4-aminopyperidine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

 

The present invention relates to new derivatives of 4-aminopiperidine, their reception and their use as pharmaceuticals.

In particular, the invention relates to compounds of formula (I):

where R1choose from a group including:

phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, lower alkoxygroup, phenyl, fenoxaprop, halogen or lower halogenation;

naphthyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop;

tetrahydronaphthyl;

With3-7cycloalkyl;

-(CHR3)m-phenyl, where m denotes 1, 2 or 3; and phenyl is unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop, and where R3independently selected from hydrogen, lower alkyl or phenyl;

-(CH2)n-heteroaryl, where n denotes 1, 2 or 3;

-(CH2)n-heteroaryl, where n denotes 1, 2, 3 and heteroaryl is mono-, di - or tizamidine lower alkyl, halogen, lower halogenation or lower alkoxygroup;

-C(O)-CH2-phenyl, where phenyl is unsubstituted or mo is about-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop;

-C(O)-CH2-heteroaryl; and

-C(O)-CH2-heteroaryl where heteroaryl is mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup; and

R2choose from a group including:

lower alkyl, lower halogenated;

phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

naphthyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

heteroaryl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

-COOH;

-C(O)-NR4R5where R4and R5represent lower alkyl or together with the nitrogen atom to which they are attached, form a 4-, 5 - or 6-membered heterocycle which can additionally contain a heteroatom selected from N, O or S, and their pharmaceutically acceptable salts.

The enzyme dipeptidyl peptidase IV ES (EC is an abbreviation for "Enzyme Committee of the International Union of biochemistry), denoted hereinafter by the abbreviation DPP-IV, a modification of the t part in regulating the activity of several hormones. In particular, DPP-IV results in an effective and rapid degradation of glucagon like peptide 1 (GLP-1), which is one of the most potent stimulators of the production and secretion of insulin. Inhibition of DPP-IV may potentiate the effects of endogenous GLP-1 and leads to higher concentrations of insulin in plasma. In patients suffering from reduced glucose tolerance and diabetes mellitus type 2, elevated concentration of plasma insulin can mitigate dangerous hyperglycemia and thereby reduce the risk of tissue damage. Therefore, DPP-IV inhibitors are considered as potential drugs for the treatment reduced glucose tolerance and diabetes mellitus type 2 (for example, Villhauer, WO 98/19998). Other related description of the prior art may be found in WO 99/38501, DE 19616486, DE 19834591, WO 01/40180, WO 01/55105, US 6110949, WO 00/34241 and US 6011155.

We have found new DPP-IV inhibitors that effectively reduce the levels of glucose in plasma. Therefore, the compounds of the present invention are used for treatment and/or prevention of diabetes, particularly non-insulin dependent diabetes mellitus, and/or decreased glucose tolerance, as well as other States, where the amplification action of the peptide, normally inactivating DPP-IV, brings therapeutic benefit. In addition, connection of the infusion is to him the invention can be applied in the treatment and/or prophylaxis of obesity, metabolic syndrome, the protection of β-cells, autoimmune diseases such as inflammatory bowel disease, encephalitis paraxially sclerosis and rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, planus and/or benign prostatic hypertrophy. Connections can also be used for the prevention of AIDS (acquired immunodeficiency syndrome) or to prevent metastasis, in particular metastasis of breast cancer and prostate cancer in the lungs. In addition, the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension.

Unexpectedly, the compounds of the present invention showed superior therapeutic and pharmacological properties, comparable with other DPP-IV inhibitors, known from the technical field, for example, in the context of pharmacokinetics and bioavailability.

Objects of the present invention are the compounds of formula I and their receipt of the medicinal product on the basis of the compounds of formula I and their production, as well as the use of compounds of formula I in accordance with the invention for the control and prevention of the diseases mentioned above, and accordingly, when receiving the drugs.

Unless otherwise specified, the following definition is Oia to illustrate and define the meaning and scope of various terms, used in the description of this invention.

In this description, the term "lower" is used to refer to groups containing from one to six, preferably one to four carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine are preferred. Most preferred is chlorine.

The term "alkyl", alone or in combination with other groups, refers to a branched or linear monovalent alkyl, the radical containing from one to six carbon atoms, preferably from one to four carbon atoms. This term is further illustrated by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, emop-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like. Preferred lower alkyl radicals are methyl, ethyl, n-propyl and n-butyl, with methyl is especially preferred.

The term "lower halogenated" refers to a lower alkyl group where at least one of the hydrogen atoms of the lower alkyl groups substituted by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. Preferred lower halogenoalkane groups are trifluoromethyl, deformity, vermeil and chloromethyl, especially prepact the sory is permetrina group.

The term "alkoxygroup" refers to the group R'-O-, where R' represents alkyl. The term "lower alkoxygroup" refers to the group R'-O-, where R' denotes a lower alkyl. Examples of the lower alkoxygroup are a methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan, isobutoxide and hexyloxy, especially preferred is a methoxy group.

The term "cycloalkyl" or "C3-C7-cycloalkyl" refers to a monovalent carbocyclic to radical containing from 3 to 7 carbon atoms. The term further refers to such radicals as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, thus are preferred cyclopropyl and cyclohexyl.

The term "heteroaryl" refers to an aromatic 5 - or 6-membered ring which may include 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur, such as furyl, pyridyl, 1,2-, 1,3 - and 1,4-diazines, thienyl, isoxazolyl, oxazolyl, imidazolyl or pyrrolyl. The term "heteroaryl" refers, in addition to bicyclic aromatic groups, including two 5 - or 6-membered ring in which one or both rings can contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulfur, such as indole or quinoline, or partially hydrogenated bicyclic aromatic group such as, for example, indoline is. Preferred heteroaryl groups are thienyl, pyridyl and indolyl, which optionally can be substituted, as described above, preferably lower alkyl or halogen.

The expression "R4and R5together with the nitrogen atom to which they are attached, form a 4-, 5 - or 6-membered heterocyclyl, which optionally contain heteroatom selected from oxygen, nitrogen or sulfur" implies that R4and R5together with the nitrogen atom to which they are attached, form a ring such as pyrrolidinyl, dihydropyrrole (pyrrolidyl), piperidyl, imidazolidinyl, morpholinyl, piperazinil, diazolidinyl, thiomorpholine, with diazolidinyl and dihydropyrrole especially preferred.

The term "pharmaceutically acceptable salt" includes salts of compounds of formula (I) with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, malic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonate acid, salicylic acid, p-toluensulfonate acid and the like, which are non-toxic to living organisms. The preferred salts are the formate, maleate, citrates, hydrochlor the water, hydrobromide and salt methanesulfonic acid, the most preferred are hydrochloride.

The invention relates to compounds of formula (I):

where R1choose from a group including:

phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, lower alkoxygroup, phenyl, fenoxaprop, halogen or lower halogenation;

naphthyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop;

tetrahydronaphthyl;

With3-7cycloalkyl;

-(CHR3)m-phenyl, where m denotes 1, 2 or 3; and phenyl is unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop, and where R3independently selected from hydrogen, lower alkyl or phenyl;

-(CH2)n-heteroaryl, where n denotes 1, 2 or 3;

-(CH2)n-heteroaryl, where n denotes 1, 2, 3 and heteroaryl is mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

-C(O)-CH2-phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine independently h is slim-alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop;

-C(O)-CH2-heteroaryl; and

-C(O)-CH2-heteroaryl where heteroaryl is mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup; and

R2selected from the group including

lower alkyl, lower halogenated;

phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

naphthyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

heteroaryl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

-COOH;

-C(O)-NR4R5where R4and R5represent lower alkyl or together with the nitrogen atom to which they are attached, form a 4-, 5 - or 6-membered heterocycle which can additionally contain a heteroatom selected from N, O or S, and their pharmaceutically acceptable salts.

In the preferred compounds of the present invention R1choose from a group including:

phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower ha what alenalki.com, lowest alkoxygroup, phenyl or fenoxaprop;

naphthyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop;

-(CHR3)m-phenyl, where m denotes 1 or 2 and phenyl is unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop and where R3denotes hydrogen;

-(CH2)n-heteroaryl, where n denotes 1 or 2;

-(CH2)n-heteroaryl, where n denotes 1 or 2, and heteroaryl is mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

-C(O)-CH2-phenyl, the phenyl is unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop;

-C(O)-CH2-heteroaryl; and

-C(O)-CH2-heteroaryl where heteroaryl is mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup.

One group of preferred compounds of formula I of the present invention are such compounds where R1choose from a group, including the surrounding:

phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop;

naphthyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop; and

-(CHR3)m-phenyl, where m denotes 1 or 2 and phenyl is unsubstituted or mono-, di - or tizamidine independently lower alkoxygroup, and where

R3denotes hydrogen.

Especially preferred compounds of formula I, where R1means:

phenyl, mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop.

More preferably R1denotes phenyl, di - or tizamidine lower alkoxygroup, most preferably when R1is 3,4-acid or 2,3,4-trimethoxyphenyl.

Another group of preferred compounds of formula I are those compounds where R1means

-(CH2)n-heteroaryl, where n denotes 1 or 2; or

-(CH2)n-heteroaryl, where n denotes 1 or 2, and heteroaryl is mono-, di - or tizamidine independently lower alkyl, halogen, lower halogena the sludge or lower alkoxygroup.

The preferred heteroaryl are indolyl or pyridyl.

Preferably n is 2.

Also preferred are the compounds of formula I, where R1means

-C(O)-CH2-phenyl, the phenyl is unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation, lower alkoxygroup, phenyl or fenoxaprop; or

-C(O)-CH2-heteroaryl.

Particularly preferred are-C(O)-CH2-phenyl, and-C(O)-CH2-thienyl.

In the preferred compounds of the present invention R2choose from a group including:

lower alkyl;

phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;

heteroaryl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;and

-C(O)-NR4R5where R4and R5together with the nitrogen atom to which they are attached, form a 5-membered heterocycle which can additionally contain a heteroatom selected from N, O or S.

Especially preferred are the compounds of formula I, where R2denotes lower alkyl and the most preferred is n-butyl.

Another group site is titeling compounds of formula I are compounds where R2denotes phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup.

Especially preferred are the compounds of formula I, where R2denotes phenyl or phenyl mono-, di - or tizamidine independently lower alkyl or halogen.

Also preferred are the compounds of formula I, where R2means:

heteroaryl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup, with heteroaryl, which pyridium or Tienam, is especially preferred.

In addition, preferred compounds of formula I are compounds where R2means:

-C(O)-NR4R5where R4and R5together with the nitrogen atom to which they are attached, form a 5-membered heterocycle which can additionally contain a heteroatom selected from N, O or S.

Especially preferred are the compounds of formula I, where R2denotes-C(O)-thiazolidines or -(CO)-dihydropyrrole.

Examples of compounds of formula I of the present invention are the following:

CIS-3-butyl-1-finetipped-4-ylamine,

TRANS-3-butyl-1-finetipped-4-ylamine,

CIS-3-butyl-1-benzylpiperidine-4-Il is in,

TRANS-3-butyl-1-benzylpiperidine-4-ylamine,

CIS-3-butyl-1-[2-(1H-indol-3-yl)ethyl]piperidine-4-ylamine,

TRANS-3-butyl-1-[2-(1H-indol-3-yl)ethyl]piperidine-4-ylamine,

CIS-3-butyl-1-[2-(3,4-acid-1-yl)ethyl]piperidine-4-ylamine,

TRANS-3-butyl-1-[2-(3,4-acid-1-yl)ethyl]piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,

hydrochloride of TRANS-3-butyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,

CIS-3-butyl-1-(4-phenoxyphenyl)piperidine-4-ylamine,

TRANS-3-butyl-1-(4-phenoxyphenyl)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-(5,6,7,8-tetrahydronaphthalen-1-yl)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(3,4-acid)piperidine-4-ylamine,

hydrochloride of TRANS-3-butyl-1-(3,4-acid)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-naphthalene-2-reparacin-4-ylamine,

hydrochloride of TRANS-3-butyl-1-naphthalene-2-reparacin-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-naphthalene-1-reparacin-4-ylamine,

hydrochloride CIS-3-butyl-1-(3,4-dichlorophenyl)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(4-chloro-3-triptoreline)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-p-tripeptides-4-ylamine,

hydrochloride of TRANS-3-butyl-1-p-tripeptides-4-ylamine,

hydrochloride CIS-3-butyl-1-(3,5-dichlorophenyl)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-(3,5-dihl henyl)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-4-methyl-1-phenylpiperidine-4-ylamine,

hydrochloride of TRANS-3-butyl-4-methyl-1-phenylpiperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(3-methoxy-5-triptoreline)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-(3-methoxy-5-triptoreline)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-cyclohexylpiperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-(3,5-bis-triptoreline)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(6-methoxybiphenyl-3-yl)piperidine-4-ylamine,

hydrochloride of TRANS-3-butyl-1-(6-methoxybiphenyl-3-yl)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-benzhydryl-4-reparacin-4-ylamine,

CIS-3-phenyl-1-finetipped-4-ylamine,

TRANS-3-phenyl-1-finetipped-4-ylamine,

CIS-3-phenyl-1-benzylpiperidine-4-ylamine,

TRANS-3-phenyl-1-benzylpiperidine-4-ylamine,

(CIS/TRANS)-methyl-1'-phenethyl-1',2',3',4',5',6'-hexahydro[2,3']bipyridinyl-4'-ylamine,

CIS-3-(3-chlorophenyl)-1-finetipped-4-ylamine,

(CIS/TRANS)-3-(3-chlorophenyl)-1-benzylpiperidine-4-ylamine,

(CIS/TRANS)-3-(3-were)-1-benzylpiperidine-4-ylamine,

CIS-3-(3-chlorophenyl)-1-[2-(3,4-acid)ethyl]piperidine-4-ylamine,

TRANS-1-benzyl-3-thiophene-2-reparacin-4-ylamine,

hydrochloride CIS-3-o-tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,

hydrochloride of TRANS-3-o-tolyl-1-(3,4,5-trimethoxyphenyl)p is peridin-4-ylamine,

hydrochloride, (CIS/TRANS)-3-o-tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-1-(3,4-acid)-3-m-tripeptides-4-ylamine,

hydrochloride, (CIS/TRANS)-1-(3,4-acid)-3-p-tripeptides-4-ylamine,

hydrochloride, (CIS/TRANS)-1-(3,4-acid)-3-(3,4-dimetilfenil)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-1-(3,4-acid)-3-(3-methoxyphenyl)piperidine-4-ylamine,

(CIS/TRANS)-1'-(3,4-acid)-1',2',3',4',5',6'-hexahydro[2,3']bipyridinyl-4'-ylamine,

((3R,4S)-4-amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol,

((3S,4R)-4-amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol,

[(3S,4R)-4-amino-1-(2-pyridin-2-retil)piperidine-3-yl]thiazolidin-3-ylmethanol,

1-[(3S,4R)-4-amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-phenylethanone,

1-[(3S,4R)-4-amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-thiophene-2-ylatason,

3-[(3S,4R) and (3R,4S)-4-amino-1-[2-(3,4-acid)ethyl]piperidine-3-carboxylic acid,

3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-acid)piperidine-3-yl]thiazolidin-3-ylmethanol

3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-acid)piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-ylmethanol,

3-[(3S,4R) and (3R,4S)-4-amino-1-(3,4-acid)piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-ylmethanol, and

their pharmaceutically acceptable salts.

Preferred compounds of formula I are selected from the group including:

CIS-3-butyl-1-phenethyl shall piperidin-4-ylamine,

CIS-3-butyl-1-[2-(1H-indol-3-yl)ethyl]piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,

CIS-3-butyl-1-(4-phenoxyphenyl)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(3,4-acid)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-naphthalene-2-reparacin-4-ylamine,

hydrochloride of TRANS-3-butyl-1-naphthalene-2-reparacin-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-naphthalene-1-reparacin-4-ylamine,

hydrochloride CIS-3-butyl-1-(3,4-dichlorophenyl)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(4-chloro-3-triptoreline)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-p-tripeptides-4-ylamine,

hydrochloride CIS-3-butyl-1-(3,5-dichlorophenyl)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-(3,5-dichlorophenyl)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-4-methyl-1-phenylpiperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(3-methoxy-5-triptoreline)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-butyl-1-(3-methoxy-5-triptoreline)piperidine-4-ylamine,

hydrochloride CIS-3-butyl-1-(6-methoxybiphenyl-3-yl)piperidine-4-ylamine,

CIS-3-phenyl-1-finetipped-4-ylamine,

(CIS/TRANS)-methyl-1'-phenethyl-1',2',3',4',5',6'-hexahydro[2,3']bipyridinyl-4'-ylamine,

CIS-3-(3-chlorophenyl)-1-finetipped-4-ylamine,

(CIS/TRANS)-3-(3-chlorophenyl)-1-benzylpiperidine-4-ylamine,

(CIS/TRANS)-3-(3-IU is ylphenyl)-1-benzylpiperidine-4-ylamine,

CIS-3-(3-chlorophenyl)-1-[2-(3,4-acid)ethyl]piperidine-4-ylamine,

hydrochloride of TRANS-3-o-tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-3-o-tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,

hydrochloride, (CIS/TRANS)-1-(3,4-acid)-3-m-tripeptides-4-ylamine,

(CIS/TRANS)-1'-(3,4-acid)-1',2',3',4',5',6'-hexahydro[2,3']bipyridinyl-4'-ylamine,

((3R,4S)-4-amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol,

((3S,4R)-4-amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol,

[(3S,4R)-4-amino-1-(2-pyridin-2-retil)piperidine-3-yl]thiazolidin-3-ylmethanol,

1-[(3S,4R)-4-amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-phenylethanone,

1-[(3S,4R)-4-amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-thiophene-2-yl-Etalon,

3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-acid)piperidine-3-yl] thiazolidin-3-ylmethanol

3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-acid)piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-ylmethanol,

3-[(3S,4R) and (3R,4S)-4-amino-1-(3,4-acid)piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-ylmethanol, and

their pharmaceutically acceptable salts.

The most preferred compounds are selected from the group including:

CIS-3-(3-chlorophenyl)-1-finetipped-4-ylamine,

(CIS/TRANS)-3-(3-chlorophenyl)-1-benzylpiperidine-4-ylamine,

(CIS/TRANS)-3-(3-chlorophenyl)-1-[2-(3,4-acid)ethyl]piperidine-4-ylamine,

hydrochloride CIS-1-(3,4-dime is oxyphenyl)-3-m-tripeptides-4-ylamine,

((3S,4R)-4-amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol,

[(3S,4R)-4-amino-1-(2-pyridin-2-retil)piperidine-3-yl]thiazolidin-3-ylmethanol,

3-[(3S,4R) and (3R,4S)-4-amino-1-(3,4-acid)piperidine-3-yl]-thiazolidin-3-ylmethanol,

3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-acid)piperidine-3-yl]-thiazolidin-3-ylmethanol, and

their pharmaceutically acceptable salts.

The compounds of formula I have two asymmetric atoms and can exist in the form of optically pure enantiomers, mixtures of diastereoisomers, racemates or mixtures diastereoisomeric racemate.

The invention includes all these forms.

In a preferred embodiment, R2and the amino group piperidinol patterns are in the TRANS configuration, for example,

or

In the following preferred embodiment, R2and the amino group piperidinol patterns are in CIS-configuration, for example,

or

In the following embodiment, the invention provides a method of producing compounds of formula I, including

or

a) the conversion of compounds of formula

where R1and R2defined above,

by reacting with hydroxylamine or its salt of the oxime of the formula

where R1and R defined above,

and further recovery of the oxime of formula III by means of catalytic hydrogenation or alternative repair using a metal hydride, to form compounds of formula I,

or

b) removing the protection derived from 4-aminopiperidine formula

where R1and R2defined above and Rpdenotes an amino protective group.

Rpdenotes the corresponding group protecting the amino group, such as benzyloxycarbonyl (Z or Cbz), allyloxycarbonyl (Aloka), 9-fluorenylmethoxycarbonyl (Fmoc), and preferably tert-butoxycarbonyl (Side).

More specifically the compounds of formula (I) can be obtained by the methods given below, by the methods given in the examples, or similar methods. Appropriate reaction conditions for the individual reaction stages known to experts in the field of engineering. Source materials are either commercially available or can be obtained by methods similar to the methods below, or by methods described in the examples or by methods known from the prior art.

The compounds of formula I of the present invention can be obtained, as indicated in figures 1-6 below.

4-Aminopiperidine formula I with R1having values -(CHR3)m- phenyl and -(CH2 n- heteroaryl, where R3n and m are defined above, and R2denotes lower alkyl, can be obtained in accordance with scheme 1:

Scheme 1

In the first stage, R2denoting lower alkyl, is introduced in the 3 position by interaction of N-protected Olkiluoto ether 4-oxopiperidine acid (Alk denotes a lower alkyl), with the corresponding alkylation. N-protection can be easily carried out using benzyl group (Bz). In the second stage N-protection is removed, for example by catalytic hydrogenation. In the third stage, R1- halide with R1having values -(CHR3)m- phenyl and -(CH2)n- heteroaryl, is introduced into the reaction without the protection of the piperidine, receiving the corresponding 3-alkyl-1-aryl-4-oxopiperidin. In the case when R1denotes benzyl, these last two stages can be skipped. The transformation of 3-alkyl-1-aryl-4-oxopiperidine in the desired 4-aminopiperidin may be carried out after the formation of the oxime interaction with hydroxylamine and subsequent reduction, for example, sociallyengaged (LAS) in an appropriate solvent.

4-Aminopiperidine formula I with R1denoting unsubstituted or mono-, di - or tizamidine phenyl, unsubstituted or mono-, di - or tizamidine naphthyl, t is traditonally or 3-7- cycloalkyl, and R2denoting while lower alkyl, can be obtained in accordance with scheme 2:

Scheme 2

In the first stage 4-oxopiperidine iodide is formed from the corresponding N-benzylamino 3-alkyl-4-oxopiperidine interaction with methyliodide in an appropriate solvent. R1administered by the reaction of 4-oxopiperidine iodide with the appropriate aniline R1NH2, resulting in the corresponding 3-alkyl-1-aryl-4-oxopiperidin. The conversion of this intermediate into the desired 4-aminopiperidin can occur through the formation of the oxime as a result of interaction with hydroxylamine, followed by catalytic hydrogenation in the presence of a conventional hydrogenation catalyst such as Raney Nickel or palladium on charcoal, in an appropriate solvent.

4-Aminopiperidine formula I with R1having values -(CHR3)m- phenyl and -(CH2)n- heteroaryl, where R3n and m are defined above, and R2denotes unsubstituted or mono-, di - or tizamidine phenyl, unsubstituted or mono-, di - or tizamidine naphthyl, or unsubstituted or mono-, di - or tizamidine heteroaryl can be obtained in accordance with scheme 3:

Scheme 3

In the first stage of synthesis of ester of acrylic acid is introduced into reaction with a suitable arylalkylamines R1NH2to obtain the corresponding ester arylalkylamines acid, which is then in turn the result of interaction with akriluksusnoy acid or galogenangidridy akriluksusnoy acid (R2COOH or R2COHal) in ether R2acetylaminophenol acid. The subsequent cycle of interaction, for example, with alkaline butyl or sodium hydride leads to the piperidine-2, 4-dione, which is then converted with hydroxylamine in the piperidine-2, 4-dione-4-oxime. This intermediate can be restored at the end of, for example, using sociallyengaged in an appropriate solvent to the desired 4-aminopiperidine.

4-Aminopiperidine formula I with R1denoting unsubstituted or mono-, di - or tizamidine independently phenyl, unsubstituted or mono-, di - or tizamidine independently naphthyl, tetrahydronaphthyl or3-7-cycloalkyl, and R2denoting unsubstituted or mono-, di - or tizamidine independently phenyl, unsubstituted or mono-, di - or tizamidine independently naphthyl, or unsubstituted or mono-, di - or tizamidine independent heteroaryl can be obtained in accordance with scheme 4:

Scheme 4

Sin is ez 1-aryl-3-aryl-4-aminopiperidine can be carried out according to the scheme 2 of N-benzylamino 3-alkyl-4-oxopiperidine, which enter into reaction with aniline R1NH2, resulting in the corresponding 3-alkyl-1-aryl-4-oxopiperidin. Treatment of this compound with hydroxylamine gives the corresponding oxime, which can then be restored to the desired 4-aminopiperidine.

Alternative N-benzylamine iodide 3-alkyl-4-oxopiperidine in the first stage is introduced into the reaction allonline R1NH2, resulting in the corresponding 1-aryl-4-oxopiperidin. The aryl group can then be put in position 3 using helgaleena R1Ha2in the presence of palladium acetate, tert-butoxide sodium and P(tBu)3. The resulting 3-aryl-1-aryl-4-oxopiperidin then converted into the desired 4-aminopiperidin, as described above.

4-Aminopiperidine formula I with R1having values -(CHR3)m- phenyl and -(CH2)n- heteroaryl, where R3n and m are defined above, and R2denotes-C(O)-NR4R5where R4and R5the above can be obtained according to scheme 5:

Scheme 5

In the first stage, the amino group of diapir 4-aminopiperidin-1,3-dicarboxylic acid protects benzyloxycarbonyloxy group (BOK). Ester group in position 3 then hydrolyzing, followed by amide formation using the-W standard conditions of peptide condensation. In subsequent stages the SIDE-protective group in position 1 is removed, for example, using triperoxonane acid, and then arylalkyl group can be introduced at N1 by processing the corresponding arylalkylamines R1Hal. At the end of the desired 4-aminopiperidin get removing benzyloxycarbonyl protective group in the presence of HBr.

4-Aminopiperidine formula I with R1denoting unsubstituted or mono-, di - or tizamidine phenyl, unsubstituted or mono-, di - or tizamidine naphthyl, tetrahydronaphthyl or3-7-cycloalkyl, and R2denoting unsubstituted or mono-, di - or tizamidine phenyl, unsubstituted or mono-, di - or tizamidine naphthyl, or unsubstituted or mono-, di - or tizamidine heteroaryl can be obtained in accordance with scheme 6:

Scheme 6

Ether 1-benzyl-4-oxopiperidine-3-carboxylic acid are initially introduced into a reaction with ammonia, receiving the corresponding tetrahydropyridine, which then restores, for example, sodium borohydride to obtain ether 4-aminopiperidines acid. BOC-protection of the amino group in the 4 position and gradient removal of benzyl groups, for example by catalytic hydrogenation in the presence of a hydrogenation catalyst, leads to the 4-N-BOC-protected ether piperidine-3-carbon is Oh acid. Arylalkyl group R1can be entered using the corresponding aldehyde R1CH=O with subsequent recovery. Removal of the BOC-protective group and hydrolysis of the ester of the corresponding alkali metal hydroxide leads to the desired 1-arylalkyl-4-aminopiperidine acid.

4-Aminopiperidine formula I with R1having values -(CHR3)m- phenyl and -(CH2)n- heteroaryl, where R3n and m are defined above, and R2denotes-C(O)-NR4R5where R4and R5the above can be obtained in accordance with scheme 7:

Scheme 7

In the first stage of the synthesis arylamine R1enter into reaction with the acrylic ester in the presence of CuCl and acetic acid, receiving the corresponding ester of 1-aryl-4-oxopiperidin-3-carboxylic acid. Treatment of this intermediate with ammonium acetate and lamborghini.com sodium ether gives 1-aryl-4-aminopiperidin-3-carboxylic acid. BOC-protection of the free amino group in the 4 position and subsequent hydrolysis leads to the free carboxylic acid, which is then used for condensation with the amine R4R5NH. The desired 4-aminopiperidin then obtained by removal of the BOC-protective group, for example, using triperoxonane acid.

The invention relates further to soedineniya formula I according to the definition above, obtained by the method according to the above definition.

The invention relates also to compounds of the formula I defined above for use as therapeutically active substances for the treatment and/or prevention of diseases associated with DPP-IV.

These diseases, which are associated with DPP-IV, are diabetes, particularly non-insulin dependent diabetes mellitus, and/or decreased glucose tolerance, as well as other States, where the amplification action of the peptide, normally inactivating DPP-IV, leads to a therapeutic effect. In addition, the compounds of the present invention can be applied also in the treatment and/or prophylaxis of obesity, metabolic syndrome, the protection of β-cells, autoimmune diseases such as inflammatory bowel disease, encephalitis paraxially sclerosis and rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, planus and/or benign prostatic hypertrophy. Connections can also be used for the prevention of AIDS (acquired immunodeficiency syndrome) or to prevent metastasis, in particular metastasis of breast cancer and prostate cancer in the lungs. In addition, the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension.

As described the ANO above, the compounds of formula I of the present invention can be used as medicines for the treatment and/or prevention of diseases associated with DPP-IV described above.

The invention therefore relates also to pharmaceutical compositions comprising a compound of formula I according to the present invention and a pharmaceutically acceptable carrier and/or adjuvant.

Further, the invention relates also to compounds of formula I of the present invention for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of diseases associated with DPP-IV described above.

In another embodiment, the invention relates to a method of treatment and/or prevention of diseases associated with DPP-IV, as defined above, including the introduction of the compounds of formula I to a human or animal.

The invention relates also to the use of compounds of the formula I according to the present invention for the treatment and/or prevention of diseases associated with DPP-IV, as defined above.

In the context of the methods and application of the definition above, preferred are the following diseases: diabetes, particularly non-insulin dependent diabetes mellitus, decreased glucose tolerance, obesity and/or metabolic syndrome or protection of β-cells, etc is doctitle non-insulin-dependent diabetes mellitus and/or decreased glucose tolerance.

To determine the activity of compounds of the formula I conducted the following tests.

The activity of DPP-IV inhibitors tested on natural human DPP-IV isolated from pooled human plasma or recombinant human DPP-IV. Human citrate plasma from different donors is collected, filtered through a membrane with a thickness of 0.2 μm in sterile conditions and aliquot in 1 ml frozen and stored until use at a temperature of -120°C. as the source of enzyme used in the calorimetric DPP-IV analysis from 5 to 10 μl of human plasma, and in the spectral analysis of the use of 1.0 µl human plasma total analyzed volume of 100 μl. The amino acid sequence of cdnc human DPP-IV from 31 to 766, subject to the restriction on the N-terminal and transmembrane domain, clone in Pichia pastoris. Human DPP-IV Express and isolated from the culture medium using standard column chromatography, including pressure, anionic and cationic chromatography. The purity obtained by Coomassie blue SDS-PAGE of the final enzyme is >95%. In colorimetric DPP-IV analysis is used as a source of enzyme, 20 ng rec-h DPP-IV, and spectral analysis of 2 ng rec-h DPP-IV total target volume of 100 μl.

In fluorometric analysis of Ala-Pro-7-amido-4-triftoretil the Rin (Calbiochem No 125510) is used as the substrate. 20 mm initial solution in 10% DMF/N2About stored at -20°C until use. When definitions IC50use the final substrate concentration of 50 μm. In the analyses for the determination of kinetic parameters such as KmVmax, Kithe substrate concentration range from 10 μm to 500 μm.

In colorimetric analysis as the substrate using H-Ala-Pro-pNA.HCl (Bachem L-1115). 10 mm initial solution in 10% Meon/the site, located between stored at -20°C until use. When IC50the definitions use the final substrate concentration of 200 μm. In the analyses for the determination of kinetic parameters such as KmVmax, Kithe substrate concentration range from 100 μm to 2000 μm

The fluorescence detected on a Perkin Elmer luminescence spectrometer LS 50 b when the wavelength of excitation 400 nm and emission wavelength of 505 nm continuously every 15 s for 10 to 30 minutes the rate Constant of excitation is calculated using the method of linear regression.

The absorbance of pNA released from the colorimetric substrate to be detected on a Packard SpectraCount at 405 nm continuously every 2 min for 30 to 120 minutes, the rate Constant of excitation is calculated using the method of linear regression.

Analysis of DPP-IV activity is carried out in a 96-cellular tablets at a temperature of 37°C With the total of the analyzed volume is ω 100 μl. Buffer for analysis consists of 50 mm Tris/HCl, pH 7.8, containing 0.1 mg/ml BSA and 100 mm NaCl. Test compounds dissolved in 100% DMSO, diluted to the desired concentration in 10% DMSO/N2O. the Final concentration of DMSO in the analysis is 1% (vol./vol.). At this concentration, inactivation of the enzyme DMSO is <5%. Connections are taken from pre-incubation with the enzyme for 10 min at 37°C) and without it. Enzyme reactions begin with the use of the substrate followed by immediate mixing.

IC50values of the test compounds is calculated using non-linear regression DPP-IV inhibiting at least 5 different concentrations of compounds. Kinetic parameters of enzymatic reactions calculate at least 5 different concentrations of substrates and at least with 5 different concentrations of the tested compounds.

Compounds of the present invention have the IC50values from 0.1 μm to 50 μm, more preferably from 0.1 μm to 1 μm, as shown in the following table:

ExampleIC50[µm]
230,16
290,59
36 0,29
400,82

The compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicines, for example in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered orally, for example in the form of tablets, pills in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or tapicerki, for example, in the form of ointments, creams or oils. It is preferable to oral administration.

The pharmaceutical preparation carried out by a method known to anyone skilled in the art, including the introduction of the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other farmatsevticheskii valuable substances, in pharmaceutically accepted insertion form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and, if desired, usual pharmaceutical adjuvants.

Suitable carriers can serve not only inorganic materials, but also the body of the static media. So, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carriers in the manufacture of tablets, pills in the shell, coated tablets and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, regardless of the nature of the active ingredient, in the case of hard gelatin capsules any media may not be required). Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural or hydrogenated oils, waxes, fats and semi-solid or liquid polyols. Suitable carriers for topical preparations are, for example, glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, wetting and emulsion agents, agents for improving the consistency, flavor agents, salts for a variable which I osmotic pressure, buffer substances, solvents, dyes and masking agents and antioxidants are considered as pharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limits depending on the controlled disease, age and individual condition of the patient and the route of administration, and must match, of course, the individual requirements in each particular case. For adult patients, the daily dose is from about 1 mg to 1000 mg, in particular from about 1 mg to 100 mg depending on the severity of the disease and specific pharmacokinetic profile of the compound can be introduced in the form of one or more daily unit doses, for example from 1 to 3 single doses.

The pharmaceutical preparations normally contain about 0.1-500 mg, preferably 1-100 mg of the compounds of formula (I).

The following examples illustrate in more detail the present invention. They are, however, in no way limit its scope.

Examples

Used abbreviations:

DHM: dichloromethane; the SPLA: acetic acid; AcOEt: ethyl acetate; DMF: dimethylformamide; DIPEA: diisopropylethylamine (base Chunga); THF: tetrahydrofuran; 'lah: sociallyengaged; CBI: carbonyldiimidazole; TPA: triperoxonane acid; EDS: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl; the MBT: 1-hydroxybenzotriazole.

CT: room temperature; BB: high vacuum; TLC: thin layer chromatography.

Example 1: 3-Butyl-1-finetipped-4-ylamine

Stage A: 1-Benzyl-3-butyl-piperidine-4-one

To a suspension of anhydrous potassium carbonate (22,8 g) and ethyl ester of 1-benzyl-4-oxopiperidine-3-carboxylic acid (10 g) in acetone (125 ml) add a solution of butylated (13,4 g of 8.3 ml) in acetone (50 ml) in an argon atmosphere for 30 minutes the Resulting suspension is stirred at room temperature for 30 min, and then heated under reflux for 12 hours, the Suspension is cooled, filtered and concentrated in vacuo. The residue is dissolved in DHM, the solution washed with water and brine, dried over Na2SO4and evaporated. To the residue add model HC1 aqueous solution (20%, 100 ml) and the solution heated under reflux for 24 hours the Solvent is evaporated, and the residue is dissolved in DHM, washed with 10%aqueous solution of Na2CO3and brine, dried and evaporated. The crude product is purified using accelerated chromatography (ethyl acetate/hexane in the ratio 1:2)to give the product as a slightly yellow oil (6.4 g). MS (ESI): 246,4 (MN).

Stage B: 3-Butyl-piperidine-4-one

To a solution of 1-benzyl-3-butyl-piperidine-4-it (1.3 g) in a mixture of SPLA/water in the ratio 3:1 (25 ml) is added 10%Pd on coal (130 mg). The hydrogen atmosphere was like the current introduction/removal of hydrogen. The suspension is vigorously stirred for 5 hours, the Catalyst was removed by filtration through dicalite, and the filtrate was concentrated in vacuo. The oily residue is treated with 10%aqueous solution of Na2CO3and then extracted with DHM. The organic layer is separated, dried over Na2SO4, filtered and evaporated, to give crude product as a slightly yellow oil (680 mg), used without further purification. MS (ESI): 156,2 (MN+).

Stage b: 3-Butyl-1-finetipped-4-one

To a solution of 3-butylpiperazine-4-it (250 mg) in DMF (5 ml) add DIPEA (468 mg), and then a solution of (2-bromacil)benzene (373 mg) in DMF (5 ml) for 45 min the Resulting mixture was stirred at room temperature for 1 h, and then heated to 60°C for 6 hours, the Reaction mixture was cooled, diluted with ether and the organic solution is twice washed with 10%aqueous solution of Na2CO3and brine. The organic layer is dried over MgSO4, filtered and evaporated, receiving the remainder, which is cleaned by rapid chromatography (ethyl acetate/hexane in the ratio 1:3)to give the product as a colourless liquid (355 mg). MS (ESI): 260,4 (MN+).

Stage D: the Reaction of 3-butyl-1-finetipped-4-it

3-Butyl-1-finetipped-4-one (300 mg), NaOAc (878 mg) and hydroxylamine hydrochloride (708 mg) suspended in a mixture of ethanol/water is in the ratio of 1:1 (10 ml), heat the mixture under reflux for 5 hours Obtained after this treatment clear solution is cooled, diluted with water and alkalinized 10%aqueous solution of Na2CO3to pH 10. The suspension is extracted with DHM and the organic layer washed with brine, dried over MgSO4and evaporated. The product is carefully cleaned for use in the next stage, getting yellowish glassy mixture of CIS - and TRANS-diastereomers (332 mg). MS (ESI): 261,4 (MN+).

Stage D: 3-Butyl-1-finetipped-4-ylamine

The oxime of 3-butyl-1-finetipped-4-it (218 mg) was dissolved in THF (10 ml) and add one portion of LAH (261 mg). The suspension is then stirred at room temperature for 24 h, the Reaction mixture carefully with a pipette and transferred into a 5%aqueous solution of NaHCO3and the aqueous layer was extracted with DHM. The organic layer was washed with brine, dried over MgSO4and evaporated, obtaining a colorless oil, which was purified using accelerated chromatography (gradient Meon in DHM containing 1% NH4OH), getting the product in the form of CIS - and TRANS-diastereomers (CIS: 127 mg; TRANS: 36 mg). MC (ESI): 261,4(MH+).

Example 2: 3-Butyl-1-benzylpiperidine-4-ylamine

This compound was synthesized analogously to example 1, except that the stages B and C were entirely excluded, and benzyl group participants the oval throughout the synthesis, the result that was obtained CIS - and TRANS-diastereomers as colorless oils. MS (ESI): 247,4 (MN+).

Example 3: 3-Butyl-1-[2-(1H-indol-3-yl)ethyl]piperidine-4-ylamine

This compound was synthesized as described in example 1 from ethyl ester of 1-benzyl-4-oxopiperidine-3-carboxylic acid and 3-(2-bromacil)-1H-indole as an alkylating agent at the stage, resulting in the obtained CIS - and TRANS-diastereomers as colorless oils. MS (ESI): 300,5 (MN+).

Example 4: 3-Butyl-1-[2-(3,4-acid-1-yl)ethyl]piperidine-4-ylamine

This compound was synthesized as described in example 1 from ethyl ester of 1-benzyl-4-oxopiperidine-3-carboxylic acid and (2-bromacil)-3,4-dimethoxybenzene as an alkylating agent at the stage, resulting in the obtained CIS - and TRANS-diastereomers as colorless oils. MS (ESI): 321,4 (MN+).

Example 5: Hydrochloride 3-butyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine

Stage A: 1-Benzyl-3-butyl-1-methyl-4-oxopiperidine iodide

To a solution of 3-butyl-1-benzylpiperidine-4-it (9080 mg) in acetone (40 ml) slowly add methyliodide (6303 mg) at room temperature, and then the solution was stirred at room temperature for 3 hours the Precipitated precipitated white solid is filtered off and then washed four times with 50 ml of acetone and dried at eigendom pressure. The filtrate is evaporated and the residue is stirred with ethyl acetate. White solid was filtered, washed with ethyl acetate and dried in vacuum. Two solids are combined to getting 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide in the form of a white powder (11200 mg). MS (ESI): 204,2 (M-G).

Stage B: 3-Butyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-one

A suspension of 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide (306 mg) in water (2 ml) is added in one portion to be heated under reflux to a solution of 3, 4, 5-trimethoxyaniline (929 mg) and anhydrous potassium carbonate (33 mg) in ethanol (4 ml). The dark solution is heated under reflux for 3 h, water is added and extracted twice the reaction mixture DHM. The combined organic layers dried over sodium sulfate, filtered and the solvent is evaporated, receiving a dark oil, which was purified using accelerated chromatography (ethyl acetate/hexane in the ratio 1:1)to give the product as colourless oil (520 mg). MS (ESI): 322,4 (MN+).

Stage: Hydrochloride 3-butyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine

The ketone obtained in the previous phase (460 mg), dissolved in ethanol (60 ml), added hydroxylamine hydrochloride (109 mg) and sodium acetate (129 mg), and the solution was stirred at room temperature for 1 h After monitoring by TLC, dobavlyautsya Raney (Nr 313 Degussa In 1132) and stirred the reaction mixture at room temperature in hydrogen atmosphere overnight. The catalyst is filtered off and the filtrate concentrated. The residue is purified by chromatography on silica gel (DHM/Meon/25%aqueous solution of NH4OH in the ratio 95:5:1). The selected products are dissolved in ethanol and add 1 ml of a saturated ethanolic solution of hydrogen chloride. The solution is evaporated, receiving CIS- (150 mg) and TRANS-diastereomers (160 mg) as slightly yellow solids. MS (ESI): 323,4 (MN+).

Example 6: Hydrochloride 3-butyl-1-(4-phenoxyphenyl)piperidine-4-ylamine

This compound was synthesized analogously to example 5 using stadii B and C from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 4-phenoxyimino, except that the stage has been replaced by another method.

Stage (modified version)]: hydrochloride 3-butyl-1-(4-phenoxyphenyl)piperidine-4-ylamine

3-Butyl-1-(4-phenoxyphenyl)piperidine-4-one (320 mg) was dissolved in ethanol (8 ml) and added hydroxylamine hydrochloride (76 mg) and sodium acetate (89 mg). The reaction mixture becomes yellow in color and was stirred at room temperature for 2 hours Monitoring by TLC indicates the formation of E/Z-oximo. After adding water (8 ml) formed suspension, which is added to the Al-Ni alloy (300 mg), and then slowly add 32%aqueous sodium hydroxide solution (1.4 ml), while the observed warming is actionnow mixture. After the final addition the reaction mixture was stirred for 2 h at room temperature and filtered the solid. The precipitate is washed DHM. The aqueous solution is extracted with DHM. The combined organic layers washed with brine, dried over sodium sulfate, filtered, and the solvent is evaporated. The residue is purified using accelerated chromatography (DHM/Meon/feast upon. aq. a solution of NH4OH in the ratio of 100:5:1). The selected products are dissolved in ethanol and add 1 ml of a saturated ethanolic solution of hydrogen chloride. The solution is evaporated, receiving CIS- (117 mg) and TRANS-diastereomers (52 mg), each in the form of a slightly yellowish solid. MS (ESI): 325,5 (MN+) of CIS - and TRANS-diastereoisomers.

Example 7: Hydrochloride 3-butyl-1-(5,6,7,8-tetrahydronaphthalen-1-yl)piperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 5-aminotetraline with the formation of a mixture of CIS - and TRANS-diastereomers as a white solid. The attempt to separate the diastereomers (in the form of free amines) using accelerated chromatography failed. MS (ESI): 287,3 (MN+).

Example 8: Hydrochloride 3-butyl-1-(3,4-acid)piperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-oxopiperidine iodide and 3,4-dimethoxyaniline with the formation of CIS - and TRANS-diastereomers as white solids. MS (ESI): 293.4 (MN) of CIS - and TRANS-diastereoisomers.

Example 9: Hydrochloride 3-butyl-1-naphthalene-2-reparacin-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 2-naphtylamine with the formation of a mixture of CIS - and TRANS-diastereomers in the ratio 5:2 and pure TRANS-diastereoisomer in the form of a white solid. MS (ESI): 283,2 (MN+) CIS - and TRANS-diastereoisomers.

Example 10: Hydrochloride 3-butyl-1-naphthalene-1-reparacin-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 1-naphtylamine with the formation of a mixture of CIS - and TRANS-diastereomers in a ratio of 1:2 in the form of a white solid. The attempt to separate the diastereomers (in the form of free amines) using accelerated chromatography failed. MS (ESI): 283,2 (MN+).

Example 11: Hydrochloride 3-butyl-1-(3,4-dichlorophenyl)piperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 3,4-dichloraniline with the formation of the CIS-diastereoisomer in the form of a white solid. MS (ESI): 301,3 (MN+).

Example 12: Hydrochloride 3-butyl-1-(4-chloro-3-triptoreline)piperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-about the of apipeline iodide and 4-chloro-3-triptorelin with the formation of the CIS-diastereoisomer and a mixture of CIS - and TRANS-diastereomers in a ratio of 1:1 as white solids. MS (ESI): 335,3 (MN+) CIS - and TRANS-diastereoisomers.

Example 13: Hydrochloride 3-butyl-1-p-tolyl-piperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 4-methylaniline with the formation of CIS - and TRANS-diastereomers as white solids. MS (ESI): 247,4 (MN+).

Example 14: Hydrochloride 3-butyl-1-(3,5-dichlorophenyl)piperidine-4-ylamine hydrochloride and 3-butyl-1-phenylpiperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 3,5-dichloro-4-methylaniline with the formation of the CIS-diastereoisomer and a mixture of CIS - and TRANS-diastereomers in a ratio of 1:1 in the form of a white solid substance. MS (ESI): 301,3 (MN+).

Incremental recovery leads to the formation of dehalogenating CIS - and TRANS-phenylpropionic, which were separated in the form of amines using accelerated chromatography. Hydrochloride CIS-and TRANS-diastereomers were isolated as white solids. MS (ESI): 233,3 (MN+).

Example 15: Hydrochloride 3-butyl-1-(3-methoxy-5-triptoreline)piperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 3-methoxy-5-triptorelin with the formation of a mixture of CIS - and TRANS-diastereomers, CIS-Diaz is eromero as white solids. MS (ESI): 331,4 (MN+).

Example 16: Hydrochloride 3-butyl-1-cyclohexylpiperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and cyclohexylamine with the formation of a mixture of CIS - and TRANS-diastereomers as a white solid.1H NMR (DMSO): δ 2,81-to 2.65 (m, 2H), 2,60-2,00 (m, 5H), 1.74-to 1.60 (m, 5H), 1.60-to of 1.40 (m, 3H), of 1.40 to 1.00 (10 N), of 0.87 (t, 3H).

Example 17: Hydrochloride 1-(3.5-bis-triptoreline)-3-butylpiperazine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 3,5-bis(trifluoromethyl)aniline with formation of a mixture of CIS - and TRANS-diastereomers as a white solid. MS (ESI): 369,3 (MN+).

Example 18: Hydrochloride 3-butyl-1-(6-methoxybiphenyl-3-yl)piperidine-4-ylamine

This compound was synthesized analogously to example 6 from 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and 6-methoxybiphenyl-3-ylamine with the formation of CIS - and TRANS-diastereomers as white solids.1H NMR (DMSO, CIS-diastereoisomer): δ 7.47 (d, 2H), 7,38 (t, 2H), 7,32 (t, 1H), 6,97 (d, 1H), 6.89 in (d, 1H), PC 6.82 (s, 1H), to 3.67 (s, 3H), of 3.07 (dd, 2H), 2,98 (m, 2H), 2,86 (dd, 1H), 1,62 (m, 3H), of 1.29 (m, 6H), 0.88 (t, 3H),1H NMR (DMCO, TRANS diastereoisomer): δ 7.47-7.20 (m, 8H), 3,62 (s, 3H), 3,54 (user. d, 2H), 2,64 (m, 2H), a 2.36 (m, 1H), 1,79 (m, 3H), of 1.33 (m, 6H), to 0.88 (t, 3H).

Example 19: Hydrochloride 1-benzhydryl-3-butylpiperazine-4-Il is in

This compound was synthesized analogously to example 6 from (rat)-1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide and diphenylethylamine as a mixture of CIS/TRANS diastereomers in a ratio of 1:1 in the form of a white solid.1H NMR (DMSO): δ 7,37 (m, 4H), 7,27 (m, 4H), 7,16 (t, 2H), 4.26 deaths-4,22 (2s, 1H), of 2.81-2.73 (m, 3H), 2,48-of 2.08 (m, 3H), 1.56 to of 1.05 (m, 8H), 0,84 of 0.77 (2t, 3H).

Example 20: 3-Phenyl-1-finetipped-4-ylamine

Stage A: Ethyl ester of 3-phenethylaminedreams acid

Phenylethylamine (10 g) is dissolved in EtOH (50 ml) and then added dropwise ethyl ester of acrylic acid (8,3 g) in an argon atmosphere at room temperature. The resulting mixture is stirred over night and after evaporation of the solvent is dried in vacuum. The remainder in the form of a colourless liquid (18,9 g) used without further purification. MS (ESI): 222,3 (MN+).

Stage B: Ethyl ester of 3-(generphentermine)propionic acid

Ethyl ester of 3-phenethylaminedreams acid (8.0 g) is dissolved in absolute pyridine (12 ml) and cooled to 0°C in an ice bath. The acid chloride phenylacetic acid (1.5 ml) then add dropwise within 10 min, receiving a yellow suspension, which was then heated to 60°C for 2.5 h, cooled to room temperature, then stirred overnight. The reaction mixture is then transferred into ice-cold water containing 25% HCl, and water with the Oh extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4and evaporated. The residue is purified using accelerated chromatography (ethyl acetate/hexane in the ratio 1:4)to give the product as a yellow oil (3.9 g). MS (ESI): 340,4 (MN+).

Stage b: 1-Phenethyl-3-phenylpiperidine-2.4-dione

Sodium hydride (1.1 g, 50%solution in mineral oil) suspended in ether (40 ml) in an argon atmosphere at RT. Ethyl ester of 3-(penicillinases-amino)propionic acid (2.5 g) is added in portions, followed by addition of abs. EtOH (0.5 ml). The resulting mixture is heated under reflux for 2 h, cooled and transferred into a mixture of water/ice/1 normal HCl. The aqueous layer was extracted with ethyl acetate, the organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue is purified using accelerated chromatography (ethyl acetate/hexane in a ratio of 1:1, and then DHM/Meon in the ratio 95:5), receiving the specified product in the form of a slightly yellowish foam (801 mg). MS (ESI: 294,4 (MN+).

Stage D: 1-Phenethyl-3-phenylpiperidine-2.4-dione-4-oxime

1-Phenethyl-3-phenylpiperidine-2,4-dione (781 mg), sodium acetate (1,15 g) and hydroxylamine hydrochloride (925 mg) suspended in a mixture of EtOH/water (ratio 1:1, 25 ml) and heat the suspension to reflux for 4 h Then the reaction mixture is PE is UNOSAT in a mixture of ice/water/1-normal NaOH solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated, to give crude product, which was purified using accelerated chromatography DHM/MeOH/NH4OH in the ratio 98:2:0.25)to give the compound as a white foam (489 mg). MS (ESI): 309,4 (MN+).

Stage D: 1-Phenethyl-3-phenylpiperidine-4-ylamine

1-Phenethyl-3-phenylpiperidine-2,4-dione-4-oxime (480 mg) is dissolved in absolute ether (30 ml) in an argon atmosphere. LAH (473 mg) is added in one portion and the resulting suspension is heated under reflux during the night. The mixture was carefully transferred into a 1-molar aqueous solution of Na/K-salt of tartaric acid, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue is purified using accelerated chromatography (gradient Meon in DHM containing 0.25% NH4OH, and then DHM/Meon/NH4OH in the ratio 85/15/0 .25), receiving a connection consisting of CIS-diastereoisomer (95 mg) and TRANS-diastereoisomer (101 mg)as a colourless oil. MS (ESI): 281,4 (MN+).

Example 21: 3-Phenyl-1-benzylpiperidine-4-ylamine

This compound was obtained according to example 20 (stages B-D) of the ethyl ester of 3-benzylaminopurine acid and acid chloride phenylacetic acid with the formation of CIS - and TRANS-diastereomers as a yellow oil. MS (ESI): 326,4 (MN+).

Example 22: metyl-1'-phenethyl-1',2',3',4',5',6'-hexahydro[2,3']bipyridinyl-4'-ylamine

This compound is obtained according to the method of example 20 (stages a-D) from phenethylamine and ethyl acetate, but with the use of a modified condensing stage B, where used (4-methylpyridin-2-yl)acetic acid instead of the acid chloride.

Stage A: (4-Methylpyridin-2-yl)acetic acid

Ethyl ester (4-methylpyridin-2-yl)acetic acid (1.0 g)obtained according to Chem. Farm. Bull. 32 (12), 1984, 4866-4872, dissolved in ethanol (30 ml) and treated with 1-molar ethanolic NaOH (of 5.83 ml). The mixture is heated under reflux for 4 h, cooled and evaporated in vacuum. The residue is dissolved in water (50 ml) and adjusted pH to 3.0 with 1-molar HCl solution. The solvent is evaporated and the residue is suspended in ethanol (150 ml) and filtered. Clean the filtrate is evaporated until dry and the residue is finally dried in vacuum, obtaining a slightly yellow solid (1.0 g). NMR (DMSO-d6): 8,65 (d, 1H); 7,72 (s, 1H), 7,68 (d, 1H), Android 4.04 (s, 2H), 2.49 USD (s, 3H).

Stage B: Ethyl ester of 3-{[2-(4-methylpyridin-2-yl)acetyl]-phenethylamine}propionic acid

(4-Methylpyridin-2-yl)acetic acid (1.0 g), carbonyldiimidazole (1.07 g) and DIPEA (0,856 g)is added to THF (15 ml), form a brown suspension, which was stirred at room temperature for 1 hour To the mixture are added dropwise ethyl ester 3-phenethylaminedreams acid (0,898 g) and the image is washouse the mixture was stirred at 55°C over night. Then the mixture is transferred into ice water, adjusted the pH value to 5.0 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue is purified using accelerated chromatography (ethyl acetate/hexane in the ratio 2:1), obtaining the specified product as a slightly brown liquid (0,462 g). MS (ESI): 355,0 (MN+).

The final product of this synthesis in the form of a yellow oil is a mixture of CIS - and TRANS-diastereoisomers. MS (ESI): usd296.4 (MN+).

Example 23: 3-(3-Chlorophenyl)-1-finetipped-4-ylamine

This compound was obtained according to example 22 from phenethylamine, acrylate and (3-chlorophenyl)acetic acid. The compound obtained in the form of a yellow oil is a CIS-diastereoisomer. MS (ESI): 315,1 (MN+).

Example 24: 3-(3-Chlorophenyl)-1-benzylpiperidine-4-ylamine

This compound was obtained according to example 20 (stages B-D) of the ethyl ester of 3-benzylaminopurine acid and acid chloride (3-chlorophenyl)acetic acid. The compound obtained in the form of a yellow oil is a mixture of CIS - and TRANS-diastereoisomers. MS (ESI): 301,2 (MN+).

Example 25: 3-(3-Were)-1-benzylpiperidine-4-ylamine

This compound was obtained according to example 20 (stages B-D) of the ethyl ester of 3-benzylaminopurine acid and acid chloride (3-m is terphenyl)acetic acid. The compound obtained in the form of a yellow oil is a mixture of CIS - and TRANS-diastereoisomers. MS (ESI): 281,3 (MN+).

Example 26: 3-(3-Chlorophenyl)-1-[2-(3,4-acid)ethyl]piperidine-4-ylamine

This compound was obtained according to example 20 from acrylate, 2-(3, 4-acid)ethylamine and the acid chloride (3-chlorophenyl) acetic acid. The compound obtained in the form of a yellow oil is a mixture of CIS - and TRANS-diastereoisomers. MS (ESI): 375.2 (MN+).

Example 27: 1-Benzyl-3-thiophene-2-reparacin-4-ylamine

This compound is obtained analogously to example 20 (stages B-D) of the ethyl ester of 3-benzylaminopurine acid and thiophene-2-acetylchloride. The compound obtained in the form of a yellow oil is a TRANS-diastereoisomer MS (ESI): 273,2 (MN+).

Example 28: Hydrochloride 3-o-tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine

Stage A: 1-Benzyl-1-methyl-4-oxo-3-o-carpipramine iodide

To a solution of 1-benzyl-3-o-tripeptides-4-it (5165 mg) in acetone (25 ml) slowly add methyliodide (3048 mg) at room temperature. The solution was stirred at room temperature overnight. Precipitated precipitated white solid is filtered off, washed four times with 50 ml of acetone and dried under reduced pressure. The filtrate is evaporated and the residue is stirred with ethyl acetate. White solid substances what about the filter, washed with ethyl acetate and dried in vacuum. Both received solid combine, getting 1-benzyl-3-butyl-1-methyl-4-oxopiperidine iodide in the form of a yellowish solid (4400 mg). MS (ESI): 294,3 (M-I-).

Stage B: 3-o-tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-one

A suspension of 1-benzyl-1-methyl-4-oxo-3-o-carpipramine iodide (1000 mg) in water (5 ml) is added to whole heated under reflux a solution of 3,4,5-trimethoxyaniline (395 mg) and anhydrous potassium carbonate (37 mg) in ethanol (10 ml). The reaction mixture is heated under reflux overnight, then add water and extracted four times DHM. The combined organic phases are dried over sodium sulfate, filtered, then the solvent is evaporated, getting red-brown oil which is purified using accelerated chromatography (diethyl ether)to give product as a yellow oil (600 mg). MS (ESI): 356,2 (MN+).

Stage: Hydrochloride 3-o-tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine

3-o-Tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-one (300 mg) is dissolved in ethanol (8 ml). After addition of hydroxylamine hydrochloride (64 mg) and sodium acetate (76 mg) yellow solution turns into a brown suspension. Then for three hours, stir the mixture at room temperature and add water (8 ml), resulting in brasaetsa suspension, which make Al-Ni alloy (300 mg), and then slowly add 32%aqueous sodium hydroxide solution (1.4 ml), while the observed heating of the reaction mixture. After the final addition the reaction mixture is stirred for 2 days at room temperature, and then filtered off the solid. The precipitate is washed DHM. The aqueous solution is extracted with DHM. The combined organic layers washed with brine, dried over sodium sulfate, filtered, and the solvent is evaporated. The residue is purified using accelerated chromatography (DHM/Meon/feast upon. aq. a solution of NH3in the ratio of 100:5:1). The selected products are dissolved in ethanol and add 1 ml of a saturated ethanolic solution of hydrogen chloride. The solution is evaporated, receiving CIS-diastereoisomer (76 mg), a mixture of CIS - and TRANS-diastereomers (170 mg) and TRANS-diastereoisomer (40 mg), each as a white solid. MS (ESI): 357,3 (MN+).

Example 29: Hydrochloride of 1-(3,4-acid)-3-m-tripeptides-4-ylamine

Stage A: 1-(3, 4-Acid)piperidine-4-one

A suspension of 1-benzyl-1-methyl-4-oxopiperidine iodide (9270 mg), 3, 4-dimethoxyaniline (3900 mg) and anhydrous potassium carbonate (437 mg) in a mixture of ethanol (90 ml)/water (45 ml) is heated under reflux for 6 hours Then further added potassium carbonate (200 mg) and the reaction mixture is heated at 10°C during the night. To the reaction mixture are added water (50 ml) and extracted three times DHM. The combined organic phases are washed with water and brine, dried over sodium sulfate, filtered, and then remove the solvent in vacuo give crude product as a dark oil. Purification using column chromatography (ethyl acetate/hexane in the ratio 1:1) gives the product as a yellow solid (3700 mg). MS (ESI): 236,1 (MN+).

Stage B: 1-(3.4-Acid)-3-m-tripeptides-4-one

The palladium acetate (23,8 mg), tert-piperonyl, sodium (306 mg) and 1-(3,4-acid)piperidine-4-one dissolved in free oxygen tetrahydrofuran (3 ml) in an argon atmosphere. The mixture was then immediately Tegaserod. After adding 3-bromthymol (363 mg) and three(tert-butyl)phosphine (from 25.8 mg) the mixture was stirred at 50°C during the night. As this is still a certain amount of the original substance, the reaction mixture is optionally heated to 70°C for 2 hours After cooling, the mixture is diluted with ethyl acetate, washed with 1 - normal aqueous solution of hydrogen chloride, water and brine. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (hexane/ethyl acetate in the ratio 2:1)to give product as a yellow oil (186 mg). MS (ESI): 326,3 (MN+).

Stage b: Guide klorid 1-(3, 4-acid)-3-m-tripeptides-4-ylamine

1-(3,4-Acid)-3-m-tripeptides-4-one (169 mg) was dissolved in ethanol (4 ml). After addition of hydroxylamine hydrochloride (40 mg) and sodium acetate (47 mg) transparent yellow solution turns into suspension. Then for three hours, stir the mixture at room temperature and add water (4 ml), resulting in a suspension that make Al-Ni alloy (150 mg), and then slowly add 32%aqueous sodium hydroxide solution (0.7 ml), while the observed heating of the reaction mixture. After the final addition the reaction mixture is stirred for 2 days at room temperature, and then filtered off the solid. The precipitate is washed DHM. The aqueous solution is extracted with DHM. The combined organic layers washed with brine, dried over sodium sulfate, filtered, and the solvent is evaporated. The residue is purified using accelerated chromatography (DHM/Meon/feast upon. aq. a solution of NH3in the ratio of 100:5:1). The selected products are dissolved in ethanol and add 1 ml of a saturated ethanolic solution of hydrogen chloride. The solution is evaporated, receiving CIS-diastereoisomer (15 mg), a mixture of CIS - and TRANS-diastereomers (144 mg) and TRANS-diastereoisomer (6 mg), each as a white solid. MS (ESI): 327,3 (MN).

Example 30: Hydrochloride of 1-(3,4-dim is toxigenic)-3-p-tripeptides-4-ylamine

This compound was synthesized analogously to example 29 (stages B and C) from 1-(3,4-acid)piperidine-4-it 4-bromthymol in the form of a white solid consisting of a mixture of CIS - and TRANS-diastereoisomers. At the stage B arilbred and three(tert-butyl)phosphine is added in the form of a solution in tetrahydrofuran and heated at 70°C for 5 h Separation of diastereomers (in the form of free bases) cannot hold with accelerated chromatography. MS (ESI): 327,3 (MN+).

Example 31: the Hydrochloride of 1-(3,4-acid)-3-(3,4-dimetilfenil) piperidine-4-ylamine

This compound was synthesized analogously to example 30 1-(3,4-acid)piperidine-4-it 4-bromo-o-xylene in the form of a white solid consisting of a mixture of CIS - and TRANS-diastereoisomers. Separation of the diastereomers (in the form of free bases) cannot hold with accelerated chromatography. MS (ESI): 341,3 (MN+).

Example 32: Hydrochloride of 1-(3,4-acid)-3-(3-methoxyphenyl)piperidine-4-ylamine

This compound was synthesized analogously to example 30 1-(3,4-acid)piperidine-4-it 4-bromoanisole in the form of a white solid consisting of a mixture of CIS - and TRANS-diastereoisomers. Separation of the diastereomers (in the form of free bases) cannot hold with accelerated chromatography. MS (ESI): 343,3 (MN+).

<> Example 33: 1'-(3,4-acid)-1',2',3',4',5',6'-hexahydro[2,3']bipyridinyl-4'-ylamine

This compound was synthesized analogously to example 30 1-(3,4-acid)piperidine-4-it 2-bromopyridine in the form of a white solid consisting of a mixture of CIS - and TRANS-diastereoisomers. Separation of the diastereomers could not be conducted using the accelerated chromatography. MS (ESI): 314,3 (MN+).

Example 34: ((3R,4S)-4-Amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol

Stage A: 1-tert-Butyl ether/3-methyl ether (3R,4S)-4-benzyloxycarbonylamino-1,3-dicarboxylic acid

1-tert-Butyl ether/3-methyl ether (3R,4S)-4-aminopiperidin-1, 3-dicarboxylic acid (540 mg, synthesized according to Duan, Jingwu et al., PCT Int. Appl. (2001), WO 2001070673 A2 and WO 2002002525) dissolved in abs. DHM and add NEt3(0,39 ml), and then benzylchloride (0.33 ml) and the mixture is left under stirring at room temperature over night. Then the reaction mixture is transferred into a mixture of ice/brine, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated, and the residue is purified using accelerated chromatography (gradient of ethyl acetate in heptane)to give a colorless resin (598 mg). MS (ESI): 393,2 (MN+).

Stage B: 1 tert-Butyl ether (3R,4S)-4-methoxycarbonylaminophenyl-1,3-dicarboxylic acid

1-tert-Butyl is a new ether/3-methyl ether (3R,4S)-4-benzyloxycarbonylamino-1,3-dicarboxylic acid (580 mg) was dissolved in THF (20 ml) and add 1-molar aqueous solution of LiOH (3.0 ml). The mixture is left under stirring at room temperature for 20 hours Then the reaction mixture is transferred into a mixture of ice/brine containing 2-molar solution of HCl (2.5 ml). The aqueous layer was extracted with ethyl acetate, the organic layer was separated, washed with brine, dried (Na2SO4) and evaporated. The residue is dried in high vacuum, obtaining a colorless foam (558 mg). MS (ESI): 377,3 (MN+).

Stage b: tert-Butyl ether (3R,4S)-4-benzyloxycarbonylamino-3-(thiazolidin-3-carbonyl)piperidine-1-carboxylic acid

1-tert-Butyl ether (3R,4S)-4-methoxycarbonylaminophenyl-1,3-dicarboxylic acid (557 mg) was dissolved in abs. DHM (20 ml). To this solution are successively added (benzotriazol-1 yloxy)-triprolidine-hexaphosphate (919 mg), triethylamine (0,47 ml) and after 5 min thiazolidin (151 mg). The mixture is left under stirring at room temperature for 5 hours Then the reaction mixture is transferred into a mixture of ice/brine, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue is purified using accelerated chromatography (gradient of ethyl acetate in heptane)to give the product as a white foam (403 mg). MS (ESI): 450,3 (MN+).

Stage D: Benzyl ether of (3R,4S)-[3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid

1-tert-BU is silt ether (3R,4S)-4-benzyloxycarbonylamino-3-(thiazolidin-3-carbonyl)piperidine-1-carboxylic acid (325 mg) was dissolved in abs. DHM (12 ml) and added dropwise TFA (of 0.44 ml). The mixture is left under stirring at room temperature overnight, and then vacuum. The residue is transferred into a mixture of ice/water, alkalinized to pH 10 with 2-normal NaOH solution and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue is purified using accelerated chromatography, receiving the specified product as a white foam (260 mg). MS (ESI): 350,1 (MN+).

Stage D: Benzyl ether (3R-4S)[1-phenethyl-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid

Benzyl ether of (3R,4S)-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid (255 mg) was dissolved in DMF (5 ml) and add DIPEA (0,28 ml). After 20 min added dropwise within 15 min a solution of 2-(bromacil)benzene (169 mg) in DMF (4 ml). The mixture is stirred at RT over night. The reaction mixture is transferred into a mixture of ice/water/saturated solution of Na2CO3and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4and evaporated. The residue is purified using accelerated chromatography, receiving the specified product in the form of a slightly yellow oil (308 mg). MS (ESI): 454,2 (MN+).

Stage E: (3R,4S)-(4-Amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol

Benzyl ether of (3R,4S)-[1-phenethyl-3-(thiazolidin-3-Carbo who yl)piperidine-4-yl]carbamino acid (216 mg) is treated with a solution of 33%HBr in acetic acid (2.5 ml) for 2 h at RT in an argon atmosphere. Then add ether (15 ml), the resulting suspension is cooled to -10°C and stirred for 1 h, the Solvent is then removed by decantation and the solid is washed with a small amount of EtOH. The residue is dissolved in water (pH adjusted to 10 using conc. NH4OH), the aqueous layer was saturated with NaCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated. The residue is purified using accelerated chromatography (gradient Meon in DHM containing 0.5% NH4OH), receiving the specified product in the form of a slightly yellow oil (92 mg). MS (ESI): 320,1 MN+.

Example 35: ((3S,4R-4-Amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol

This compound is obtained as described in example 34, the opposite enantiomer of 1-tert-butyl ether/3-methyl ester (3S,4R)-4-aminopiperidin-1,3-dicarboxylic acid, thiazolidine and 2-(bromacil)benzene as a yellow oil. MS (ESI): 320,4 (MN+).

Example 36: [((3S,4R-4-Amino-1-(2-pyridin-2-retil)piperidine-3-yl thiazolidin-3-ylmethanol

This compound is obtained as described in example 34, the opposite enantiomer of 1-tert-butyl ether/3-methyl ester (3S,4R)-4-aminopiperidin-1,3-dicarboxylic acid, thiazolidine and 2-(bromacil)pyridine (obtained by the method: Synthesis, 5, 1987, 452-455) as a yellow oil. MS (ESI): 321,4 (MN+).

Por the measures 37: 1-[(3S,4R)-4-Amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-phenylethanone]

This compound is obtained as described in example 34, but with a modification stages D and E:

Stage D: Methyl ester [1-phenylacetyl-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid

Benzyl ester 3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid (250 mg) was dissolved in abs. DHM (8 ml) and add DIPEA (0,184 ml). The mixture is left under stirring at -15°C. (ice bath/salt) for 20 min and then added dropwise to phenylacetylene (0.104 g ml). The mixture is heated to 0°C and stirred for 30 minutes, the Reaction mixture was transferred into a mixture of ice/water/saturated solution of NaHCO3and the aqueous layer was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4and evaporated in vacuum. The residue is purified using accelerated chromatography, receiving the specified product methyl ether [1-phenylacetyl-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid (304 mg) as a white foam. MS (ESI): 468,1 (MN+).

Stage E: 1-[(3S,4R)-4-Amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-phenylethanone

The reaction is carried out analogously to example 34 (stage E) of the methyl ester [1-phenylacetyl-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid (295 mg) and HBr in the SPLA (3 ml), but with a modified stage of purification: product purified using preparative HPLC (RPC18, the gradient of CH3CN in water containing 0.05% formic acid). Evaporation of the appropriate fractions gives the specified product in the form of a salt of formic acid (white solid, 12 mg). MS (ESI): 334,4 (MN, free base).

Example 38: 1-[(3S 4R-4-Amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-thiophene-2-ylatason

This compound was obtained according to example 37 with the appropriate reagents in the form of a colorless resin: MS (ESI): 340,4 (MN+) free base).

Example 39: 3[(3S,4R) and (3R,4S)-4-Amino-1-(3,4-acid)piperidine-3-yl]thiazolidin-3-ylmethanol

Stage A: Methyl ester of 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid

Methyl ether rat-1-benzyl-4-oxopiperidine-3-carboxylic acid (25 g) is suspended in 100 ml of 25%ammonium hydroxide and heated at 50°C for 18 hours the Mixture is cooled with ice and then add parts NaBH4(1 g). Stirred for 18 h at room temperature, diluted with water with ice cooling and extracted with AcOEt. The organic extract was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gives a brown oil which is purified by column chromatography (silica gel, heptane/AcOEt in the ratio 1:1) and precipitated (AcOEt/heptane)to give 12.1 g (56%) named in the title compounds as white solids, and 6 g (25%) named in the title compound in the form of Borovo orodno salt.

Methyl ester of 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid: MS: OF 247.2 (M+N)+

NMR: (DMSO, 1H, 400 MHz, δ, TMS): 2,28 (t, 2H), 2,46 (t, 2H). to 2.99 (s, 2H), 3,49 (s, 3H), 3,53 (s, 2H), 7,22-7,34 (m, 5H), 6.90 to and 7,80 (2 s large, 2H).

Methyl ester of 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid; NR3salt: MS: OF 247.2 (M+N)+

NMR: (DMSO, 1H, 400 MHz, δ, TMS) 2,45-2,60 (m, 2H), 2,80-2,90 (m, 1H), 2,92-to 3.02 (m. 1H), 3,30-3,45 (2d, 2H), 3,53 (s, 3H), of 3.80-4.00 points (2d, 2H), 7,31-7,40 (m, 5H), 6.90 to and 7,80 (2 s large, 2H).

Stage B: Ethyl ether rat-4-amino-1-benzylpiperidine-3-carboxylic acid

NR3salt of methyl ester of 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid is heated in ethanol with 25% NaOH. After 72 h of heating at 50°C. the mixture is cooled, washed with water with ice and extracted with AcOEt. The extract was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure giving a yellow oil. To a suspension of methyl ester of 4-amino-1-benzyl-1, 2, 5, 6-tetrahydropyridine-3-carboxylic acid (21 g) in 200 ml of THF are added 50 ml of TFA at 10°C in argon atmosphere. After stirring for 15 min at 0°C is added NaBH4(to 6.43 g) for 75 min at 10°C. the Mixture is stirred additionally for 90 min at 0°C. After saturation of 100 ml of NH4Cl solution was twice extracted with CH2Cl2. The combined extracts washed with water with ice and RA is Saul and dried over sodium sulfate. Removal of solvent gives named the title compound as a yellow oil, which is used in the next stage without purification.

Stage b: Ethyl ester of (3S,4R) and (3R,4S)-1-benzyl-4-tert-butoxycarbonylamino-3-carboxylic acid and ethyl ester of (3S,4S) and (3R,4R-1-benzyl-4-tert-butoxycarbonylamino-3-carboxylic acid

Ethyl ester rat-4-amino-1-benzylpiperidine-3-carboxylic acid (80.7 mmol, 21 grams) and VOS2On (20.5 g) in 200 ml of CH2Cl2stirred for 17 h at room temperature. The solution is evaporated and chromatographic (silica gel, AcOEt/heptane 1:1, receiving 7,05 g of racemic TRANS-isomer, 1.88 g of racemic CIS-isomer and 13,87 g racemic mixture of diastereomers.

Ethyl ester of (3S,4R) and (3R,4S)-1-benzyl-4-tert-butoxycarbonylamino-3-carboxylic acid: MS: 363,3 (M+N)+.

NMR: (DMSO, 1H, 400 MHz, δ, TMS) of 1.11 (t, 3H), of 1.36 (s, 9H), 1,65-1,71 (m, 2H), 2,30-is 2.37 (m, 2H), 2.49 USD is 2.55 (m, 1H), 2,63 is 2.80 (m, 2H), 3,38 (d, 1H), 3,51 (d, 1H), 3,80-to 3.92 (m, 1H), was 4.02 (q, 2H), 6,60 (s large, 1H), 7,21-to 7.32 (m, 5H).

Ethyl ester of (3S,4S) and (3R,4R)-1-benzyl-4-tert-butoxycarbonylamino-3-carboxylic acid: MS: 363,3 (M+N)+.

NMR: (DMSO, 1H, 400 MHz, δ, TMS) of 1.13 (t, 3H), of 1.35 (s, 9H), of 1.40-1.50 (m, 1H), 1,62-1,71 (m, 1H), 1,97-2,11 (m, 2H), 2,43-of 2.50 (m, 2H), 2,74-and 2.83 (m, 2H), 3.45 points (s, 2H), 3.95 to Android 4.04 (m, 2H), 6,85 (d, 1H), 7,22-7,33 (m, 5H).

Stage G: Ethyl ester of (3R,4R) and (3S,4S)-4-tert-butoxycarbonylamino-1-[2-(3,4-dimatix is phenyl)ethyl]piperidine-3-carboxylic acid

A suspension of ethyl ester of (3S,4S) and (3R,4R)-1-benzyl-4-tert-butoxycarbonylamino-3-carboxylic acid (700 mg) and 200 mg of Pd/C (10%) in 10 ml of EtOH and 1 ml of base Hunga hydronaut at 22°C/1 bar during the night. The suspension is filtered, the filtrate is evaporated and the residue purified by column chromatography (silica gel, AcOEt)to give a pale yellow solid (538 mg). To a solution of above product (272 mg) and 3, 4-dimethoxybenzaldehyde (CAS 5703-21-9, 191 mg) in ethanol at 0°C. add 8-molar solution of pyridine-borane complex (0.5 ml). After 2 h stirring at 0°C and 3 h of stirring at room temperature the mixture is diluted with water with ice and extracted twice with ethyl acetate. The combined organic layers washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gives an oil which is purified by column chromatography (silica gel, AcOEt)to give 196 mg (45%) named the title compound as a yellow oil.

MS: 437,4 (M+H)+

NMR: (DMSO, 1H, 400 MHz, δ, TMS) 1,14-of 1.23 (m, 3H), of 1.36 (s, 9H), 1,40-of 1.52 (m, 1H), 1,65-1,71 (m, 1H), 2,02 (ddd, 1H), 2,12 (ddd, 1H), 2,42-of 2.50 (m, 2H), 2,58-2,69 (m, 2H), 2,85 (d, 1H), 2,98 (d, 1H), 3.45 points is 3.57 (m, 1H), 3,62-and 3.72 (m, 1H), 3,70 (s, 3H), and 3.72 (s, 3H), was 4.02 (q, 2H), 6,70 (dd, 1H), for 6.81-6,86 (m, 3H).

Stage D: Ethyl ester of (3R,4R) and (3S,4S)-4-amino-1-[2-(3,4-acid)ethyl]piperidine-3-carboxylic acid

A solution of (3R,4R) and (3S,4S)-4-tert-BU is oxycarbonyl-1-[2-(3,4-acid)ethyl]piperidine-3-carboxylic acid (24 mg) in 1 ml of TFA is stirred for 1 h at 0°Ssmes transferred into a 1-molar solution of NaOH/ice and extracted with AcOEt. The combined organic layers washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gives an oil which is purified by column chromatography (Isolute SPE Flash NH2, 10 g, AcOEt/heptane 1:2)to give 9 mg (50%) named in the connection header.

MS: 337,4 (M+H)+

Stage E: (3R,4R) and (3S,4S)-4-Amino-1-[2-(3,4-acid)ethyl]piperidine-3-carboxylic acid

Ethyl ester of (3R,4R) and (3S,4S)-4-amino-1-[2-(3,4-acid)ethyl]piperidine-3-carboxylic acid (262 mg) and lithium hydroxide (166 mg) in 5 ml THF, 5 ml Meon and 1 ml of N2About stirred for 24 h at room temperature. The mixture is diluted with buffer pH 7 and extracted with AcOEt. The combined organic layers washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gives an oil which is purified by column chromatography (Isolute SPE Flash NH2, AcOEt) and precipitated (AcOEt/heptane)to give 90 mg (37%) named the title compound as a white solid.

MS: 309,2 (M+N)+

NMR: (DMSO, 1H, 400 MHz, δ, TMS) 1,92-2,02 (m, 1H), 2,10-of 2.20 (m, 1H), 2,75-3,10 (2m, 6H). 3,35-of 3.48 (m, 2H), 3,55-3,62 (m, 1H), 3,70-of 3.80 (m, 1H), 3,71 (s, 3H), of 3.75 (s, 3H), 6,76 (dd, 1H), 6,85-of 6.90 (m, 2H), 8,3-8,7 (s, user., 3H).

Example 40: 3[(3S,4R) and (3R,4S)-4-Amino-1-(3,4-acid)piperidine-3-yl]thiazolidin-3-ylmethanol

Stage A: Ethyl ether rat-1-(3,4-acid)-4-about copperized-3-carboxylic acid

A mixture of 3,4-dimethoxyaniline (12 g), copper chloride (1) (1.7 g), acetic acid (9 ml) and ethylacrylate acid (26 ml) is heated for 17 h at 140°C, cooled with ice, diluted with CH2Cl2and successively washed with water, 10%ammonium hydroxide solution, water and brine. The organic layers dried over MgSO4, filtered and evaporated. Chromatography (silica gel, AcOEt/heptane 1:1) gives a yellow oil (22,8 g)which is dissolved in 50 ml of xylene and add ethoxide sodium (4.42 g). Then the suspension is stirred for 2 h at 140°C, cooled, diluted with AcOEt and washed with water and brine. The aqueous phase is twice extracted with AcOEt, the organic layers dried over MgSO4, filtered, evaporated and chromatographic (silica gel, AcOEt/heptane 1:3), getting named the title compound as a white solid (yield 13,53 g, 68%).

MS: 308,2 (M+H)+

Stage B: Ethyl ether rat-4-amino-1-(3,4-acid)piperidine-3-carboxylic acid

A suspension of ethyl ether rat-1-(3,4-acid)-4-oxopiperidin-3-carboxylic acid (640 mg) and ammonium acetate (3 g) in 10 ml of methanol is stirred for 18 h at RT, and then add Lamborghini sodium (2 g). After stirring for 18 h at RT the mixture is diluted with AcOEt, washed twice with water and brine. The organic layers dried over MgSO4/sub> , filtered, evaporated and chromatographic (silica gel, AcOEt/heptane 1:1), getting named the title compound (yield 450 mg, 70%).

Stage b: Ethyl ether rat-4-tert-butoxycarbonylamino-1-(3,4-acid)piperidine-3-carboxylic acid

A solution of ethyl ester rat-4-amino-1-(3,4-acid)piperidine-3-carboxylic acid (6,47 g) and SAI2On (5,02 g) in 50 ml of CH2Cl2stirred for 24 h at RT, then diluted with AcOEt, washed with water and brine. The organic layers dried over MgSO4, filtered, evaporated and chromatographic (silica gel, AcOEt/heptane 1:1), getting named the title compound as a mixture of CIS - and TRANS-diastereomers (output 4,50 g, 53%).

MS: 409,4 (M+H)+

Stage D: rat-4-tert-Butoxycarbonylamino-1-(3,4-acid)piperidine-3-carboxylic acid

To a solution of ethyl ester rat-4-tert-butoxycarbonylamino-1-(3,4-acid)piperidine-3-carboxylic acid (170 mg) in 2 ml of THF was added 1 ml of 1 molar NaOH solution and lithium hydroxide (100 mg). The suspension is stirred for 24 h at RT, diluted with water and twice extracted with tert-butylmethylamine ether. The aqueous layer was acidified to pH 4, saturated with NaCl and then the product three times extracted with AcOEt. The organic layers dried over MgSO4, filtered, evaporated and chromatographic (silica gel, AcOEt), p is the ray named the title compound (38 mg, 55%).

MC: 381,3 (M+H)+

Stage D: tert-Butyl ether [(3S,4R) and (3R,4S)-1-(3,4-acid)-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid tert-butyl ether [3S,4S) and (3R,4R)-1-(3,4-acid)-3-(thiazolidin-3-carbonyl)piperidine-4-yl]-carbamino acid

To a solution of rat-4-tert-butoxycarbonylamino-1-(3,4-acid)piperidine-3-carboxylic acid (200 mg) in acetonitrile (5 ml) under cooling with ice add base Hunya (0.5 ml), EDC (191 mg), NOT (135 mg) and thiazolidine (0.3 ml). The reaction mixture was stirred for 3 h at 0°C and incubated for 24 h at RT, diluted with AcOEt, washed with 5%solution of NaHCO3and brine, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on silica gel using AcOEt, getting tert-butyl ester [(3S,4R) and (3R,4S)-1-(3,4-acid)-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid (73 mg) and tert-butyl ester [(3S,4S) and (3R,4R)-1-(3,4-acid)-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid (81 mg).

MS: (M+N)+452,4.

Stage E: [(3S,4R) and (3R,4S)-4-Amino-1-(3,4-acid)piperidine-3-yl]thiazolidin-3-ylmethanol

tert-Butyl ester [(3S,4R) and (3R,4S)-1-(3,4-acid)-3-(thiazolidin-3-carbonyl)piperidine-4-yl]carbamino acid (50 mg) is treated with 2 ml TFA for 1 h at 0°C. the Reaction mixture is diluted with the AcOEt, washed with 1-molar NaOH solution and brine, the organic layers dried over MgSO4, filtered, evaporated and chromatographic (Isolute Flash SPE NH2, AcOEt)to give [(3S,4R) and (3R,4S)-4-amino-1-(3,4-acid)piperidine-3-yl]thiazolidin-3-ylmethanol (23 mg).

MS: 352,1 (M+H)+

NMR: (DMSO, 1H, 400 MHz, δ, TMS, 110°C) 1,70-of 1.78 (m, 1H), 1,80-1,90 (m, 1H), 2,98 totaling 3.04 (m, 3H), 3,12-3,20 (m, 3H), 3.27 to to 3.36 (m, 2H), 3,68 (s, 3H), 3,76 (s, 3H), 3,74-of 3.80 (m, 2H), 4,55 (d, 2H), 6.42 per (dd, 1H), 6,55 (d, 1H), 6,79 (d, 1H).

Example 41: 3[(3S,4S) and (3R,4R)-4-Amino-1-(3,4-acid)piperidine-3-yl]thiazolidin-3-ylmethanol

This compound was obtained from racemic TRANS-isomer, isolated in example 40 (stage D), using methods described in example 40 (stage E). The obtained 28 mg specified in the connection header.

MS: 352,1 (M+H)+

NMR: (DMSO, 1H, 400 MHz, δ, TMS, 110°C) 1,40-of 1.55 (m, 1H), 1,78 is 1.86 (m. 1H), 2,55-2,90 (m, 4H), 2,90-a 3.01 (m, 1H), 3,03 (t, 2H), 3,50-3,60 (m, 2H), 3,68 (s, 3H), 3,76 (s, 3H), 3,74-3,90 (2m, 2H), 4,59 with 4.65 (m, 2H), 6.42 per (dd, 1H), 6,56 (d, 1H), 6,79 (d, 1H).

Example 42: 3[(3S,4S) and (3R,4R)-4-Amino-1-(3,4-acid)piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-ylmethanol

This compound is obtained analogously to example 40 (stages D and E)using 2,5-dihydropyrrole.

MS: 332,2 (M+1)+

Example 43: 3[(3S,4R) and (3R,4S)-4-Amino-1-(3,4-acid)piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-ylmethanol

This compound is obtained analogously to example 40 (stages D and E) using 2, 5-di is droparray.

MS: 332,2 (M+N)+

Pharmaceutical examples

Example

The coated tablets containing the following ingredients can be obtained with the standard method:

IngredientsPills
Core:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Water lactose60,0 mg70.0 mg
Polydon C12.5 mg15,0 mg
Alkaline starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(Earth core)120,0 mg350,0 mg
Shell:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredients are screened, mixed with microcrystalline cellulose and granularit mixture in a solution of polyvinylpyrrolidone in water. The granulate is mixed with an alkaline starch glycolate and magnesium stearate and pressed, receiving the core tablets weighing 120 or 350 mg, respectively. The core varnished using an aqueous solution / suspension of the above-mentioned film shell.

Example B

Capsules containing the following ingredients can be obtained with the standard method:

IngredientsOn capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

Components sift, mix and make into capsules of size 2.

The example In

Injectable solutions may have the following composition:

Ingredients
The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidto pH 5.0
Water for injection solutionsto 1.0 ml

The active ingredient dissolved in a mixture of polyethylene glycol 400 and water for injection (part). Bring the pH to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled into vials, using the appropriate device, and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be obtained with the standard method:

ingrediente
The contents of the capsules
The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
Mass content capsules165,0 mg
Gelatin capsule
Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient is dissolved in warm melt the other ingredients and the mixture is filled soft gelatin capsules of appropriate size. Filled soft gelatin capsules fruit is s treated using conventional methods.

Example D

A wafer containing the following ingredients can be obtained with the standard method:

Ingredients
The compound of formula (I)50.0 mg
Lactose, finely ground powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
The sodium carboxymethyl cellulose14,0 mg
Polyvinylpyrrolidone K 3010.0 mg
Magnesium stearate10.0 mg
Flavorings1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, and then granularit with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavors and bring in Sasha.

1. The compounds of formula (I)

where R1choose from a group including:
phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, lower ALK is syruppy, halogen or lower halogenation;
naphthyl;
tetrahydronaphthyl;
With3-7cycloalkyl;
-(CHR3)m-phenyl, where m denotes 1, 2 or 3; and phenyl is unsubstituted or mono-, di - or tizamidine lower alkoxygroup, and where R3independently selected from hydrogen and lower alkyl;
-(CH2)n-heteroaryl, where n denotes 1, 2 or 3; and the term "heteroaryl" refers to an aromatic 5 - or 6-membered ring or a bicyclic 9-membered aromatic groups that may include 1, 2 or 3 atoms selected from a nitrogen and/or sulfur;
-(CH2)n-heteroaryl, where n denotes 1, 2 or 3, with the term "heteroaryl" refers to an aromatic 5 - or 6-membered ring or a bicyclic 9-membered aromatic groups that may include 1, 2 or 3 atoms selected from a nitrogen and/or sulfur, and heteroaryl is mono-, di - or tizamidine independently lower alkoxygroup; and
R2choose from a group including:
n-butyl;
phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen or lower alkoxygroup;
heteroaryl, the term "heteroaryl" refers to an aromatic 5-membered ring which may include 1, 2 or 3 atoms selected from a nitrogen and/or sulfur, unsubstituted or mono-, di - or tizamidine independently lower alkoxy what upoi;
-C(O)-NR4R5; where R4and R5represent lower alkyl or together with the nitrogen atom to which they are attached, form a 5-membered heterocycle which can optionally contain heteroatom selected from N or S, and their pharmaceutically acceptable salts.

2. The compounds of formula I according to claim 1, where R1choose from the group
including:
phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl or lower alkoxygroup;
naphthyl;
-(CHR3)m-phenyl, where m denotes 1 or 2 and phenyl is unsubstituted or mono-, di - or tizamidine independently lower alkoxygroup, and where R3denotes hydrogen;
-(CH2)n-heteroaryl, where n denotes 1 or 2;
-(CH2)n-heteroaryl, where n denotes 1 or 2, and heteroaryl is mono-, di - or tizamidine independently lower alkoxygroup.

3. The compounds of formula I according to claim 1, where R1choose from a group including:
phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup;
naphthyl; and
-(CHR3)m-phenyl, where m denotes 1 or 2 and phenyl is unsubstituted or mono-, di - or tizamidine lower alkoxygroup and where R3denotes hydrogen.

4. The compounds of formula I according to claim 1, where R1oznachaet
phenyl, mono-, di - or tizamidine independently lower alkyl, halogen, lower halogenation or lower alkoxygroup.

5. The compounds of formula I according to claim 1, where R1does
-(CH2)n-heteroaryl, where n denotes 1 or 2; or
-(CH2)n-heteroaryl, where n denotes 1 or 2, and heteroaryl is mono-, di - or tizamidine independently lower alkoxygroup.

6. The compounds of formula I according to claim 1, where R2choose from a group including:
n-butyl;
phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen or lower alkoxygroup;
heteroaryl, unsubstituted or mono-, di - or tizamidine independently lower alkoxygroup; and
-C(O)-NR4R5; where R4and R5together with the nitrogen atom to which they are attached, form a 5-membered heterocycle which can additionally contain a heteroatom selected from N or S.

7. The compounds of formula I according to claim 1, where R2represents n-butyl.

8. The compounds of formula I according to claim 1, where R2does
phenyl, unsubstituted or mono-, di - or tizamidine independently lower alkyl, halogen or lower alkoxygroup.

9. The compounds of formula I according to claim 1, where R2denotes thienyl, which is unsubstituted or mono-, di - or tizamidine independently lower alkoxygroup.

10. The connection forms of the crystals of I according to claim 1, where R2does
-C(O)-NR4R5; where R4and R5together with the nitrogen atom to which they are attached, form a 5-membered heterocycle which can additionally contain a heteroatom selected from N or S.

11. The compounds of formula I according to claim 1, selected from the group:
3-butyl-1-finetipped-4-ylamine,
3-butyl-1-benzylpiperidine-4-ylamine,
3-butyl-1-[2-(1H-indol-3-yl)ethyl]piperidine-4-ylamine,
3-butyl-1-[2-(3,4-acid-1-yl)ethyl]piperidine-4-ylamine,
hydrochloride 3-butyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,
hydrochloride 3-butyl-1-(4-phenoxyphenyl)piperidine-4-ylamine,
hydrochloride 3-butyl-1-(5,6,7,8-tetrahydronaphthalen-1-yl)piperidine-4-ylamine,
hydrochloride 3-butyl-1-(3,4-acid)piperidine-4-ylamine,
hydrochloride 3-butyl-1-naphthalene-2-reparacin-4-ylamine,
hydrochloride 3-butyl-1-naphthalene-1-reparacin-4-ylamine,
hydrochloride 3-butyl-1-(3,4-dichlorophenyl)piperidine-4-ylamine,
hydrochloride 3-butyl-1-(4-chloro-Z-triptoreline)piperidine-4-ylamine,
hydrochloride 3-butyl-1-p-tripeptides-4-ylamine,
hydrochloride 3-butyl-1-(3,5-dichlorophenyl)piperidine-4-ylamine,
hydrochloride 3-butyl-1-phenylpiperidine-4-ylamine,
hydrochloride 3-butyl-1-(3-methoxy-5-triptoreline)piperidine-4-ylamine,
hydrochloride 3-butyl-1-cyclohexylpiperidine-4-ylamine,
hydrochloride of 1-(3,5-bis-triptoreline)-3-butylpiperazine-4-silts is a,
hydrochloride 3-butyl-1-(6-methoxybiphenyl-3-yl)piperidine-4-ylamine,
hydrochloride of 1-benzhydryl-3-butylpiperazine-4-ylamine,
3-phenyl-1-finetipped-4-ylamine,
3-phenyl-1-benzylpiperidine-4-ylamine,
4-methyl-1'-phenethyl-1',2',3',4',5',6'-hexahydro[2,3']bipyridinyl-4'-ylamine,
3-(3-chlorophenyl)-1-finetipped-4-ylamine,
3-(3-were)-1-benzylpiperidine-4-ylamine,
3-(3-chlorophenyl)-1-[2-(3,4-acid)ethyl]piperidine-4-ylamine,
1-benzyl-3-thiophene-2-reparacin-4-ylamine,
hydrochloride 3-o-tolyl-1-(3,4,5-trimethoxyphenyl)piperidine-4-ylamine,
hydrochloride of 1-(3,4-acid)-3-m-tripeptides-4-ylamine,
hydrochloride of 1-(3,4-acid)-3-p-tripeptides-4-ylamine,
hydrochloride of 1-(3,4-acid)-3-(3,4-dimetilfenil)piperidine-4-ylamine,
hydrochloride of 1-(3,4-acid)-3-(3-methoxyphenyl)piperidine-4-ylamine,
1'-(3,4-acid)-1',2',3',4',5',6'-hexahydro[2,3']bipyridinyl-4'-ylamine,
((3R,4S)-4-amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol,
((3S,4R)-4-amino-1-finetipped-3-yl)thiazolidin-3-ylmethanol,
[(3S,4R)-4-amino-1-(2-pyridin-2-retil)piperidine-3-yl]thiazolidin-3-ylmethanol,
1-[(3S,4R)-4-amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-phenylethanone,
1-[(3S,4R)-4-amino-3-(thiazolidin-3-carbonyl)piperidine-1-yl]-2-thiophene-2-ylatason,
3-[(3S,4R) and (3R,4S)-4-amino-1-(3,4-acid)piperidine-3-yl]thiazolidin-3-ylmethanol,
3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-dimethoxyphenyl the l)piperidine-3-yl]thiazolidin-3-ylmethanol,
3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-acid)piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-ylmethanol,
3-[(3S,4R) and (3R,4S)-4-amino-1-(3,4-acid)piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-ylmethanol, and
their pharmaceutically acceptable salts.

12. Compounds according to claim 1, intended for use as therapeutically active substances capable of inhibiting DPP-IV.

13. The pharmaceutical composition capable of inhibiting DPP-IV comprising the compound according to one of claims 1 to 11 and a pharmaceutically acceptable carrier and/or adjuvant.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzyloxy-derivatives of general formula (I) , where R1 is a halogen; R2 is a 5-member heteroaryl group containing 2 or 3 heteroatoms selected from a group consisting of N, O or S, which can be substituted with R3, where R3 is a lower alkyl or -C(O)R; R is -NR'R" or lower alkoxy; R'/R" independently represent H; as well as to their pharmaceutically acceptable salts. Formula I compounds inhibit monoamine oxidase B.

EFFECT: compounds can be used for preparing a medicinal agent.

5 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I , where X is N or CH; R1 is -C(O)-NR8R9 or -C(O)-OR10, and R2 is hydrogen; or alternatively R2 is and R1 is hydrogen or halogen; Y is N or CH; R3, R4, R5 and R6 are independently selected from a group consisting of hydrogen, halogen, (lower)alkoxy, (lower)fluoroalkyl, (lower)fluoroalkoxy and (lower)fluoroalkylsulfanyl; or R3 and R4 together with carbon atoms with which they are bonded form a 6-member unsaturated ring which can contain one nitrogen heteroatom; R7 is hydrogen or (lower)alkyl; R8 is hydrogen or NH2; R9 is selected from a group consisting of (lower)alkyl, (lower)alkenyl, (lower)alkoxyalkyl, -(CH2)m-(C3-C7)cycloalkyl, -(CH2)m-piperidinyl, -(CH2)m-phenyl, where the phenyl ring is unsubstituted or substituted with one or two groups selected from halogen, (lower)alkoxy, (lower)fluoroalkyl and (lower)fluoroalkoxy, -(CH2)m-naphthyl and pyridylamino; R10 is (lower)alkenyl; R11 is selected from a group consisting of -C(O)-R12, -SO2-R13 and -SO2-NR14R15; R12 is selected from a group consisting of (lower)alkyl, (lower)alkoxyalkyl, -(CH2)n-(C3-C7)-cycloalkyl, -(CH2)n-phenyl and -(CH2)n-pyridyl, where phenyl or pyridyl are unsubstituted or substituted with one (lower)alkyl; R13 is selected from (lower)alkyl or -(CH2)n-phenyl, where phenyl is unsubstituted or substituted with one (lower)alkyl; R14 is (lower)alkyl; R15 is (lower)alkyl; m equals 0, 1 or 2; n equals 0 or 1; and all their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: novel indole and benzimidazole derivatives which have modulating effect on the CB1 receptor are obtained.

26 cl, 3 tbl, 148 ex

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