the integration of methanol

1H-NMR (1H-NMR): proton nuclear magnetic resonance

Examples

Reference example 1

2,3-Dihydro-2-[[4-(4-methoxyphenyl)-1-piperazinil]methyl]-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

In the autoclave was stirred under gaseous argon at 180oC for 15 hours a mixture of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.5 g), 1-(4-methoxyphenyl)piperazine (2.0 g) and triethylamine (1.6 g). After cooling, the reaction mixture was treated with a saturated solution of sodium bicarbonate (NaHCO3) in water and was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate (MgSO4), and then drove away under reduced pressure the solvent. The residue was purified by column chromatography on silica gel (ethyl acetate: hexane = 9:1) and treated with 4 N solution of hydrogen chloride in ethanol to obtain trihydrochloride. This product was recrystallized from ethanol to obtain 0,53 g specified in the connection header. A yield of 20%.

So pl. 194-196oC.

1H-NMR (DMSO-d6) : of 1.62 (3H, s), of 2.08 (3H, s in), 2.25 (6H, s), 3,05 (1H, d, J = 16,2 Hz), 3,34-3,63 (11H, m), 3,71 (3H, s), to 6.88 (2H, d, J = 9,0 Hz), 7,05 (2H, d, J = 9,0 Hz), 9,92 (2H, br, s).

Reference >/BR>A suspension of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.4 g), 1-(2-chlorophenyl)piperazinecarboxamide (1.4 g) and potassium carbonate (2.1 g) in N,N-dimethylformamide (15 ml) was stirred under nitrogen gas at 145oC for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate (Na2SO4) and silica gel (elyuirovaniya with ethyl acetate) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 5:1-2:1). The resulting 2-[[4-(2-chlorophenyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7 - tetramethyl-5-benzofuranyl was dissolved in methanol and was added a stoichiometric excess of a 10% aqueous solution of hydrogen chloride in methanol. The mixture was concentrated under reduced pressure and recrystallized from a mixture of ethanol-diethyl ether to obtain 1.0 g specified in the connection header. Yield 44%.

So pl. 167-171oC.

1H-NMR (DMSO-d6) : to 1.61 (3H, s), 2,07 (3H, s), of 2.23 (3H, s), 3 of 2.25 (3H, s), 3,06 (1H, d, J = 16,6 Hz), 3,1-3,9 (11H, m), 7,0-of 7.25 (2H, m), 7,3-7,5 (2H, m).

Reference example 3

2,3-D-2,4,6,7-tetramethyl-5-benzoguanamine (0.85 grams), 4-(4-piperidinyl) pyridine (0.97 g) and triethylamine (1.3 ml) was stirred under nitrogen gas at 180oC for 15 hours. To this reaction mixture were added saturated aqueous solution of NaHCO3and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol = 20:1) and was led from a mixture of ethyl acetate-hexane to obtain 0,77 g specified in the connection header. Yield 70%.

So pl. 126-128oC.

1H-NMR (CDCl3) : of 1.45 (3H, s), of 1.5-1.9 (4H, m), 2.0 to 2.5 (3H, m), of 2.08 (6H, s), 2,11 (3H, s), 2,52 (1H, d, J = a 13.9 Hz), 2,61 (1H, d, J = a 13.9 Hz), and 2.83 (1H, d, J = 15,4 Hz), 2.95 and-3,3 (2H, m), 3,13 (1H, d, J = to 15.4 Hz), 7,1-7,2 (2H, m), 8,45-8,55 (2H, m).

Reference example 4

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] - N-phenyl-4-piperidylamine

Using N-phenyl-4-piperidylamine and in other ways acting as in reference example 3, has been specified in the header connection. Yield 69%.

So pl. 116-118oC (crystallized from a mixture of ethyl acetate-hexane).

1(1H, d, J = 15,0 Hz), a 3.0 to 3.35 (2H, m), 3,11 (1H, d, J = 15,0 Hz), 6,5-6,7 (3H, m), 7,1-7,2 (2H, m).

Reference example 5

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -4-(4-chlorophenyl)-4-piperidinol

A suspension of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.4 g) and 4-(4-chlorophenyl)-4-hydroxypiperidine (1.3 g) in xylene (10 ml) was stirred under nitrogen gas at 120oC for 1.5 hours and then heated under reflux for 16 hours. After this was added to 0.85 g of 4-(4-chlorophenyl)-4-hydroxypiperidine and the mixture was heated under reflux for 24 hours. After cooling, the reaction mixture was filtered and washed with diethyl ether. The filtrate was extracted with 1 N chloroethanol acid and the aqueous layer was made weakly acidic with a saturated aqueous solution of sodium bicarbonate (NaHCO3). This aqueous layer was washed with diethyl ether and made weakly basic with a saturated aqueous solution of NaHCO3. This solution was extracted with ethyl acetate and the organic layer washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was led from a mixture of diethyl ether-hexane to obtain 0,58 g specified in the connection header. B0 (3H, s), to 2.5-2.7 (4H, m), 2,7-2,9 (1H, m), and 2.83 (1H, d, J = 15,4 Hz), 2,9-3,05 (1H, m), 3,13 (1H, d, J = 15,4 Hz), 7,29 (2H, d, J = 8,8 Hz), 7,42 (2H, d, J = 8,8 Hz).

Reference example 6

N-[2,3-Dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperidinyl)methyl]benzofuran-5-yl]ndimethylacetamide

To a suspension of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperidinyl)methyl]-5-bestfurniturestore (1.3 g) in tetrahydrofuran (10 ml) was added a solution of sodium carbonate (0.95 g) in water (5 ml) under ice cooling and the mixture was stirred for 5 minutes. Then was added dropwise 0,26 ml acetylchloride and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with water and was extracted with 2 portions of ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was led from a mixture of ethyl acetate-diisopropyl ether to obtain 1.1 g specified in the connection header. Output 90%.

So pl. 94-96oC.

1H-NMR (CDCl3) : 1,4-1,5 (3H, m), 1,6-1,9 (4H, m), 2,0-2,7 (17H, m), of 2.81 (1H, d, J = 15,4 Hz), 2,9-3,3 (3H, m), 6,5-6,7 (1H, m) and 7.1 to 7.4 (5H, m).

Reference example 7

N-[2,3-Dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperazinil)methyl]benzofuran-5-yl]ndimethylacetamide

Ispolzovaniya reference example 6 to obtain N-[2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperazinil)methyl] benzofuran-5-yl]ndimethylacetamide. Yield 94%. This product was dissolved in tetrahydrofuran and, diluting the solution with methanol, was added a stoichiometric excess of 10% HCl solution in methanol. The mixture was concentrated under reduced pressure and was led from a mixture of ethanol-diethyl ether to obtain specified in the connection header.

So pl. 195-199oC.

1H-NMR (CDCl3) : of 1.62 (3H, s), of 1.97 (3H, s), 1,99 (3H, s), 2,02 (3H, s), is 2.05 (3H, s), 3,01 (1H, d, J = 15,8 Hz), 3,1-4,2 (11H, m), 6,85 (1H, t, J = 7,1 Hz), of 6.99 (2H, d, J = 8,2 Hz), 7,26 (2H, t, J = 7,7 Hz), 9,11 (0.5 H, s), 10,5-10,9 (0.5 H, br).

Reference example 8

N-Ethyl-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperidinyl)methyl] -5-benzofuranyl

To a solution of N-[2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl] benzofuran-5-yl] ndimethylacetamide (0.56 g) in tetrahydrofuran (8 ml) was added 0.11 g of sociallyengaged small portions under ice cooling. Then the mixture was heated under reflux for 30 hours. Then the reaction mixture was cooled with ice, was added at 0.42 g of Hyflo-Super-Cel (trademark) and ethyl acetate, after which was added water (0.2 ml). The mixture is vigorously stirred, then filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane: ethyl acetate = 5:1) DCl3) : of 1.20 (3H, t, J = 7,1 Hz) of 1.46 (3H, s), 1,6-1,9 (4H, m), of 2.08 (3H, s), of 2.15 (3H, s), to 2.18 (3H, s), 2,2-2,6 (3H, m), 2,52 (1H, d, J = 14,0 Hz), 2,61 (1H, d, J = 14,0 Hz), 2,75 of 3.1 (4H, m) to 3.09 (1H, d, J = to 15.4 Hz), 3,15 to 3.3 (1H, m) and 7.1 to 7.4 (5H, m).

Reference example 9

N-Ethyl-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperazinil)methyl] -5-benzophenonetetracarboxylic

Using N-[2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperazinil)methyl] benzofuran-5-yl]acetamide", she repeated in other respects, the procedure of reference example 8 to obtain N-ethyl-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperazinil)methyl]-5-benzofuranyl. This product was dissolved in methanol and was added an excess of 10% HCl solution in methanol. This mixture was concentrated under reduced pressure and the residue was led from a mixture of ethanol-diethyl ether to obtain specified in the connection header. Yield 64%.

So pl. 210-216oC.

1H-NMR (DMSO-d6) : of 1.33 (3H, t, J = 7,1 Hz), of 1.64 (3H, s), of 2.08 (3H, s), 2,32 (3H, s), to 2.35 (3H, s), 3,0-3,9 (13H, m), of 3.07 (1H, d, J = 16,0 Hz), 6,86 (1H, t, J = 7,2 Hz), 7,00 (2H, d, J = 8,0 Hz), 7,26 (2H, t, J = 7,7 Hz).

Reference example 10

2,3-Dihydro-2,4,6,7-tetramethyl-2-[(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)methyl]-5-benzoguanamine

Using 2,3,4,5-tetrahydro-1H-3-benzazepin) was repeated in other respects the procedure sulochna. This product was dissolved in methanol and was added an excess of 10% HCl solution in methanol. This mixture was concentrated under reduced pressure and the residue was led from methanol-diethyl ether to obtain specified in the connection header. A 71% yield.

So pl. 180-183oC.

1H-NMR (DMSO-d6) : of 1.64 (3H, s), is 2.09 (3H, s), 2,24 (6H, s), 3,0-3,9 (11H, m), is 3.08 (1H, d, J = 16,6 Hz), 7,19 (4H, s).

Reference example 11

4-Benzyloxypyridine

To a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (5.0 g) in tetrahydrofuran (50 ml) was added sodium hydride (1.0 g, 66% dispersion in liquid paraffin) and the mixture was stirred at room temperature for 10 minutes. Then there was added 3.6 ml of benzylbromide and the mixture was heated under reflux for 1 hour. The reaction mixture was poured into aqueous ammonium chloride and was extracted with 2 portions of ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate, followed by addition of 15 ml of 4 N solution of HCl in ethyl acetate and the mixture was stirred at room temperature for 2 hours. SWAT is SUP>1H-NMR (CDCl3) : 1.9 to 2.3 (4H, m), 3,1-3,5 (4H, m), of 3.7-3.8 (1H, m) to 4.52 (2H, s), 7,2 was 7.45 (5H, m), 9,2-9,7 (2H, br).

Reference example 12

4-[(3-Phenyl-2-propenyl)oxy]piperidineacetic

Using 3-bromo-1-phenyl-1-propene and following the procedure described in reference example 11, has been specified in the header connection. Yield 42%.

So pl. 211-213oC.

1H-NMR (CDCl3) : of 1.9-2.3 (4H, m), 3,1-3,5 (4H, m), of 3.7-3.8 (1H, m), is 4.15 (2H, dd, J = 5,8 and 1.3 Hz), 6,24 (1H, dt, J = 16,2, 5,8 Hz), 6,60 (1H, d, J = 16,2 Hz), 7,2-7,5 (5H, m), 9,2-9,8 (2H, br).

Reference example 13

2,3-Dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinil)methyl] -5 - benzophenonetetracarboxylic

A mixture of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-benzyl-1 - piperazinil)methyl] -5-benzoguanamine (12 g) and 10% palladium on carbon (1.0 g, 50% water) and 150 ml of ethanol was stirred in hydrogen gas at a pressure of 5 atmospheres and 50oC for 15 hours. After cooling, the reaction mixture was filtered, the catalyst and the filtrate was concentrated. The residue was recrystallized from a mixture of ethyl acetate-diisopropyl ether to obtain and 7.1 g of the free base specified in the connection header. Yield 80%. This free base was treated with a 4.8 N HCl solution in ethanol, resulting in the corresponding hydrochloride, LASS="ptx2">

So pl. 228-231oC.

1H-NMR (DMSO-d6) : of 1.53 (3H, s), is 2.05 (3H, s), 2,24 (6H, s), 2,8-4,5 (12H, m), 9,2-10,0 (3H, br, s).

Reference example 14

1-[2-(Diphenylmethoxy)ethyl]piperazine

In a reactor equipped with a water separator (trap Dean-stark), was heated under reflux for 6 hours a mixture of benzhydrol (5.0 g), 1-(2-hydroxyethyl)piperazine (3.5 g), camphor-10-sulfonic acid (14 g) and toluene (80 ml). Then was added 1 N chloroethanol acid and the mixture was divided into two phases. The aqueous layer was podslushivaet 5 N aqueous solution of sodium hydroxide, saturated with sodium chloride, and was extracted with chloroform. The extract was washed with a small amount of saturated aqueous NaCl, dried over MgSO4and concentrated under reduced pressure to obtain 1.9 grams specified in the connection header. Yield 24%. This connection is not further purified but directly subjected to the next reaction.

Oil.

1H-NMR (CDCl3) : 2,42-of 2.54 (4H, m) 2,60 (2H, t, J = 6,0 Hz), 2,89 (4H, t, J = 5,0 Hz), of 3.60 (2H, t, J = 6,0 Hz), lower than the 5.37 (1H, s), 7,20-7,38 (10H, m).

Reference example 15

3-(Diphenylmethoxy)propyl bromide

In a reactor equipped with a water separator was heated under reflux for 2 hours the mixture was benzylacrylamide and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 95:5) to obtain 7.0 g specified in the connection header. Yield 85%.

Oil.

1H-NMR (CDCl3) : of 2.16 (2H, quintet, J = 6,0 Hz), to 3.58 (4H, t, J = 6,0 Hz), are 5.36 (1H, s), 7,20-7,38 (10H, m).

Reference example 16

1-[3-(Diphenylmethoxy)propyl]piperazine

In 20 ml of ethanol was dissolved 20 g of piperazine when heated. Then was added dropwise a solution of 3-(diphenylmethoxy)propyl bromide (7.0 g) in ethanol (20 ml) and the mixture was stirred at 70oC for 1 hour. This reaction mixture was diluted with saturated aqueous NaCl and was extracted with chloroform. The extract was washed with saturated aqueous NaCl solution to remove the original piperazine, dried over MgSO4, and concentrated under reduced pressure, resulting in a 7.1 g specified in the connection header. Yield 99%). This product is not further purified but directly subjected to the next reaction.

Oil.

1H-NMR (CDCl3) : 1,75-of 1.92 (2H, m), 2,38-of 2.50 (6H, m), is 2.88 (4H, t, J = 5,0 Hz), 3,50 (2H, t, J = 6,2 Hz), 5,33 (1H, s), 7.18 in-7,41 (10H, m).

Reference example 17

4-(Diphenylmethoxy)butyl chloride

Using as starting materials the benzhydrol and 4-chloro-1-butanol, and otherwise repeating the procedure of reference example 15 to obtain specified in the connection header. Output 90%.

Oil.


1-[4-(Diphenylmethoxy)butyl]piperazine

Using 4-(diphenylmethoxy)butyl chloride and piperazine, otherwise repeating the procedure of reference example 16 to obtain specified in the connection header. Yield 54%.

Oil.

1H-NMR (CDCl3) : 1,36-of 1.52 (2H, m), 1.60-to of 1.73 (2H, m), 2,28-to 2.42 (6H, m), is 2.88 (4H, t, J = 4,8 Hz), of 3.45 (2H, t, J = 6,6 Hz), 5,33 (1H, s), 7,20-7,40 (10H, m).

Reference example 19

5-(Diphenylmethoxy)pantellaria

Using the benzhydrol and 5-chloro-1-butanol, and otherwise repeating the procedure of reference example 15 to obtain specified in the connection header. Yield 96%.

Oil.

1H-NMR (CDCl3) : 1,45-of 1.85 (6H, m), of 3.46 (2H, t, J = 6,2 Hz), 3,53 (2H, t, J = 6,6 Hz), 5,33 (1H, s), 7.18 in-7,42 (10H, m).

Reference example 20

1-[5-(Diphenylmethoxy)pentyl]piperazine

Using 5-(diphenylmethoxy)pantellaria and piperazine, otherwise repeating the procedure of reference example 16 to obtain specified in the connection header. Yield 93%.

Oil.

1H-NMR (CDCl3) : 1,34-of 1.55 (4H, m), 1,58-of 1.74 (2H, m), 2.26 and-to 2.42 (6H, m), 2,89 (4H, t, J = 5,0 Hz), 3,44 (2H, t, J = 6,4 Hz), 5,32 (1H, s), 7.18 in-7,42 (10H, m).

Reference example 21

6-(Diphenylmethoxy)vexilloid

Using the benzhydrol and 6-chloro-1-hexanol,I. Yield 88%.

Oil.

1H-NMR (CDCl3) : 1,40-is 1.51 (4H, m), 1.60-to of 1.85 (4H, m), of 3.45 (2H, t, J = 6,4 Hz), 3,52 (2H, t, J = 6,8 Hz), 5,33 (1H, s), 7,20 was 7.36 (10H, m).

Reference example 22

1-[6-(Diphenylmethoxy)hexyl]piperazine

Using 6-(diphenylmethoxy)vexilloid and piperazine, otherwise repeating the procedure of reference example 16 to obtain specified in the connection header. Yield 94%.

Oil.

1H-NMR (CDCl3) : 1,22-and 1.54 (6H, m), 1,58-1,71 (2H, m), 2,25-to 2.42 (6H, m), 2,89 (4H, t, J = 4,8 Hz), 3,41-to 3.49 (2H, m), 5,32 (1H, s), 7,19-7,39 (10H, m).

Reference example 23

4-[(Diphenylmethoxy)methyl]piperidine

In a reactor equipped with a water separator was heated under reflux for 2 hours a mixture of benzhydrol (3.7 g), 4-piperidinemethanol (2.3 g), camphor-10-sulfonic acid (7.0 g) and toluene (30 ml). After cooling, was added 35 ml of 1 N aqueous sodium hydroxide solution and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated under reduced pressure to get 5.3g specified in the connection header. Yield 94%. This product is not further purified but directly subjected to the next reaction.

Oil.

1Reference example 24

4-[2-(Diphenylmethoxy)ethyl]piperidine

Using the benzhydrol and 4-piperidinemethanol, otherwise repeating the procedure of reference example 23 to obtain specified in the connection header. Yield 94%.

Oil.

1H-NMR (CDCl3) : 1,06 of 1.28 (2H, m), 1,54-1,71 (3H, m), 2,52-2,63 (4H, m), 3,02-3,14 (2H, m), of 3.48 (2H, t, J = 6,2 Hz), 5,31 (1H, s), 7,20-7,40 (10H, s).

Reference example 25

4-[3-(Diphenylmethoxy)propyl]piperidine

Using the benzhydrol and 1-(tert-butoxycarbonyl)-4-piperidinemethanol, otherwise repeating the procedure of reference example 23 to obtain specified in the connection header. Output 90%.

Oil.

1H-NMR (CDCl3) : 0,99-1,19 (2H, m), 1,21-to 1.38 (2H, m), 1,60-1,75 (3H, m) of 1.97 (2H, s), to 2.55 (2H, dt, J = 2.0 a, 12,0 Hz), 3,03-3,10 (2H, m), of 3.43 (2H, t, J = 6,4 Hz), 5,33 (1H, s), 7,17-7,37 (10H, m).

Reference example 26

1-(2-Phenylethyl)piperazine

Using geneticbased and piperazine, otherwise repeating the procedure of reference example 16 to obtain specified in the connection header. Yield 92%.

Oil.

1H-NMR (CDCl3) : 2,47-2,63 (6H, m), was 2.76-2.91 in (2H, m), with 2.93 (4H, t, J = 4,8 Hz), 7.18 in-to 7.35 (5H, m).

Reference example 27

4-[Bis (4-forfinal)methoxy]piperidine

In a reactor equipped with videoclairol (6.2 g) and monohydrate p-toluensulfonate acid (6.3 g) in toluene (30 ml). This reaction mixture is washed with 1 N aqueous sodium hydroxide solution and saturated aqueous NaCl and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 9.8 g of a mixture containing specified in the title compound in the form of oil. This product is not further purified but directly subjected to the next reaction.

Reference example 28

2,3-Dihydro-2-[[4-(4-methoxybenzoyl)-1-piperazinil] methyl]-2,4,6,7 - tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1 - piperazinil)methyl]-5-benzofuranyl and p-anisic acid, in other respects, followed the procedure of example 10, below, to obtain specified in the connection header. Yield 67%.

So pl. 120-123oC (recrystallized from a mixture of ethyl acetate-diisopropyl ether).

1H-NMR (CDCl3) : USD 1.43 (3H, s), 2.06 to (9H, s), 2,30-2,70 (6H, m), 2,82 (1H, d, J = 15,6 Hz), 3,11 (1H, d, J = 15,6 Hz), 3,20-of 3.80 (6H, m), 3,83 (3H, s), make 6.90 (2H, d, J = 8,8 Hz), was 7.36 (2H, d, J = 8,8 Hz).

Reference example 29

2,3-Dihydro-2-[[4-(3-methoxybenzoyl)-1-piperazinil] methyl]- 2,4,6,7-tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1 - piperazinil)methyl]-5-benzofuranyl and m-anisic acid, in other otnoshenia 73%.

So pl. 95-98oC (recrystallized from a mixture of ethyl acetate-hexane).

1H-NMR (CDCl3) : USD 1.43 (3H, s), 2.06 to (9H, s), 2,30-2,70 (6H, m), 2,82 (1H, d, J = 15,0 Hz), 3,11 (1H, d, J = 15,0 Hz), 3,20-of 3.80 (6H, m), 3,82 (3H, s), 6,91-6,97 (3H, m), 7,28-7,40 (1H, m).

Reference example 30

2,3-Dihydro-2-[[4-(2-methoxybenzoyl)-1-piperazinil] methyl]- 2,4,6,7-tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1 - piperazinil)methyl]-5-benzofuranyl and o-anisic acid, in other respects, followed the procedure of example 10, below, to obtain specified in the connection header. Yield 42%.

So pl. 128-131oC (recrystallized from a mixture of ethyl acetate-hexane).

1H-NMR (CDCl3) : USD 1.43 (3H, s), 2.06 to (9H, s), 2,30-2,70 (5H, m), 2,82 (1H, d, J = 15,0 Hz), 3.00 and-of 3.80 (8H, m), 3,81 (3H, s), 6,85-7,01 (2H,m), 7,20-7,40 (2H, m).

Reference example 31

2-[[4-(3,4-Dimethoxybenzoyl)-1-piperazinil]methyl]-2,3-dihydro - 2,4,6,7-tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1 - piperazinil)methyl]-5-benzofuranyl and 3,4-dimethoxybenzoic acid, in other respects, followed the procedure of example 10, below, to obtain specified in the connection header. Yield 74%.

So pl. 113-116oC (recrystallized from a mixture of these is 1H, d, J = 14,8 Hz), 3,20-of 3.80 (6H, m), with 3.89 (3H, s), 3,90 (3H, s), at 6.84 (1H, d, J = 9,2 Hz), 6.90 to-7,00 (2H, m).

Reference example 32

2-[[4-(4-Chlorobenzoyl)-1-piperazinil]methyl]-2,3-dihydro-2,4,6,7 - tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1 - piperazinil)methyl]-5-benzofuranyl and 4-chlorbenzoyl acid, in other respects, followed the procedure of example 10, below, to obtain specified in the connection header. Yield 64%.

So pl. 136-138oC (recrystallized from a mixture of ethyl acetate-diisopropyl ether).

1H-NMR (CDCl3) : USD 1.43 (3H, s), 2.06 to (9H, s), 2,30-2,70 (6H, m), 2,86 (1H, d, J = 14,3 Hz), 3,11 (1H, d, J = 14,3 Hz), 3,30-of 3.80 (6H, m), 7,30-7,40 (4H, m).

Reference example 33

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(4-methylbenzoyl)-1 - piperazinil] methyl]-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1 - piperazinil)methyl]-5-benzofuranyl and 4-methylbenzoic acid, in other respects, followed the procedure of example 10, below, to obtain specified in the connection header. Yield 53%.

So pl. 131-133oC (recrystallized from a mixture of ethyl acetate-diisopropyl ether).

1H-NMR (CDCl3) : USD 1.43 (3H, s), 2,07 (9H, s), of 2.38 (3H, s), 2.40 a is 2.80 (6H, m), 2,84 (1H, d, J = 14,6 Hz), 3,12 (1H, d, J = 14,6 Hz), 3,20-are 3.90 (6H, m), 7.1 yl]-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1 - piperazinil)methyl]-5-benzofuranyl and 4-nitrobenzoic acid, in other respects, followed the procedure of example 10, below, to obtain specified in the connection header. Yield 51%.

So pl. 154-158oC (recrystallized from a mixture of ethyl acetate-diisopropyl ether).

1H-NMR (CDCl3) : USD 1.43 (3H, s), 2.06 to (9H, s), 2.40 a is 2.80 (6H, m), 2,84 (1H, d, J = 15,2 Hz), 3,12 (1H, d, J = 15,2 Hz), 3,30-of 3.85 (6H, m), 7,55 (3H, d, J = 8,8 Hz), of 8.27 (2H, d, J = 8,8 Hz).

Reference example 35

4,4-Diphenyl-1-butanol

In 70 ml ice diethyl ether added to 1.9 g of sociallyengaged, and then was added dropwise a solution of 4,4-diphenylmethane acid (6.0 g) in diethyl ether (50 ml). Upon completion of the drop addition, the mixture was heated under reflux for 2 hours and then allowed it to cool. To this reaction mixture was added to 1.9 ml of water, 1.9 ml of 15% aqueous sodium hydroxide solution and 5.7 ml of water in that order and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered and the filtrate was concentrated to obtain 5.6 g specified in the connection header. A yield of 99%.

Oil.

1H-NMR (CDCl3) : 1,20 (1H, is butylmalonate

It chilled with ice to a solution of 4,4-diphenyl-1-butanol (5.6 g) in dichloroethane (100 ml) was added dropwise 11 ml of triethylamine and 2.9 ml of methanesulfonanilide in the specified order. After 30 minutes of stirring, the reaction mixture was poured into water and was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated to obtain 7.5 g specified in the connection header. A yield of 99%.

Oil.

1H-NMR (CDCl3) : of 1.73 (2H, m) to 2.18 (2H, dt, J = 7,9, and 7.8 Hz), 2,95 (3H, s), 3,91 (1H, t, J = 7,9 Hz), 4,22 (2H, t, J = 6,3 Hz), 7,10-7,40 (10H, m).

Reference example 37

5,5-Diphenylacetonitrile

A solution of 4,4-diphenylmethanediisocyanate (7.5 g) and sodium cyanide (2.5 g) in dimethyl sulfoxide (70 ml) was stirred at 60oC for 15 hours. Allowing the reaction mixture to cool, was extracted with her diethyl ether. The extract was dried over MgSO4and concentrated, resulting in quantitatively obtained 5.8 g specified in the connection header.

Oil.

1H-NMR (CDCl3) : 1,50-1,72 (2H, m), are 2.19 (2H, dt, J = 7,9, and 7.8 Hz), was 2.34 (2H, t, J = 7,1 Hz), 3,91 (1H, t, J = 7,9 Hz), 7,10-7,40 (10H, m).

Reference example 38

5,5-Diphenylalanine acid

To a solution of 5,5-diphenylacetonitrile (6.5 g) in methanol (30 ml) is actionnow mixture to cool, washed her diethyl ether and brought to pH 1 with concentrated chloroethanol acid. This acidic solution was extracted with diethyl ether and the extract washed with saturated aqueous NaCl, dried over MgSO4and concentrated. The residue was recrystallized to obtain 5.5 g specified in the connection header. Yield 86%.

So pl. 87-90oC (recrystallized from diethyl ether).

1H-NMR (DMSO-d6) : 1,30-1,50 (2H, m), 1,95-of 2.09 (2H, m), of 2.23 (2H, t, J = 7,6 Hz), 3,92 (1H, t, J = 7,6 Hz), 7,12-to 7.35 (10H, m).

Reference example 39

Ethyl 4-[(Diphenylmethyl)amino]-1-piperidinecarboxylate

In a reactor equipped with a water separator was heated under reflux for 4 hours a solution of 1,1-diphenylethylamine (5.0 g) and 1-etoxycarbonyl-4-piperidone (4.7 g) in toluene (70 ml). This reaction mixture was concentrated under reduced pressure and the residue was dissolved in 50 ml of ethanol. After cooling the solution with ice was added 2.1 g of lamborginid sodium and a small amount of bromcresol greens. Then was added dropwise 4 N solution of HCl in methanol until the reaction mixture became yellow, after which the mixture was stirred for 20 minutes. This reaction mixture was poured into excess amount of NaCl, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 5:1-65:35) with the receipt of 8.4 g specified in the connection header. Yield 91%. Amorphous solid.

1H-NMR (CDCl3) : 1,20-to 1.38 (2H, m), of 1.24 (3H, t, J = 7,0 Hz), 1,87 is 1.96 (2H, m), 2,54-of 2.66 (1H, m), 2,70-2,84 (2H, m), 3,99-4,17 (2H, m), 4,10 (1H, q, J = 7,0 Hz), 5,02 (1H, s), 7,19-7,41 (10H, m).

Reference example 40

N-(Diphenylmethyl)-4-piperidinemethanol

A solution of ethyl 4-[(diphenylmethyl)amino] -1-piperidinecarboxylate (42 g) and sodium hydroxide (50 g) in methanol (300 ml) was heated under reflux for 24 hours. This reaction mixture was diluted with water and was extracted with chloroform. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated under reduced pressure to obtain N-(diphenylmethyl)piperidine. This product was converted to the dihydrochloride, using 4 N HCl solution in ethanol, and the precipitate was collected by filtration and dried, resulting in 31 g specified in the connection header. The yield was 73%.

So pl. 228-234oC.

1H-NMR (DMSO-d6) : 1,91-of 2.08 (2H, m), 2.40 a-2,50 (2H, m), 2,78-2,90 (2H, m), 3,07-to 3.41 (3H, m), of 5.75 (1H, br s), 7,34-7,47 (6H, m), 7,87 (4H, d, J = 6,6 Hz) is ethyl] - 4-piperidinemethanol

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 4-piperidinemethanol, otherwise repeating the procedure of example 1, below, obtaining specified in the connection header. Yield 88%.

So pl. 94-95oC (recrystallized from a mixture of ethyl acetate-hexane).

1H-NMR (CDCl3) : 1,20-1,63 (7H, m), of 1.42 (3H, s), 1,98-to 2.18 (2H, m), 2,07 (6H, s), is 2.09 (3H, s), 2,46 (1H, d, J = 13,8 Hz), of 2.54 (1H, d, J = 13,8 Hz), was 2.76-is 2.88 (2H, m), 2.06 to-3,14 (2H, m) to 3.67 (2H, t, J = 6,6 Hz).

Reference example 42

Tert-butyl [(2,3-dihydro-2-[[4-(2-hydroxyethyl)-1 - piperidinyl]methyl]-2,4,6,7-tetramethylbenzidin-5-yl]carbama

To a solution of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -4-piperidinemethanol (3.1 g) and di-tert-BUTYLCARBAMATE (2.1 g) in tetrahydrofuran (20 ml) was added 10 ml of 1 N aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol = 95:5) to obtain 3.9 g is specified in the header soy is(3H, s) of 2.10 (3H, s), 2,12 (3H, s), 2,43-of 2.58 (2H, m), 2,73-2,90 (2H, m), 3,01-3,13 (2H, m), 3,68 (2H, t, J = 6,6 Hz), 5,78 (1H, br, s).

Reference example 43

Tert-butyl [2-[[4-(formylmethyl)-1-piperidinyl] methyl] -2,3 - dihydro-2,4,6,7-tetramethylbenzidin-5-yl]carbamate

To a solution of DMSO (2.6 ml) in dichloromethane (40 ml) at -78oC was added dropwise under gaseous argon 2.4 ml of oxalicacid and the mixture was stirred for 20 minutes. Then was added dropwise a solution of tert-butyl [(2,3-dihydro-2-[[4-(2-hydroxyethyl)-1-piperidinyl] methyl] -2,4,6,7 - tetramethylbenzidin-5-yl]carbamate (3.6 g) in dichloromethane (10 ml) and the mixture was stirred for another 1 hour. To this reaction mixture was added to 8.0 ml of triethylamine. Then the mixture at room temperature was podslushivaet aqueous solution of sodium bicarbonate and was extracted with dichloromethane. The extract was washed with saturated aqueous NaCl solution and dried over MgSO4, then drove away under reduced pressure the solvent. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 1:1 to ethyl acetate) to obtain 3.0 g specified in the connection header. Yield 85%.

Oil.

1H-NMR (CDCl3) : 1,20 was 2.25 (7H, m), of 1.41 (3H, s), of 1.50 (9H, s), is 2.05 (3H, s), is 2.09 (3H, s), 2,12 (3H, s), 2,30-of 2.36 (2H, m), of 2.51 (2H, s), 2,72-is 2.88 (2H, m), 3,02-3,13 (2H, m), 5L]methyl]-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl]-carbamate

A solution of tert-butyl [2-[[4-(formylmethyl)-1-piperidinyl]methyl]-2,3 - dihydro-2,4,6,7-tetramethylbenzidin-5-yl] carbamate (1.5 g) and 1,1-diphenylethylamine (of 0.60 ml) in ethanol (20 ml) was stirred on an ice bath for 30 minutes. Then was added 0.26 g of lamborginid sodium and a small amount of bromcresol greens. After this was added 4 N HCl solution in ethanol, until the reaction mixture became yellow. The mixture was stirred for 1 hour, after which it was poured into excess aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate and the extract washed with saturated aqueous NaCl and dried over MgSO4. Drove away under reduced pressure, the solvent and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane = 4:1 to ethyl acetate) to obtain 1.6 g specified in the connection header. Yield 77%.

Oil.

1H-NMR (CDCl3) : 1,20-1,78 (7H, m), of 1.40 (3H, s), of 1.50 (9H, s), 2.00 in of 2.21 (2H, m), 2,04 (3H, s), is 2.09 (3H, s), 2,12 (3H, s), 2,41-2,60 (4H, m), 2,72-2,84 (2H, m), 2,98-of 3.12 (2H, m), 4,79 (1H, s), 5,77 (1H, br, s), 7,18-7,40 (10H, m).

Reference example 45

Tert-butyl[2-[[4-[2-[(3,3-diphenylpropyl)amino] ethyl] -1 - piperidinyl] methyl]-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl]carbama

Using tert-butyl [2 - [[the, in other respects, repeated the procedure of reference example 44 to obtain specified in the connection header. Yield 97%.

Amorphous solid.

1H-NMR (CDCl3) : 1,20-1,60 (9H, m), of 1.40 (3H, s), of 1.50 (9H, s), 2,04 (3H, s), of 2.08 (3H, s), 2,11 (3H, s), 2,23-2,70 (8H, m), 2,72-of 2.86 (2H, m), 2,98-3,11 (2H, m), of 3.97 (1H, t, J = 7,8 Hz), 5,79 (1H, br, s), 7,13-7,30 (10H, m).

Reference example 46

Ethyl 1-[(5-amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2 - yl)methyl] -4-piperidinecarboxylate

In the autoclave was stirred under nitrogen gas at 180oC for 15 hours a mixture of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (8,4 g), utilisedictated (14 g) and xylene (20 ml). To the reaction mixture were taken of the supernatant and washed with water saturated aqueous NaHCO3and saturated aqueous NaCl, dried over MgSO4, was treated with activated charcoal, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 5: 1-2: 1) and was led from hexane to obtain 2.9 g specified in the connection header. The output is 27%.

So pl. 74-76oC.

1H-NMR (CDCl3) : of 1.24 (3H, t, J = 7,1 Hz), of 1.41 (3H, s), 1,6-1,9 (4H, m), of 1.9-2.3 (3H, m), 2,07 (6H, s), is 2.09 (3H, s), 2,46 (1H, d, J = 13,7 Hz), of 2.54 (1H, d, J = 13,7 but-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2 - yl)methyl]-4-piperidinecarboxylate sodium

To a solution of ethyl 1-[(5-amino-2,4,6,7-tetramethyl-2,3 - dihydrobenzofuran-2-yl)methyl] -4-piperidinecarboxylate (10 g) in ethanol (40 ml) was added 5.7 ml of 5 N aqueous sodium hydroxide solution and the mixture was stirred under nitrogen gas at room temperature for 2 hours. The precipitate was collected by filtration and washed with diethyl ether, resulting in 7.5 g specified in the connection header. A yield of 75%. The filtrate was concentrated under reduced pressure and the solid residue was thoroughly washed with diethyl ether obtaining additional 1.4 g specified in the connection header. Exit 14%. These products are not further purified but directly subjected to the next reaction.

So pl. 237-241oC.

1H-NMR (CD3OD) : 1,35 (3H, s) of 1.5-1.9 (4H, m), 1,9-2,2 (3H, m), 2,02 (3H, s), is 2.05 (6H, s), 2.49 USD (2H, s), was 2.76 (1H, d, J = and 15.3 Hz), of 2.8-3.0 (1H, m), to 3.0-3.2 (1H, m), 3,12 (1H, d, J = 15,3 Hz).

Reference example 48

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(diphenylmethyl)-4-piperidinecarboxylic

To a suspension of 1-[(5-amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran - 2-yl)methyl]-4-piperidinecarboxylate sodium (0,89 g) in N,N-dimethylformamide (10 ml) was added 0.35 g of trietilenglikole and the mixture was stirred at room temperature for 5 minutes. To AI ice of 0.48 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimides. This mixture was stirred under nitrogen gas at room temperature for 23 hours. This reaction mixture was diluted with water and was extracted with 2 portions of ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was recrystallized from methanol-diisopropyl ether to obtain 0.71 g specified in the connection header. Yield 57%.

So pl. 175-177oC.

1H-NMR (CDCl3) : of 1.40 (3H, s), 1.4 and 2.3 (7H, m), of 2.06 (6H, s), of 2.08 (3H, s), 2,46 (1H, d, J = a 13.9 Hz), to 2.55 (1H, d, J = a 13.9 Hz), and 2.79 (1H, d, J = 14,8 Hz), 2,9-3,4 (4H, m), 3,10 (1H, d, J = 14,8 Hz), 6,01 (1H, d, J = 7,9 Hz), 6,24 (1H, d, J = 7,9 Hz), and 7.1 to 7.4 (10H, m).

Reference example 49

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(2,2-diphenylether)-4-piperidinecarboxylic

Using 2,2-diphenylethylamine, otherwise repeating the procedure of reference example 48 to obtain specified in the connection header. Yield 62%.

So pl. 168-170oC (recrystallized from a mixture of tetrahydrofuran-methanol).

1H-NMR (CDCl3) : of 1.39 (3H, s), 1.4 to about 2.2 (7H, m), of 2.06 (3H, s), 2,07 (3H, s), of 2.08 (3H, s), 2,43 (1H, d, J = a 14.1 Hz), 2,52 (1H, d, J = a 14.1 Hz), 2,78 (1H, d, J = 15,0 Hz), 2.8 to 3.5 (4H, m), is 3.08 (1H, d, J = 15,0 Hz), 3,88 (2H,-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(3,3-diphenylpropyl)-4-piperidinecarboxylate

Using 3,3-diphenylpropylamine, otherwise repeating the procedure of reference example 48 to obtain 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] - N-(3,3-diphenylpropyl)-4-piperazinecarboxamide. This product was dissolved in methanol, was added thereto dropwise a stoichiometric excess of a 10% aqueous solution of hydrogen chloride in methanol and the mixture was concentrated under reduced pressure. The residue was led from a mixture of ethanol-diethyl ether to obtain specified in the connection header. Yield 52%.

So pl. 166-171oC.

1H-NMR (DMSO-d6) : of 1.57 (3H, s), of 1.7 to 2.6 (7H, m), is 2.05 (3H, s), of 2.23 (6H, s), 2,8-3,8 (10H, s), 3,98 (1H, t, J = 7,7 Hz), and 7.1 to 7.4 (10H, m), with 8.05 (1H, br, s), and 9.4 to 10.6 (4H, m).

Reference example 51

Ethyl 4-[N-benzyl-N-(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate

In a reactor equipped with a water separator was heated under reflux for 2 hours, a solution of 3,3-diphenylpropylamine (4.9 g) and 1-etoxycarbonyl-4-piperidone (4.0 g) in toluene (100 ml). This reaction mixture was concentrated under reduced pressure and the residue was dissolved in 80 ml of ethanol. After cooling this solution with ice was added 1.8 g of lamborginid sodium and a small amount of bromcresol greens. Then were added to kanchana drip of addition, the mixture was stirred for another 30 minutes. This reaction mixture was poured into excess aqueous sodium hydrogen carbonate solution and was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated under reduced pressure to obtain ethyl 4-[(3,3-diphenylpropyl)amino] -1-piperidinecarboxylate. This product was dissolved in 80 ml of N,N-dimethylformamide, followed by addition of 2.8 ml of benzylbromide and 3.2 g of potassium carbonate and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 9: 1-7: 3) to obtain 7.8 g specified in the connection header. Output based on 3,3-diphenylpropylamine was 73%.

Oil.

1H-NMR (CDCl3) : 1,18-of 1.40 (5H, m), 1,59 by 1.68 (2H, m), 2,10-of 2.20 (2H, m), 2.40 a-2,62 (5H, m), of 3.60 (2H, s), 3,90-4,17 (5H, m), 7,10-to 7.35 (15H, m).

Reference example 52

N-Benzyl-N-(3,3-diphenylpropyl)-4-piperidylamine

Using ethyl 4-[N-benzyl-N-(3,3-diphenylpropyl)amino] -1-piperidinecarboxylate, otherwise repeating the procedure of reference note the 3
) : 1,22 was 1.43 (2H, m), 1,63 is 1.75 (2H, m), 2,08-2,19 (2H, m), 2.40 a-2,61 (5H, m), 3,02-is 3.08 (2H, m), 3,62 (2H, s), of 3.97 (1H, t, J = 7,4 Hz), 7,10 and 7.36 (15H, m).

Reference example 53

N-(2-Lanmeter-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl)formamide

A solution of N-(2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethylbenzidin - 5-yl)formamide (20 g) and sodium cyanide (17 g) in dimethyl sulfoxide (100 ml) was stirred under gaseous argon at 100oC for 13 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous NaCl, dried over MgSO4and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate-diisopropyl ether to obtain 14 g specified in the connection header. Yield 86%.

So pl. 183-185oC.

1H-NMR (CDCl3) : of 1.66 (3H, s), 2,08-2,17 (9H, m), 2,73 is 2.75 (2H, m), 3,03-up 3.22 (2H, m), 6,65-6,76 (1H, m), of 7.96 (0,4 H, d, J = and 12.2 Hz), to 8.41 (0,6 H, d, J = 1,4 Hz).

Reference example 54

5-Amino-2,3-dihydro-2,4,6,7-tetramethyl-2-benzofuroxan acid

To a solution of N-(2-Lanmeter-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl)formamide (14 g) in methanol (50 ml) was added 120 ml of 4.6 N aqueous sodium hydroxide solution and the mixture was heated under reflux under gaseous argon in Tekeli chloroform. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated under reduced pressure. The residue was led from a mixture of chloroform-diisopropyl ether to obtain 11 g specified in the connection header. Yield 82%.

So pl. 186-188oC.

1H-NMR (DMSO-d6) : USD 1.43 (3H, s), 1,95 (9H, s), 2,60 (2H, s), 2,84 (1H, d, J = 15,6 Hz), 3,18 (1H, d, J = 15,6 Hz).

Reference example 55

5-[(Tert-butoxycarbonyl)amino] -2,3-dihydro-2,4,6,7 - tetramethyl-2-benzofuroxan acid

To a suspension of 5-amino-2,3-dihydro-2,4,6,7-tetramethyl-2-benzofuroxans acid (8,3 g) in tetrahydrofuran (50 ml) was added a solution of di-tert-BUTYLCARBAMATE (7.6 g) in tetrahydrofuran (5 ml) and 34 ml of 1 N aqueous sodium hydroxide solution and the resulting mixture was stirred at room temperature for 30 minutes. After cooling with ice, the reaction mixture was acidified with 0.5 M aqueous citric acid solution and was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 2:3) to obtain 11 g specified in the connection header. Yield 92%.

Oil.), 5,80 (1H, s).

Reference example 56

Tert-butyl [2,3-dihydro-2-(2-hydroxyethyl)-2,4,6,7 - tetramethylbenzidin-5-yl]carbamate

To a solution of 5-[(tert-butoxycarbonyl)amino]-2,3-dihydro-2,4,6,7 - tetramethyl-2-benzofuroxans acid (11 g) in 50 ml of tetrahydrofuran was added dropwise under ice cooling 64 ml of 1 M solution of borane-tetrahydrofurane complex in tetrahydrofuran, and the mixture was stirred at room temperature for 12 hours. This reaction mixture was poured into water and was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 2:1) to obtain 7.8 g specified in the connection header. Yield 76%.

Oil.

1H-NMR (CDCl3) : of 1.47 (3H, s), of 1.50 (9H, s), 1,89-of 2.16 (2H, m), 2,07 (3H, s), 2,10 (3H, s) by 2.13 (3H, s), 2,35 (1H, br, s), 2.91 in (1H, d, J = 15,4 Hz), 3,06 (1H, d, J = 15,6 Hz), 3,71-of 3.97 (2H, m), 5,79 (1H, br, s).

Reference example 57

Tert-butyl [2-(2-bromacil)-2,3-dihydro-2,4,6,7 - tetramethylbenzidin-5-yl]carbamate

To a solution of tert-butyl [2,3-dihydro-2-(2-hydroxyethyl)-2,4,6,7 - tetramethylbenzidin-5-yl] carbamate (7.7 g) and tetrabromide carbon (8.0 g) in tetrahydrofuran (80 who were intervali and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 97:3 to 4:1) to obtain 7.5 g specified in the connection header. Yield 82%.

Amorphous solid.

1H-NMR (CDCl3) : the 1.44 (3H, s), of 1.50 (9H, s), 2,07 (3H, s), of 2.08 (3H, s) by 2.13 (3H, s), 2.26 and to 2.35 (2H, m), is 2.88 (1H, d, J = 15,8 Hz), 3,01 (1H, d, J = 15,8 Hz), 3,40-to 3.49 (2H, m), 5,77 (1H, br, s).

Reference example 58

Tert-butyl[2-[2-[4-(diphenylmethoxy)-1-piperidinyl]ethyl]-2,3 - dihydro-2,4,6,7-tetramethylbenzidin-5-yl]carbamate

A suspension of tert-butyl [2-(2-bromacil)-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl] carbamate (1.2 g), 4-(diphenylmethoxy)piperidine (0.85 grams) and potassium carbonate (0,44 g) in N,N-dimethylformamide (20 ml) was stirred at 60oC for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol = 98:2-95: 5) to obtain 1.6 g specified in the connection header. Yield 92%.

Oil.

1H-NMR (CDCl3) : of 1.39 (3H, s), of 1.50 (9H, s), 1,66 is 1.96 (6H, m), 2,03-of 2.20 (2H, m), of 2.06 (3H, s), 2,07 (3H, s), 2,12 (3H, s), 2.40 a-2,48 (2H, m), 2.70 height is 2.80 (2H, m), 2,82 (1H, d, J = 15,4 Hz), 3,01 (1H, d, J = to 15.4 Hz), 3,35-3,50 (1H, shall piperidinyl] ethyl]-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl]carbamate

Using tert-butyl [2-(2-bromacil)-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl] carbamate and 4-[(diphenylmethoxy)methyl] piperidine, otherwise repeating the procedure of reference example 58 with obtaining specified in the connection header. Yield 82%.

Oil.

1H-NMR (CDCl3) : 1,18 of 1.50 (2H, m), of 1.40 (3H, s), of 1.50 (9H, s), 1.60-to 1,97 (7H, m), 2,07 (6H, s), 2,12 (3H, s), 2,41-of 2.50 (2H, m), 2,78 totaling 3.04 (4H, m), 3,29 (2H, d, J = 6,4 Hz), and 5.30 (1H, s), USD 5.76 (1H, br, s), 7,20-7,37 (10H, m).

Reference example 60

Tert-butyl[2-[2-[4-[2-(diphenylmethoxy)ethyl]-1-piperidinyl]ethyl]- 2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl]carbamate

Using tert-butyl [2-(2-bromacil)-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl] carbamate and 4-[2-(diphenylmethoxy)ethyl] piperidine, otherwise repeating the procedure of reference example 58 with obtaining specified in the connection header. Yield 83%.

Oil.

1H-NMR (CDCl3) : 1,18 is 1.70 (4H, m), of 1.39 (3H, s), for 1.49 (9H, s), 1,80-2,00 (7H, m), 2,07 (6H, s), 2,11 (3H, s), 2,35-of 2.50 (2H, m), 2,78 was 3.05 (4H, m), 3,40-to 3.52 (2H, m), and 5.30 (1H, s), 5,77 (1H, br, s), 7,19-7,38 (10H, m).

Reference example 61

2-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] - 2H-isoindole-1,3-dione

A suspension of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (2.0 g) and phthalimide potassium (2.2 g) in N,N-dimethyl the mixture was diluted with water and was extracted with 2 portions of ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was led from a mixture of ethyl acetate-diisopropyl ether to obtain 1.4 g specified in the connection header. Yield 56%.

So pl. 147-150oC.

1H-NMR (CDCl3) : of 1.52 (3H, s), to 1.98 (3H, s), 2,03 (3H, s), of 2.08 (3H, s), with 2.93 (1H, d, J = 15,8 Hz), of 3.0-3.4 (2H, br), 3,26 (1H, d, J = 15,8 Hz), 3,86 (1H, d, J = a 13.9 Hz), 3,95 (1H, d, J = a 13.9 Hz), and 7.6 to 7.9 (4H, m).

Reference example 62

2,3-Dihydro-2,4,6,7-tetramethyl-2-[(1,2,3,4-tetrahydroisoquinoline-2-yl)methyl]-5-benzofuranol

A suspension of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.4 g), 1,2,3,4-tetrahydroisoquinoline (1.3 g) and potassium carbonate (1.4 g) in N, N-dimethylacetamide (10 ml) was heated under reflux under nitrogen gas for 15 hours. This reaction mixture was diluted with water and was extracted with 2 portions of ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 3:1) to give 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1,2,3 is the group of 1 equivalent of oxalic acid in ethanol. This mixture was heated and the resulting solution was concentrated under reduced pressure. Was collected crystals, resulting in 1.5 g specified in the connection header. Yield 68%.

So pl. 153-156oC.

1H-NMR (DMSO-d6) : of 1.41 (3H, s), 1,99 (6H, s), 2,02 (3H, s), 2,7-3,2 (6H, m), 2,84 (1H, d, J = 15,8 Hz), 3,11 (1H, d, J = 15,8 Hz), with 3.89 (1H, d, J = 15,4 Hz), 4,00 (1H, d, J = 15,4 Hz), 6,95 to 7.2 (4H, m).

Reference example 63

2-[[4-(2,3-Dihydro-2-oxo-1H-benzimidazole-1-yl)-1 - piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl the dihydrochloride

In the autoclave was stirred under nitrogen gas at 180oC for 15 hours a suspension of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.4 g) and 4-(2-keto-1-benzimidazolinyl)piperidine (2.3 g) in xylene (20 ml). Then the reaction mixture was cooled, filtered and washed with diethyl ether. The filtrate was washed with water and was extracted with 1 N chloroethanol acid. The aqueous layer was neutralized with a saturated aqueous solution of NaHCO3and was extracted with 2 portions of ethyl acetate.

The combined organic layer was washed saturated aqueous NaCl, dried over anhydrous sodium sulfate (Na2SO4) and silica gel (blueraven with ethyl acetate) and concentrated in pangendered] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine. Yield 55%. This product was dissolved in tetrahydrofuran by heating and after dilution of the solution, methanol was added a stoichiometric excess of 10% HCl solution in methanol. The resulting solution was concentrated under reduced pressure and was led from methanol-diethyl ether to obtain specified in the connection header.

So pl. 202-208oC.

1H-NMR (DMSO-d6) : 1,5-2,3 (3H, m), of 1.65 (3H, m), 2,07 (3H, s), 2,22 (3H, s in), 2.25 (3H, s), is 2.8-3.2 (3H, m), of 3.07 (1H, d, J = a 16.4 Hz), a 3.2 to 3.7 (4H, m), 3,8-4,0 (1H, m), 4,4-4,7 (1H, m), 6,9-7,1 (3H, m), of 7.6 to 7.8 (1H, m), 9,5 to 10.1 (2H, br), 10,7-11,0 (1H, m).

Reference example 64

2-[[4-[(9-Feranil)oxy] -1-piperidinyl]methyl]-2,3-dihydro - 2,4,6,7-tetramethyl-5-benzofuranol

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 4-[(9-forfinal)oxy] piperidine, in other respects, followed the procedure of example 1, below, obtaining 2-[[4-[(9-feranil)oxy]-1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine. Yield 63%. Part of the product was converted to the oxalate and recrystallized from ethanol to obtain specified in the connection header.

So pl. 121-123oC.

1H-NMR (DMSO-d6) : of 1.36 (3H, s), and 1.63 (2H, br, s), 1,86 e 2.06 (2H, m), a 1.96 (9H, s), 2,50-of 3.12 (8H, m), and 3.72 (1H, br, s),in

Using 9-fluorenol and 4-piperidinol, otherwise repeating the procedure of reference example 23 to obtain specified in the connection header. Yield 38%.

Amorphous solid.

1H-NMR (CDCl3) : 1,45 by 1.68 (2H, m), 1,75-1,90 (2H, m), 2,50-2,62 (2H, m), 3.04 from-3,18 (2H, m), 3.45 points-to 3.58 (1H, m), 5,62 (1H, s), 7,22-7,40 (4H, m), 7,56-to 7.67 (4H, m).

Reference example 66

2-Bromo-3-(methoxyethoxy)-1,4,5-trimethylbenzene

Under gaseous nitrogen to a solution of 2-bromo-3,5,6-trimethylphenol (10 g) in N, N-dimethylformamide (50 ml) was added dropwise to a suspension of 60% sodium hydride (2.1 g) in N,N-dimethylformamide (20 ml) under ice cooling and the mixture was stirred for 10 minutes. To this mixture was further added dropwise a solution of chloromethylmethylether ether (3.9 ml) in N,N-dimethylformamide (5 ml) and the mixture was stirred for another 30 minutes. This reaction mixture was diluted with ice water and was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 97:3) to obtain the specified title compound (12 g). A yield of 99%.

Oil.

1H-NMR (CDCl34,6-trimetilfenil]methyl]-1-methyloxiran

To a solution of 2-bromo-3-(methoxyethoxy)-1,4,5-trimethylbenzene (3.0 g) in tetrahydrofuran (30 ml) was added dropwise at -78oC 1.6 M solution of n-utility in hexane (7.0 ml) and the mixture was stirred for 15 minutes. To this mixture was added (R)-methylglycerol (2.8 g) and boron TRIFLUORIDE-diethyl ether (1.5 ml) and the resulting mixture was stirred for another 15 minutes. The reaction mixture was heated to room temperature, then was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane:ethyl acetate = 3: 1) to give (R)-2-hydroxy-3-[2-(methoxyethoxy)-3,4,6-trimetilfenil] -2 - methylpropyl-4-methylbenzenesulfonate. This compound was dissolved in methanol (20 ml) followed by addition of potassium carbonate (1.6 g) under ice cooling and the mixture was stirred for 30 minutes. To this reaction mixture were added ethyl acetate and water and the resulting two layers were separated. The aqueous layer was extracted with ethyl acetate and the extract was combined with the separated, as described above, the organic layer. The combined organic solution was washed with a saturated aqueous solution of chloride n is ecografia on silica gel (hexane: ethyl acetate = 9:1) to obtain the specified title compound (0.73 g). The yield of 2-bromo-3-(methoxyethoxy)-1,4,5-trimethylbenzene was 25%.

Oil.

1H-NMR (CDCl3) : of 1.35 (3H, s), of 2.15 (3H, s), measuring 2.20 (3H, s), and 2.26 (3H, s), 2,44 (1H, d, J = 5,2 Hz), 2,50 (1H, d, J = 5,2 Hz), 3.00 and is 3.15 (2H, m), 3,61 (3H, s), 4,88-of 4.95 (2H, m), 6,78 (1H, s).

Reference example 68

(S)-2,3-Dihydro-2,4,6,7-tetramethyl-2-benzofuranyl

To a solution of (R)-1-[[2-(methoxyethoxy)-3,4,6 - trimetilfenil]methyl]-1-methyloxirane (0,60 g) in tetrahydrofuran (5 ml) was added a mixture of triperoxonane acid (1 ml) and water (1 ml) dropwise under ice cooling and the mixture was stirred for 30 minutes. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 8:2) to obtain the specified title compound as a solid (0,41 g). Yield 83%.

1H-NMR (CDCl3) : the 1.44 (3H, s), of 2.08 (3H, s), of 2.15 (3H, s), measuring 2.20 (3H, s), 2,80 (1H, d, J = 15,4 Hz), 3,13 (1H, d, J = 15,4 Hz), 3,55-to 3.73 (2H, m), 6,51 (1H, s).

This product is not further purified but directly subjected to the next reaction.

Reference example 69

(S)-(2,3-Dihydro-2,4,6,7-tetramethylbenzidine (0,41 ml) in tetrahydrofuran (5 ml) was added dropwise under ice cooling methanesulfonanilide (0.17 ml) and the mixture was stirred for 10 minutes. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed successively 1 N chloroethanol acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over MgSO4and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate-hexane to obtain specified in the connection header (0,43 g). Yield 78%.

[]D= +1,4(c = 0,41, ethanol).

So pl. 70-71oC.

1H-NMR (CDCl3) : of 1.52 (3H, s), is 2.05 (3H, s), of 2.15 (3H, s), are 2.19 (3H, s), is 2.88 (1H, d, J = 15,6 Hz), to 3.02 (3H, s), 3,13 (1H, d, J = 15,6 Hz), 4.26 deaths (2H, s), of 6.52 (1H, s).

Reference example 70

(S)-1-[(2,3-Dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] - N-(diphenylmethyl)-4-piperidylamine

A suspension of (S)-(2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methylmethanesulfonate (0.34 g), N-(diphenylmethyl)-4-piperidylamine (0.73 g) and potassium carbonate (0,38 g) in N,N-dimethylacetamide (2 ml) was stirred under gaseous argon at 177oC for 6 hours. This reaction mixture was diluted with water and was extracted with diisopropyl ether. The organic layer was washed with water and was extracted with 1 N chloroethanol acid. The aqueous layer was podslushivaet 2 N solution HYDR what astora sodium chloride, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 7:3) to obtain specified in the connection header (0,49 g). Yield 79%.

[]D= +3.0V(c = 0,20, ethanol).

Oil.

1H-NMR (CDCl3) : 1,25-of 1.52 (2H, m), of 1.41 (3H, s), 1,80 is 1.96 (2H, m), 2.00 in of 2.23 (2H, m), 2,03 (3H, s) by 2.13 (3H, s), to 2.18 (3H, s), 2,31-of 2.56 (3H, m), 2.71 to 2,87 (2H, m), 2.95 and-is 3.08 (2H, m) 5,00 (1H, s), 6,46 (1H), 7,16-7,39 (10H, m).

Reference example 71

1-[(2,3-Dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl]- N-(diphenylmethyl)-4-piperidylamine

A suspension of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethylbenzidine (1.0 g), N-(diphenylmethyl)-4-piperidylamine (1.5 g) and potassium carbonate (0,77 g) in N, N-dimethylacetamide (4 ml) was stirred under gaseous argon at 177oC for 4 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 7: 3) to obtain the specified title compound (1.5 g). Yield 97%.

Oil.

1H-NMR (CDCl3) : 1,25-19 (10H, m).

Reference example 72

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[1,2,3,6-tetrahydro-4-(3 - indolyl)-1-pyridyl]methyl]-5-benzofuranyl

A suspension of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (0.85 grams), 3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (1.1 g) and potassium bicarbonate (0,83 g) in N, N-dimethylacetamide (6 ml) was heated under reflux under nitrogen for 7.5 hours. To the mixture was added water and the product was extracted twice with ethyl acetate. The combined extract was washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 1:1) and recrystallized from a mixture of acetone-diisopropyl ether to obtain 0,99 g specified in the connection header. Yield 82%.

So pl. 169-173oC.

1H-NMR (CDCl3) : 1,49 (3H, s), of 2.08 (3H, s), is 2.09 (3H, s), and 2.14 (3H, s), 2,50-to 2.65 (2H, m), 2,66 (1H, d, J = a 13.9 Hz), 2,75 (1H, d, J = a 13.9 Hz), 2,75-of 3.06 (3H, m), 3,21 (1H, d, J = 15,4 Hz), 3,23-3,51 (2H, m), 6,15-6,24 (1H, m), 7,06-7,29 (3H, m), 7,35-7,40 (1H, m), 7,86-7,94 (1H, m), 8,08 (1H, br, s).

Reference example 73

1-Phenyl-1H-indole

A suspension of indole (8,2 g), sodium bicarbonate (12 g) and copper iodide (I) (2.7 g) in bromobenzene (70 ml) was heated with obratimtes fridge for another 6 hours. Was removed by filtration of the insoluble material and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 50:1) to obtain specified in the connection header (8,4 g). Yield 62%.

Oil.

1H-NMR (CDCl3) : of 6.68 (1H, dd, J = 3.2, and 0.8 Hz), 7,11-7,27 (2H, m), 7,29-the 7.43 (2H, m), 7,44-7,63 (5H, m), 7,65-7,22 (1H, m).

Reference example 74

1-Phenyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole

To a heated (110oC) a mixture of 4-piperidinemethanol (8,2 g), acetic acid (15 ml) and triperoxonane acid (30 ml) was added under nitrogen atmosphere for 25 minutes 1-phenyl-1H-indole (3.1 g). The mixture was stirred for 30 minutes at 120oC, then cooled and poured into ice. Neutralized it with concentrated ammonia water when cooled and the product was extracted three times with ethyl acetate. The combined extract was washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was used for next reaction without further purification. Yield 63%.

Amorphous solid.

1H-NMR (CDCl3) : 2,48-of 2.66 (2H, m), 3,21 (2H, t, J = 5,7 Hz), 3,53-of 3.94 (3H, m), 6,23-6,34 (1H, m), 7,00-of 7.70 (9H-indolyl)-1-pyridyl]methyl]-5-benzofuranyl]trioxane

Using 1-phenyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole, otherwise repeating the procedure of reference example 72 to obtain 2,3-dihydro-2,4,6,7-tetramethyl-2-[[1,2,3,6-tetrahydro-4-(1-phenyl-3-indolyl)-1-pyridyl] methyl] -5-benzoguanamine. Yield 61%. Part of this product was converted to the oxalate with obtaining specified in the connection header.

Amorphous solid.

1H-NMR (DMSO-d6) : to 1.48 (3H, s), 1,99 (6H, s), is 2.05 (3H, s), 2,64-2,90 (2H, m), 2,89 (1H, d, J = 15,4 Hz), 3,05-of 3.48 (5H, m), 3,62-of 3.95 (2H, m), 6,27 (1H, br, s), 7,14-7,30 (2H, m), 7,37-to 7.67 (6H, m), 7,79 (1H, s), 7,93-8,02 (1H, m).

Reference example 76

2,3-Dihydro-2-[[4-(3-indolyl)-1-piperidinyl] methyl] -2,4,6,7 - tetramethyl-5-benzogeneratorami

A mixture of 2,3-dihydro-2,4,6,7-tetramethyl-2-[[1,2,3,6-tetrahydro-4-(3-indolyl)-1-pyridyl] methyl] -5-benzoguanamine (0.40 g), platinum oxide (80 mg), tetrahydrofuran (2 ml) and methanol (4 ml) was stirred 2 hours at 60oC under a hydrogen environment. The mixture was cooled, removed by filtration of the catalyst and the filtrate was concentrated in vacuum. The residue was dissolved in methanol and the resulting solution was added an excess of 10% hydrogen chloride in methanol. The mixture was concentrated and the resulting crystalline product was collected to obtain 0.20 g of the specified header Conn), a 2.01 (6H, s), 2,70-are 3.90 (7H, m) to 2.94 (1H, d, J = 16,0 Hz), 4,50-5,50 (2H, br), 6,92-7,19 (3H, m), 7,35 (1H, d, J = 8,0 Hz), 7,50-7,76 (1H, m), 9,40-and 10.20 (1H, br), 10,89 (1H, br, s).

Reference example 77

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(1-phenyl-3-indolyl)-1 - piperidinyl] methyl]-5-benzofuranol

A mixture of 2,3-dihydro-2,4,6,7-tetramethyl-2-[[1,2,3,6-tetrahydro-4-(1 - phenyl-3-indolyl)-1-pyridyl] methyl] -5-benzoguanamine (0.36 g), platinum oxide (72 mg), tetrahydrofuran (2 ml) and methanol (4 ml) was stirred 3.5 hours at 60oC under a hydrogen environment. The mixture was cooled, removed by filtration of the catalyst and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 5:1) to give 2,3-dihydro-2,4,6,7-tetramethyl-2-[[4-(1-phenyl-3-indolyl)-1 - piperidinyl]methyl] -5-benzoguanamine. The obtained product was dissolved in methanol and to the solution was added 1 equivalent of oxalic acid in methanol. The mixture was concentrated and to the residue was added ethanol and diethyl ether. The obtained powder product was collected, resulting in 0.10 g specified in the connection header. Yield 24%.

Amorphous solid.

1H-NMR (DMSO-d6) : 1,49 (3H, s), 1,84-of 2.36 (5H, m) of 1.97 (3H, s), 1,99 (3H, s), a 2.01 (3H, s), 2,90-3,70 (6H, m), 2.91 in (1H, d, J = 16,0 Hz), 3,12 (1H, d, J = 16,6-trimethylbenzoyl-5-yl]formamide

To a suspension of N-[4-hydroxy-2,6-dimethyl-3-(2-methyl-2 - propenyl)phenyl]formamide (16 g) and calcium carbonate (9.3 g) in tetrahydrofuran (60 ml) and methanol (60 ml) was slowly added benzyltrimethylammonium (27 g). The mixture was stirred for 10 minutes. Was removed by filtration of the insoluble material and the filtrate was concentrated in vacuum. To the residue were added ethyl acetate and water. Separated the organic layer and the aqueous layer was extracted with ethyl acetate. The combined organic layer washed with 10% hydrogen sulfite solution sodium, water, saturated aqueous sodium bicarbonate and aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuum. The residue was led from a mixture of ethyl acetate-diisopropyl ether to obtain 23 g specified in the connection header. Yield 93%.

So pl. 135-138oC.

1H-NMR (CDCl3) : 1,66, to 1.67 (3H, s), 2,13, 2,17 (3H, s), 2,21, of 2.24 (3H, s), 2,97 (1H, d, J = 15,7 Hz), 3,24 (1H, d, J = 15,7 Hz), 3,43, 3,44 (2H, s), 6,53, is 6.54 (1H, s), 6,58-6,87 (1H, m), 8,00 (0,45 H, d, J = and 12.2 Hz), to 8.41 (0,55 H, J = 1,4 Hz).

Reference example 79

N-[2,3-Dihydro-2-(iodomethyl)-7-isopropyl-2,4,6 - trimethylbenzene-5-yl] formamide

To a mixture of N-[2,3-dihydro-2-(iodomethyl)-2,4,6-trimethyl the cooling water. The mixture was stirred at room temperature for 1.5 hours and poured into ice. The product was extracted twice with a mixture of tetrahydrofuran and diisopropyl ether (1:2). The combined organic layer was washed saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuum. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 1:1) obtaining of 7.3 g specified in the connection header. Yield 94%.

Amorphous solid.

1H-NMR (CDCl3) : 1,27, of 1.28 (3H, d, J = 6,6 Hz), 1,30, of 1.32 (3H, d, J = 6,8 Hz), 1,64, to 1.67 (3H, s), 2,09, to 2.13 (3H, s), 2,19, of 2.23 (3H, s), with 2.93 (1H, d, J = 15,8 Hz), 3.04 from-with 3.27 (2H, m), 3,44, of 3.45 (2H, s), 6,72 (0.5 H, br, s), for 6.81 (0.5 H, br, d, J = and 12.2 Hz), 7,97 (0.5 H, d, J = and 12.2 Hz), to 8.41 (0.5 H, d, J = 1,6 Hz).

Reference example 80

2,3-Dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzofuranyl

To a solution of N-[2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6 - trimethylbenzene-5-yl] formamide (7,3 g) in methanol (40 ml) was added concentrated chloroethanol acid (10 ml). The mixture was heated under reflux for 1.5 hours under a nitrogen atmosphere, and poured into a slurry of sodium bicarbonate (20 g) in water and ethyl acetate. Separated organicstm aqueous solution of sodium chloride, was dried over magnesium sulfate, treated with activated carbon, filtered and the filtrate evaporated in vacuum. The residue was led from hexane to obtain 5.7 g specified in the connection header. Yield 84%.

So pl. 84-86oC.

1H-NMR (CDCl3) : of 1.29 (3H, d, J = 7,0 Hz), is 1.31 (3H, d, J = 7,0 Hz), of 1.62 (3H, s), of 2.06 (3H, s) by 2.13 (3H, s), of 2.92 (1H, d, J = 15,8 Hz), 3,11-of 3.27 (2H, m), 3,42 (2H, s).

Reference example 81

2,3-Dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1 - piperidinyl)methyl] -5-benzofuranyl

A suspension of 2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzoguanamine (1.1 g), 4-phenylpiperidine (0.87 g) and potassium carbonate (0,83 g) in N,N-dimethylacetamide (6 ml) was heated under reflux for 4.5 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuum. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 30:1-10:1) and recrystallized from a mixture of hexane-ethyl acetate to obtain 0.55 g specified in the connection header. Yield 47%.

So pl. 128-131oC.

1H-NMR (CDCl3) : 1,25 H, m).

Reference example 82

N-[2,3-Dihydro-2-(iodomethyl)-7-isopropyl-2,4,6,7 - tetramethylbenzidin-5-yl]formamide

To a suspension of N-[4-hydroxy-2,3,6-trimethyl-5-(2-methyl-2-propenyl)phenyl] formamide (187 g) and calcium carbonate (104 g) in tetrahydrofuran (600 ml) and methanol (600 ml) was slowly added benzyltrimethylammonium (307 g). The mixture was stirred for 10 minutes. Was removed by filtration of the insoluble material and the filtrate was concentrated in vacuum. To the residue were added ethyl acetate (800 ml) and water (400 ml). Separated the organic layer and the aqueous layer was extracted with ethyl acetate (400 ml). The combined organic layer washed with 10% hydrogen sulfite solution of sodium (400 g), water (300 ml), saturated aqueous sodium bicarbonate (300 ml) and aqueous solution of sodium chloride (300 ml). The organic layer was dried over magnesium sulfate, treated with activated carbon, filtered and the filtrate was concentrated in vacuum. The residue was led from a mixture of ethyl acetate-diisopropyl ether to obtain 271 g specified in the connection header. Yield 94%.

So pl. 145-147oC.

1H-NMR (CDCl3) : 1,66, to 1.67 (3H, s), 2,05-of 2.20 (9H, m), 2,98 (1H, d, J = 15,9 Hz), 3,24 (1H, d, J = 15,9 Hz), 3,42, of 3.43 (2H, s), 6,63-8,82 (1H, m), of 7.96 (0,45 H, d, J = 12,0 H

To a solution of N-[2,3-dihydro-2-(iodomethyl)-2,4,6,7-tetramethylbenzidin-5-yl] formamide (6.5 g) in methanol (40 ml) was added concentrated chloroethanol acid (10 ml). The mixture was heated under reflux for 1.5 hours under a nitrogen atmosphere, and was poured into a suspension of sodium bicarbonate (12 g) in water and ethyl acetate. Separated the organic layer and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, treated with activated carbon, filtered and the filtrate evaporated in vacuum. The residue was led from hexane to obtain 5.5 g specified in the connection header. Yield 91%.

So pl. 105-107oC.

1H-NMR (CDCl3) : of 1.64 (3H, s), 2,07 (6H, s), 2,12 (3H, s), 2,98 (1H, d, J = 15,6 Hz) at 3.25 (1H, d, J = 15,6 Hz), to 3.41 (2H, s).

Example 1

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(2-phenylethyl)-1 - piperidinyl]methyl] -5-benzofuranyl

In the autoclave was stirred under gaseous argon at 180oC for 15 hours a mixture of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.5 g), 4-(2-phenylethyl)piperidine (2.0 g) and triethylamine (5.3g). After cooling, the reaction mixture was diluted with saturated aqueous NaHCO3 , then drove under reduced pressure the solvent. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1:1) and recrystallized from diisopropyl ether to obtain 0.88 g specified in the connection header. Yield 42%.

So pl. 91-92oC.

1H-NMR (CDCl3) : of 1.17 and 1.35 (3H, m), of 1.42 (3H, s), 1,48 is 1.70 (4H, m), 1,99-2,17 (2H, m), 2,07 (6H, s), 2,10 (3H, s), a 2.45 (1H, d, J = 13,8 Hz), 2,53 (1H, d, J = 13,8 Hz), 2,55-to 2.65 (2H, m), and 2.79 (1H, d, J = 15,2 Hz), 2,82 of 2.92 (1H, m), 3,06-3,14 (1H, m), 3,10 (1H, d, J = 15,2 Hz), 7,13-7,20 (3H, m), 7,22-7,31 (2H, m).

Example 2

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(3-phenylpropyl)-1 - piperidinyl] methyl]-5-benzofuranyl

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 4-(3-phenylpropyl)piperidine, otherwise repeating the procedure of example 1 to obtain specified in the connection header. Yield 42%.

So pl. 79-80oC (recrystallized from a mixture of diisopropyl ether-hexane).

1H-NMR (CDCl3) : 1,15-1,30 (5H, m), of 1.41 (3H, s), 1,52-to 1.67 (4H, m), 1,98-2,17 (2H, m), of 2.06 (3H, s), 2,07 (3H, s), is 2.09 (3H, s), 2,44 (1H, d, J = 13,6 Hz), 2,53 (1H, d, J = 13,6 Hz), 2.57 m, t, J = 7,6 Hz), 2,78 (1H, d, J = 15,0 Hz), 2,81-is 2.88 (1H, m), 3.00 and-3,10 (1H, m) to 3.09 (1H, d, J = 15,0 Hz), 7,13-7,21 (3H, m), 7,22-7,30 (2H, m).

Example 3

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(4-phenylbutyl)-1 - piperidinyl] methyl]-5-Benin, in other respects repeating the procedure of example 1 to obtain specified in the connection header. Yield 62%.

So pl. 70-71oC (recrystallized from pentane).

1H-NMR (CDCl3) : 1,10-1,39 (7H, m), of 1.41 (3H, s) and 1.51-of 1.65 (4H, m), 1,98-to 2.18 (2H, m), of 2.06 (3H, s), 2,07 (3H, s), is 2.09 (3H, s), 2,44 (1H, d, J = 13,8 Hz), 2,52 (1H, d, J = 13,8 Hz), at 2.59 (2H, t, J = 7,4 Hz), and 2.79 (1H, d, J = 15,2 Hz), 2,83-is 2.88 (1H, m), 3.00 and-3,10 (1H, m), 3,10 (1H, d, J = 15,2 Hz), 7,12-7,20 (3H, m), 7.23 percent-7,30 (2H, m).

Example 4

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-[(3,4-methylenedioxyphenyl)methyl] -1 - piperazinil]methyl]-5-benzophenonetetracarboxylic

In the autoclave was stirred under gaseous argon at 180oC for 15 hours a mixture of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.5 g), 1-[(3,4-methylenedioxyphenyl)methyl]piperazine (2.5 g) and triethylamine (1.6 g). After cooling, the reaction mixture was diluted with saturated aqueous NaHCO3and were extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over MgSO4, then drove away under reduced pressure the solvent. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol = 100:0-95:5) and was treated with 4 N HCl solution in ethanol to convert trihydrochloride. This product SS="ptx2">

1H-NMR (DMSO-d6) : is 1.51 (3H, s), 2,03 (3H, s), 2,22 (3H, s), of 2.23 (3H, s), 2,96 (1H, d, J = 16,8 Hz) at 3.25 (1H, d, J = 16,8 Hz), 3,40 (10H, br, s), 4,25 (2H, s), the 6.06 (2H, s), 6,97 (1H, d, J = 8,9 Hz), was 7.08 (1H, d, J = 8,0 Hz), 7,29 (1H, s), 9,85 (2H, br, s).

Example 5

2-[(4-Benzyl-1-piperidinyl)methyl] -2,3-dihydro-2,4,6,7 - tetramethyl-5-benzofuranyl

In the autoclave was stirred under nitrogen gas at 180oC for 15 hours a mixture of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (0.85 grams), 4-benzylpiperidine (1.1 g) and triethylamine (1.3 ml). This reaction mixture was diluted with saturated aqueous NaHCO3and was extracted with 2 portions with ethyl acetate. The combined organic layer was washed saturated aqueous NaCl and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane:ethanol = 10:1) and was led from hexane to obtain 0,86 g specified in the connection header. Yield 78%.

So pl. 71-73oC.

1H-NMR (CDCl3) : 1,1-1,7 (5H, m), of 1.41 (3H, s), 1,9-2,2 (2H, m), 2.06 to (9H, s), of 2.3 to 2.6 (4H, m), 2,7-2,9 (1H, m), and 2.79 (1H, d, J = 15,4 Hz), to 3.0-3.2 (1H, m), 3,10 (1H, d, J = 15,4 Hz), 7,1-7,3 (5H, m).

Example 6

2-[(4-Benzyl-1-piperazinil)methyl] -2,3-dihydro-2,4,6,7 - tetramethyl-5-benzophenonetetracarboxylic

So pl. 210-215oC.

1H-NMR (DMSO-d6) : 1,50 (3H, s), 2,02 (3H, s), 2,22 (3H, s), of 2.23 (3H, s), 2,97 (1H, d, J = 16,1 Hz), is 3.0-4.2 (10H, m) of 3.25 (1H, d, J = 16,1 Hz), 4,35 (2H, s), between 7.4 to 7.5 (3H, m), 7,55 to 7.7 (2H, m), from 9.6 to 10.2 (2H, br).

Example 7

2-[(4-Benzyloxy-1-piperidinyl)methyl] -2,3-dihydro-2,4,6,7 - tetramethyl-5-benzofuranyl

The ethyl acetate suspended 2.0 g of 4-benzyloxybenzaldehyde and the suspension was neutralized 1 N aqueous solution of sodium hydroxide. Separated the organic layer and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4was filtered and the filtrate was concentrated under reduced pressure. To a solution prepared by dissolving the obtained 4-benzyloxypyridine in 0.5 ml of toluene, was added 1.1 g of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine and 2.8 ml of triethylamine and the mixture was stirred autoclave under nitrogen gas at 180oC for 15 hours. This reaction mixture Ruzbachy layer was washed with water and saturated aqueous NaCl, dried over MgSO4was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane:ethyl acetate = 1:1) and recrystallized from a mixture of ethyl acetate-hexane to obtain 1.1 g specified in the connection header. Yield 67%.

So pl. 85-86oC.

1H-NMR (CDCl3) : of 1.42 (3H, s), of 1.5-2.1 (4H, m), 2,07 (6H, s), is 2.09 (3H, s) 2,1-of 2.45 (2H, m), 2,47 (1H, d, J = 13,8 Hz), 2,56 (1H, d, J = 13,8 Hz), of 2.7-3.1 (2H, m), 2,80 (1H, d, J = 15,4 Hz), 3,10 (1H, d, J = to 15.4 Hz), 3,3 is-3.45 (1H, m), a 4.53 (2H, s), of 7.2 to 7.4 (5H, m).

Example 8

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-[(3-phenyl-2 - propenyl)oxy] -1-piperidinyl]methyl]-5-benzofuranyl

Using 4-[(3-phenyl-2-propenyl)oxy] piperidinedione, otherwise repeating the procedure of example 7 to obtain specified in the connection header. A 71% yield.

So pl. 77-79oC (crystallized from a mixture of diethyl ether-hexane).

1H-NMR (CDCl3) : 1,4-2,0 (4H, m), of 1.42 (3H, s), 2,07 (6H, s), 2,10 (3H, s), of 2.1-2.4 (2H, m), 2,48 (1H, d, J = 13,8 Hz), 2,56 (1H, d, J = 13,8 Hz), of 2.7-3.1 (2H, m), 2,80 (1H, d, J = 15,4 Hz), 3,10 (1H, d, J = to 15.4 Hz), of 3.25 to 3.45 (1H, m), 4,16 (2H, dd, J = 5,9, 1,1 Hz), of 6.29 (1H, dt, J = 15,8, 5,9 Hz), 6,60 (1H, d, J = 15,8 Hz), 7,15 was 7.45 (5H, m).

Example 9

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-[(3-phenylpropyl)oxy] -1 - piperidinyl]methyl]-5-benzofuranyl

Suspe palladium on carbon (0,23 g) in tetrahydrofuran (10 ml) was stirred under a hydrogen environment at room temperature for 1 hour. Then the catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was led from hexane to obtain 0.36 g specified in the connection header. Yield 31%.

So pl. 53-54oC (crystallized from hexane).

1H-NMR (CDCl3) : 1,4-1,7 (2H, m), of 1.42 (3H, s), 1,7-2,0 (4H, m), 2,07 (6H, s), 2,10 (3H, s) of 2.1-2.4 (2H, m), 2,47 (1H, d, J = 14,0 Hz), 2,56 (1H, d, J = 14,0 Hz), 2,69 (2H, t, J = 7,5 Hz), of 2.7-3.1 (2H, m), 2,80 (1H, d, J = to 15.4 Hz), 3,10 (1H, d, J = 15,4 Hz), 3,1-3,3 (1H, m), 3,42 (2H, t, J = 6,4 Hz), 7,1-to 7.35 (5H, m).

Example 10

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(4-phenylbutyl)-1 - piperazinil]methyl]-5-benzofuranyl

To a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimides (0,22 g) and 1-hydroxybenzotriazole (0,13 g) in N,N-dimethylformamide (5 ml) was added 0.12 g of 4-phenylalkanoic acid at 0oC and the mixture was stirred at this temperature for 5 minutes and then at room temperature for 2 hours. This reaction mixture was added to a solution of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinil)methyl] -5-benzoguanamine (0.20 g) in N,N-dimethylformamide (2 ml) at 0oC and the mixture was stirred for another 30 minutes. This reaction mixture was poured into water and was extracted with ethyl acetate. The extract was dried on MgSO4and drove away under reduced pressure the solvent. OST is in the connection header. Yield 74%.

Oil.

1H-NMR (CDCl3) : of 1.42 (3H, s), of 1.97 (2H, m), is 2.05 (3H, s), 2,07 (6H, s), is 2.30 (2H, t, J = 8,0 Hz), 2.4 to 2.8 (10H, m), 2,80 (1H, d, J = 15,1 Hz), 3,10 (1H, d, J = 15,1 Hz), 3,32 (2H, t, J = 4,8 Hz), of 3.57 (2H, t, J = 5,0 Hz), 7,1-7,3 (5H, m).

Example 11

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(4-phenylbutyl)-1 - piperazinil] methyl]-5-benzophenonetetracarboxylic

A mixture of 2,3-dihydro-2,4,6,7-tetramethyl-2-[[4-(4-phenylbutyl)-1 - piperazinil)methyl] -5-benzoguanamine (0,47 g), sociallyengaged (83 mg) and tetrahydrofuran (7 ml) was heated under reflux under gaseous argon for 1 hour. After cooling, the reaction mixture was poured on crushed ice and extracted with ethyl acetate. The extract was dried on MgSO4and drove away under reduced pressure the solvent. The residue was purified by column chromatography on silica gel (ethyl acetate) and recrystallized from a mixture of hexane-diisopropyl ether to obtain 0.35 g of the free base specified in the connection header. Yield 76%. This free base was treated with a 4.8 N solution of HCl in ethanol to convert trihydrochloride and then recrystallized from methanol-diisopropyl ether to obtain 0.12 g specified in the connection header. The output of 21%.

So pl. 190-193oC.

Example 12

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(3-phenylpropionyl)-1 - piperazinil] methyl]-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinil]methyl]-5-benzofuranyl and 3-phenylpropionate acid, otherwise repeating the procedure of example 10 to obtain specified in the connection header. The yield was 73%.

Oil.

1H-NMR (CDCl3) : of 1.41 (3H, s), 2,07 (9H, s), 2,4-3,1 (12H, m) to 3.33 (2H, t, J = 5,1 Hz), to 3.58 (2H, t, J = 5,1 Hz), 7,1-7,3 (5H, m).

Example 13

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(3-phenylpropyl)-1 - piperazinil] methyl]-5-benzophenonetetracarboxylic

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[[4-(3- phenylpropionyl)-1-piperazinil]methyl]-5-benzofuranyl, otherwise repeating the procedure of example 11 to give specified in the connection header. Exit 19%.

So pl. 200-202oC (recrystallized from methanol-diethyl ether).

1H-NMR (DMSO-d6) : 1,49 (3H, s), 2,03 (5H, m), 2,22 (6H, s) of 2.64 (2H, t, J = 7,7 Hz), 2,8-3,7 (14H, m) and 7.1 to 7.4 (5H, m), a 9.7-9,9 (2H, br, s).

Example 14

2-[[4-(2,2-Diphenylether)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl

Using 2-[[4-(2,2-diphenylacetyl)-1-piperazinil]methyl]-2,3 - dihydro-2,4,6,7-tetramethyl-5-benzofuranyl, in other relations who 130-132oC (recrystallized from a mixture of ethyl acetate-diisopropyl ether).

1H-NMR (CDCl3) : of 1.39 (3H, s), of 2.06 (3H, s), 2,07 (6H, s), 2,10-2,70 (10H, m), 2,78 (1H, d, J = 15,4 Hz), 2,96 (2H, s, J = 7,4 Hz), 3,10 (1H, d, J = 15,4 Hz), 4,20 (1H, t, J = 7,4 Hz), 7,00-7,40 (10H, m).

Example 15

2-[[4-(3,3-Diphenylpropyl)-1-piperazinil] methyl] -2,3 - dihydro-2,4,6,7-tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinil)methyl]-5-benzofuranyl and 3.3-diphenylpropionic acid, otherwise repeating the procedure of example 10 to obtain specified in the connection header. Yield 72%.

So pl. 77-78oC (recrystallized from a mixture of ethyl acetate-diisopropyl ether).

1H-NMR (CDCl3) : of 1.40 (3H, s), 2,07 (3H, s), is 2.09 (6H, s), 2.00 in 2,60 (6H, m), of 2.81 (1H, d, J = 15,0 Hz), 3,03 (2H, d, J = 7,4 Hz), 3,06 (1H, d, J = 15,0 Hz), and 3.31 (2H, t, J = 4,6 Hz), 3,52 (2H, t, J = 4,6 Hz), of 4.66 (1H, t, J = 7,4 Hz), 7,10-7,40 (10H, m).

Example 16

2-[[4-(3,3-Diphenylpropyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using as starting material 2-[[4-(3,3-diphenylpropyl)-1-piperazinil] methyl]-2,3-dihydro-2,4,6,7 - tetramethyl-5-benzofuranyl got free base as in example 11. Yield 78%.

Oil.

1H-NMR (CDCl3) : of 1.41 (3H, s), the article was treated with a 4.8 N solution of HCl in ethanol and the resulting trihydrochloride recrystallized from methanol-diisopropyl ether to obtain specified in the connection header.

So pl. 200-203oC.

Example 17

2-[[4-(Diphenylmethoxy)-1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7 - tetramethyl-5-benzofuranol

Using 4-(diphenylmethoxy)piperidine, otherwise repeating the procedure of reference example 3 to obtain 2-[(4-diphenylmethoxy-1-piperidinyl)methyl]-2,3-dihydro-2,4,6,7 - tetramethyl-5-benzoguanamine. This product was dissolved in ethanol followed by addition of one equivalent of oxalic acid in ethanol. This mixture was heated and the resulting solution was cooled. Then to the solution was added diethyl ether for crystallization and the result has been specified in the header connection. Yield 26%.

So pl. 173-175oC.

1H-NMR (DMSO-d6) : of 1.41 (3H, s), 1,6-2,1 (4H, m), a 1.96 (9H, s), 2,7-3,4 (8H, m), 3,4-3,6 (1H, m), 5,64 (1H, s), 7,15-of 7.3 (10H, m).

Example 18

2-[[4-(2,2-Diphenylacetyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7 - tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinil)methyl]-5-benzofuranyl and 2,2-diphenylacetate, otherwise repeating the procedure of example 10 to obtain specified in the connection header. Yield 67%.

So pl. 113-115oC (recrystallized from a mixture of ethyl acetate-diisopropyl ether).<, ,39 (2H, t, J = 4,8 Hz), the 3.65 (2H, t, J = 4,8 Hz), 5,19 (1H, s), 7,10-7,40 (10H, m).

Example 19

2-[14-[2-(Diphenylmethoxy)ethyl] -1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 1-[2-(diphenylmethoxy)ethyl]piperazine, otherwise repeating the procedure of example 4 to obtain specified in the connection header. Exit 33%.

So pl. 173-176oC (recrystallized from a mixture of ethanol-diethyl ether).

1H-NMR (DMSO-d6) : and 1.54 (3H, s), 2,03 (3H, s), 2,24 (6H, s), 2.95 and-3,78 (16H, m), to 5.57 (1H, s), 7,25-7,44 (10H, m).

Example 20

2-[[4-[3-(Diphenylmethoxy)propyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 1-[3-(diphenylmethoxy)propyl] piperazine, otherwise repeating the procedure of example 4 to obtain specified in the connection header. Yield 54%.

So pl. 193-196oC (recrystallized from ethanol).

1H-NMR (DMSO-d6) : and 1.54 (3H, s), is 2.05 (5H, br, s), 2,24 (6H, s), 2.95 and-3,63 (16H, m), of 5.48 (1H, s), 7,34 and 7.36 (10H, m).

Example 21

2-[[4-[4-(Diphenylmethoxy)butyl] -1-piperazinil)methyl] -2,3 - dihydro-2,4,6,7-tetramethyl-5-benzofurans)butyl]piperazine, in other respects repeating the procedure of example 4 to obtain specified in the connection header. Yield 43%.

So pl. 203-205oC (recrystallized from ethanol).

1H-NMR (DMSO-d6) : and 1.54 (3H, s), of 1.62 (2H, br, s), of 1.80 (2H, br s), is 2.05 (3H, s), of 2.23 (3H, s), 2,24 (3H, s), 2,94-to 3.58 (16H, m), 5,44 (1H, s), 7,20-7,38 (10H, m).

Example 22

2-[[4-[5-(Diphenylmethoxy)pentyl] -1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 1-[5-(diphenylmethoxy)pentyl] piperazine, otherwise repeating the procedure of example 4 to obtain specified in the connection header. Yield 45%.

So pl. 186-189oC (Razlog., recrystallized from ethanol).

1H-NMR (DMSO-d6) : 1,31-to 1.70 (6H, m), of 1.53 (3H, s), is 2.05 (3H, s), 2,24 (6H, s), 2,94-to 3.58 (16H, m), 5,42 (1H, s), 7,20-7,39 (10H, m).

Example 23

2-[[4-[6-(Diphenylmethoxy)hexyl] -1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 1-[6-(diphenylmethoxy)hexyl] piperazine, otherwise repeating the procedure of example 4 to obtain specified in the connection header. Yield 60%.

So pl. 183-186o

Example 24

2-[[4-[(Diphenylmethoxy)methyl] -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranol

In the autoclave was stirred under gaseous argon at 180oC for 15 hours a mixture of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.5 g), 4-[(diphenylmethoxy)methyl)piperidine (3.0 g) and triethylamine (7.4 ml). This reaction mixture was diluted with water and was exagerately with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1:1) to give 2.4 g of 2-[[4-[(diphenylmethoxy)methyl] -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine. Yield 95%. This product was treated with 0.45 g of oxalic acid and then recrystallized from ethanol to obtain 1.8 g specified in the connection header. Yield 58%.

So pl. 125-127oC.

1H-NMR (DMSO-d6) : 1,36-to 1.79 (5H, m) of 1.39 (3H, s), a 1.96 (9H, s), 2,60-3,34 (10H, m), of 5.40 (1H, s), 7,21-7,34 (10H, m).

Example 25

2-[[4-[2-(Diphenylmethoxy)ethyl] -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranol

Using 2-methyl bromide-2,3 is rocedure example 24 to obtain specified in the connection header. Yield 32%.

So pl. 107-110oC (recrystallized from ethanol).

1H-NMR (DMSO-d6) : 1,36-1,72 (7H, m), USD 1.43 (3H, s), a 1.96 (9H, s), 2,70-is 2.88 (3H, m) 3,00-3,25 (4H, m), 3,38 is-3.45 (3H, m), of 5.40 (1H, s), 7,20-7,39 (10H, m).

Example 26

2-[[4-[3-(Diphenylmethoxy)propyl] -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranol

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 4-[3-(diphenylmethoxy)propyl] piperidine, otherwise repeating the procedure of example 24 to obtain specified in the connection header. Yield 40%.

So pl. 109-111oC (recrystallized from ethanol).

1H-NMR (DMSO-d6) : 1,22 and 1.80 (9H, m), of 1.40 (3H, s), to 1.98 (9H, s), 2,65 is 3.40 (10H, m), of 5.40 (1H, s), 7,20-7,38 (10H, m).

Example 27

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(2-phenylethyl)-1-piperazinil] methyl] -5-benzofuranyl

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and 1-(2-phenylethyl)piperazine, otherwise repeating the procedure of example 1 to obtain specified in the connection header. The yield is 50%.

So pl. 99-100oC (recrystallized from a mixture of diisopropyl ether-pentane).

1H-NMR (CDCl3) : of 1.33 (3H, s), to 1.98 (6H, s), from 2.00 (3H, s), 2,38-2,75 (15H, m), 3.04 from (1H, d, J = 15,0 Hz), 7,08-7,19 (5H, m).

exalt

A suspension of 4-[bis(4-forfinal)methoxy]piperidine (3.8 g) obtained as in reference example 27, 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.4 g) and potassium carbonate (1.4 g) in N,N-dimethylacetamide (10 ml) was heated under reflux under nitrogen gas for 15 hours. This reaction mixture was diluted with water and was extracted with 2 portions with ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane: ethyl acetate = 2: 1-1: 1) to obtain 2-[[4-[bis(4-forfinal)methoxy] -1 - piperidinyl)methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine. This product was dissolved in ethanol followed by addition of 1 equivalent of oxalic acid in ethanol. This mixture was heated and the resulting solution was concentrated under reduced pressure and recrystallized from methanol to obtain 1.5 g specified in the connection header. Yield 52%.

So pl. 181-185oC.

1H-NMR (DMSO-d6) : of 1.40 (3H, s), 1,6-2,1 (4H, m), a 1.96 (9H, s), 2,6-3,3 (8H, m), 3,3-3,6 (1H, m), of 5.68 (1H, s), to 7.15 (4H, t, J = 9,0 Hz), 7,39 (4H, dd, J = 8,6, 5,6 Hz).

Example 29

2,3-Digue is AB 2,3-dihydro-2-[[4-(4-methoxybenzoyl)-1 - piperazinil]methyl] -2,4,6,7-tetramethyl-5-benzofuranyl, in other respects repeating the procedure of example 11 to give specified in the connection header. Yield 85%.

So pl. 197-202oC (recrystallized from water-ethanol mixture).

1H-NMR (DMSO-d6) : to 1.48 (3H, s), 2,03 (3H, s), of 2.23 (6H, s), 2,70-4,40 (17H, m), of 6.99 (2H, d, J = 8,8 Hz), 7,53 (2H, d, J = 8,8 Hz), 9,80 (2H, br, s).

Example 30

2,3-dihydro-2-[[4-(3-methoxybenzyl)-1-piperazinil]methyl]-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2,3-dihydro-2-[[4-(3-methoxybenzoyl)-1-piperazinil]methyl]-2,4,6,7-tetramethyl-5-benzofuranyl, otherwise repeating the procedure of example 11 to give specified in the connection header. Yield 74%.

So pl. 196 to 199oC (recrystallized from water-ethanol mixture).

1H-NMR (DMSO-d6) : and 1.54 (3H, s), 2,04 (3H, s), 2,24 (6H, s), 2,97 (1H, d, J = 16,2 Hz), 3,20-4,50 (16H, m), 7,01 (1H, d, J = 8,0 Hz), 7,18 (1H, d, J = 7,0 Hz), 7,30-7,46 (2H, m), 9,90 (2H, br, s).

Example 31

2,3-Dihydro-2-[[4-(2-methoxybenzyl)-1-piperazinil]methyl]-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2,3-dihydro-2-[[4-(2-methoxybenzoyl)-1-piperazinil]methyl]-2,4,6,7-tetramethyl-5-benzofuranyl, otherwise repeating the procedure of example 11 to give specified in the connection header. Yield 67%.

So pl. 202-204oH, s), 2,70-of 3.80 (10H, m), 3,86 (3H, s), 4,10-4,70 (4H, m), 7,00-7,20 (2H, m), 7,40-of 7.70 (2H, m), 9,83 (2H, br, s).

Example 32

2-[[4-(3,4-Dimethoxybenzyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2,3-dihydro-2-[[4-(3,4-dimethoxybenzoyl)-1-piperazinil] methyl] -2,4,6,7-tetramethyl-5-benzofuranyl, otherwise repeating the procedure of example 11 to give specified in the connection header. Yield 77%.

So pl. 176-179oC (recrystallized from water-ethanol mixture).

1H-NMR (DMSO-d6) : 1,49 (3H, s), 2,03 (3H, s), 2,22 (6H, s), 2,70-4,40 (20H, m), 6,98 (1H, d, J = 7,6 Hz), was 7.08 (1H, d, J = 7,6 Hz), 7,39 (1H, s), 9,80 (2H, br, s).

Example 33

2-[[4-(4-Chlorobenzyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2-[[4-(4-chlorobenzoyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl, otherwise repeating the procedure of example 11 to give specified in the connection header. Yield 91%.

So pl. 198-200oC (recrystallized from water-ethanol mixture).

1H-NMR (DMSO-d6) : USD 1.43 (3H, s), 2,02 (3H, s), measuring 2.20 (3H, s), 2,22 (3H, s), 2,70-4,40 (14H, m), 7,54 (2H, d, J = 7,6 Hz), 7,63 (2H, d, J = 7,6 Hz), 9,75 (2H, br, s).

Example 34

2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(4-methylbenzyl)-1-pipe)-1-piperazinil]methyl]-5-benzofuranyl, in other respects repeating the procedure of example 11 to give specified in the connection header. Yield 36%.

So pl. 183-186oC (recrystallized from water-ethanol mixture).

1H-NMR (DMSO-d6) : 1,50 (3H, s), from 2.00 (3H, s), measuring 2.20 (6H, s), of 2.34 (3H, s), 2,80-4,20 (12H, m), 4,28 (2H, s), 7,25 (2H, d, J = 7,6 Hz), 7,49 (2H, d, J = 7,6 Hz), 9,78 (2H, br, s).

Example 35

2-[[4-(4,4-Diphenylbutyric)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinil]methyl]-5-benzofuranyl 4,4-diphenylmethane acid, otherwise repeating the procedure of example 10 to obtain specified in the connection header. Yield 29%.

So pl. 135-138oC (recrystallized from a mixture of ethyl acetate-diisopropyl ether).

1H-NMR (CDCl3) : of 1.41 (3H, s), 2,07 (9H, s), 2,10-2,70 (10H, m), 2,80 (1H, d, J = 14,7 Hz), to 3.09 (1H, d, J = 14,7 Hz), 3,10 is 3.40 (4H, m), 3,55 (2H, t, J = 5,2 Hz), 3,95 (1H, t, J = 7,7 Hz), 7,10-of 7.70 (10H, m).

Example 36

2-[[4-(4,4-Diphenylmethyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2-[[4-(4,4-diphenylbutyric)-1-piperazinil] methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl, otherwise repeating the procedure of example 11 to give specified in the header with the LASS="ptx2">

1H-NMR (DMSO-d6) : 1,50 (3H, s), 1,55-1,65 (2H, m), 2,03 (5H, br, s), of 2.23 (6H, s), 2,60-4,30 (15H, m), 7,10-7,40 (10H, m), 9,70-10,00 (2H, br, s).

Example 37

2-[[4-(5,5-Diphenylvinyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl

Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinil]methyl]-5-benzofuranyl and 5.5-diphenylalanine acid, otherwise repeating the procedure of example 10 to obtain specified in the connection header. Yield 86%.

Oil.

1H-NMR (CDCl3) : of 1.41 (3H, s), 1,50-1,70 (2H, m), 2,20-2,70 (21H, m), of 2.81 (1H, d, J = 15,4 Hz), to 3.09 (1H, d, J = 15,4 Hz), or 3.28 (2H, t, J = 4,8 Hz), 3,53 (2H, t, J = 4,8 Hz), 3,90 (1H, t, J = 8,2 Hz), 7,20-7,40 (10H, m).

Example 38

2-[[4-(5,5-Diphenylmethyl)-1-piperazinil] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

Using 2-[[4-(5,5-diphenylvinyl)-1-piperazinil] methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl, otherwise repeating the procedure of example 11 to give specified in the connection header. Yield 86%.

So pl. 177-181oC (recrystallized from methanol-diethyl ether).

1H-NMR (DMSO-d6) : 1,05-1,25 (2H, m), the 1.44 (3H, s), 1,60-1,80 (2H, m), 1,90-2,10 (5H, m), of 2.21 (6H, s), 2.40 a-4,00 (15H, m), 7,10-7,40 (10H, m), 9,75 (2H, br, s).

Example 39

1-[(5-Amino-2,3-dihydro-2,4,6,7-tet is rameil-5-benzofuranyl and N-(diphenylmethyl)-4-piperidylamine, in other respects repeating the procedure of example 1 to obtain specified in the connection header. Yield 38%.

So pl. 128-129oC (recrystallized from a mixture of ethyl acetate-hexane).

1H-NMR (CDCl3) : 1,25-for 1.49 (2H, m), of 1.39 (3H, s), 1,79-of 1.92 (2H, m), 2.00 in 2,19 (2H, m), is 2.05 (3H, s), of 2.06 (3H, s), of 2.08 (3H, z), 2,30-of 2.54 (3H, m), 2,73-2,84 (2H, m), 2,96-3,11 (2H, m) to 5.00 (2H, s), 7,17-7,39 (10H, m).

Example 40

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidinemethanol

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidine (2.2 g) was treated with 4 N HCl solution in ethanol and the resulting trihydrochloride recrystallized from a mixture of ethanol-diethyl ether to obtain 2.5 g specified in the connection header. Yield 87%.

So pl. 200-203oC (Razlog.).

1H-NMR (DMSO-d6) : of 1.57 (3H, s), 2,04 (3H, s), 2,18 at 2.59 (4H, m), of 2.23 (6H, s), 2,98-3,76 (9H, m), 5,74 (1H, s), 7,30-7,44 (6H, m), 7,86-of 7.90 (4H, m).

Example 41

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(diphenylmethyl)-4-piperidinecarbonitrile

To a solution of tert-butyl[2-[[4-[2-[(diphenylmethyl)amino]ethyl]-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl]carbamate (1.6 g) in ethanol (3 ml) was added 10 MESI was podslushivaet aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over MgSO4. Drove under reduced pressure the solvent to obtain 1.3 g of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl]-N-(diphenylmethyl)-4-piperidylamine. Yield 97%. This product was treated with 4 N HCl solution in ethanol and the resulting trihydrochloride recrystallized from a mixture of ethanol-diethyl ether to obtain 1.3 g specified in the connection header. Yield 76%.

So pl. 197-199oC (Razlog.).

1H-NMR (DMSO-d6) : 1,50-1,80 (7H, m), of 1.57 (3H, s), 2,04 (3H, s), 2,24 (6H, s), 2,80-3,75 (10H, m), the ceiling of 5.60 (1H, br, s), 7,38-7,58 (6H, m), 7,78 (4H, d, J = 7,8 Hz).

Example 42

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(3,3-diphenylpropyl)-4-piperidinecarbonitrile

Using tert-butyl[2-[[4-[2-[(3,3-diphenylpropyl)amino]ethyl]-1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl]carbamate, otherwise repeating the procedure of example 41 with obtaining specified in the connection header. Yield 23%.

So pl. 180-181oC (recrystallized from a mixture of ethanol-diethyl ether).

1H-NMR (DMSO-d6) : was 1.58 (3H, s), 1.77 in (9H, br, s), is 2.05 (3H, s), of 2.23 (6H, s), 2,73-3,69 (12H, m), 4,10-to 4.14 (1H, m), 7.18 in-to 7.32 (10H, m).

Example 43

1-[(5-Aminoester 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(diphenylmethyl)-4-piperazinecarboxamide (1.3 g) in tetrahydrofuran (20 ml) was added 17 ml of 1 M solution of borane tertrahydrofuran ring complex in tetrahydrofuran under ice cooling and the mixture was heated under reflux under a gaseous nitrogen for 23 hours. After cooling the reaction mixture with ice, was added dropwise 12 ml of 5 N chloroethanol acid and the mixture was concentrated under reduced pressure. The residue was neutralized with sodium bicarbonate and was extracted with 2 portions of ethyl acetate. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgS04, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane: ethanol = 10: 1) to obtain the 0,89 g of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] - N-(diphenylmethyl)-4-piperidinylidene. Yield 68%. This product was dissolved in methanol and added dropwise stoichiometric excess 10% HCl solution in methanol. The mixture was concentrated under reduced pressure to obtain specified in the connection header.

Amorphous solid.

1H-NMR (DMSO-d6) : 1,3-2,2 (5H, m) to 1.48 (3H, s), to 1.98 (3H, s), from 2.00 (6H, s), 2,3-3,7 (10H, m), 4,0-4,3 (1H, br), of 5.48 (1H, br, s), 7,2-7,6 (6H, m), and 7.6 to 7.9 (4H, m).

Example 44

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(2,2-diphenylether)-4-piperidinecarbonitrile

To a solution of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(2,2-diphenylether)-4-Pipa is Lex in tetrahydrofuran dropwise under ice cooling and the mixture was heated under reflux under nitrogen gas for 6 hours. After cooling the reaction mixture with ice was added dropwise 8 ml of 5 N chloroethanol acid, followed by stirring. The mixture was added dropwise to a suspension of sodium bicarbonate (4 g) in a mixture of water-diisopropyl ether to neutralize it and was extracted with 2 portions of ethyl acetate. The combined organic layer was washed saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. After dissolution of the residue in methanol was added 10 ml of 5 N chloroethanol acid and the mixture was heated under reflux for 1 hour. After cooling with ice and the mixture was diluted with 20 ml of 5 N aqueous sodium hydroxide solution and was extracted with 3 portions of diethyl ether. The combined organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane: ethyl acetate: triethylamine= 30:10:1-20:10:1) obtaining 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(2,2-diphenylether)-4-piperidinylidene. After dissolving the product in methanol was added dropwise a stoichiometric excess of 10% HCl solution in methanol and the resulting mixture concentrate is isomorphous solid.

1H-NMR (DMSO-d6) : of 1.4-2.3 (5H, m), of 1.57 (3H, s), 2,04 (3H, s), of 2.23 (6H, s), 2,6-3,8 (12H, m), 4,6-4,8 (1H, m) and 7.1 and 7.5 (10H, m), 8,9-9,2 (2H, br), 9,5 to 10.1 (3H, br), or 10.3 to 10.6 (1H, br).

Example 45

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(3,3-diphenylpropyl)-4-piperidinecarbonitrile

Using 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl]-N-(3,3-diphenylpropyl)-4-piperidinecarboxylic (free base obtained in reference example 50), otherwise repeating the procedure of example 44 to obtain specified in the connection header. Yield 46%.

So pl. 168-172oC (crystallized from methanol-diethyl ether).

1H-NMR (DMSO-d6) : 1,3-2,2 (5H, m) of 1.46 (3H, br, s), to 1.98 (9H, s), 2,3-3,5 (14H, m), 4.09 to (1H, t, J = 7,5 Hz), and 7.1 to 7.4 (10H, m).

Example 46

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-benzyl-N-(3,3-diphenylpropyl)-4-piperidinemethanol

Using 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranyl and N-benzyl-N-(3,3-diphenylpropyl)-4-piperidylamine, otherwise repeating the procedure of example 1 to obtain 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-benzyl-N-(3,3-diphenylpropyl)-4-piperidylamine. Yield 60%.

Oil.

1H-NMR (CDCl7,6 Hz), 7,11-7,30 (15H, m).

Obtained in the manner described above 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N - benzyl-N-(3,3-diphenylpropyl)-4-piperidine (1.0 g) was treated with 4 N HCl solution in ethanol and the resulting trihydrochloride recrystallized from a mixture of ethanol-diethyl ether to obtain 0.65 g specified in the connection header. Yield 53%.

So pl. 185-187oC.

1H-NMR (DMSO-d6) : to 1.59 (3H, s), 1.93 and is 2.55 (6H, m), of 2.06 (3H, s), 2,24 (6H, s), was 2.76-3,60 (9H, m), 3,79-of 3.94 (3H, m), 4,23-of 4.49 (2H, m), 7,16-of 7.23 (10H, m), 7,38-7,42 (3H, m), 7,66-7,71 (2H, m).

Example 47

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(3,3-diphenylpropyl)-4-piperidinemethanol

To a solution of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-benzyl-N-(3,3-diphenylpropyl)-4-piperidylamine (1.5 g) in ethanol (50 ml) was added to 0.30 g of 5% palladium on carbon (50% aqueous solution) and the mixture was stirred in a hydrogen environment at a pressure of 5 atmospheres and at 40oC for 6 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 1.2 g of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] - N-(3,3-diphenylpropyl)-4-piperidylamine. Yield 94%. This product was treated with 4 N HCl solution in ethanol the CSOs in the connection header. Yield 82%.

So pl. 187-189oC (Razlog.).

1H-NMR (DMSO-d6) : was 1.58 (3H, s), 2,02-of 2.26 (4H, m), is 2.05 (3H, s), of 2.23 (6H, s), 2,78 (2H, br, s), 3.00 and-3,55 (10H, m), of 3.77-3,91 (1H, m), 4,14 (1H, t, J = 7,6 Hz), 7,20-7,33 (10H, m).

Example 48

2-[2-[4-(Diphenylmethoxy)-1-piperidinyl] ethyl] -2,3-dihydro-2,4,6,7 - tetramethyl-5-benzofuranol

Using as starting material tert-butyl[2-[2-[4-(diphenylmethoxy)-1-piperidinyl] ethyl] -2,3-dihydro-2,4,6,7 - tetramethylbenzidin-5-yl] carbamate, otherwise repeating the procedure of example 41 to obtain 2-[2-[4-(diphenylmethoxy)-1-piperidinyl]ethyl]-2,3-dihydro-2,4,6,7 - tetramethyl-5-benzoguanamine. Yield 84%. This compound was converted to the oxalate and recrystallized from ethanol to obtain specified in the connection header. Yield 45%.

So pl. 137-139oC.

1H-NMR (DMSO-d6) : 1,31 (3H, s), 1,62 is 2.01 (6H, m), of 1.94 (6H, s), a 1.96 (3H, s), 2.77-to 3,20 (8H, m), 3,53 (1H, br, s), the 5.65 (1H, s), 7,20-7,38 (10H, m).

Example 49

2-[2-[4-[(Diphenylmethoxy)methyl] -1-piperidinyl] ethyl] -2,3 - dihydro-2,4,6,7-tetramethyl-5-benzofuranyl

Using tert-butyl[2-[2-[4-[(diphenylmethoxy)methyl]-1 - piperidinyl] ethyl] -2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl] carbamate, otherwise repeating the procedure of example 48 with Poluchenie).

1H-NMR (DMSO-d6) : 1,28-of 1.66 (2H, m), of 1.36 (3H, s), of 1.84-2.10 (5H, m), 1,99 (9H, s), 2,81-and 3.16 (6H, m), 3.25 to 3,30 (2H, m), 3,41 of 3.56 (2H, m), 5,43 (1H, s) 7,20-7,37 (10H, m).

Example 50

2-[2-[4-[2-(Diphenylmethoxy)ethyl] -1-piperidinyl] ethyl] -2,3 - dihydro-2,4,6,7-tetramethyl-5-benzofuranol

Using tert-butyl[2-[2-[4-[2-(diphenylmethoxy)-ethyl]-1 - piperidinyl] ethyl] -2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl]carbamate, otherwise repeating the procedure of example 48 with obtaining specified in the connection header. Yield 54%.

So pl. 119-121oC (recrystallized from ethanol).

1H-NMR (DMSO-d6) : 1,24 is 2.10 (9H, m) of 1.34 (3H, s), a 1.96 (6H, s), to 1.98 (3H, s), 2,79-3,14 (6H, m), 3,36-of 3.43 (4H, m), 5,41 (1H, s), 7,20-7,38 (10H, m).

Example 51

N-2-[[4-[4-(Diphenylmethoxy)butyl] -1-piperazinil] methyl] -2,3 - dihydro-2,4,6,7-tetramethylbenzidin-5-yl]ndimethylacetamide

To the suspension 2-[[4-[4-(diphenylmethoxy)butyl] -1-piperazinil]methyl]-2,3 - dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic (0,60 g) in tetrahydrofuran (10 ml) was added 8 ml of 1 N aqueous sodium hydroxide solution and 0.10 ml of acetic anhydride under ice cooling and the mixture was stirred for 1 hour. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution,the her on silica gel (ethyl acetate: methanol = 9:1) to obtain the 0,48 g specified in the connection header. Yield 93%.

Oil.

1H-NMR (CDCl3) : of 1.42 (3H, s), of 1.62 (4H, br, s), 2.05 is-2,82 (25H, m), is 3.08-3,17 (1H, m), 3,41-3,47 (2H, m), 5,32 (1H, s), 6,58-6,62 (1H, m), 7,20-7,33 (10H, m).

Example 52

2-[[4-[4-(Diphenylmethoxy)butyl] -1-piperazinil] methyl] -N - ethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzophenonetetracarboxylic

To a solution of N-2-[[4-[4-(Diphenylmethoxy)butyl] -1-piperazinil] methyl] - 2,3-dihydro-2,4,6,7-tetramethylbenzidin-5-yl] ndimethylacetamide (0,48 g) in tetrahydrofuran (20 ml) was added 64 mg of sociallyengaged and the mixture was heated under reflux under gaseous argon for 15 hours. This reaction mixture was diluted with a small amount of water was added ethyl acetate, MgSO4and Hyflo Super-Cel (trademark). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol = 95:5) to obtain 0.32 g 2-[[4-[4-(diphenylmethoxy)butyl] -1-piperazinil] methyl]-N - ethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine. Yield 68%. This product was treated with 4 N HCl solution in ethanol and the resulting trihydrochloride recrystallized from a mixture of ethanol-diethyl ether to obtain 0.32 g specified in the connection header. Yield 55%.

So pl. 156-158oC.

Example 53

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-[bis(4-forfinal)methyl]-4-piperidylamine

A suspension of 2-methyl bromide-2,3-dihydro-2,4,6,7-tetramethyl-5-benzoguanamine (1.4 g), N-[bis(4-forfinal)methyl] -4-piperidylamine (4.5 g) and potassium carbonate (1.4 g) in N,N-dimethylacetamide (20 ml) was stirred under gaseous argon at 172oC for 4.5 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel/ethyl acetate and basic silica gel/hexane:ethyl acetate = 9:1-85:15) and recrystallized from a mixture of ethyl acetate-hexane to obtain specified in the title compound (0.97 g, yield 39%).

So pl. 133-134oC.

1H-NMR (CDCl3) : of 1.24 to 1.47 (2H, m), of 1.40 (3H, s), 1,78 is 1.91 (2H, m), 1,96-to 2.18 (2H, m), is 2.05 (3H, s), 2,07 (3H, s), of 2.08 (3H, s), 2,23-to 2.55 (3H, m), 2,74-2,96 (2H, m), 2.95 and-of 3.12 (2H, m), equal to 4.97 (1H, s), 6,97 (4H, t, J = 8,8 Hz), 7,20-7,40 (4H, m).

Example 54

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-[bis(4-methoxyphenyl)methyl]-4-piperidylamine

Using as starting materials 2-methyl bromide-2,3-derale the procedure of example 53 to obtain specified in the connection header. Yield 43%.

So pl. 109-111oC.

1H-NMR (CDCl3) : 1,25-of 1.46 (2H, m), of 1.40 (3H, s), 1,76-2,55 (9H, m), is 2.05 (3H, s), 2,07 (3H, s), of 2.08 (3H, s), 2,72-of 2.86 (2H, m), 2,96-of 3.12 (2H, m), of 3.77 (6H, s) to 4.92 (1H, s), PC 6.82 (4H, d, J = 8,8 Hz), 7,26 (4H, d), J = 8,8 Hz).

Example 55

(R)-1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl]-N-(diphenylmethyl)-4-piperidylamine

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(diphenylmethyl)-4-piperidylamine was subjected to preparative high performance liquid chromatography (column: CHIRALCEL OD (20 x 250 mm, Daicel Chemical Industry co., Ltd.), mobile phase: hexane-2-propanol = 95:5); flow rate: 80 ml/min, column temperature: 30oC) obtaining specified in the connection header.

[]D= -21,4(c = 0,496, ethanol)

Example 56

(S)-1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl]-N-(diphenylmethyl)-4-piperidylamine

1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl] -N-(diphenylmethyl)-4-piperidylamine was subjected to preparative high performance liquid chromatography (column: CHIRALCEL OD (20 x 250 mm, Daicel Chemical Industry co., Ltd.), mobile phase: hexane-2-propanol = 95:5); flow rate: 80 ml/min, column temperature: 30oC) obtaining specified in the connection header.

[]D= +21,5
To a solution of (R)-1-[(5-amino-2,3-dihydro-2,4,6,7 - tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine (3.5 g) in a mixture of methanol (15 ml) and ethyl acetate (5 ml) was added 2 N sulfuric acid (7.5 ml) and the mixture was concentrated under reduced pressure. To the residue was added methanol (15 ml) and the mixture stood for 18 hours. The resulting solid is collected, dried and recrystallized from methanol-water to obtain 3.5 g specified in the connection header. Yield 76%.

[]D= -8,0(c = 0,51, ethanol)

So pl. 154-156oC.

1H-NMR (DMSO-d6) : of 1.33 (3H, s), 1,52-of 2.20 (4H, m), 1,95 (9H, s), 2,15-2,30 (1H, s), 2,58-2,82 (4H, m), 2,97-of 3.25 (4H, m), 5,52 (1H, br, s), 7,28-7,42 (6H, m), 7,52-7,58 (4H, m).

Example 58

(S)-1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl]-N-(diphenylmethyl)-4-piperidineacetate

Using (S)-1-[(5-amino-2,3-dihydro-2,4,6,7 - tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine and 2 N sulfuric acid, otherwise repeating the procedure of example 57 to obtain specified in the connection header. Yield 68%.

[]D= +8,5(c = 0,52, ethanol)

So pl. 155-157oC (recrystallized from methanol-water).

1H-NMR (DMSO-d6) : of 1.34 (3H, s)1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2 - yl)methyl]-N-(diphenylmethyl)-4-piperidylamine

4-Nitroaniline (0.14 g) was dissolved in 2 N chloroethanol acid (3 ml) under heating and the solution was cooled with ice. To this solution was added dropwise a solution of sodium nitrite (72 mg) in water (0.5 ml) and the mixture was stirred for 15 minutes. An aqueous solution obtained by this 4-nitrobenzaldehyde was added to a solution of (S)-1-[(2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] - N-(diphenylmethyl)-4-piperidylamine (0,43 g) in acetic acid (3 ml) under cooling and the mixture was stirred at room temperature for 12 hours. This reaction mixture was poured into a saturated aqueous solution of sodium carbonate and was extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over MgSO4, and concentrated under reduced pressure. To the obtained (S)-1-[[2,3-dihydro-2,4,6,7-tetramethyl-5-(4 - nitrophenylazo)benzofuran-2-yl]methyl]-N-(diphenylmethyl)-4-piperidylamine was added ethanol (30 ml) and Raney Nickel (Kawaken Fine Chemical NDHT-90) (0.6 g) and the mixture was stirred in an environment of hydrogen at 5 bar and room temperature for 1 hour. This reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 1: 1) who(3H, s), 1,78-of 2.20 (4H, m), is 2.05 (3H, s), of 2.06 (3H, s), of 2.08 (3H, s), 2,30-of 2.54 (3H, m), 2,72-and 2.83 (2H, m), 2.95 and-3,11 (2H, m), 5,01 (1H, s), 7,15-7,40 (10H, m).

Example 60

1-[(5-Amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl)methyl] -N-(diphenylmethyl)-4-piperidylamine

A suspension of 2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzoguanamine (1.1 g), N-(diphenylmethyl)-4-piperidylamine (1.4 g) and potassium carbonate (0,83 g) in N,N-dimethylacetamide (6 ml) was heated under reflux for 4.5 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The residue was purified by column chromatography on basic silica gel (hexane: ethyl acetate = 20:1-5:1) and recrystallized from a mixture of hexane-ethyl acetate to obtain 1.4 g specified in the connection header. Yield 91%.

Amorphous solid.

1H-NMR (CDCl3) : 1,20-1,50 (2H, m), 1,25 (3H, d, J = 7,4 Hz), of 1.26 (3H, d, J = 6,8 Hz) of 1.33 (3H, s), 1.70 to to 2.55 (5H, m), 2,04 (3H, s), 2,12 (3H, s), of 2.51 (2H, s), to 2.67 (1H, d, J = 15,0 Hz), 2,78 be 3.29 (3H, m), 3,12 (1H, d, J = 15,0 Hz), free 5.01 (1H, s), 7,12-7,47 (10H, m).

Chemical formulas of the compounds obtained in examples 1-60 shown in tables 1-5.

Example 1 production is the PR of polyethylene glycol 400 in physiological solution with obtaining a 0.01% aqueous solution of the compounds. This solution was filtered through a bacterial filter and poured vials (10 ml per vial), resulting in injection solution for intravenous injection containing 1 mg of compound in each vial.

Example 2 manufacture of the medicinal product

(S)-2,3-Dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1 - piperidinyl)methyl] -5-benzoguanamine was dissolved in 30% (weight/volume) solution of polyethylene glycol 400 in physiological solution with obtaining a 0.01% aqueous solution of the compounds. The solution was filtered through a bacterial filter and poured vials (10 ml per vial), resulting in injection solution for intravenous injection containing 1 mg of compound in each vial.

Example 3 manufacture of the medicinal product

(1) Connection example 5 - 1.0 g

(2) Lactose - 60,0

(3) Corn starch - 35,0 g

(4) Gelatin - 3.0 g

(5) magnesium Stearate - 2.0 grams

Using 30 ml of 10% by weight aqueous solution of gelatin (3.0 g as gelatin), a mixture of 1.0 g of the compound obtained in example 5, by 60.0 g of lactose and of 35.0 g of corn starch was granulated through a sieve with the hole diameter of 1 mm, dried at 40oC and again passed through a sieve. The obtained granules is, is ioxide titanium, talc and Arabian gum in water. Coated tablets were glazurowane beeswax and he got 1000 tablets are coated.

Example 4 manufacture of the medicinal product

The compound obtained in example 40 was dissolved in 30% (weight/volume) solution of polyethylene glycol 400 in physiological solution with obtaining a 0.01% aqueous solution of the compounds. This solution was filtered through a bacterial filter and poured vials (10 ml per vial), resulting in injection solution for intravenous injection containing 1 mg of compound in each vial.

Experimental example 1

Test for binding to the sodium channel using a fraction of the cerebral cortex of rats

For tests used Wistar rats (age 10-15 weeks). The rats were killed by decapitation and immediately took the cerebral cortex. Then using a homogenizer extracted cortical substance homogenized in 10 volumes of ice of 0.32 M sucrose solution in 5 mm potassium hydrogen phosphate (pH 7,4,oC). The obtained homogenate was centrifuged at 1000g for 10 minutes and then the supernatant was centrifuged at 20000g for 15 minutes. Precipitation was proveravao at 20000g for 15 minutes. Extracted residue. Collected in this way the membrane sample suspended in butatriene buffer for testing (50 mm HEPES, 5.4 mm KCl, 0.8 mm MgSO4, 5.5 mm glucose, 130 mm choline chloride (pH 7,4)) and test the binding was carried out as follows. To 0.2 ml of the buffer for the test containing the test compound, 1 μm tetrodotoxin, 100 μg/ml of toxin Scorpion and 5 nm [3H]-batrachotoxinin A-20-a-benzoate (34,0 CI/mmol), was added 0.2 ml of the above suspension membrane sample to obtain a final volume of 0.4 ml and the reaction was carried out in an incubator at 37oC for 1 hour. This reaction mixture was immediately filtered by suction on the filter CF/B, and the filter was washed with 2 ml of wash buffer (5 mm HEPES, 1.8 mm CaCl2, 0.8 mm MgSO4, 130 mm choline chloride and 0.01% BSA (BSA) (pH of 7.4, 4oC)) a total of 3 times. The filter was added 4 ml of scintillator and measured the radioactivity using a liquid scintillation counter. To determine nonspecific binding was added 0.3 mm veratridine.

The test compound was added at final concentrations 0,03, 0,1, 0,3, 1, 3, 10 and 30 μm and ingibiruet calculated value IC50.

The results shown below.

Connect the 2

Example 6 - 0,79

Example 17 - 0,32

Example 24 - 0,41

Example 25 - 0,34

Example 26 - 0,22

Example 27 - 0,20

Example 28 - 0,22

Example 29 - 0,21

Example 30 - 0,39

Example 31 - 0,49

Example 32 - 0,25

Example 33 - 0,31

Example 34 - 0,42

Example 40 - 0,16

Example 41 - 0,14

Example 42 - 0,16

Reference example 8 - 0,64

Reference example 10 - 0,47

The above data show that the compounds (I) and (Ia) have an affinity for sodium channel.

Industrial application

The compound (I) of the present invention and the compound (Ia) exhibit high affinity for sodium channel, in particular at site 2, with low toxicity and low risk of side effects. Therefore, they can act as modulators of sodium channels and, therefore, are useful as preventive and therapeutic agents for diseases and disorders of the Central nervous system, such as ischemia of the Central nervous system, trauma of the Central nervous system (e.g. brain injury, spinal cord injury, injury from sharp movements of the limbs and so on), epilepsy, neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, chorea hunt is dementia, disease Binswanger and so on), manic-depressive psychosis, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine and brain swelling. In addition, compound (I) and (Ia) have high anti-oxidant activity and modulating activity in relation to transport of dopamine and therefore are useful as preventive and therapeutic agents for other ischemic cardiovascular disease (e.g. myocardial infarction, angina, and so on), atherosclerosis and other diseases.

1. Cyclic simple ester of the formula I

< / BR>
where each R1and R2represents a hydrogen atom, lower alkyl or C1-6alkylsulphonyl;

R3, R4R5each represents lower alkyl;

R6is lower alkyl;

Ar represents C6-14aryl which may be substituted with halogen, C1-6the alkyl, C1-6alkoxy or C1-3alkylenedioxy;

ring a represents a 5-8-membered saturated nitrogen-containing heterocyclic ring;

X represents a lower alkylene;

Y represents a carbon atom or nitrogen;

Za represents a group of the formula

< / BR>
< / BR>
where R7represents a hydrogen atom or a C6-14and the and C7-16aralkyl;

Zb is a bond or a divalent hydrocarbon group selected from the group comprising C1-8alkylene, C2-8albaniles or a group of the formula - (CH2)p-M-(CH2)q- where p and q each represents an integer from 0 to 8, and p + q is an integer from 1 to 8; M represents O or NR9where R9represents a hydrogen atom, each of the divalent group may be substituted C6-14by aryl;

m = 1 - 3,

or its salt.

2. Connection on p. 1, where each R1and R2represents (i) hydrogen atom, (ii) C1-6alkyl, (iii) acyl selected from the group comprising formyl and1-6alkylaryl; R3, R4and R5each represents C1-6alkyl; R6represents C1-6alkyl; Ar represents C6-14aryl which may be substituted by 1 to 5 substituents selected from the group comprising halogen, C1-6alkyl, C1-6alkoxy or C1-3alkylenedioxy; ring a represents a 5-8-membered saturated nitrogen-containing heterocyclic ring; X represents C1-6alkylene; Y represents (i) a nitrogen atom or ii) a group of the formula: >C(R8)-, where R8is a hydrogen atom; R7represents the atom ways halogen or C1-6alkoxy; R10represents a hydrogen atom or a C7-16aralkyl; Zb represents a divalent hydrocarbon group selected from the group including (i) C1-8alkylene, (ii) C2-8albaniles or (iii) a group of the formula -(CH2)p-M-(CH2)q- where p and q each represents an integer from 0 to 8, and p + q is an integer from 1 to 8; M represents O or NR9where R9represents a hydrogen atom, each of the divalent group may be substituted C6-14the aryl.

3. Connection on p. 1, where Za represents a group of the formula

< / BR>
where R7matter specified in paragraph 1.

4. Connection on p. 1, where R1and R2each represents a hydrogen atom.

5. Connection on p. 1, where R3, R4, R5each represents C1-6alkyl.

6. Connection on p. 1, where R6represents C1-6alkyl.

7. connection on p. 1, where Ar represents a C6-14which may be substituted by 1-3 substituents selected from the group consisting of halogen, C1-6the alkyl and C1-6alkoxy.

8. Connection on p. 1, where the ring a represents a 6-membered saturated nitrogen-containing heterocyclic ring.

11. Connection on p. 1, where Za represents a group of the formula

< / BR>
in which the symbols have the meanings given in paragraph 1.

12. Connection on p. 1, where R7represents C6-10aryl which may be substituted with halogen or C1-6alkoxy.

13. Connection on p. 1, where R10represents a hydrogen atom.

14. Connection on p. 1, where Zb is the link.

15. Connection on p. 1, where m = 1.

16. Connection on p. 1, where each R1and R2represents a hydrogen atom; R3, R4, R5and R6each represents C1-6alkyl; Ar represents phenyl which may be substituted by 1-3 substituents selected from the group comprising halogen, C1-6alkyl and C1-6alkoxy; ring a represents a 6-membered saturated nitrogen-containing heterocyclic ring; X is methylene; Y is CH or N; Za represents a group of the formula

< / BR>
where R7represents phenyl which may be substituted by 1-3 substituents selected from the group consisting of halogen and C1-6alkoxy;

R10represents a hydrogen atom;

Zb is a bond or C1-6alkylene, which can be zames the m hydrogen; R3, R4, R5and R6each represents C1-6alkyl; Ar represents C6-10aryl which may be substituted, methylendioxy; ring a represents a 6-membered saturated nitrogen-containing heterocyclic ring; X is methylene; Y is CH or N; Za represents a group of the formula

< / BR>
where R7arepresents a hydrogen atom or a C6-10aryl;

Zb is a bond or (i) C1-6alkylene or (ii) C2-6albaniles, which may be substituted C6-10by aryl; and m = 1.

18. Connection on p. 1, where each R1and R2represents a hydrogen atom; R3, R4, R5and R6each represents C1-6alkyl; Ar represents C6-10aryl which may be substituted by 1-3 substituents selected from the group comprising halogen, methylenedioxy, C1-6alkyl and C1-6alkoxy; ring a represents a 6-membered saturated nitrogen-containing heterocyclic ring; X is methylene; Y is CH or N; Za represents a group of the formula

< / BR>
< / BR>
where R7brepresents a hydrogen atom or a C6-10aryl which may be substituted with halogen;

R10Arepresents a hydrogen atom or a C7-11aralkyl;

Zb B> albaniles, and (iii) a group of the formula -(CH2)p-M-(CH2)qwhere p' and q' each represent an integer from 0 to 5 and p' + q' represents an integer from 1 to 6 and M' is O or NH, each of the divalent group may be substituted C6-10by aryl; and m = 1 or 2.

19. Connection on p. 1, representing 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidine, (-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl]-N-(diphenylmethyl)-4-piperidine, (+)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzidin-2-yl)methyl] -N-(diphenylmethyl)-4-piperidine, 1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl)methyl]-N-(diphenylmethyl)-4-piperidine, (-)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl)methyl] -N-(diphenylmethyl)-4-piperidine, (+)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzoyl-2-yl)methyl] -N-(diphenylmethyl)-4-piperidinyl, or its salt.

20. A method of obtaining a connection on p. 1, which includes the interaction of the compounds of formula

< / BR>
where L represents a leaving group;

each R1and R2represents a hydrogen atom, lower alkyl or C1-6alkylsulphonyl;

R3, R4, R5and R6each of its salt with the compound of the formula

< / BR>
where ring a represents a 5-8-membered saturated nitrogen-containing heterocyclic ring;

Y represents a carbon atom or nitrogen;

Za represents a group of the formula

< / BR>
< / BR>
where R7represents a hydrogen atom or a C6-14aryl which may be substituted with halogen or C1-6alkoxy;

R10represents a hydrogen atom or a C7-16aralkyl;

Zb is a bond or divalent carbon group selected from the group comprising C1-8alkylene, C2-8albaniles or a group of the formula -(CH2)p-M-(CH2)q- where p and q each represents an integer from 0 to 8, and p + q is an integer from 1 to 8; M represents O or NR9where R9represents a hydrogen atom, each of the divalent group may be substituted C6-14by aryl;

Ar represents C6-14aryl which may be substituted with halogen, C1-6the alkyl, C1-6alkoxy or C1-3alkylenedioxy,

or its salt.

21. A method of obtaining a connection on p. 1 consists in the fact that compounds of the formula

< / BR>
where each R1and R2represents a hydrogen atom, lower alkyl or C1-6alkylsulphonyl;

R3, R4
ring a represents a 5-8-membered saturated nitrogen-containing heterocyclic ring;

or its salt is subjected to (a) density, (b) acylation or (C) the acylation followed by reduction.

22. A method of obtaining a connection on p. 1 consists in the fact that compounds of the formula

< / BR>
where R3, R4, R5and R6each represents lower alkyl;

X represents a lower alkylene;

ring a represents a 5-8-membered saturated nitrogen-containing heterocyclic ring;

Y represents a carbon atom or nitrogen;

Za represents a group of the formula

< / BR>
< / BR>
where R7represents a hydrogen atom or a C6-14aryl; which may be substituted with halogen or C1-6alkoxy;

R10represents a hydrogen atom or a C7-16aralkyl;

Zb is a bond or a divalent hydrocarbon group selected from the group comprising C1-8alkylene, C2-8albaniles or a group of the formula -(CH2)p-M-(CH2)q- where p and q each represents an integer from 0 to 8, and p + q is an integer from 1 to 8; M represents O or NR9where R9represents a hydrogen atom, each divalent group magery may be substituted with halogen, C1-6the alkyl or C1-3alkylenedioxy,

or its salt is subjected to (a) the nitration and subsequent reduction or (b) reaction diazoacetate with subsequent recovery.

23. Pharmaceutical composition, which is designed to modulate sodium channel, including a connection on p. 1.

24. Method of modulating sodium channel in a mammal, in need thereof, which includes an introduction to such mammal an effective amount of the compounds under item 1 or its pharmaceutically acceptable salt together with a pharmaceutically acceptable excipient, carrier or diluent.

25. Pharmaceutical composition for modulating sodium channel, which contains a compound of the formula Ia

< / BR>
where Q represents a group of formula Zc-Ar, where Zc represents a divalent aliphatic hydrocarbon group selected from C1-8alkylene or a group of the formula -(CH2)p-M-(CH2)q- where each of the symbols p and q represents an integer from 0 to 8, and p + q is an integer from 1 to 8; M represents O or NR9where R9represents a hydrogen atom; and each of the divalent group may be substituted C6-14by aryl; and Ar is collidescope ring; and other relevant symbols have the same meanings as defined in paragraph 1,

or its salt.

26. Method of modulating sodium channel in a mammal, in need thereof, comprising an introduction to such mammal an effective amount of the compounds of formula Ia

< / BR>
where Q represents a group of formula Zc-Ar, where Zc represents a divalent aliphatic hydrocarbon group selected from C1-8alkylene or a group of the formula (CH2)p-M-(CH2)q- where each of the symbols p and q represents an integer from 0 to 8, and p + q is an integer from 1 to 8; M represents O or NR9where R9represents a hydrogen atom; and each of the divalent group may be substituted C6-14by aryl; and Ar has the same meaning as defined in paragraph 1;

ring AA represents a 5-8 membered saturated nitrogen-containing heterocyclic ring; and other relevant symbols have the same meanings as defined in paragraph 1,

or its pharmaceutically acceptable salt with a pharmaceutically acceptable excipient, carrier or diluent.

Priority points:

29.08.1996 on PP.3,7,21,26,28;

04.04.1997 on PP.1,2,4 - 16,18,20,24;

28.08.1997 on PP.19, 22 the.

 

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