Derivatives of 2-acylamino-4-phenylthiazol, their obtainment and application in therapy

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

 

The present invention relates to derivatives of 2-acylamino-4-phenylthiazole, their reception and their use in therapy.

The object of the present invention are compounds corresponding to the formula (I):

in which

R1means a hydrogen atom or halogen, (C1-C4)-alkyl, triptorelin, hydroxyl, (C1-C4-alkoxyl, cryptometer, triptracker, (C3-C8)-cycloalkylation, alliancegroup, cyclopropylmethoxy, (C1-C4)-allylthiourea;

R2means a hydrogen atom or halogen, (C1-C8)-alkyl, triptorelin, PERFLUORO-(C1-C4)-alkyl, (C3-C10-cycloalkyl, phenyl, (C1-C8-alkoxyl, cryptometer, triptracker, alliancegroup, (C3-C8)-cycloalkylcarbonyl, (C3-C8)-cycloalkylation, (C3-C8-cycloalkenyl;

R3means a group selected from:

a) A1) -O-(C2-C4)-alk-A;

a2) -O-(C1-C4)-alk-B;

a3) -O-E;

b) -(C1-C4)-alk-A;

c) -B;

d) d1) -(C1-C4)-alk-NR4-(C2-C3)-alk-A;

d2) -(C1-C4)-alk-NR4-(C1-C3)-alk-B;

e) e1) -CONR4-(C2-C4)-alk-A;

e2) -CONR4-(C1-C4)-alk-B;

e3) -CONR4-E;

f) f1) CO-D-(C 1-C2)-alk-A;

f2) -CO-G-A;

f3)

f4)

f5)

f6)

f7)

R4means a hydrogen atom or (C1-C4)-alkyl;

A represents a group NR5R6;

In the mean group

D means the group

E. means formula

G means group

R5and R6each, independently of one another, mean a hydrogen atom, (C1-C6)-alkyl, allyl, (C2-C4)-alk-O-(C1-C4)-alkyl, (C2-C4)-alk-OH, (C1-C3)-alk-CON(R4)2, (C2-C3)-alk-NHCO-(C1-C4)-alkyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkenyl, -CO-(C1-C4)-alkyl; pyrrolidinyl, possibly substituted WITH-(C1-C4)-alkyl; benzyl, tetrahydropyranyl, tetrahydropyranyl, dimethyltetrahydrofuran, tetrahydrofuryl, tetrahydrofuranyl;

or R5and R6together with the nitrogen atom to which they are linked, form a heterocyclic radical selected from aziridinyl, azetidine, pyrrolidine, piperidine, perhydroanthracene, morpholinyl, Pipa is azinil, tapanila, hinokitiol, 2-azabicyclo[2,2,1]heptane, 2-azabicyclo[2,2,2]-octane, and the above-mentioned heterocyclic radicals are unsubstituted or substituted by phenyl, halogenfree, reformational, trifluoromethyl, hydroxyl, methoxy group, hydroxymethyl, methoxymethyl, formamido, triftoratsetofenona, the group-NR4R7, tetrahydropyran-4-yl-amino group, a group-CON(R4)2, -CONR4R'4, -CH2CON(R4)2, (C1-C4)-alkyl-CONR4-, (C3-C8-cycloalkyl-CONR4-, (C1-C4)-alkyl-OCONR4-, (C3-C8-cycloalkyl-OCONR4-, ((C1-C4)-alkyl-TOC)2-N-, (C1-C4)-alkyl-COO-; or substituted by one or more methyl groups;

R'4mean group (CH2)sassociated with the carbon atom-media-CONR4R'4;

R7means a hydrogen atom, (C1-C4)-alkyl, a group-SO2CH3; or

R4and R7together with the nitrogen atom to which they are bound, form pyrrolidinyl or piperidinyl radical;

P denotes 1, 2, 3, 4 or 5;

Q denotes 0, 1 or 2;

R is 1 or 2;

S represents 2 or 3;

and

p+q is less than or equal to 5;

p+r is less than or equal to 5;

alk means alkylen;

provided that R1and R2at the same time n the mean of a hydrogen atom.

The compounds of formula (I) may include one or more asymmetric carbon atoms. Therefore, they can be in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as mixtures thereof, including racemic mixtures, are within the scope of the invention. Similarly, axial and Equatorial stereoisomers, endo - and Exo-isomers as well as mixtures thereof, are within the scope of the invention.

The compounds of formula (I) can be in the form of bases or addition salts of the acids. Such additive salts are within the scope of the invention.

These salts mainly get with pharmaceutically acceptable acids but the salts of other suitable acids, for example, for the purification or separation of compounds of formula (I), are also included in the scope of the invention.

The compounds of formula (I) can also be in the form of a hydrate or of a solvate and in the form of aggregates or combinations with one or more water molecules or with a solvent. Such hydrate and solvate are also included in the scope of the invention.

In the scope of the present invention

under a halogen atom understand the atom of fluorine, chlorine, bromine or iodine;

under the alkyl understand monovalent, linear or branched, aliphatic group with 1-4 carbon atoms or, if necessary, 1-8 carbon atoms. As examples are methyl group, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl etc.;

under cycloalkyl understand cyclic alkyl group with 3-8 carbon atoms or, if necessary, 3-10 carbon atoms, possibly connected bridge connection. As examples of groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, substituted;

under alkoxyl understand-About-alkyl radical, where alkyl has the above meaning;

under alkalinous group understand divalent, linear or branched, saturated aliphatic group with 1-3 carbon atoms or, if necessary, 2-3 or 2-4 carbon atoms.

Of the compounds of formula (I)which are subjects of the invention, can be called a first subgroup of compounds that meet the General formula (I'):

in which

R1means a hydrogen atom or halogen, (C1-C4)-alkyl, triptorelin, hydroxyl, (C1-C4-alkoxyl, cryptometer, triptracker, (C3-C8)-cycloalkylation, alliancegroup, cyclopropylmethoxy, (C1-C4)-allylthiourea;

R2means a hydrogen atom or halogen, (C1-C8)-alkyl, triptorelin, PERFLUORO-(C1-C4)-alkyl, (C3-C10)-cloacal, phenyl, (C1-C8-alkoxyl, cryptometer, triptracker, alliancegroup, (C3-C8)-cycloalkylcarbonyl, (C3-C8)-cycloalkylation, (C3-C8-cycloalkenyl;

R3means a group selected from:

a) A1) -O-(C2-C4)-alk-A;

a2) -O-(C1-C4)-alk-B;

a3) -O-E;

b) -(C1-C4)-alk-A;

c) -B;

d) d1) -(C1-C4)-alk-NR4-(C2-C3)-alk-A;

d2) -(C1-C4)-alk-NR4-(C1-C3)-alk-B;

e) e1) -CONR4-(C2-C4)-alk-A;

e2) -CONR4-(C1-C4)-alk-B;

e3) -CONR4-E;

f) f1) -CO-D-(C1-C2)-alk-A;

f2) -CO-G-A;

f3)

f4)

f5)

f6)

R4means a hydrogen atom or (C1-C4)-alkyl;

A represents a group NR5R6;

In the mean group

D means the group

E. means

G means group

R5and R6each, independently of one another, mean a hydrogen atom, (C1-C6)-alkyl, allyl, (C2-C4)-alk-O-(C1-C4)-alkyl, (C2-C4)-alk-OH, (C1-Csub> 3)-alk-CON(R4)2, (C2-C3)-alk-NHCO-(C1-C4)-alkyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkenyl, benzyl, tetrahydropyranyl, tetrahydropyranyl, dimethyltetrahydrofuran, tetrahydrofuryl, tetrahydrofuranyl;

or R5and R6together with the nitrogen atom to which they are linked, form a heterocyclic radical selected from aziridinyl, azetidine, pyrrolidine, piperidine, perhydroanthracene, morpholinyl, piperazinil, tapanila, hinokitiol, 2-azabicyclo[2,2,1]heptane, 2-azabicyclo[2,2,2]-octane, and the above-mentioned heterocyclic radicals are unsubstituted or substituted by phenyl, halogenfree, reformational, trifluoromethyl, hydroxyl, methoxy group, hydroxymethyl, methoxymethyl, formamido, triftoratsetofenona, the group-NR4R7, tetrahydropyran-4-yl-amino group, a group-CON(R4)2, -CONR4R'4, -CH2CON(R4)2, (C1-C4)-alkyl-CONR4-, (C1-C4)-alkyl-OCONR4-, (C1-C4)-alkyl-COO-; or are substituted by methyl groups;

R'4mean group (CH2)sassociated with the carbon atom-media-CONR4R'4;

R7means a hydrogen atom, (C1-C4)-alkyl, or

R4and R7together with the nitrogen atom which, with which they are linked, form pyrrolidinyl or piperidinyl radical;

P denotes 1, 2, 3, 4 or 5;

Q denotes 0, 1 or 2;

R is 1 or 2;

S represents 2 or 3;

and

p+q is less than or equal to 5;

p+r is less than or equal to 5;

alk means alkylen;

provided that R1and R2at the same time do not represent a hydrogen atom.

Of the compounds of formula (I)which are subjects of the invention, can be called a second subgroup of compounds, which are defined as follows:

R1is in position 2 of the phenyl, and/or R2is in position 5 and/or R3is in position 4 of the other phenyl; more preferably, include compounds of formula (Ia):

in which R1, R2, R3have the above for formula (I) values.

Of these compounds, another subset of compounds of formula (Ia) are compounds in which:

R1means a halogen atom, (C1-C4)-alkyl, hydroxyl, (C1-C4-alkoxy, (C3-C8)-cycloalkylation, alliancegroup, cyclopropylmethoxy, (C1-C4)-allylthiourea;

and/or R2means a halogen atom, (C1-C8)-alkyl, trifluoromethyl, (C3-C8-cycloalkyl, phenyl, (C1-C8-alkoxyl, alliancegroup, ( 3-C8)-cycloalkylcarbonyl, (C3-C8)-cycloalkylation, (C3-C8-cycloalkenyl;

and/or R3means a group selected from the groups a), b), c), d), e), f), such as those indicated above for formula (I).

In particular, these compounds include compounds in which:

R1means (C1-C4-alkoxyl, cyclopropylmethoxy or (C1-C4)-allylthiourea; and/or R2means a halogen atom, (C1-C8)-alkyl, trifluoromethyl, (C3-C10-cycloalkyl or (C1-C8-alkoxyl;

and/or R3mean group f2 or e2.

Of the compounds of formula (I) according to the invention include, in particular, the following connections:

- 4-((4-[3-(R)-(acetylamino)pyrrolidin-1-yl]piperidine-1-yl)-carbonyl)-N-[4-(5-butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]benzamide;

ethyl ester (1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbonyl)piperidine-4-yl)pyrrolidin-3-yl)carbamino acids;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylpyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(tetrahydropyran-4-ylamino)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(2-(tetrahydropyran-4-ylamino)ethoxy)benzamide;

- N-(4-(5-ethyl-2-methoxyphenyl)thiazol-2-yl)-4-(3-(tetrahydropyran-4-yl) - Rev. Ino)propyl) benzamide;

- N-(4-(5-cyclohexyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-N'-pyrrolidin-2-illiterately;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-(cyclopropanecarbonyl)pyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-isobutylpyrazine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-pyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-hydroxypyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-N'-((S)-(1-ethylpyrrolidin-2-yl)methyl)terephthalamide;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-hydroxyazetidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(S)-acetyl-aminopyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-N'-piperidine-3-yl-terephthalamide;

- N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-hydroxypyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-N'-((S)-(1-ethyl-pyrrolidin-2-yl)methyl)terephthalamide;

- N-(4-(5-cyclohexyl-2-ethoxyphenyl)thiazol-2-yl)-N'-((S)-(1-ethylpyrrolidin-2-yl)methyl)terephthalamide;

- N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-N'-(()-(1-ethylpyrrolidin-2-yl)methyl)terephthalamide;

- N-(4-(5-cyclopentyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(tetrahydropyran-4-ylamino)piperidine-1-carbonyl)benzamide;

- N-(4-(5-hexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(tetrahydropyran-4-ylamino)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylpyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-formelementname-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(S)-hydroxyethylpyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-propyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylpyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclopentyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylpyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

ethyl ester 1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbonyl)benzoyl)piperidine-4-yl)pyrrolidin-3-(R)-yl-propionic acid;

- N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-propiomelanocortin-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-butyrylthiocholine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclohexyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylpyrrolidine-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-pyrrolidin-1-yl)piperidine-1-to bonil)benzamide;

- N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-N'-((R)-(1-ethyl-pyrrolidin-2-yl)methyl)terephthalamide;

methyl ether 1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbonyl)piperidine-4-yl)pyrrolidin-3-yl)carbamino acids;

- N-(4-(5-cyclopentyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-propiomelanocortin-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-butyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-propiomelanocortin-1-yl)piperidine-1-carbonyl)benzamide;

- N-(4-(5-cyclopentyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-propiomelanocortin-1-yl)piperidine-1-carbonyl)benzamide;

ethyl ester 1-(1-(4-(4-(5-cyclopentyl-2-ethoxyphenyl)thiazol-2-ylcarbonyl)piperidine-4-yl)pyrrolidin-3-yl)carbamino acid.

Some of the compounds of formula (I) can also serve as intermediates for other compounds of formula (I), as shown in the following examples.

In the following context under the protective group Pg to understand a group, which allows, on the one hand, to protect a reactive functional group such as hydroxyl or amino group, during a synthesis and, on the other hand, to regenerate the intact reactive functional group at the end of the synthesis. Examples of protective groups and methods of protection and removal of the protective groups represented in "Protective Groups in Organic Synthesis", Green and the RV, second edition (John Wiley and Sons, Inc., New York).

Under the deleted group in the following context to understand a group, which can be easily derived from a molecule by breaking the heterolytic connection with the disposal of e-pairs. This group can also be easily replaced by another group, for example, during the substitution reaction. Such groups are removed, for example, Halogens or an activated hydroxyl group such as mesyl, tosyl, triflate, acetyl, etc. Examples delete groups, as well as links to receive presents in "Advances in Organic Chemistry", J. March, third edition, Wiley Interscience, c. 310-316.

According to the invention it is possible to obtain compounds of General formula (I) in the following way.

This method differs in that the functional derivative of the acid of formula (II):

in which R'3means R3such as specified above for formula (I), or a predecessor of R3handle derived 2-aminothiazole formula (III):

in which R'1and R'2mean, respectively, R1and R2or the predecessors of R1and R2such as indicated for formula (I);

then, if necessary, the thus obtained compound of the formula (IV):

in which R'1, R'2 and R'3mean, respectively, R1, R2or R3or the predecessors of R1, R2and R3into the compound of formula (I).

Under the predecessor of R1, R2and, respectively, R3see Deputy, which can be converted into R1, R2and, respectively, R3by one or more chemical reactions.

Under the functional derivative of the acid of formula (II) understand the acid chloride acid, mixed or symmetrical anhydride or another acid, suitably activated, for example, using benzotriazol-1-yloxytris(dimethylamino)phosphodiesterase (THIEF) or O-benzotriazol-1-yl-N,N,N',N'-tetramethylethylenediamine (HBTU) or O-benzotriazol-1-yl-N,N,N',N'-tetramethylethylenediamine (TBTU).

The first stage is carried out in an aprotic solvent such as dichloromethane, acetonitrile, tetrahydrofuran or dimethylformamide, in an alkaline environment.

The compounds of formula (II) are obtained by known methods, which change depending on values of the substituent R3or R'3in the compound of formula (II).

The following schemes take into account that the groups R'1and R'2which mean, respectively, R1and R2or the predecessor of R1and R2at the subsequent stage can be subjected to conversion of PU is eaten using well-known specialist of reactions.

When one or more substituents R'1, R'2and/or R'3means a group containing an amino group or a hydroxyl, these functional groups can be protected intermediate: the amino group may be protected, for example, alkanoyloxy, benzyl, tert-butoxycarbonyl (Vos), benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc) group; hydroxyl can be protected, for example, in the form of a simple or complex ester.

To obtain the compounds of formula (I)in which R3means group a), such as indicated for formula (I), it is possible to obtain the compound of formula (II)in which R3means group a), acting according to the following scheme of reaction, where the example is for A1), then use the method according to the invention.

SCHEME 1

Y - deleted group;

R - (C1-C4)-alkyl.

You can also do according to scheme 1, but substituting the compound of the formula (V) delete the group Y is a hydroxyl group according to the Mitsunobu reaction, Bull. Chem. Soc. Japan,40, 2380 (1967).

Alternatively, to obtain the compounds of formula (I)in which R3means group a), it is possible to obtain the compound of formula (IV)containing the group R'3, the predecessor of R3then, at a subsequent stage to turn it into a group of R3according to the following scheme reacts and:

SCHEME 2

Y - deleted group;

Pg - protective for oxygen group, such as, for example, tert-butyl, benzoyl or arylsulfonyl.

Replacing the compound of formula (V) compound of the formula Y-E, in which E has the above value, and the substituent R5may be substituted for protective nitrogen group, get the connection formula (I)in which R3=A3).

The compound of formula (I)in which R3means (a)can also be obtained from a compound including a group R'3, the predecessor of R3according to the following scheme of reactions:

SCHEME 3

At the last stage of the accession of the amine is carried out according Synth. Commun.,28(10), 1897-1905 (1998); J. Org. Chem.,57(11), 3218-3225 (1992); J. Org. Chem.,61, 3849-3862 (1996); Tetrahedron Lett.,31, 5595-5598 (1990).

Another method of obtaining the compounds of formula (I)in which R3means group a), based on the compounds of formula (IV)containing R'3, the predecessor of R3presented on the following scheme of reactions:

SCHEME 4

R' is methyl or tolyl;

TNR - tetrahydropyran-2-yl.

The transformation of compounds of formula (XVIII) by oxidation can be carried out, for example, Swern oxidation.

<> An example of obtaining the compounds of formula (II)in which R'3=A1), is shown below:

SCHEME 5

From the thus obtained compounds of formula (XX) then you can get a variety of compounds of formula (II) by substitution of the appropriate primary amine.

To obtain the compounds of formula (I)in which R3mean group A2) or A3), also may be affected by the compound of formula (II)in which R3=A2) or A3), the compound of formula (III); and the compound of formula (II) are obtained according to the following reaction scheme, according to the given example for A2):

SCHEME 5BIS

Acid of the formula:

make it possible to obtain compounds of formula (IV)in which R'3=c), by affecting aminothiazol formula (III).

To obtain the compounds of formula (I)in which R3means group b), may be affected by the compound of formula (II)in which R3=b), the compound of formula (III); and the compound of formula (II) or its ester receive according to the following reaction scheme:

SCHEME 6

The compound of formula (I)in which R3means group b)can also be obtained by following the following scheme of reaction, which includes the adiya's scheme 3, adapting them to the present occasion:

SCHEME 7

In the specific case where the receive connection of the formula (I)in which R3mean group (b), (C1-C4)-alk = (CH2)3the compound of formula (IV)in which R'3means the predecessor of b)can be converted to a compound of formula (I) according to the following reaction scheme:

SCHEME 8

The compound of formula (XXVII) can also be obtained by exposure iodobenzoyl acid compound of the formula (III), then by the impact of prop-2-EN-1-ol on the thus obtained compound of the formula (XXVIIbis):

The compound of formula (I)in which R3means (b), can also be obtained according to the following reaction scheme:

SCHEME 9

Hal is a halogen atom, preferably chlorine.

This way you can also obtain the compound of formula (I)in which R3=b), based on the compounds of formula (II)obtained according to the following scheme:

SCHEME 10

The compounds of formula (II)in which R3=c)can be obtained according Syn. Lett.,4, 379-380 (1998).

Methods for obtaining compounds of formula (I), W is R 3mean group d), carry out similar to those described for preparing compounds of formula (I)in which R3=b).

To obtain the compounds of formula (I)in which R3means substituted amide group (group e) and (f)), you can do one of the following schemes 11 and 12, which illustrate the case where R3=e1):

SCHEME 11

SCHEME 12

According to this technique, when used as the initial product of the compounds of formula (XXXIIIbis), which enter into interaction with the diamine of the formula with other4-(C2-C4)-alk-A, directly receive the compound of formula (I) with R3= E1).

In the particular case where R3mean group f2) and G means piperidino group, it is possible to act according to the following scheme:

SCHEME 13

Thus, the compounds can then be converted into compounds in which NR5R6is specified for the General formula (I) is, by removing the protection and functionalization of amine NR'5R'6according to well-known specialist methods.

The compounds of formula (XXXVIII) can also be obtained from compounds of formula (XXXIIIbis) according to the following scheme:

To obtain the compounds of formula (I)in which R3mean group f2) and G means piperidinyl, you can also do according to the following scheme:

SCHEME 14

From the thus obtained compounds of formula (XXXXI) then you can get a variety of compounds of formula (I)in which R3=f2), by appropriate substitution of the primary amino group.

For example, by exposure tetrahydropyran-4-she will be receiving a connection formula (I)in which R3means:

To obtain the compounds of formula (I)in which R3= e) or f), it is possible to act according to the following diagram, which illustrates the case where R3= f2) and G means piperidine:

SCHEME 15

or, changing the order of the first stages, proceed according to the following scheme:

SCHEME 16

or according to another alternative:

Ph is phenyl;

TNR - tetrahydropyran-4-yl.

The ways presented on figures 14, 15 and 16, as protective for nitrogen group, you can use the Vos, as specified, or any other protective group Gp, corresponding, for example, alkanoyloxy group, such as formyl or acetyl, benzyl group, 9-fluorenyl ethoxycarbonyl group (Fmoc) or benzyloxycarbonyl group or tert-butoxycarbonyl group (Vos).

Aminothiazole formula (III) are obtained by known methods, such as methods described in the documents: European patent 518731, European patent 611766 and international patent application WO-99/15525.

In General, the thiourea enter into interaction with a halogenated ketone of the formula4according to the following reaction scheme:

SCHEME 17

The substituents R'1and R'2have the above values, that is, R'1and R'2mean, respectively, R1and R2such as indicated for formula (I), or groups predecessors R1and R2; Hal means a halogen atom, preferably a bromine atom, chlorine or iodine.

Halogenated ketones formula4can be obtained well-known specialist of ways. For example, brometane can be obtained by exposure to bromine, bromide divalent copper or phenyltrimethylammonium (PTT) on the acetophenone of the formula5:

in which R'1and R'2have the above significance, in an organic solvent such as ethyl acetate, chlorinated solvent or their mixture or even alcohol.

When the derivative of acetophenone of the formula5is not commercially available, it can be obtained in various ways:

- reaction Friedel-Crafts when using the insole, substituted groups R'1and R'2, which is injected into the interaction with acetylchloride or acetic anhydride in the presence of a Lewis acid such as, for example, AlCl3or TiCl4;

- the impact of acetylchloride in the presence of palladium on benzene, substituted groups R'1and R'2after deprotonation of benzene, for example, by influencing utility, then adding zinc chloride or iodide manganese. This technique is used to obtain the derivative of acetophenone of the formula5in which R'2= R2= (C1-C4)-perfluoroalkyl;

- regrouping for Fries: derived from acetoxybenzoic formula6:

by acid exposure Lewis get derived hydroxyacetophenone formula7:

Hydroxyl functional group corresponds to the group R'1that, at a subsequent stage can be transformed into the group-O-Z, such as (C1-C8-alkoxyl, tripterocarpa, triftoratsetata, alliancegroup, (C3-C8-cycloalkylcarbonyl, (C3-C8-cycloalkylation.

The transformation R'1in R1can be carried out either in the case of aminotriazole formula (III), or in the case of the compounds of formula (I).

Derivatives of benzene, substituted the s groups R' 1and R'2available commercially or you can get them well-known specialist of ways.

For example, to obtain compounds in which R1means a group of-O-Z, such as the above, proceed as follows:

SCHEME 18

You can also substitute the derived halogenase according to the following scheme:

SCHEME 19

In the particular case where R2means (C1-C4)-perfluoroalkyl, you can also do according to the following scheme of reactions:

SCHEME 20

Acid of formula (II)in which R'3means R3that represents an ether group, such as indicated for formula (I) in the form (a), is described, in particular, in Arch. Pharm.,295, 292-304 (1962); Eur. J. Med. Chem.,26(9), 675-686 (1994); J. Med. Chem.,45(16), 3406-3417 (2002); and in the documents: WO-02/53534; WO-01/00206; WO-96/21656; WO-00/39087; application for a European patent A-62504; application for a European patent A-393607; application for a European patent A-997465.

Acid of formula (II)in which R'3means R3representing group b) or (C), such as indicated for formula (I), as a rule, are new. Esters of 4-(1-methylpiperidin-4-yl)methylbenzoic acid and 4-(1-ethylpiperazin-4-yl)methylbenzoic acid are described in the Pesticide Sciences,44(1), 96-102 (1995).

Thus, an object of the present invention are also the compounds of formula (IIb):

in which R'3means R3selected from group b): (C1-C4)-alk-A or C): b, where group a and b have the above for formula (I) values, provided that when (C1-C4)-alk means methylene, differs from piperidinyl; or R'3means the predecessor of R3in particular, the group in which it is possible to available amino groups and/or hydroxyl group is protected.

Esters, in particular, (C1-C4)-aliphatic or benzyl esters, unsubstituted or substituted on the phenyl by a methoxy group, an acid of the formula (IIb), are also new and form part of the invention.

Acid of formula (II)in which R'3means R3that represents a group (e) or f), such as those described for formula (I)are, as a rule, new. The compounds of formula (II)in which R3mean group E1), are described in the documents: the international patent application WO-98/56760 and U.S. patent 5411984.

Thus, an object of the present invention are also the compounds of formula (IIe):

in which R'3means R3selected from the group consisting of E2), E3), f1)f2)f3)f4)f5)f6), such as those described for formula (I); or R'3on the mean group-the predecessor of R 3in particular, the group in which you may present the amino and/or hydroxyl group is protected.

Esters, in particular, (C1-C4)-aliphatic or benzyl esters, unsubstituted or substituted on the phenyl by a methoxy group, an acid of the formula (IIe) are also new and form part of the invention.

In particular, the acid of the formula:

where G p is a hydrogen atom or a protective for nitrogen group, such as BOC, Fmoc, benzyloxycarbonyl, benzyl or (C1-C4-alkanoyl, and their (C1-C4)-alkalemia esters of the formula (XXXXIV) or benzyl esters, unsubstituted or substituted on the phenyl by a methoxy group, are new and represent a specific object of the present invention.

Intermediate compounds of formula (XXXXVI), (XXXXVII) and (XXXXVIII), can be used to produce compounds of formula (XXXXV), are also new.

Thus, an object of the present invention is a compound of formula (XXXXVIIIbis):

in which amino groups are free or protected by a protective group such as, for example, a group Fmoc, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or (C1-C4-alkanoyl.

2-Aminothiazole formula (III), generally known, in particular, of the following documents: application for a European patent A-89681, application for a European patent A-44442 or Indian J. Chem., part b,26V(3), 287-289 (1987).

Intermediate compounds of formula (IV), namely the compounds of formula X, XIII, XIV, XVII, XVIII, XIX, XXVI, XXVII, XXVIIbis, XXIX, XXXIII, XXXIIIbis, XXXIV, XXXIVbis, XXXVIII, XXXX, XXXXIX, are novel and constitute another object of the present invention.

In addition, the intermediate compounds of formula (IV), in which the group R'3includes a protected amino group, namely the group-NGp instead of the group-NR5also are new.

The object inventions are the compounds of formula (IV):

in which:

R'1and R'2mean, respectively, R1or R2or the predecessors of R1and R2such as indicated for compounds of formula (I); in particular R'1and R'2mean, respectively, R1and R2;

R'3means a group chosen among:

- -OPg, and Pg denotes a protective group such as tert-butyl, benzoyl or arylsulfonyl (phenylsulfonyl, tamilselvan or naphthylmethyl);

- -O-(C1-C3)-alk-Q, and Q means dimethoxymethyl, diethoxylates or formyl;

- -O-(C2-C4)-alk-OH, and X means a hydrogen atom, tetrahydropyranyl or group SO2R', where R' is stands or tailam;

- -(C1-C3)-alk-Q;

- -(C1-C4)-alk-Hal, and Hal oz is achet halogen atom;

- -I;

- -COOH; -COOR, where R is a hydrogen atom, (C1-C4)-alkyl or benzyl, unsubstituted or substituted on the phenyl by a methoxy group;

- -CONH-(C1-C3)-alk-Q;

-

-

moreover, Gp protective means for nitrogen group, such as Fmoc, (C1-C4-alkanoyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl;

-

- a), A1) -O-(C2-C4)-alk-A';

a2) -O-(C1-C4)-alk-B';

a3) -O-E's;

- b) -(C1-C4)-alk-A';

- c) -B';

- d) d1) -(C1-C4)-alk-NR4-(C2-C3)-alk-A';

d2) -(C1-C4)-alk-NR4-(C1-C3)-alk-B';

- e) e1) -CONR4-(C2-C4)-alk-A';

e2) -CONR4-(C1-C4)-alk-B';

e3) -CONR4-E's;

f) f1) -CO-D-(C1-C2)-alk-A;

f2) -CO-G-A;

f3)

f4)

f5)

where:

- A', B', E' denote, respectively, groups a, b, E, such as indicated for formula (I)in which R5substituted by a group Gp;

- Gp protective means for nitrogen group, such as BOC, Fmoc, (C1-C4-alkanoyl, benzyloxycarbonyl or benzyl.

More specifically, the present invention relates to compounds of the formula (IV)in which:

- R'1the loc is in position 2 of the phenyl and is therefore, as R1indicated for formula (I);

- R'2is in position 5 of the phenyl and is the same as R2indicated for formula (I);

- R'3is in position 4 of the other phenyl group and a is as indicated above.

The following examples of the preparation and examples illustrate the obtaining of some compounds according to the invention. These examples do not limit the scope of protection of the invention, but only to explain the present invention. Non confirmed by examples of the compounds correspond to those given in the tables below. Description use the following abbreviations:

TA: room temperature

dec.: decomposition

DCM: dichloromethane

DMF: dimethylformamide

NEt3: triethylamine

THIEF: benzotriazol-1-yloxytris(dimethylamino)fosfodiesterasa

BOC: tert-butoxycarbonyl

ether: diethyl ether

MTBE: methyl tert-butyl ether

Me: methyl

Et: ethyl

Pr: propyl

Bu: butyl

Pn: pencil

Neh: hexyl

DIPEA: diisopropylethylamine

TNR: tetrahydropyran-4-yl

Connection harakteryzuyutsya as follows:

proton nuclear magnetic resonance spectrum (1H-NMR) recorded at 200 MHz in DMSO-d6(hexacyanometallate), using the peak of DMSO-d6as a standard. Chemical shift δ expressed as parts per mil is ion (ppm). The observed signals are expressed as follows: s: singlet (s); se: broadened singlet (ush. C); d: doublet (d); d.d: unleashed doublet (DD); t: triplet (t); td: unleashed doublet (TD); q: quadruplet (K); m: array; mt: multiplet (m).

For all compounds synthesized according to examples of the preparation and the examples that follow, confirmed that the recorded NMR spectra consistent with the expected structure.

Compounds according to the invention analyzed by a combination of LC/UV/MS (liquid chromatography/UV detection /mass spectrometry). Determine the peak of the molecular ion (MN+) and retention time (t).

Use the device, manufactured by Waters, and column 2.1 mm x 50 mm, particle size 3.5 µm at room temperature; flow rate 0.4 ml / min.

Elution is as follows:

- solvent: 0,005% triperoxonane acid (TFUC) in water;

- solvent: 0.005% TFUK in acetonitrile.

GradientTime (minutes)%
00
1090
1590
15,50
200

UV detection is carried out at a wavelength of 210 ± 8 nm and the distribution of mass is carried out after electroionization (English: ionization electron spray, or ESI) according to the method of registration of positive ions.

The intermediate products of the formula (III)

Getting 1.1

4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-amine

A) 1-(2-Hydroxy-5-propoxyphenyl)alanon

In a flask with a capacity of 500 ml was placed 10 g 2.5 dihydroxyacetophenone in suspension in 100 ml of acetone, add 9,14 g of anhydrous K2CO3then 12.4 g of propyliodide. The reaction medium is refluxed for 30 hours. After returning to room temperature, the medium is filtered through Celite®then concentrate. The resulting brown oil is treated with ethyl acetate, filtered off, washed with water, 2 M hydrochloric acid, then saturated NaCl. The organic phase is evaporated, obtaining a paste black color. Pasty mass is treated with chloroform and filtered. Wednesday concentrate, receiving 11.4 g solid black. This is the last process of absolute ethanol. The solution is placed for 10 minutes in the refrigerator, solid matter is deposited, it is collected by filtration. The filtrate is concentrated and the residue is treated with ethanol, cooled in the refrigerator, then again filtered. This operation is repeated 4 times, getting 8,35 g of target compound in powder form.

C) 1-(2-Methoxy-5-propoxyphenyl)alanon

2CO3then of 22.4 ml under the conditions. The reaction medium is heated for 12 hours at a temperature of 60°C. After returning to room temperature, the medium is filtered through Celite®, diluted with diethyl ether and washed with 2 M hydrochloric acid. The aqueous phase is extracted 2 times with diethyl ether. The combined organic phases are washed with diluted sodium hydroxide solution, then washed 2 times with water and saturated NaCl solution. The organic phase is dried over magnesium sulfate, then evaporated, getting 35,55 g of brown oil. The oil is distilled under reduced pressure at a temperature of 115°receiving 32,8 g of target compound in the form of oil.

C) 2-Bromo-1-(2-methoxy-5-propoxyphenyl)alanon

To a solution of 16.4 g obtained at the previous stage of the oil in 100 ml of methanol are added dropwise 4.8 ml of bromine. The medium is stirred for 30 minutes at room temperature, then evaporated. The oil obtained is treated with dichloromethane, washed 3 times with water, then dried over magnesium sulfate and evaporated, receiving 24.5 g of brown oil.

D) 4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-amine

To a solution of 42 g obtained at the previous stage of bracelona in 200 ml of ethanol is added 24.5 g of thiourea. The medium is refluxed for 1 hour and 30 minutes. Then Wednesday is placed in a DVD player is inik 12 hours, then filtered. Thus the collected solid washed with a small amount of cold ethanol and then diethyl ether. Get 25 g of the hydrobromide.

The solid is suspended in a mixture of water/dichloromethane and alkalinized by adding sodium hydroxide. The aqueous phase is extracted 2 times with dichloromethane. The combined organic phases are dried over magnesium sulfate, then evaporated. The oil obtained chromatographic on silica gel, receiving 12 g of the target product in powder form. TPL=76°C.

Getting 1.2

4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-amine

A) 4-Butylferrocene

A solution of 10 g of 4-n-butylphenol, 10 ml of acetic anhydride and 8 ml of pyridine in 10 ml of dichloromethane is refluxed. After 2 hours the medium is cooled to room temperature, diluted with dichloromethane, washed with water, 1 M hydrochloric acid, a saturated solution of CuSO4, water and dried over magnesium sulfate. After evaporation obtain 10.8 g of the target compound in the form of oil.

C) 1-(5-Butyl-2-hydroxyphenyl)alanon

To 5 g videolooking oil in the flask with a capacity of 100 ml are added in several portions 3,22 g AlCl3. The medium is heated at a temperature of 130°C for 1 hour. After returning to room temperature in a raw reaction medium was poured onto a mixture of ice water, podkislennuyu with 35%HCl. The environment is placed in an ultrasonic bath. Add ethyl acetate, reaching after 15 minutes of dissolution medium. The aqueous phase is extracted 3 times with ethyl acetate, the organic phase washed with water, then saturated NaCl. After drying over magnesium sulfate and evaporation to obtain 4.5 g of a yellow oil.

C) 1-(5-Butyl-2-methoxyphenyl)alanon

To a solution of 1 g videolooking oil in 10 ml of dimethylformamide added 1.44 g2CO3then 0,648 ml under the conditions. The medium is heated at a temperature of 60°With during the night. After returning to room temperature, the medium is filtered through Celite®, diluted with diethyl ether and washed with 2 M hydrochloric acid. The aqueous phase is extracted 2 times with diethyl ether. The combined organic phases are washed with diluted sodium hydroxide solution, then washed 2 times with water and saturated NaCl solution. The organic phase is dried over magnesium sulfate, then evaporated, getting 1.27 g of brown oil. The oil is purified by chromatography, getting 0.66 g of the target compound.

D) 4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-amine

To a solution of 0.66 g obtained at the previous stage of the product in 10 ml of methanol dobavlaut 19 ml of bromine. The medium is stirred for 10 minutes, then evaporated and treated with dichloromethane. The organic phase is washed 3 times with water is, then dried over magnesium sulfate. After evaporation gain of 0.79 g of the target product. This compound is dissolved in 5 ml ethanol in the presence and 0.46 g of thiourea and the medium is refluxed for 2 hours 30 minutes. While returning to room temperature the precipitated solid. The thus obtained solid is washed with a small amount of cold ethanol and then diethyl ether. Thus obtain 0.6 g of the hydrobromide.

The solid is suspended in a mixture of water/dichloromethane and alkalinized by adding sodium hydroxide. The aqueous phase is extracted 2 times with dichloromethane. The combined organic phases are dried over magnesium sulfate, then evaporated, getting 0.34 g of yellow oil, which slowly crystallizes. Manifold water is evaporated, then stirred in a mixture of water/dichloromethane and alkalinized by adding sodium hydroxide. The aqueous phase is extracted 2 times with dichloromethane. The combined organic phases are dried over magnesium sulfate, then evaporated. The oil obtained chromatographic on silica gel, receiving 0.18 g of the target compound. TPL=48°C.

Getting 1.3

4-(5-Cyclohexyl-2-methoxyphenyl)-1,3-thiazol-2-amine

A) 1-Cyclohexyl-4-methoxybenzoyl

To a solution of 5 g of 4-cyclohexylphenol in 60 ml of dimethylformamide add to 7.84 g2 CO3then of 3.53 ml under the conditions. The medium is heated at a temperature of 60°With during the night. After returning to room temperature, the medium is filtered through Celite®, then diluted with diethyl ether and hydrolyzing water. The aqueous phase is acidified, then extracted with 3 times 50 ml of diethyl ether. The combined organic phases are washed with diluted sodium hydroxide solution, 2 times with water and saturated NaCl solution. The organic phase is dried over magnesium sulfate, then evaporated, receiving or 4.31 g of target compound in the form of solids. TPL=67°C.

C) 1-(5-Cyclohexyl-2-methoxyphenyl)alanon

A suspension of 5.6 g of AlCl3in 40 ml of dichloromethane cooled to a temperature of -10°C. Add 3 ml of acetylchloride and 4 g obtained at the previous stage of the connection. The medium is stirred for 1 hour at a temperature of -10°C, then poured into a beaker containing ice, mixed with 35%HCl. After decanting, the combined organic phases are dried over magnesium sulfate, then evaporated, receiving of 4.54 g of the target product.

C) 4-(5-Cyclohexyl-2-methoxyphenyl)-1,3-thiazol-2-amine

To a solution of 4.5 g obtained at the previous stage of the product in 25 ml of methanol are added dropwise to 1.16 ml of bromine. The medium is stirred for 30 minutes at room temperature, after which it becomes very viscous. Add 5 ylmethanol, then 3,23 g of thiourea. The medium is refluxed for 2 hours. After returning to room temperature the precipitated solid. The solid is collected, then washed with a small amount of cold methanol. The solid is suspended in a mixture of water/dichloromethane and alkalinized by adding sodium hydroxide. The aqueous phase is extracted 2 times with dichloromethane. The combined organic phases are dried over magnesium sulfate, then evaporated, receiving 3.33 g of target compound in the form of solids. TPL=113°C.

Getting 1.24

4-(5-Pentafluoroethyl-2-methoxyphenyl)thiazol-2-ylamine

A) 1-Methoxy-4-pentafluorobenzoyl

In an inert atmosphere in a three-neck flask with a capacity of 500 ml, equipped with a nozzle Dean-stark and refrigerator, enter 8,3 g pentafluoropropionate potassium and 9.8 g of CuI. Add 90 ml of dimethylformamide and 110 ml of toluene. The medium is heated at a temperature of 140°C in an atmosphere of nitrogen, 80 ml of distilled toluene. Then the medium is cooled to room temperature, then toxigenic by ozonation of nitrogen. Then add 6 g of iodoanisole, then heated at a temperature of 155°C for 20 hours. After returning to room temperature, the medium is diluted with 200 ml of a mixture water/diethyl ether. Wednesday then filtered through Celite®. The organic the second phase is washed 3 times with water, dried over magnesium sulfate, then evaporated, obtaining 4.3 g of oil brown color.

B) 1-(2-Methoxy-5-pentabromodiphenyl)alanon

To a solution of 3.5 g of 1-methoxy-4-pentabromoethylbenzene in 50 ml of anhydrous tetrahydrofuran at -70°add to 7.4 ml of 2.5 M solution of utility in hexane. The medium is stirred for 30 minutes at -70°S, then for 45 minutes at a temperature of 0°C. After this type of 15.5 ml of 1 M solution of zinc chloride in diethyl ether. After stirring for 10 minutes at a temperature of 0°add to 1.33 ml acetylchloride. Wednesday then toxigenic nitrogen and injected 332 mg of benzyl(chloro)bis(triphenylphosphine)palladium in 5 ml of anhydrous tetrahydrofuran. The medium is stirred for 2 hours 30 minutes at a temperature of 0°S, then for 72 hours at room temperature. Wednesday pour in 2.5 M HCl, then extracted with diethyl ether. The organic phase is washed with 5%aqueous solution of NaHCO3, water, then saturated NaCl. After drying over magnesium sulfate and evaporation the crude substance is purified flash chromatography on silica, receiving 2.25 g solid white. TPL=47°C.

C) 4-(2-Methoxy-5-pentafluorophenyl)thiazol-2-ylamine

To a solution of 2.25 g obtained at the previous stage of the product in 10 ml of methanol is added 0.5 ml of the Roma in the form of a solution in 8 ml of methanol. The medium is stirred for 10 minutes, then evaporated and treated with dichloromethane. The organic phase is washed 3 times with water, then dried over magnesium sulfate. After evaporation receive 2,63 g prosteradlo product. This compound is dissolved in 15 ml of methanol in the presence of 1.25 g of thiourea and the medium is refluxed for 2 hours. While returning to room temperature the precipitated solid. The thus obtained solid substance was washed with diethyl ether. The solid is suspended in a mixture of water/dichloromethane and alkalinized by adding sodium hydroxide. The aqueous phase is extracted 2 times with dichloromethane. The combined organic phases are dried over magnesium sulfate, then evaporated, getting 1.63 g solid yellow color. TPL=125°C.

Following the above techniques get the compounds of formula (III), specified in the following table.

Table 1
Getting noR1R2SolDescription
1.1-OMe-O-Propyl-TPL=76°
1.2-OMe -n-Butyl-TPL=48°
1.2 bis-OMe-n-ButylHBrTPL=186°
1.3-OMe-TPL=113°
1.4-OMe-n-Propyl-TPL=85°
1.5-OEt-Ethyl-TPL=83°
1.6-OMe-Ethyl-TPL=100°
1.7-OEt-TPL=110°
1.8-OMe-TPL=110°
1.9-OEt-n-Butyl-TPL=65°
1.10-OMeCF3-TPL=144°
1.11-OMe-ISO-Propyl-TPL=109°
1.12-OMe-Methyl-TPL=121°
1.13 -n-Butyl-TPL=59°
1.14-OMe-TPL=91-93°
1.15-OMephenyl-TPL=116°
1.16-ClCF3-TPL=110°
1.17-OEtMethyl-TPL=124°
1.18-SO2Et-n-Butyl-TPL=121°
1.19-OMe-CH(n-propyl)2HClMN+=305,4

t=to 7.61
1.20-OnPr-n-Butyl-TPL=63°
1.21-OMe-n-Hexyl-TPL=43°
1.22-OMeof substituted-TPL=81-82°
1.23-OEt-n-Hexyl-TPL=75°
1.24-OMeCF3CF2-TPL=125°
1.25-OEtCF3 CF2-MN+=338

t=7,88
1.26-OEt-n-Propyl-TPL=87°
1.27-OEtcyclopentyl-TPL=128°
t: retention time

Getting 2.1

N-(Boc) - N-(Tetrahydro-2H-Piran-4-yl)piperidine-4-amine

A) 1-Benzyl-N-(tetrahydro-2H-Piran-4-yl)piperidine-4-amine (XXXXVI)

In a dry nitrogen atmosphere 19 g of 4-amino-1-benzylpiperidine injected in 50 ml of 1,2-dichloroethane, add 10 g tetrahydropyran-4-it in 20 ml of 1,2-dichloroethane; after stirring for 10 minutes add up 29.6 g of NaBH(OAc)3then stand under stirring in the course of the day. To the reaction medium, add 10%solution of Na2CO3and ethyl acetate, and then decanted. The organic phase is washed with 10%solution of Na2CO3then a saturated solution of NaCl, then dried over magnesium sulfate and evaporated in vacuum. Get to 23.4 g of the target compound. TPL=60°C.

B) 1-Benzyl-N-BOC-N-(tetrahydro-2H-Piran-4-yl)piperidine-4-amine

14,92 g obtained in the previous phase connections make 100 ml of ethyl acetate, then cooled in a bath with ice and add 12,46 g (Vos)2About 30 ml of ethyl acetate. Heated at a temperature of 50°t is the significance of 4 days then stirred for 2 days at room temperature. The reaction medium is washed with water (3 times), dried over magnesium sulfate, then evaporated. The oil obtained is crystallized solid proscout in pentane, filtered and dried at a temperature of 60°With over R2About5. Obtain 15.9 g of target compound. TPL=104°C.

C) N-(Boc) - N-(Tetrahydro-2H-Piran-4-yl)piperidine-4-amine

15,8 g obtained in the previous phase compounds is introduced into 100 ml of methanol together with 1 g of 10%palladium-on-coal and hydronaut at atmospheric pressure at a temperature of 30°With during the day. The medium is filtered through Celite®, then washed with methanol. After evaporation of the filtrate get of 11.15 g of target compound, which crystallizes. TPL=125°C.

The intermediate products of the formula (II)

Getting 3.1

4-(2,2-Diethoxyethane)benzoic acid

(II): R'3= 4-base2CH(OEt)2

A) Methyl ester of 4-(2,2-diethoxyethane)benzoic acid

At a temperature of 100°C for 5 minutes to heat the mixture containing 10 g of methyl-4-hydroxybenzoate and 22,71 g2CO3in 100 ml of tetrahydrofuran, return the mixture to room temperature and add 15,54 g of 2-bromo-1,1-diethoxyethane and incubated with stirring for 2 hours at room t is mperature, then for 32 hours at a temperature of 100°then leave to stand until they return to room temperature. The inorganic part is filtered off, then washed with dimethylformamide. The filtrate is evaporated, and then treated with dichloromethane, washed with water (3 times), then with saturated NaCl solution, dried over magnesium sulfate and evaporated. Get 16,68 g of target compound (more theoretically calculated mass).

B) 4-(2,2-Diethoxyethane)benzoic acid

8,08 g obtained at the previous stage of ester is introduced into 50 ml of methanol with 16 ml of 5N NaOH solution and kept under stirring for 6 hours. After the solvent is evaporated, treated with water, then add 1.2 M HCl until pH 3; filtered and washed with water, getting the precipitate, which is dried in vacuum. The filtrate is extracted 2 times with dichloromethane, then dried over magnesium sulfate. In General receive 7,29 g of target compound.

Getting 3.2

Salt of triethylamine and 4-((4-(N-BOC)tetrahydro-2H-Piran-4-yl)amino)-piperidine-1-yl)carbonyl)benzoic acid

A) Methyl ester of 4-((4-N-BOC-amino)piperidine-1-ylcarbonyl)-benzoic acid

At room temperature for 4 days incubated with stirring, a mixture containing of 5.39 g nanometrology ester of terephthalic acid is, 40 ml of CH3CN, 6 ml of triethylamine, 14.8 g a THIEF and 5 g of 4-(N-BOC-amino)piperidine. The reaction medium is diluted with ethyl acetate, then washed 4 times with 10%solution of Na2CO3then 4 times with water. Dried over magnesium sulfate, and then concentrated to dryness and treated with a mixture of diethyl ether/cyclohexane. Filtered off, then dried, obtaining of 6.66 g of the target compound. TPL=128-130°C.

B) Hydrochloride of the methyl ester of 4-((4-aminopiperidin-1-yl)-carbonyl)benzoic acid

Stand under stirring and at room temperature for 2 hours 17,66 g obtained at the preceding stage connection in 120 ml of 4 M HCl solution in dioxane. Add diethyl ether, and then continue stirring for 1 hour. Filtered off, washed with diethyl ether, then dried, obtaining 15 g of target compound. TPL=236-238°C.

C) Methyl ester of 4-((4-(tetrahydro-2H-Piran-4-ylamino)-piperidine-1-yl)carbonyl)benzoic acid

Stand under stirring over night the mixture containing 15 g obtained at the previous stage of the compound in 50 ml of dimethylformamide, 5 g of tetrahydro-4H-Piran-4-it 4 ml of triethyl-amine. Type of 1.36 ml of acetic acid, 12.7 g NaBH(OAc)3and 50 ml of dimethylformamide and incubated with stirring for 3 hours. Reaction medium was concentrated to dryness, then the process of dihl what Rotana, washed with 10%solution of Na2CO3. Decanted, and then the organic phase is washed with water (3 times), dried over magnesium sulfate and concentrated to dryness. Obtain 9.5 g of target compound in the form of solids. TPL=129°C.

D) Methyl ester of 4-((4-((N-BOC)tetrahydro-2H-Piran-4-ylamino)-piperidine-1-yl)carbonyl)benzoic acid

Within 10 hours refluxed mixture of 3.16 g obtained at the previous stage of the compound in 12 ml of dichloromethane in the presence of 4.5 g Vos2Oh and of 1.65 ml of triethylamine. After cooling, the reaction medium is washed with a buffer solution with a pH of 2 (3 times), then water (3 times). The organic phase is dried over magnesium sulfate, and then concentrated to dryness, obtaining 4,63 g of the target product.

E) Salt of triethylamine and 4-((4-(N-BOC)tetrahydro-2H-Piran-4-yl)amino)piperidine-1-yl)carbonyl)benzoic acid

Within 48 hours incubated under stirring 4 g obtained at the previous stage of the compound in 100 ml of 5N NaOH solution in methanol. The methanol is removed by evaporation, the crude product is treated with water, the aqueous phase washed with dichloromethane and then acidified with HCl to pH 3. Filtered off and washed with diethyl ether, after which the solid is treated with dichloromethane, water, triethylamine. The aqueous phase is extracted with dichloromethane, C is the dried over magnesium sulfate and concentrated to dryness, receiving 700 mg of target compound in the form of solids. MN+= 433,3; t (retention time) = of 6.71.

Get the corresponding free acid: TPL=190°; MN+=433,3; t=6,70.

Getting 3.3

4-(4-((R)-3-(N-BOC)pyrrolidin-1-yl)piperidine-1-carbonyl)-benzoic acid

A) tert-Butyl methyl ether (1-(benzylpiperidine-4-yl)pyrrolidin-3-yl)carbamino acid

To a solution of 4.6 g of (3R)-3-(tert-butoxycarbonyl)amino)-pyrrolidine in 5 ml of dichloroethane type of 4.66 g of 1-benzyl-4-piperidone in 6 ml of dichloroethane. After incubation for 20 minutes at room temperature add 7,31 g NaBH(OAc)3maintaining the environment at a temperature below 20°C, followed by 20 ml of dichloro-ethane for dissolution environment, which seizes in mass. The medium is stirred at room temperature for 24 hours, hydrolyzing by adding a 10%aqueous solution of Na2CO3and diluted with ethyl acetate. After decanting, the organic phase is washed with 10%aqueous solution of Na2CO3then a saturated solution of NaCl, then dried over magnesium sulfate, then evaporated. The crude product proscout in diethyl ether, filtered off, washed with diethyl ether, then dried, obtaining 7,38 g solid white. TPL=118°C.

C) tert-Butyl methyl ether (1-(piperidine-yl)pyrrolidin-3-yl)-carbamino acid

The solution 7,37 g obtained at the previous stage of the compound in 50 ml of methanol hydronaut at atmospheric pressure and at room temperature in the presence of 1 g 10%Pd/C for 12 hours. The medium is filtered through Celite®, the solid is washed with methanol. After evaporation of the filtrate gain of 5.2 g of oil, which solidifies after powdering used the same in the next stage.

C) Methyl ester of 4-(4-((R)-3-(N-BOC)pyrrolidin-1-yl)piperidine-1-carbonyl)benzoic acid

To a solution of 4.75 g obtained at the preceding stage connection in 35 ml of acetonitrile added 3.8 g nanometrology ester of terephthalic acid, then 9.4 g a THIEF, then 2.2 g of triethylamine. The medium is stirred at room temperature for 24 hours, then concentrated. The crude product is treated with ethyl acetate, washed twice with water, then twice 10%aqueous solution of Na2CO3then a saturated solution of NaCl. After drying the organic phase over magnesium sulfate and evaporating get to 8.62 g of crude product, which proscout in a mixture of diethyl ether and ethyl acetate. After filtering off get 5,28 g of the target product.

D) 4-(4-((R)-3-(N-BOC)pyrrolidin-1-yl)piperidine-1-carbonyl)-benzoic acid

To a solution of 5.05 g obtained at the previous stage of ester in 20 ml of methanol to ablaut of 1.17 g of sodium hydroxide. The medium is stirred at room temperature for 12 hours, then evaporated and treated with water. The aqueous phase is washed with diethyl ether, then acidified to pH 5 and extracted twice with ethyl acetate. The organic phase is dried over magnesium sulfate, then concentrated. The aqueous phase is evaporated, then dried by azeotropic distillation with ethanol. The residue is treated with ethanol, filtered through Celite®and the filtrate is evaporated. Both crude product combine, getting the 3.65 g of the target acid. MN+=418 at t=4.7 minutes.

The intermediate products of the formula (IV)

Obtaining 4.1.1.

N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-((4-oxo-piperidine-1-yl)carbonyl)benzamide

For 3 days at room temperature stirred suspension containing 0,86 g aminothiazole according to the Receiving 1.2, 1 g of 4-((4-oxopiperidin-1-yl)carbonyl)benzoic acid and 0.6 ml of triethylamine in 8 ml of acetonitrile and added to 1.9 g of the THIEF. The precipitation is filtered off, then washed with 0.3 ml of CH3CN, then 1 ml of diethyl ether; gain of 0.85 g of the target compound. TPL=184°C.

The compound of formula (XXXVIII) can be obtained according to the following method:

to a solution of 10.4 g of the acid obtained by the method described in 4.2.1, in 50 ml of acetonitrile add 4.7g guide is ochloride monohydrate 4-piperidone, then 15.7 g a THIEF. At a temperature of 0°add to 13.3 ml of DIPEA and leave the temperature to rise to room. After stirring for 24 hours at room temperature, the reaction medium is filtered, the solid washed with acetonitrile, and then the filtrate is concentrated and the residue is treated with dichloromethane. The organic phase is washed with 10%solution of Na2CO3then with 0.5 M HCl, then saturated NaCl. After drying the organic phase over magnesium sulfate receive 11,33 g of the target product.

Following a similar methodology, receive connections described in the following table.

tr>
Table 2
Getting noR1R2Description
4.1.1MeON-ButylTPL=184°
4.1.2 (compound No. 242)MeON-Propyl-OTPL=196°
4.1.3MeOMethylTPL=183°
4.1.4MeOEthylTPL=180°
4.1.5MeON-PropylTPL=172°
4.1.6 (compound No. 243)MeOCyclohexylTPL=186°
4.1.7 (compound No. 244)EtOCyclohexylTPL=236°
4.1.8EtOEthylTPL=160°
4.1.9MeOCyclopentylMN+=504,5

t=10,55
4.1.10-OEt-n-ButylMN+=506

t=10,3
t: retention time

Obtaining 4.2.1.

4-(((4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)amino)-carbonyl)benzoic acid

(XXXIIIbis): R1=2-OMe; R2=5-n-Bu; R'3=4-COOH

Mix 5 g of aminothiazole according to the Receiving 1.2, 4.12 g of methyl-4-carboxybenzoyl, then of 1.85 ml of triethylamine, and 25 ml of CH3CN and 10,13 g a THIEF and stirred for 4 days at room temperature. The precipitation is filtered off, then washed his acetonitrile. The precipitate is then treated with a mixture of ethyl acetate and a saturated solution of Na2CO3. After decanting, the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. Get 3,18 g of target compound in the form of a complex methyl ester. This ester is suspended in 34 ml of meth is Nola, then add 5,3 ml of 5N sodium hydroxide solution. After stirring for 5 days at room temperature the reaction medium was concentrated to dryness. The resulting residue is dissolved in 5 ml of water, then washed with 2 times 50 ml of ethyl acetate. The aqueous phase is acidified with 1 M HCl to pH 2, the precipitation is filtered off, then washed with diethyl ether. After drying receive 2,78 g of target compound in the form of retinoid substance. TPL=160°C.

Following the above methodology, receive intermediate compounds listed in the following table.

- MeO-
Table 3
ReceivingR1R2RSolDescription
4.2.1MeO-n-ButylN-MN+=410

t=21,53
4.2.2MeO-n-Propyl-OMethyl-TPL=180°
4.2.3MeO-n-Propyl-ONHClMN+=412

t=6,11
4.2.4MeO-n-ButylMethylMN+=424

t=21,35
4.2.5MeO-n-PropylMethyl--
4.2.6MeO-n-PropylN-MN+=396

t=8,17
4.2.7EtO-EthylNTFUKMN+=396

t=accounted for 14.45

TPL°
4.2.8EtO-Ethylt-Butyl-NMR
4.2.9MeO-CyclohexylMethyl-MN+=440

t=8,11
4.2.10MeO-CyclohexylN-MN+=436

t=10,49

TPL>260°
4.2.11EtO-CyclohexylMethyl--
4.2.12EtO-CyclohexylN-MN+=450

t=11,05
4.2.13MeO-EthylMethyl-NMR
4.2.14MeO-EthylN-NMR
4.2.15n-HexylMethyl-MN+=453

t=11,9
4.2.16MeO-n-HexylN-MN+=439

t=11,0
4.2.17EtO-n-ButylMethyl-MN+=439

t=12,1
4.2.18EtO-n-ButylN-MN+=425

t=8,6
t: retention time

NMR: Getting 4.2.8.: 1,2 ppm: t: 3H; 1,6 ppm: t: 3H; 1,7 ppm: s: 9H; 2,7 ppm m: 2H; 4,2 ppm: q: 2H; 7,0-7,2 ppm: m: 2H; to 7.8 ppm: s: 1H; of 8.0 to 8.3 ppm: m: 5H ; 12,9 ppm: OSS: 1H.

NMR: Getting 4.2.13.: 1,2 ppm: t: 3H; 2,6 ppm: q: 2H; 3,9 ppm: s: 6H; 7,0-7,2 ppm: m: 2H; and 7.7 ppm: s: 1H; 8,0 an 8.4 ppm: m: 5H; to 12.8 ppm: OSS: 1H.

NMR: Getting 4.2.14.: 1,2 ppm: t: 3H; 2,7 ppm: q: 2H; 3,9 ppm: s: 3H; 7,0-7,2 ppm: m: 2H; and 7.7 ppm: s: 1H; 8,0 an 8.4 ppm: m: 5H; 12,6-13 ppm: OSS: 1H; 13,2-13,5 ppm: OSS: 1H.

Getting 4.3.1.

N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-(2-chloroethyl)-benzamide

(XXIX): R1=2-OMe; R2=5-n-Bu; R'3=4-(CH2)2Cl

Prepare a mixture containing 3 g of aminothiazole according to the Receipt of 1.2, 10 ml of CH3CN, of 2.54 g of 4-(2-chloroethyl)benzoic acid, 1,11 ml of triethylamine and 6.1 g of a THIEF, and incubated with stirring for 48 hours. The reaction medium is diluted with the with ethyl acetate, then washed with a saturated solution of Na2CO3(2 times) and saturated NaCl solution, then dried over magnesium sulfate and concentrated to dryness. After powdering in ethanol formed insoluble portion removed by filtration, then the filtrate is concentrated to dryness, obtaining of 7.7 g of the target compound. Its clear by chromatography on silica, elwira gradient toluene/cyclohexane (9:1, volume/volume) up to pure toluene.

Following the above methodology obtain the compounds of formula (XXIX)specified in the following table.

Table 4
Getting nonR1R2Description
4.3.12MeO-n-ButylNMR
4.3.22MeO-EthylNMR
4.3.32MeO-n-Propyl-OMN+=431,2

t=to 9.91
4.3.41MeO-n-Butyl
4.3.51MeO-EthylTPL=141°
t: retention time

NMR: Getting 4.3.1.: of 0.85 ppm: t: 3H; of 1.05 to 1.6 ppm: m: 4H; 2,5-2,6 ppm: m: 2H; 3,0 ppm: m: 2H; 3,8-4,0 ppm: m: 5H; 7,0 ppm: m: 2H; between 7.4 to 7.6 ppm: d: 2H; and 7.7 ppm: s: 1H; 8,0 ppm: m: 3H; of 12.6 ppm: OSS: 1H.

NMR: Getting 4.3.2.: 1,2 ppm: t: 3H; 2,7 ppm: q: 2H; 3,2 ppm: t: 2H; to-4.0 ppm: m: 5H; 7,0-7,2 ppm: m: 2H; to 7.6 ppm: d: 2H; to 7.8 ppm: s: 1H; of 8.0 to 8.3 ppm: m: 3H; of 12.7 ppm: OSS: 1H.

Getting 4.4.1

N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-(3-oxopropyl)benzamide

R1= 2-OMe; R2= 5-n-Bu; R'3= 4-(CH2)2SNO

A) N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-iodobenzene

Within 8 hours at room temperature stirred mixture containing 6,62 g aminothiazole according to the Receiving 1.2, 75 ml of CH3CN, 7,53 g of 4-iodobenzoyl acid and 4.2 ml of triethylamine and 13,45 g a THIEF. The resulting product is filtered, then washed with CH3CN. The precipitate is again dissolved in dichloromethane, washed with 7%NaOH solution (2 times), then dried over magnesium sulfate and evaporated. Parallel to the filtrate in CH3CN is evaporated, the residue is treated with dichloromethane, then washed 4 times in 7%NaOH solution and dried over magnesium sulfate. So generally get the value of 16,81 g of target compound. MN+=492; t=12,01 minutes.

C) N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-(3-oxopropyl)benzamide

In nitrogen atmosphere, 2 g obtained at the previous stage is connected to the I in 15 ml of dimethylformamide is mixed with 0,79 g of molecular sieves 4A, 0,42 ml of allyl alcohol, of 1.31 g of dried Tetra(n-butyl)ammoniumbromide and 0.85 grams dried NaHCO3. After stirring for 2 hours at room temperature, add 50 mg of Pd(OAc)2and stirred at room temperature for 20 hours in an atmosphere of dry nitrogen. Filtered through Celite®, washed with dimethylformamide, then add water and diethyl ether. After decanting again extracted 3 times with diethyl ether. Dried over magnesium sulfate and evaporated in vacuum. Receive 2 g of the target compound.

Following the above methodology, obtain the compounds of formula (XXVII) and their iododerma predecessors, such as the one described on the stage And above Receipt.

OEt
Table 5
Receipt No.R1R2RDescription
OMen-ButylIMN+=493,2

t=12,01
4.4.1OMen-Butyl-(CH2)2CHO-
OEtEthylITPL=180°
4.4.2Ethyl-(CH2)2CHO-
OMeEthylIMN+=465,1

t=11,35
4.4.3OMeEthyl-(CH2)2CHO-
t: retention time

Getting 4.5

The hydrochloride of N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-N'-(2-oxoethyl)terephthalamide

(XXXIVbis), HCl: R1=2-OMe; R2=5-O-n-Pr; R'3=4-CONHCH2CHO

A) N-(2,2-Dimethoxymethyl)-N'-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)terephthalamide

For three and a half hours at room temperature stirred mixture containing 2.6 g of the compound according to the Receiving 4.2.3, 30 ml of CH3CN, 1,61 ml of triethylamine, 0.53 diethylenetriaminepentaacetate and 2,56 g a THIEF. After filtration is washed with CH3CN, then dichloromethane. The filtrate is evaporated, the residue proscout using CH3CN, filtered and receive 2 g of the target compound.

B) Hydrochloride of N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-N'-(2-oxoethyl)terephthalamide

In a dry nitrogen atmosphere, 0.2 g obtained in the previous phase compounds injected in 2 ml dioxane, heated to the boiling temperature under reflux for dissolution and cooled to room the second temperature, then add 3 ml of 4 M solution of HCl in dioxane and kept under stirring for 7 hours. Filtered in an atmosphere of nitrogen precipitated sludge receiving 0.15 g of the target compound.

Obtaining 4.6

4-(2-Hydroxyethoxy)-N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)benzamid

(XVIII): R1= 2-OMe; R2= 5-O-n-Pr; R'3= 4-O-(CH2)2OH

A) Methyl-4-(2-(tetrahydro-2H-Piran-2-yloxy)ethoxy)benzoate

Heated to a temperature of 100°With a mixture containing 40 g of methyl-4-hydroxybenzoate and 90,84 g2CO3in 400 ml of dimethylformamide and slowly add 71,47 g 2-(2-bromoethoxy)tetrahydro-2H-Piran, then aged by heating for 8 hours. The filtrate is evaporated in vacuo, then the residue is treated with dichloromethane, washed 3 times with water, dried over magnesium sulfate, then evaporated. Get 77,66 g of target compound.

B) 4-(2-(Tetrahydro-2H-Piran-2-yloxy)ethoxy)benzoic acid

Stand under stirring and at room temperature, in dry nitrogen atmosphere for one day, the mixture containing 77,66 g of the product obtained in the previous phase, 400 ml of methanol and 135 ml of 5 M NaOH solution. The reaction medium is evaporated, then treated with water and set pH 5 by adding HCl. Filtered off, then washed with water. The filtrate is extracted 2 times with dichloromethane, C is the dried over magnesium sulfate and evaporated. Obtain 72 g of target compound.

C) N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(tetrahydro-2H-Piran-2-yloxy)ethoxy)benzamide

(XVII): R'3=4-O-(CH2)2-OTHP

For 4 days at room temperature stirred mixture containing a 3.83 g of compound according to the Receipt 1.1, 30 ml of CH3CN, 4,63 g obtained at the previous stage of the acid, of 7.69 g a THIEF and 2.4 ml of triethylamine. The precipitation is filtered off, washed with CH3CN and dried over P2About5at a temperature of 60°C. Obtain 5.5 g of the target compound. TPL=114°C.

D) 4-(2-Hydroxyethoxy)-N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)benzamid

5,41 g obtained in the previous phase compounds is introduced into 25 ml of 4 M solution of HCl in dioxane and stirred for 30 minutes. The precipitation is filtered off, then washed with dioxane and diethyl ether and dried over P2About5at a temperature of 60°C. Obtain 4.6 g of the target compound.

Getting 4.7

N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(2-oksidoksi)benzamid

(XIV): R1=OMe; R2=O-n-Pr; R'3=4-och2SNO

A) 4-(2,2-Diethoxyethane)-N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)benzamid

Within 3 days stirred mixture containing 4,56 g of compound according to the Receipt 1.1, 5,26 g a derivative of benzoic acid according to the Receiving 3.1 in 40 ml of CH 3CN from 9.16 g a THIEF and 2.9 ml of triethylamine. After evaporation the residue is treated with dichloromethane, then washed 3 times with water, dried over magnesium sulfate and evaporated. The resulting product chromatografic on the silicon dioxide, elwira a mixture of toluene/ethyl acetate (95:5; volume/volume). Treated with diethyl ether, filtered off, washed, then dried at a temperature of 60°With over R2About5getting 6,12 g of target compound. TPL=107°C.

C) N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(2-oxo-ethoxy)benzamide

1.52 g obtained in the previous phase compounds injected 3.8 ml of formic acid and heated at a temperature of 50°C for 3 hours. After returning to room temperature, add water, then filtered off, washed with water and dried at a temperature of 60°With over R2About5. Earn 1.25 g of the target product.

Getting 4.7bis

N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(2-oksidoksi)benzamid

In a dry nitrogen atmosphere cooled to a temperature of -60°With a mixture containing 0.4 g of the compound according to Receipt of 4.6 at 0.36 ml of dimethyl sulfoxide and 5 ml of dichloromethane, and stirred for 2 hours. Type of 0.83 ml of triethylamine and allowed to stand until the temperature rises to room. The inorganic part is filtered off, then washed with dichloromethane. Phil is spending washed with water, 10%solution of Na2CO3then 2 times with saturated solution of NaCl. Dried over sulfate magnify and evaporated. Obtain 0.39 g of the target compound.

Getting 4.8

2-(4-(((4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)amino)-carbonyl)phenoxy)ethylmethanesulfonate

Prepare a mixture containing 0.4 g of the compound according to the Receipt 4.6 in 5 ml of dichloromethane, and 0.28 ml of triethylamine and 120 μl of CH3SO2Cl. Stirred for a half hour while cooling in a bath with ice. Filtered off the insoluble portion, which was washed with dichloromethane. The filtrate is washed 3 times with water. The organic phase is dried over magnesium sulfate, filtered, washed with dichloromethane and evaporated, receiving of 0.38 g of the target product.

EXAMPLE 1: connection 65

N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-((4-[2-(S)-(hydroxymethyl)pyrrolidin-1-yl]piperidine-1-yl)carbonyl)benzamide

Within 30 minutes, stirred solution containing 82 mg of the compounds according to the Receiving 4.1.1 and 45 mg (S)-prolinol in 2 ml of dichloromethane and 5 drops of CH3CO2N, then add 100 mg of NaBH(OAc)3and stirred for 12 hours. The medium is diluted with 200 ml ethyl acetate, then washed 2 times with a solution of Na2CO3, dried over magnesium sulfate and evaporated. The resulting product is stirred under the influence of ul is rasluka in the presence of 5 ml of diethyl ether, then filtered off, receiving 70 mg of the target compound. TPL=199°C.

The NMR spectrum of 0.85 ppm: t: 3H; 1,1-2 ppm: m: 12H; 2,2-4,6 ppm: m: 15H; 6,8-7,2 ppm: DD: 2H; 7,45 ppm: d: 2H; the 7.65 ppm: s: 1H; 7,95 ppm: s: 1H; 8,1 ppm: d: 2H; of 12.6 ppm: OSS: 1H.

EXAMPLE 2: connection 120

4-((4-[3-(R)-(Acetylamino)pyrrolidin-1-yl]piperidine-1-yl)-carbonyl)-N-[4-(5-butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-benzamide

In an atmosphere of dry nitrogen was placed a mixture containing 0.25 g of the compound according to the Receiving 4.1.1, with 0.13 g of (3R)-3-ndimethylacetamide-pyrrolidine and 2 ml of dichloromethane, and stirred for 15 minutes, then add 0,22 g NaBH(OAc)3and 8 drops of acetic acid and incubated under stirring at room temperature for 3 hours and 50 minutes. Add a 10%solution of Na2CO3and ethyl acetate. After decanting, the organic phase is washed with 10%solution of Na2CO3, then dried over magnesium sulfate and evaporated. The remainder proscout in diethyl ether, then filtered off, washed with diethyl ether and dried at a temperature of 60°With over R2About5. Obtain 0.25 g of the target compound. TPL > 200°C (decomposition).

The NMR spectrum of 0.85 ppm: t: 3H; 1-2,1 ppm: m: 13H; 2,1-4,5 ppm: m: 15H; 6,8-7,2 ppm: DD: 1H; 7,45 ppm: d: 2H; the 7.65 ppm: s: 1H; a 7.85 ppm: d: 1H; 8,15 ppm: d: 2H; 12,65 ppm: OSS: 1H.

EXAMPLE 3: connection 107

The dihydrochloride of N-[4-(5-butyl-2-methoxyphenyl)-1,3-ti is evil-2-yl]-4-((4-pyrrolidin-1-reparacin-1-yl)carbonyl)benzamide

At room temperature for 9 days stirred mixture containing 0.6 g of the compound according to the Receiving 4.2.1, 6 ml of CH3CN, 0,31 ml ethyldiethanolamine, 0.27 g of 4-(pyrrolidin-1-yl)piperidine in 2 ml of CH3CN and 0.78 g of a THIEF. After evaporation of the solvent environment is treated with ethyl acetate, then washed with 10%aqueous solution of Na2CO3(3 times), then with saturated NaCl solution, then dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira a mixture of dichloromethane/methanol (100:3; volume/volume), receiving of 0.43 g of the base. TPL=128°; MN+=547,4; t=6,83.

The resulting base is treated with dichloromethane, then add hydrochloric acid in diethyl ether. After filtration and drying gain of 0.44 g of the target compound.

The NMR spectrum of 0.85 ppm: t: 3H; 1,05-2 ppm: m: 12H; to 2.25 ppm: m: 1H; 2,5 ppm: t: 2H; 2.8 to and 4.40 ppm: m: 12H; 6,95 ppm: d: 1H; 7,05 ppm: DD: 1H; 7,5 ppm: d: 2H; the 7.65 ppm: s: 1H; 7,95 ppm: d: 1H; 8,15 ppm: d: 1H; 12,55 ppm: OSS: 1H.

EXAMPLE 4: compound 68

The dihydrochloride of N-[4-(5-butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-((4-(tetrahydro-2H-Piran-4-ylamino)piperidine-1-yl)carbonyl)-benzamide

0.3 g of the compound according to the Receiving 4.2.1 injected into 3 ml of CH3CN and add 153 μl of ethyldiethanolamine, 0.25 g amine according to the Receiving 2.1 and 0.39 g Is R. Stirred at room temperature overnight, then filtered off, washed with diethyl ether and dried over P2About5at a temperature of 60°C. Obtain 0.36 g of the target compound. TPL=152°C.

In)

0.35 g obtained in the previous phase compounds injected into 3 ml of 4 M solution of HCl in dioxane and incubated for 35 minutes under stirring at room temperature. Add diethyl ether, filtered off, washed with diethyl ether and dried over P2About5at a temperature of 60°C. Obtain 0.32 g of the target compound. TPL=181°C.

The NMR spectrum of 0.85 ppm: t: 3H; 1,25 ppm: sextet: 2H; 1,15-1,90 ppm: m: 10H; 2,5 ppm: t: 2H; 2,65-4,70 ppm: m: 15H; 6,95 ppm: d: 1H; 7,05 ppm: DD: 1H; 7,45 ppm: d: 2H; the 7.65 ppm: s: 1H; 7,95 ppm: d: 1H; 8,1 ppm: d: 2H; to 9.3 ppm: OSS: 1H; 12,65 ppm: OSS: 1H.

On the basis of intermediate compounds listed in the following table, followed by the method of example 4, step B, by treatment in acidic medium, to obtain the compounds of formula (I) according to the invention.

Table 6
ReceivingR2R'3Description
5.1-nBuPL=152°
5.2-EtTPL=221°
5.3-OnPrMN+=581,4

t=10,12
5.4-OnPrMN+=581,4

t=9,74
5.5-nBuMN+=566,4

t=12,11
5.6-nBuMN+=is 552.5

t=11,84
5.7-nBuMN+=566,5

t=12,37
5.8-nBuMN+=591,4

t=10,63

TPL=115°
5.9-nBuTPL=98°
5.10CyclopentylTPL=180°
5.11-nBuTPL=82°
5.12-nPrMN+=596,3

t=a 10.74
5.13-nBuMN+=579

t=10,6
5.14-nBuMN+=579

t=10,6
t: retention time

EXAMPLE 4bis: connection 68

The dihydrochloride of N-[4-(5-butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-((4-(tetrahydro-2H-Piran-4-ylamino)piperidine-1-yl)carbonyl)-benzamide

A)

At room temperature for 48 hours stirred mixture containing 370 mg of the compounds according to the Receiving 1.2, 3 ml of CH3CN, 378 mg THIEF and 151 mg of the compounds according to the Receipt of 3.2. The reaction medium is diluted with ethyl acetate, then washed 3 times with 10%aqueous solution of Na2CO3then 3 times with an aqueous solution of NaCl. The organic phase is dried over magnesium sulfate, and then concentrated to dryness. Treated with diisopropyl ether, then filtered off and dried, receiving 325 mg of target compound. TPL=152°C.

In)

Stirred for 1 hour 320 mg obtained in the previous phase compound in 3 ml of 4 M HCl solution in dioxane. Add diethyl ether, filtered off, then the solid is washed with diethyl ether and dried, obtaining 259 mg of the target compound. TPL=181°C.

EXAMPLE 5: compound 161

4-[3-(3-(Acetylamino)pyrrolidin-1-yl)propanol]-N-[4-(5-butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]benzamide

Stirred at a temperature of 50°C for 2 days the mixture containing 0.3 g of the compound according to the Receiving 4.3.1, 0.12 g of KI, 0.06 g NaHCO3in 3 ml of dimethylformamide and 897,3 mg pyrrolidin-3-ndimethylacetamide. Wednesday concentrated to dryness and then treated with dichloromethane. The organic phase is washed 2 times with saturated NaCl solution, then dried over magnesium sulfate and concentrated to dryness. The product crystallizes in the presence of methyl tert-butyl ether. After filtering off and drying obtain 0.02 g of target compound. TPL=112°C.

EXAMPLE 6: compound 185

Trihydrochloride N-[4-(5-ethyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-[N-((1-ethylpyrrolidin-2-yl)methyl)glycyl]benzamide

For five and a half hours refluxed mixture containing 0.25 g of the compound according to the Receiving 4.3.5 in 3 ml of CH3CN and 0.21 g of 2-aminomethyl-1 ethylpyrrolidin in 1 ml of CH3CN. After stirring overnight at room temperature, evaporated, treated with dichloromethane, then washed 3 times with water, then dried over magnesium sulfate and evaporated. The resulting product chromatografic on the silicon dioxide, elwira is a mixture of dichloromethane/methanol (100:5; volume/volume).

The compound obtained is treated with dichloromethane, add hydrochloric acid in diethyl ether, then the precipitation is filtered off and washed with diethyl ether. Dried over P2About5at a temperature of 60°receiving 0.17 g of the target compound. TPL=163°C (decomposition).

EXAMPLE 7: the connection 182

N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-[3-(tetrahydro-2H-Piran-4-ylamino)propyl]benzamide

Placed in a nitrogen atmosphere a mixture of 0.38 g of compound according to the Receiving 4.4.1 in 3 ml of dichloromethane and 0.15 g of 4-aminotetrahydrofuran in 1 ml dichloromethane. After stirring for 15 minutes added 0.31 g NaBH(OAc)3and kept under stirring for 6 hours. Add a 10%solution of Na2CO3and ethyl acetate, then decanted, washed with 10%solution of Na2CO3, then dried over sodium sulfate and evaporated. The resulting product chromatografic on the silicon dioxide, elwira a mixture of dichloromethane/methanol (100:4; volume/volume). Obtain 0.11 g of the target compound.

EXAMPLE 8: compound 95

N-[4-(5-Ethyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-N'-(2-pyrrolidin-1-retil)terephthalamide

At room temperature for 2 days stirred mixture containing 0.3 g of the compound according to the Receiving 4.2.1, 3 ml of CH3CN, 0.25 ml of ethyldiethanolamine, 98 mg of 1-(2-amino-ethyl)pyrrolidine in 2 ml of CH3CN, 0,38 g a THIEF and 1 ml of dimethylformamide. Filtered off, washed with CH3CN, then dried over P2About5at a temperature of 60°C. Receive 0,22 g of target compound. TPL=170°C.

EXAMPLE 9: compound 9

4-[2-(2-(S)-(hydroxymethyl)pyrrolidin-1-yl)ethoxy]-N-[4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl]benzamide

Stirred for 18 hours, the mixture containing 0.2 g of the compound according to Obtain 4.7, 3 ml of dichloromethane, 112 μl of (S)-(+)-2-pyrrolidineethanol, 0.2 g of NaBH(OAc)3and 5 drops of CH3CO2N. To the reaction medium was added a saturated solution of Na2CO3, water, dichloromethane, then decanted. The organic phase is washed with water, then dried over magnesium sulfate and evaporated. Purify by chromatography on silica, elwira a mixture of dichloromethane/methanol (100:2; volume/volume). Receive 100 mg of the target compound.

MN+=511; t=5.72 minutes.

[α]D20=-11,2° (C=0,848; dimethyl sulfoxide).

EXAMPLE 10: compound 183

N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-[(4-Tetra-hydro-2H-Piran-4-ylamino)piperidine-1-yl)methyl]benzamide

Within one hour boil with education is essential fridge mixture, containing 0.25 g of compound according to the Receiving 4.3.4 and 0.34 g of compound according to Getting 2.1 in 1 ml of CH3CN. Filtered off, washed with CH3CN, then diethyl ether and dried over P2About5at a temperature of 60°C. Obtain 0.35 g of the target compound.

In)

0.34 g obtained in the previous phase compounds injected into 3 ml of 4 M solution of HCl in dioxane and stirred for 5 hours at room temperature. Add water, filtered off, then washed with diethyl ether and dried over P2About5at a temperature of 60°C. is Treated with a mixture of ethyl acetate/10%solution of Na2CO3. After decanting, washed with 10%solution of Na2CO3, then with water and dried over magnesium sulfate, and then evaporated. Purify by chromatography on silica, elwira a mixture of dichloromethane/methanol (90:3; volume/volume). Obtain 93 mg of the target compound.

MN+=562; t=5.8 minutes.

EXAMPLE 11: the connection 17

N-[2-(2-(S)-(Hydroxymethyl)pyrrolidin-1-yl)ethyl]-N'-[4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl]terephthalamide

In a dry nitrogen atmosphere mixed with 0.13 g of compound according to the Receiving 4.5 in 2 ml of dichloromethane with 54 mg of (S)-(+)-2-pyrrolidineethanol. After stirring for 15 minutes add 107 mg NaBH(OAc)3and 5 drops of acetic acid, for whom eating is stirred for 4 hours. To the reaction medium was added a saturated solution of Na2CO3water and dichloromethane, and then decanted. Again extracted with dichloromethane, then washed 2 times with saturated solution of NaCl. The combined organic phases are dried over magnesium sulfate. After partial evaporation add CH3CN and diethyl ether, the precipitated precipitate is filtered off and dried over P2About5at a temperature of 45°C. Obtain 57 mg of target compound in the form of solids. TPL=168°C (decomposition).

EXAMPLE 12: the connection 14

The dihydrochloride of N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(2-piperidine-1-ylethoxy)benzamide

Within 2 hours 40 minutes at a temperature of 80°heat the mixture containing at 0.19 g of compound according to the Receipt 4.8, 62 mg2CO3and 38 mg of piperidine in 3 ml of dimethylformamide. Leave to stand until it returns to room temperature, then add dichloromethane and water. The reaction medium is washed with water, then with dilute NaOH solution. Dried over magnesium sulfate and evaporated. The remainder chromatographic on the silicon dioxide, elwira a mixture of dichloromethane/methanol (100:2; volume/volume). Treated with dichloromethane, then add hydrochloric acid in diethyl ether, filtered and washed with diethyl ether. After drying over P2O5the ri temperature 60° To obtain 54 mg of the target compound.

NMR spectrum:: 0,97 ppm: t: 3H; 1,2-2, 0. M. D.: m: 8H; 2,9-3,1 ppm: m: 2H; 3,4-3,6 ppm: m: 4H; 3,8-4,0 ppm: m: 5H; 4,49 ppm: t: 2H; 6,88 ppm: DD: 1H; 7,02 ppm: d: 1H; 7,13 ppm: d: 2H; 7,74 ppm: s: 1H; to 7.77 ppm: d: 1H; 8,17 ppm: d: 2H; 10,4 ppm: OSS: 1H; 12,5 ppm: OSS: 1H.

EXAMPLE 13: compound No. 186

Ethyl ether (1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl-carbarnoyl)piperidine-4-yl)pyrrolidin-3-yl)carbamino acid

A) tert-Butyl methyl ether (1-(1-(4-(4-(5-butyl-2-methoxyphenyl)-thiazol-2-yl-carbarnoyl)piperidine-4-yl)pyrrolidin-3-yl)-carbamino acid

To a solution of 0.4 g of the compound according to the Receiving 4.1.1 in 3 ml of dichloroethane add 0.3 g of (3R)-3-(tert-butoxy-carbylamine)pyrrolidine, then 0.35 g NaHB(OAc)3. In the reaction medium was added 3 drops of acetic acid, the medium is then stirred at room temperature for 2 hours. Wednesday hydrolyzing by adding water, and then diluted with dichloromethane and washed 3 times with 1 M sodium hydroxide solution. The organic phase is washed with saturated NaCl solution, dried over magnesium sulfate, then evaporated, receiving and 0.37 g of the target compound. The thus obtained crude product can be used as is in the next stage.

TPL=104°for the fraction of the crude product is purified flash chromatography.

B) 4-(4-(3-Aminopyrrolidine-1-yl)Pipa is one-1-carbonyl)-N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)benzamid

To a solution of 2.7 g of compound No. 151, dissolved in 9 ml of dichloromethane, at a temperature of 0°add 3 ml triperoxonane acid. Environment survive to return to room temperature. After 2 hours of incubation at room temperature, the medium is evaporated, then three times, treated with dichloromethane and evaporated. The oil obtained is treated with dichloromethane, then 10%solution of Na2CO3. The organic phase is washed with 10%solution of Na2CO3then a saturated solution of NaCl, then dried over magnesium sulfate and evaporated, getting to 2.18 g solid beige color. The free base is purified by powdering in a mixture of dichloromethane/methanol, getting to 1.9 g of the target product.

The hydrochloride is obtained by the slow addition of 2 M solution of hydrogen chloride in diethyl ether to a solution of free base in a mixture of chloroform/methanol. The suspension is evaporated, then dried in vacuum, obtaining 2 g of the hydrochloride. TPL=188°C.

(C) Ethyl ester (1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbonyl)piperidine-4-yl)pyrrolidin-3-yl)carbamino acid

To a solution of 2 g of compound No. 152 in the main form in 7 ml of dichloromethane add 0,46 g ethylchloride. The medium is cooled to a temperature of 0°C. Then added dropwise 0.7 g of diisopropylethylamine. The medium is stirred until in the surata to room temperature. Wednesday hydrolyzing with water, then diluted with dichloromethane. The organic phase is washed with 1 M sodium hydroxide solution, then with water, then saturated NaCl. The organic phase is dried over magnesium sulfate, then evaporated. The crude product was purified flash chromatography, obtaining 1.7 g of the target product. TPL=126°C.

The obtained solid is dissolved in dichloromethane, and then converted into the salt by slow addition of 2 M solution of hydrogen chloride in diethyl ether. After evaporation receive 1,72 g of the hydrochloride. TPL=178°C.

EXAMPLE 14: connection # 187

N-(4-(5-Butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-methane-sulfonilmorpholid-1-yl)piperidine-1-carbonyl)benzamide

To a solution of 0.14 g of compound No. 152 in the main form in 2 ml of a mixture of ethyl acetate and dimethylformamide in a ratio of 1:1 add 57 mg methanesulfonanilide and 0.14 ml of triethylamine. After conditioning for 24 hours at room temperature, the medium is filtered, then evaporated and treated with ethyl acetate. The organic phase is washed twice with saturated NaCl solution, dried over magnesium sulfate and evaporated. The crude product was purified flash chromatography getting 65 mg solid white. TPL=125°C.

EXAMPLE 15: connection # 153

N-(4-(5-Butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-propionyl aminopyrrolidine-1-yl)piperidine-1-carbonyl)benzamide

To a solution of 0.1 g of compound No. 152 in its basic form in 0.5 ml ethyl acetate added 0.04 g of propionic anhydride and 0.05 ml of triethylamine. After incubation for 2 hours at room temperature, the medium is diluted with dichloromethane. The organic phase is washed with water, saturated NaCl solution, dried over magnesium sulfate and evaporated. The crude product was purified flash chromatography, receiving 67 mg solid white. TPL=128°C.

EXAMPLE 16: compound No. 188

1-(1-(4-(4-(5-Butyl-2-methoxyphenyl)thiazol-2-ylcarbonyl)-benzoyl)piperidine-4-yl)pyrrolidin-3-silt ether acetic acid

To a solution of 0.2 g of compound No. 66 in the form of a solution in 1 ml dichloromethane added 73 mg of acetic anhydride. After incubation for 2 hours at room temperature, added 73 mg of acetic anhydride and stirred for 12 hours at room temperature. The medium is diluted with dichloromethane. The organic phase is washed with 3 times 10%solution of Na2CO3then water, then saturated NaCl solution, then dried over magnesium sulfate and evaporated, getting 194 mg solid white. TPL=99°C.

EXAMPLE 17: compound No. 189

4-(4-(1-Acetylpyrrolidine-3-ylamino)piperidine-1-carbonyl)-N-4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)benzamide (S)

A) tert-Butyl ether 3-(1-(4-(4-(5-butyl-2-methoxyphenyl)-thiazol-2-ylcarbonyl)benzoyl)piperidine-4-ylamino)pyrrolidin-1-carboxylic acid

A solution of 0.23 g (S)-3-amino-1-N-BOC-pyrrolidine and 0.5 g of compound according to the Receiving 4.1.1 in 2 ml of dichloromethane is stirred for 30 minutes at room temperature. To the reaction mixture of 0.43 g of NaHB(OAc)3and 8 drops of acetic acid. Reaction medium was then stirred at room temperature for 4 hours. Wednesday hydrolyzing by adding water, then diluted with dichloromethane and washed 3 times with 1 M sodium hydroxide solution. The organic phase is washed with saturated NaCl solution, dried over magnesium sulfate, then evaporated, getting 0.65 g of the target compound. The thus obtained crude product can be used as is in the next stage.

MN+=662; t=7.3 minutes.

C) N-4-(5-Butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(pyrrolidin-3-ylamino)piperidine-1-carbonyl)benzamide

To a solution of 0.61 g obtained at the previous stage of the compound in 2 ml of dichloromethane is added 2 ml of hydrochloric acid in diethyl ether. After keeping for 4 hours 30 minutes at room temperature, the medium is evaporated. The crude substance proscout in diethyl ether, filtered off, washed with diethyl ether and dried, obtaining 0.51 g of the target compound.

The n +=562; t=of 5.83 minutes.

C) 4-(4-(1-Acetylpyrrolidine-3-ylamino)piperidine-1-carbonyl)-N-4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)benzamid

A suspension of 0.5 g obtained in the previous phase compounds in a mixture of dichloromethane/ethyl acetate, treated with 10%solution of Na2CO3. After decanting, the aqueous phase is extracted with ethyl acetate and then dichloromethane. The combined organic phases are dried over magnesium sulfate, then evaporated.

So get 0,37 g of free base, which was dissolved in 2 ml dichloromethane. Add 0,062 ml acetic anhydride and stirred for 3 hours 30 minutes at room temperature. The medium is evaporated, then chromatographic on the silicon dioxide, receiving 0.3 g of the target product.

MN+=604; t=6,68 minutes.

In the following tables explain the chemical structure and physical properties of some examples of compounds according to the invention. In these tables:

- in the column "Salt" the sign "-" means that the compound is in free base form, whereas "HCl" means that the compound is in the form of the hydrochloride;

- Me, Et, nPr, iPr, nBu, iBu, tBu, nHex mean respectively the group: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl;

- Ph and Bn denote, respectively, the phenyl and benzyl;

- TNR means tetrahydropyran-4-yl.

Connections to the characteristics of eresource or spectrum of nuclear magnetic resonance (NMR), presented at the end of the table, or by their melting point (F), or their mass spectrum: MN+and the retention time (t), expressed in minutes.

Table 7

NMR spectrum: connection 1: 0,98 ppm: t: 3H; 1,24 ppm: t: 6H; 1,72 ppm: sextet: 2H; 3,1-3,3 ppm: m: 4H; 3,4-3,6 ppm: m: 2H; 3,8-4,0 ppm: m: 5H; 4,50 ppm: t: 2H; 6.87 in ppm: DD: 1H;? 7.04 baby mortality ppm: d: 1H; 7,16 ppm: d: 2H; of 7.7 to 7.8 ppm: m: 2H; 8,16 ppm: d: 2H; 10,6 ppm: OSS: 1H; 12,5 ppm: OSS: 1H.

NMR spectrum of compound 33:1,00 ppm: t: 3H; of 1.26 ppm: t: 6H; 1,74 ppm: sextet: 2H; 2,9-3,5 ppm: m: 8H; 3,8-4,0 ppm: m: 5H; 6,88 ppm: DD: 1H;? 7.04 baby mortality ppm: d: 1H; 7,5 ppm: d: 2H; of 7.7 to 7.8 ppm: m: 2H; 8,14 ppm: d: 2H.

NMR spectrum of compound 67: to 0.80 ppm: t: 3H; 0,95-of 1.95 ppm: m: 12H; at 2.45 ppm: t: 2H; 2,55-4,4 ppm: m: 13H; 6,95 ppm: d: 1H; 7,05 ppm: DD: 1H; 7,45 ppm: d: 2H; the 7.65 ppm: s: 1H; of 7.90 ppm: s: 1H; 8,1 ppm: d: 2H.

NMR spectrum of compound 69: 1,1 ppm: t: 3H; 1,15-1,90 ppm: m: 4H; 2,20-4,50 ppm: m: 17H; 6,95 ppm: d: 1H; 7,05 ppm: DD: 1H; 7,45 ppm: d: 2H; 7,60 ppm: s: 1H; 7,95 ppm: s: 1H; 8,1 ppm: d: 2H; 12,65 ppm: OSS: 1H.

NMR spectrum of compound 70: 0,85-of 1.95 ppm: m: 11H; 2,30 and 4.4 ppm: m: 15H; 6,95 ppm: d: 1H; 7,05 ppm: DD: 1H; 7,40 ppm: d: 2H; 7,60 ppm: s: 1H; of 7.90 ppm: s: 1H; 8,1 ppm: d: 2H.

Compounds according to the invention were the subject of pharmacological tests to determine their modulating effect on the activity of receptors for chemokines.

Chemokines are proteins with a low molecular weight, which belong to the family of proinflammatory cytokines and take an active part in the chemotaxis of leukocytes and endothelial cells. Chemokines control many biological processes and is associated with inflammatory disorders occurring during stressful conditions during injury or infection; modulation effects chemokines can prevent or cure diseases, like asthma, arthritis, allergies, autoimmune diseases, arteriosklerose or angiogenesis (C.D. Paavola, etc., J. Biol. Chem. 273(50), 33157-33165 (1998)).

Of chemokines distinguish hMCP-1 (in English: Human Monocyte Chemotactic Protein (human monocytic chemotactic protein), which belongs to the group of CC chemokines and whose actions are mediated by receptor R2b.

Determined the inhibitory activity of the compounds according to the invention in the cells producing the human CCR2b receptor. The concentration of the natural agonist hMCP-1, which inhibits 50% (CI50) the activity of the receptor CCR2b, is 0.57 nm. Compounds according to the invention have CI50usually below 0.1 ám.

For example, compound No. 12 is CI50making of 0.081 μm; compound No. 244 has a CI50making 0,088 μm; compound No. 203 has CI50making 0,093 microns.

Also determined the inhibition of chemotaxis in the case of macrophage TNR-1 in human cells (produced by the firm DSMZ Germany), using adapted for this purpose, the method described by A. Albini and others, Cancer Res.,47, 3239-3245 (1987). Under these conditions, hMCP-1 is CI50making 6 nm. Compounds according to the invention have CI50usually below 1 micron.

Inhibition of chemotaxis by the compounds according to the invention is a sign of their antagonistic activity against receptors chemokines and, in particular, CCR2b.

Therefore, it appears that the compounds according to the invention are the two which are antagonists of the actions of chemokines, in particular, hMCP-1.

Determined the inhibitory activity of the compounds according to the invention in relation to RPMS (peripheral blood mononuclear cells)infected with HIV-1 Bal, according suited for this method described by V. Dolle, etc., J. Med. Chem.,43, 3949, 3962 (2000). According to this method RVMS infected with HIV-1 Bal, then into the culture medium for 5 days was added to the test compounds. At the end of this time interval in the supernatant measured the content of reverse transcriptase, which correlates with the level of viral replication in cells.

Under these conditions, AZT, standard molecule that inhibits viral replication, has CI50below 0.1 μm. Compounds according to the invention also have CI50usually below 0.1 μm. For example, compound No. 104 showed CI50equal 0,063 mm.

Compounds according to the invention, therefore, can be used to produce medicines, especially medicines, antagonistic against the action of chemokines.

Thus, according to another of its aspects, the object of the present invention are medicaments that include a compound of formula (I) or additive salt of the latter with a pharmaceutically acceptable acid, or a hydrate or MES.

These medicinal cf is DSTV find application in therapy in particular, for the prevention and treatment of various pathologies, such as:

- acute and chronic immune-inflammatory diseases and syndromes, atherosclerosis, restenosis, chronic lung disease, particularly COPD (English: chronic obstructive pulmonary disease (chronic obstructive pulmonary disease)); respiratory distress syndrome, bronchial hyperactivity; colitis; silicosis; fibrotic pathology, pulmonary fibrosis, cystic fibrosis; viral or bacterial infection, AIDS, meningitis, malaria, leprosy, tuberculosis, herpes, infections due cytomegalovirus; septic shock, sepsis, endotoxic shocks; rejection of transplants; bone diseases, such as osteoporosis, osteoarthritis; conjunctivitis; atypical or contact dermatitis; eczema; glomerulonephritis; pancreatitis; ulcerative colitis; autoimmune diseases as rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, systemic lupus erythematosus, scleroderma, psoriasis; Parkinson's disease; Alzheimer's disease; diabetes; cachexia; obesity;

- treatment of pain, particularly neuropathic and inflammatory;

allergic diseases such as allergic respiratory diseases, asthma, rhinitis, pulmonary hypersensitivity, allergic reaction delayed-type;

- sableman the I and violations in which case take an active part angiogenic processes such as malignant tumors (intratumoral angiogenesis), retinal disease (macular degeneration, age related: DMLA);

- heart disease: hemodynamic shock; cardiac ischemia; seizures post-ischemic reinfused; myocardial infarction, coronary thrombosis, heart failure, angina.

According to another of its aspects the present invention relates to pharmaceutical compositions comprising, as an active start, the connection according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, hydrate or MES the above compounds, and at least one pharmaceutically acceptable excipient.

The above-mentioned excipients chosen, depending on the pharmaceutical form and the desired method of administration, among the usual excipients which are known to the expert.

In the pharmaceutical compositions according to the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, local, topical, intratracheal, intranasal, transparency or rectal introduction of the active principle of the above forms of the crystals (I) or its salt, possible MES or hydrate, can be entered in one form of administration, mixed with classical pharmaceutical excipients, to animals and to humans for the prophylaxis or treatment of the above disorders or diseases.

The corresponding one-forms introduction include forms for oral administration such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions; sublingual, buccal, intratracheal, intraocular, motrinonline forms of administration by inhalation; local, percutaneous, subcutaneous, intramuscular or intravenous forms of administration; rectal forms of administration and implants. For local application of the compounds according to the invention can be used in creams, gels, lipsticks or lotions.

As an example, one form of the introduction of the compounds according to the invention in tablet form can include the following components, mg:

the connection according to the invention50,0
mannitol223,75
nutritionnelles6,0
corn starch15,0
the hypromellose2,25
magnesium stearate3,0

the oz the beginning of the current, enter a day, orally can reach 0.1-1000 mg/kg for one or more methods.

May be special cases where the use of higher or lower dosages; these dosages are not beyond the invention. According to conventional practice, the appropriate dosage for each patient is determined by the doctor depending on the method of administration, the weight and response of the patient.

According to the next aspect the present invention relates also to a method of treating the above disorders, which includes an introduction to the patient an effective dose of the compounds according to the invention or one of its pharmaceutically acceptable salt, or hydrate, or solvate.

1. Compounds corresponding to the formula (I)

in which

R1means a hydrogen atom (C1-C4)-alkyl, (C1-C4-alkoxyl, cyclopropylmethoxy, (C1-C4)-allylthiourea;

R2means a halogen atom, (C1-C8)-alkyl, PERFLUORO-(C1-C4)-alkyl, (C3-C10-cycloalkyl, phenyl, (C1-C8-alkoxyl;

R2means a group selected from:

a) a1) -O-(C2-C4)-alk-A;

A2) -O-(C1-C4)-alk-B;

A3) -O-S;

b) -(C1-C4)-al-A;

c);

d) d1) -(C1-C4)-alk-NR4-(C2-C3)-alk-A;

d2)-(C1-C4)-alk-NR4-(C1-C3)-alk-B;

e) e1) -CONR4-(C2-C4)-alk-A;

e2) -CONR4-(C1-C4)-alk-B;

e3) -CONR4-E;

f) f1) -CO-D-(C1-C2)-alk-A;

f2) -CO-G-A;

f3)

f4)

f5)

f6)

f7)

R4means a hydrogen atom or (C1-C4)-alkyl;

A represents a group NR5R6;

In the mean group

D means the group

E. means

G means group

R5and R6each independently of one another mean a hydrogen atom, (C1-C6)-alkyl, (C2-C4)-alk-OH, (C1-C3)-alk-CON(R4)2, (C2-C3)-alk-NHCO-(C1-C4)-alkyl, -CO-(C1-C4)-alkyl; pyrrolidinyl, possibly substituted WITH-(C1-C4)-alkyl; tetrahydropyranyl, tetrahydropyranyl;

or R5and R6together with the nitrogen atom, with which whom they are associated, form a heterocyclic radical selected from azetidine, pyrrolidine, piperidine, morpholine, and the above-mentioned heterocyclic radicals are unsubstituted or substituted by phenyl, hydroxyl, hydroxymethyl, methoxymethyl, formamido, triftoratsetofenona, the group-NR4R7, tetrahydropyran-4-yl-amino group, (C1-C4)-alkyl-CONR4-, (C3-C8-cycloalkyl-CONR4-, (C1-C4)-alkyl-OCONR4-, (C1-C4)-alkyl-OCO-N-, (C1-C4)-alkyl-COO-;

R7means a hydrogen atom, a group-SO2CH3;

p denotes 1, 2, 3, 4 or 5;

q denotes 0, 1 or 2;

r is 1 or 2;

and

p+q is less than or equal to 5;

p+r is less than or equal to 5;

alk means alkylen;

provided that R1and R2at the same time do not represent a hydrogen atom;

in the form of pharmaceutically acceptable salts.

2. Compounds according to claim 1, corresponding to the formula (I′):

in which

R1means a hydrogen atom, (C1-C4)-alkyl, (C1-C4-alkoxyl, cyclopropylmethoxy, (C1-C4)-allylthiourea;

R2means a halogen atom, (C1-C8)-alkyl, PERFLUORO-(C1-C4)-alkyl, (C3-C 10-cycloalkyl, phenyl, (C1-C8-alkoxyl;

R3means a group selected from:

a) a1) -O-(C2-C4)-alk-A;

A2) -O-(C1-C4)-alk-B;

A3) -O-S;

b) -(C1-C4)-alk-A;

c);

d) d1) -(C1-C4)-alk-NR4-(C2-C3)-alk-A;

d2)-(C1-C4)-alk-NR4-(C1-C3)-alk-B;

f) e1) -CONR4-(C2-C4)-alk-A;

e2) -CONR4-(C1-C4)-alk-B;

e3) -CONR4-E;

g) f1) -CO-D-(C1-C2)-alk-A;

f2) -CO-G-A;

f3)

f4)

f5)

f6)

R4means a hydrogen atom or (C1-C4)-alkyl;

A represents a group NR5R6;

In the mean group

D means the group

E. means

G means group

R5and R6each independently of one another mean a hydrogen atom, (C1-C6)-alkyl, (C2-C4)-alk-OH, (C1-C3)-alk-CON(R4)2, (C2-C3)-alk-NHCO-(C1-C4)-alkyl, tetrahydropyran is, tetrahydropyranyloxy;

or R5and R6together with the nitrogen atom to which they are linked, form a heterocyclic radical selected from azetidine, pyrrolidine, piperidine, morpholine, and the above-mentioned heterocyclic radicals are unsubstituted or substituted by phenyl, hydroxyl, hydroxymethyl, methoxymethyl, formamido, triftoratsetofenona, the group-NR4R7, tetrahydropyran-4-yl-amino group, (C1-C4)-alkyl-CONR4-, (C1-C4)-alkyl-OCONR4-, (C1-C4)-alkyl-COO-;

R7means a hydrogen atom;

p denotes 1, 2, 3, 4 or 5;

q denotes 0, 1 or 2;

r is 1 or 2;

and

p+q is less than or equal to 5;

p+r is less than or equal to 5;

alk means alkylen;

provided that R1and R2at the same time do not represent a hydrogen atom;

in the form of pharmaceutically acceptable salts.

3. Compounds according to claim 1 or 2 of formula (Ia)

in which R1, R2, R3have the above for formula (I) values, in the form of pharmaceutically acceptable salts.

4. Compounds according to claim 3 of formula (Ia), in which

R1means atom (C1-C4)-alkyl, (C1-C4-alkoxyl, cyclopropylmethoxy, (C1-C4

R2means a halogen atom, (C1-C8)-alkyl, (C3-C10-cycloalkyl, phenyl, (C1-C8-alkoxyl;

and/or

R3means a group selected from the groups a), b), C), (d), (e), (f), such as those described for formula (I) according to claim 1.

5. Compounds according to claim 4 of formula (Ia), in which

R1means (C1-C4-alkoxyl, cyclopropylmethoxy or (C1-C4)-allylthiourea;

and/or

R2means a halogen atom, (C1-C8)-alkyl, (C3-C10-cycloalkyl or (C1-C8)alkoxyl; and/or

R3mean group f2 or E2;

in the form of pharmaceutically acceptable salts.

6. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 5, characterized in that

the functional derivative of the acid of formula (II)

in which R'3means R3such as specified above for formula (I), or R'3denotes a carboxy, (C1-C6)alkoxycarbonyl, halogen, halogeno(C1-C6)alkyl, oxo(C1-C6)alkyl, -CO-NH-(C1-C6)alkyl-CHO, -O-(C1-C6)alkyl-OH,

process derived 2-aminothiazole formula (III)

in which R'1and R'2means with the responsible R 1and R2,

in an aprotic solvent in the alkaline environment,

then, if necessary, the thus obtained compound of the formula (IV)

in which R'1, R'2and R'3above, into a compound of formula (I).

7. The compounds of formula (IIe)

in which R'3means R3selected from the group consisting of E2), f1), f2)f4)f5)f6), such as those described for formula (I), and R3located in the para-position.

8. Acid formula

where G p is a hydrogen atom or a protective for nitrogen group selected from Boc, Fmoc, benzyloxycarbonyl, benzyl or (C1-C4)-alkanoyl;

and their (C1-C4)-alkalemia esters of the formula (XXXIV) or benzyl esters, unsubstituted or substituted on the phenyl by a methoxy group.

9. The compound of formula (XXXXVIIIbis)

in which amino groups are free or protected by a protective group, such as group Fmoc, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or (C1-C4-alkanoyl.

10. The compounds of formula (IV)

in which

R'1and R'2oznacza is t, respectively, R 1or R2specified for compounds of the formula (I);

R'3means a group selected from the

-O-(C1-C3)-alk-Q, and Q means a formyl;

-O-(C2-C4)-alk-OX, and X means a hydrogen atom;

-(C1-C3)-alk-Q, where Q denotes formyl;

-(C1-C4)-alk-Hal, and Hal means a halogen atom;

-I;

-COOH; -COOR, where R is (C1-C4)-alkyl;

-CONH-(C1-C3)-alk-Q, where Q denotes formyl;

- a) a1) -O-(C2-C4)-alk-A';

a2) -O-(C1-C4)-alk-B';

a3)-O-E's;

b) -(C1-C4)-alk-A';

c)';

d) d1) -(C1-C4)-alk-NR4-(C2-C3)-alk-A';

d2) -(C1-C4)-alk-NR4-(C1-C3)-alk-B';

e) e1)-CONR4-(C2-C4)-alk-A';

e2) -CONR4-(C1-C4)-alk-B';

e3) -CONR4-E's;

f) f1) -CO-D-(C1-C2)-alk-A';

f2) -CO-G-A';

f3)

f4)

f5)

where

A', B', E' denote, respectively, groups a, b, E, such as indicated for formula (I)in which R5replace the EN group Gp;

Gp protective means for nitrogen group selected from Boc, Fmoc, (C1-C4)-alkanoyl, benzyloxycarbonyl or benzyl.

11. The compound of claim 10 of formula (IV), in which

R'1is in position 2 of the phenyl and is the same as R1indicated for formula (I);

R'2is in position 5 of the phenyl and is the same as R2indicated for formula (I);

R'3is in position 4 of the other phenyl group and a is as defined in item 10.

12. Drug, possessing properties of antagonists of chemokines, characterized in that it contains a compound of the formula (I) according to any one of claims 1 to 5 or additive salt of this compound pharmaceutically acceptable acid in an effective amount.

13. Pharmaceutical composition having properties antagonists of chemokines, characterized in that it comprises an effective amount of the compounds of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient.

14. The use of the compounds of formula (I) according to any one of claims 1 to 5 for a medicinal product having the properties of antagonists of chemokines.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to novel individual compounds of series 2,5a-methano[1,4]diazepino[1,7-a]-quinoxaline-5-carboxylates, namely, to isopropyl-12-aroyl-2-hydroxy-1,6-dioxo-4-(3-pyridinyl)-7-phenyl-1,3,6,7-tetrahydro-2,5a-methano[1,4]diazepino[1,7-a]-quinoxaline-5-carboxylates of the formula (1) wherein Ar means phenyl or p-methoxyphenyl, and to a method for their synthesis. Method for synthesis of compound of the formula (1) involves interaction of 3-aroyl-5-phenylpyrrolo[1,2-a]-quinoxaline-1,2,4(5H)-triones with isopropyl-3-amino-3-(3-pyridinyl)-2-propenoate in an inert aprotonic solvent medium and the following isolation of end substances. The proposed method provides synthesis of novel compounds of the formula (1) possessing antibacterial effect with high yield and selectivity.

EFFECT: improved method of synthesis.

4 cl, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new individual compounds of azapentacycloeicosanes class. Invention describes 20-aroyl-12-hydroxy-17,17-dimethyl-3-phenyl3,10,13-triazapentacyclo[10.7.1.01,10.O4,9.O14,19]eicosa-4,6,14(19)-2,11,15-triones of the formula:

wherein R means hydrogen atom; Ar means phenyl; or R means benzyl and Ar means p-methoxyphenyl group. Also, the invention describes a method for preparing these compounds. Invention provides preparing new compounds that can be used as the parent substances for synthesis of new heterocyclic systems.

EFFECT: improved preparing method, valuable chemical properties of compounds.

4 cl, 1 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): their using (variants) for preparing a drug used in treatment of diseases modulation of activity of chemokine receptors is useful, and to a pharmaceutical composition modulating chemokine receptors and comprising abovementioned compound. In compound of the formula (I) m = 0 or 1; R1 means halogen atom; X, Y and Z represent independently a bond, -CH2- or -O-, or X and Y form in common -CH=C(CH3)- or -C(CH3)=CH- under condition that only one radical among X, Y and Z can represents a bond, and under condition that X and Y both don't represent -O- simultaneously; n = 0, 1 or 2; R2 represents halogen atom, or (C1-C6)-alkyl; q = 0 or 1; R3 represents -NHC(O)R10, -C(O)NR11R12 or -COOR12a; each radical among R4, R5, R6, R7 and R8 represents independently hydrogen atom (H) or (C1-C6)-alkyl; t = 0, 1 or 2; R9 represents halogen atom, -OH, -COOH, (C1-C6)-alkoxy group, (C1-C6)-alkoxycarbonyl; R10 represents group (C1-C6)-alkyl, (C3-C6)-cycloalkyl, or R10 represents -NR14R15; each R11 and R12 represents independently (1) H; (2) 3-6-membered saturated cycloalkyl or phenyl or 5-membered unsaturated heterocyclyl comprising from 1 to 4 heteroatoms N wherein indicated cycloalkyl, phenyl and heterocyclyl are substituted possibly with one or two substitutes chosen from -OH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl; (3) (C1-C6)-alkyl substituted possibly at least with one substitute chosen from halogen atom, -OH, -COOH, (C1-C6)-alkylcarbonylamino group, phenyl, 5-membered unsaturated heterocyclyl comprising oxygen atom (O), or from 1 to 2 N atoms, bicycloheptyl wherein this phenyl, heterocyclyl or bicycloheptyl is substituted possibly at least with one substitute chosen from halogen atom, -OH, =O, or (4) (C1-C6)-alkylsulfonyl, or R11 and R12 in common with N atoms to which they are bound form 5-membered unsaturated heterocyclyl comprising one N atom or 5-6-membered heterocyclyl comprising from 1 to 2 heteroatoms, such as S, O and N, or 5-6-membered saturated heterocyclyl, ortho-condensed with benzene ring and comprising one N atom and wherein indicated heterocyclic systems are substituted possibly with one or two substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-hyroxyalkyl, (C1-C6)-halogenalkyl, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino group, phenyl, halogenphenyl and hydroxydiphenylmethyl; R12a represents H or (C1-C6)-alkyl; each radical among R14 and R15 represents independently H or (C1-C6)-alkylsulfonyl, or R14 and R15 in common with N atom to which they are bound form 5-membered saturated heterocyclyl comprising one N atom and substituted possibly with one -OH, or its pharmaceutically acceptable salt or solvate. Also, invention relates to a method (variants) for synthesis of compound of the formula (I) according to one of the following method: by one variant, compound of the formula (II): is subjected for interaction with compound of the formula (III): by other variant, compound of the formula (IV): is subjected for interaction with compound of the formula (V): by other variant, compound of the formula (VI): wherein R3 represents -NHC(O)R10 and L1 represents a leaving group is subjected for interaction with L1C(O)R10; by other variant, compound of the formula (VIII): wherein R3 represents -C(O)NR11R12 and L2 represents a leaving group is subjected for interaction with compound of the formula (IX) given in the invention description. Also, invention relates to an intermediate compound of the formula (IIA): (wherein R1a is chosen from F, Cl, -CH3 and -CF3; s = 1 or 2; q = 0 or 1; w = 0 or 1; R2a represents F, and when q and s = 1 and w = 0 then R1a can't represent chlorine atom), and to a method for synthesis of compound of the formula (IIA) (wherein s = 1) and wherein compound of the formula (XX): is subjected for interaction with compound of the formula (XXII): (wherein R20 represent a protective group) before formation of compound of the formula (XXIV): followed by carrying out the cyclization reaction and removing the protective group R20.

EFFECT: improved methods of synthesis.

25 cl, 236 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel compounds of class quinoxalin-2-spiropyrroles of the general formula (I): wherein R1 = R2 mean hydrogen atom (H) (I); R1 means H; R2 means CH3 (II); R1 = R2 mean CH3 (III). Compound can be used as parent substances for synthesis of novel heterocyclic systems, and in medicine as antibacterial agents. Also, invention describes a method for synthesis of these compounds.

EFFECT: improved method of synthesis, valuable properties of compounds.

3 cl, 4 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

EFFECT: improved method of treatment, valuable medicinal properties of compounds.

35 cl, 3 tbl, 2 dwg, 45 ex

FIELD: chemical industry, organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel spiropyrazole compounds of the general formula (I): wherein W means hydrogen atom, (C1-C10)-alkyl, (C3-C7)-cycloalkyl, cyano-(C1-C10)-alkyl, -(C1-C4)-alkyl-COOV1 wherein V1 means hydrogen atom (H) or (C1-C6)-alkyl, -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-group, or -(C1-C5)-alkyl-NHS(=O)2-W1 wherein W1 means -(C1-C10)-alkyl; Q means phenyl; n mean a whole number 0 or 1; A, B and C mean hydrogen atom; Z means a simple bond, methylene or ethylene group; R1 means (C3-C12)-cycloalkyl substituted optionally with (C1-C10)-alkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl, norbornyl, dibenzocycloheptyl, 9-acenaphthyl, phenyl substituted optionally with benzyloxy-group, biphenyl or (C1-C10)-alkyl substituted optionally with 1-3 substitutes chosen from phenyl, cyano-group, -COOV1 wherein V1 means (C1-C6)-alkyl and -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-, (C1-C4)-alkylamino- or di-(C1-C4)-alkylamino-group; R2 means (C1-C10)-alkyl, (C3-C7)-cycloalkyl or halogen atom. Also, invention to their pharmaceutically acceptable salts, solvates, pharmaceutical composition containing thereof, a method for treatment of pain and a method for modulation of pharmacological response of described ORL-1- or μ-receptors. Invention can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 3 tbl, 5 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

The invention relates to (DL)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-ONU formula (1)

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 8-ethyl-6,7-fullero[60]-3-oxa-8-azabicyclo[3.2.1]octane of the general formula (1): . Method involves interaction of fullerene[60] with N-ethylmorpholine in the mole ratio fullerene-C60 : N-ethylmorpholine = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as a catalyst taken in the amount 15-25 mole% with respect to fullerene[60], in toluene medium as a solvent at temperature ˜20°C for 18-30 h. The yield of the end product is 73-90%. Synthesized compound can be used as chelating agent, sorbent, biologically active compound and in creature of novel materials with desired electronic, magnetic and optical properties.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

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