Beta karbolinovye compounds, pharmaceutical compositions and methods of binding achieve agonistic/antagonistic effect

 

-Karbolinovye compounds of General formula (I) or (II)

their racemic and diastereomeric mixtures and optical isomers, pharmaceutically acceptable salts, where---- represents an optional bond; X is N or N-R4where X is N, when there are both optional connection, and X is NR4when these relationships are absent; R1represents H; R2is (C1-C12)alkyl, (C0-C6)alkyl-C(O)-NH-(CH2)mZ3or optionally substituted C1-C6)alkyl, (C1-C6)alkoxy or nitro-group is phenyl; Z3is (C6H6)2SN- (diphenylmethylene), N,N-di(C1-C12)alkylamino, imidazolyl, pyridinyl, morpholinyl, pyrrolidinyl, piperidinyl, substituted benzyl group, pyrazolidine, substituted (C1-C6)alkyl, piperazinil, substituted (C1-C6)alkyl; R3represents H; R4represents H or-C(=Y) N(X1X2) , where Y is O; X2represents -(CH2)m-Y1-X3where X3represents unsubstituted phenyl; Rn, (C3-C12)cycloalkyl, -(CH2)m-S-(C1-C12)alkyl, (C1-C12)alkyl-S-S-(C1-C12)alkyl, -(CH2)m-(C2-C12)alkenyl, phenyl, unsubstituted or substituted (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, halogen, nitro, phenyl, (C1-C6)alkylthio, amino, cyano, CF3, -O-CF3di(C1-C6)alkylamino(C1-C6)alkoxy, (C1-C6)alkylcarboxylic or;, unsubstituted or substituted by a nitro-group; Y1means-On or connection; R6and R7are N; X1is hydrogen; m is an integer from 0 to 2 and n represents an integer from 0 to 5, R8-(C1-C12)alkyl, or R5and R8taken together with the C to which they are attached, form a Spiro(C4-C12)cycloalkyl or fragmentAnd bond, -CO-, -C(O)O-, -C(O)NH - or-C(S)NH, In - bond or -(CH2)qwhere q is an integer of 1-6, J1- N-R6or S; J2- NR1, O or S; J3- H1(C1-C6)alkyl, phenyl, possibly substituted (C1-C6)alkyl or CF3pharmaceutical knogo or more receptors somatostatinomas subtype. 6 BC and 6 C.p. f-crystals, 4 PL.

Background of invention

The present invention relates to compounds of formula (I) and (II) and compositions containing these compounds that selectively bind with subtypes somatostatinoma receptors, and to the use of these compounds for the treatment of pathological disorders mediated by subtypes somatostatinoma receptors. It is shown that somatostatin (factor inhibiting the release of growth hormone, SRIF), tetradecapeptide hormone originally isolated from bovine hypothalamus (Brazeau P. et al., Science 179, 77-79, 1973), provides a wide range of regulatory action on the release of various hormones such as growth hormone, prolactin, glucagon, insulin, gastrin (Bloom S. R. & Poldack J. M., Brit. Med. J. 295, 288-289, 1987). In addition, it was found that somatostatin analogues exhibit antiproliferative properties (Reichlin S. N., Engl. J. Med. 309, 1495-1501, 1983) in the case of metastasis of prostate cancer (H. Parmar et al., Clin. Exp. Metastasis, 10, 3-11, 1992) and some other neuroendocrine tumors in men (Anthony L. et al., Acta Oncol. 32, 217-223, 1993). Metabolism of somatostatin under the action of aminopeptidase and carboxypeptidase leads to a reduction in the duration of its validity.

their function was the basis for research to identify the relationship "structure-activity" peptide analogues for somatostatinoma receptors which led to the discovery of the five subtypes of receptors (Yamada et al., Proc. Natl. Acad. Sci., USA, 89, 251-255, 1992; Raynor, K. et al., Mol. Pharmacol. 44, 385-392, 1993). Conducted extensive research on the functional role of these receptors. Linking different types of subtypes of somatostatin associated with the treatment of the following conditions and/or diseases. Activation types 2 and 5 is associated with suppression of growth hormone (GH), and more specifically with G-secreting adenomas (acromegaly) and TSH-secreting adenomas. Activation of type 2 but not type 5, is associated with the treatment of prolactin-secreting adenomas. Other indicators associated with activation somatostatinoma subtypes, is the inhibition of insulin and/or glucagon, and more specifically, diabetes mellitus, hyperlipidemia, resistance to insulin, syndrome X, angiopathy, proliferative retinopathy, the phenomenon of "dawn" and nephropathy; inhibition of gastric juice, and more specifically, peptic ulcers, skin, intestinal, skin and pancreatic fistula, irritable bowel syndrome, dumping syndrome, watery diarrhoeal syndrome, diarrhea associated with AIDS, diarrhea associated with chemotherapy, acute or chronic pancreatitis, tumors, screenplaying diseases, such as arthritis, chronic allograft rejection, disorders related to angioplasty, the prevention of bleeding in the transplantation of blood vessels and gastrointestinal bleeding. Agonists of somatostatin can also be used to reduce the body weight of the patient.

In the study of medicines key objective is to minimize side effects by developing highly efficient and selective drug molecules. In recently published work on the development of ones structures (R. Hirschmann et al., J. Am. Chem. Soc. 115, 12550-12568, 1993; Papageorgiou C. & Borer X., Bioorg. Med. Chem. Lett. 6, 267-272, 1966) described compounds with low affinity to somatostatinoma receptor.

In addition, the compounds of formula I and II are blockers of sodium channels, and thus, they exhibit useful pharmacological properties, they are particularly suitable for the attenuation of neuropathic pain. Neuropathic pain may be described as pain associated with disorders or permanent changes in the peripheral or Central nervous system. Clinical manifestations of neuropathic pain include burning sensation or electric shock, feeling of General discomfort, allodynia, and GI is different pathological conditions. They are especially useful as local analiziruemykh funds and in the treatment of arrhythmia. For many years it was also reported that agents that block sodium channels, may be useful in the treatment of pain, including neuropathic pain, see, for example, Tanelian et al., Pain Forum., 4(2), 75-80 (1995). There is evidence that agents that block sodium channels selectively inhibit the occurrence of ectopic nerve impulses in the diseased nerve tissue, and believe that through this mechanism, they are useful for relief of pain. However, studies regarding the well-known nutrilicious agents such as carbamazepine, phenytoin, lidocaine, meksiletina and so on, indicate that these agents, at moderate doses, is not very effective for the treatment of neuropathic pain States, and that even at these moderate doses, they are associated with a number of undesirable side effects such as dizziness, nausea, drowsiness, tremor, slurred speech, etc., Preclinical data suggest that agents that block sodium channels, selectively suppress the occurrence of abnormal ectopic nerve impulses in the affected peripheral and Central natronomonas been shown that sodium channels are accumulated in peripheral nervous tissue in areas of damaged axons (Devor et al., J. Neurosci, 1993, 132, 1976-1992). Therefore, changes in the levels or expression, or distribution of sodium channels in the affected nervous tissue have a great influence on the pathophysiology of pain associated with injuries of this type. This concept is confirmed by the relative success of agents modulating sodium channels (e.g., anticonvulsant agents, local anastatica), for the treatment of neuropathic pain. However, the pain often occurs in parallel with numerous negative effects and/or efficiency constraints that limit the portability of these medicines. It is clear that there is still a need for orally active agent that is effective for treating neuropathic pain, but has fewer side effects.

Brief description of the invention

In one of its aspects the present invention relates to the compound of formula (I)

racemic diastereomeric mixtures and optical isomers of the compounds of formula (I), their pharmaceutically acceptable salts or policestate;

X represents N or N-R4where X is N, when there are both optional connection, and X is N-R4when these optional links were missing;

R1represents H, -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1, -(CH2)m-O-Z1or (C0-C6)alkyl-C(O)-NH-(CH2)m-Z3;

Z1is optionally substituted fragment selected from the group consisting of (C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazole, indolyl,

;

R2is (C1-C12)alkyl, (C0-C6)alkyl-C(O)-O-Z5; And (C0-C6)alkyl-C(O)-NH-(CH2)m-Z3or optionally substituted phenyl;

Z5is H, (C1-C12)alkyl or (CH2)m-aryl;

Z3represents an amino group, (C1-C12)alkylamino, N,N-di-(C1-C12)-alkylamino, -NH-C(O)-O-(CH2)m-phenyl, -NH-C(O)-O-(CH2)m-(C1-C6)alkyl or optionally substituted group selected from imidazolyl, pyridinyl and morpholinyl, piperidinyl, piperazinil, pyrazolidine, sup>2;

Y represents O or S;

X2represents -(CH2)m-Yl-X3;

X3represents H or an optionally substituted group selected from (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkoxy, aryloxy, (C1-C12)alkylamino, N,N-di(C1-C12)alkylamino, -CH di(C1-C12)alkoxy or phenyl;

R5is (C1-C12)alkyl, -(CH2)m-Yl-(CH2)m-phenyl-(Xl)n, (C3-C12)cycloalkyl, -(CH2)m-S-(C1-C12)alkyl, (C1-C12)-alkyl-S-S-(C1-C12)alkyl, -(CH2)m-(C1-C12)alkenyl or an optionally substituted group selected from phenyl, furanyl, thiophene, pyrrolyl, pyridinyl and

;

Y1means O, S, NH or a bond;

R6represents H or SO2is phenyl;

R7represents H, alkyl, optionally substituted by alkoxygroup or dialkylamino;

where the optionally substituted group (fragment) or optionally substituted phenyl optionally substituted by one or more substituents, each of which is independently selected from the group sotoyama)m-phenyl-(X1)n, -NH-CO-(C1-C6)alkyl, -S-phenyl-(X1)n, -O-(CH2)m-phenyl-(Xl)n, -(CH2)m-C(O)-O-(C1-C6)alkyl, -(CH2)m-C(O)-(C1-C6)alkyl, -O-(CH2)m-NH2, -O-(CH2)m-NH-(C1-C6)alkyl, -O-(CH2)mN-di-(C1-C6)alkyl and -(C0-C12)alkyl-(Xl)n;

X1in each case, independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2HE-CF3, -F3, -(C1-C12)alkyl, (C1-C12)alkoxy, -S-(C1-C6)alkyl, -(CH2)m-amino, -(CH2)m-NH-(C1-C6)alkyl, -(CH2)m-N-di(C1-C6)alkyl, -(CH2)m-phenyl and -(CH2)m-NH-(C3-C6)cycloalkyl;

m in each case independently represents 0 or an integer from 1 to 6 and

n in each case independently represents an integer from 1 to 5.

The preferred compound of formula (I) is a compound in which X is NH, R1represents H; R2represents-CH(CH3)2-CO-NH-(CH2)m-Z3where m in the definition of R2is 1, 2 or 3;

Z<-butyl, n-pentyl, -(CH2)-O-(CH2)phenyl, 2-nitro-3-OMe-phenyl, p-tert-VI-phenyl, m-OMe-phenyl, o-OMe-phenyl, p-nitrophenyl, -(CH2)2-S-Me, cyclohexyl, m-Br-phenyl, p-S-Me-phenyl, p-N,N-dimethylaminophenyl, m-or were

;

R6is N and

R7is N.

Another preferred compound of formula (I) is a compound in which X represents NH;

R1is N;

R2represents phenyl;

R5represents propyl, n-butyl, n-pentyl, n-heptyl, isobutyl, neopentyl, cyclopropyl, cyclohexyl, -(CH2)2-S-Me, phenyl, -(CH2)-O-(CH2)-phenyl, 2-nitro-3-OMe-phenyl, p-tert-VI-phenyl, o-OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, 3,4,5-tri-OMe-phenyl, p-butoxyphenyl, 3 ethoxy-4-methoxyphenyl, o-nitrophenyl, p-nitrophenyl, p-F3-phenyl, o-CF3-phenyl, 3-F-4-OMe-phenyl, o-F-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, 2,4-di-CL-phenyl, 3,4-di-CL-phenyl, p-(3-(N,N-dimethylamino)-propoxy)phenyl, -(CH2)2-S-Me, cyclohexyl, n-(Me-CO-NH)-phenyl, p-tert-VI-phenyl, p-OH-phenyl, p-(S-Me), phenyl, p-(-3-tert-VI)phenyl, p-N,N-dimethylaminophenyl, m-were, 3-HE-4-OMe-phenyl, p-phenylphenyl,

or;

R6before the group in which X is NH, R1represents H; R2is p-OMe-phenyl or p-nitrophenyl;

R5represents n-butyl, n-pentyl, n-hexyl, isobutyl, cyclohexyl, -(CH2)2-S-Me, phenyl, m-OMe-phenyl, 2-nitro-3-OMe-phenyl, p-nitrophenyl, p-tert-VI-phenyl, p-dimethylphenyl, m-Br-phenyl, 2-OMe-4-dimethylaminophenyl, n-(3-(N,N-dimethylamino)propoxy)phenyl, p-dimethylaminophenyl, 3-nitro-4-Cl-phenyl, -(CH2)-O-(CH2)-phenyl or;

R6is N and

R7is N.

In another aspect the present invention relates to the compound of formula (II)

racemic diastereomeric mixtures and optical isomers of the compounds of the formula (II), their pharmaceutically acceptable salts or prodrugs or pharmaceutically acceptable salts of the specified prodrugs,

where---- represents an optional bond;

J1means N-R6or S;

J2means N-R1, O or S;

X represents N or N-R4where X is N, if there are both optional connection, and X is N-R4if the optional communication are absent;

R1represents H, -(CH2)m-C(O)-(CH22)m-Z3;

Z1is optionally substituted group selected from (C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazole, indolyl,

;

R2is (C1-C12)alkyl, (C0-C6)alkyl-C(O)-O-Z5; And (C0-C6)alkyl-C(O)-NH-(CH2)m-Z3or optionally substituted phenyl;

Z5is H, (C1-C12)alkyl or (CH2)m-aryl;

Z3represents amino, (C1-C12)alkylamino, N,N-di(C1-C12)-alkylamino, -NH-C(O)-O-(CH2)m-phenyl, -NH-C(O)-O-(CH2)m-(C1-C6)alkyl or optionally substituted group selected from phenyl, imidazolyl, pyridinyl and morpholinyl, piperidinyl, piperazinil, pyrazolidine, furanyl and thiophene;

R3is H, (C1-C1)alkyl or optionally substituted phenyl;

R4represents H, -C(=Y) N(X1X2), C(=O)X2or X2;

Y represents O or S;

X2represents H or -(CH2)m-Yl-X3;

X3represents H or an optionally substituted group selected from (C1- is ylamino, N,N-di(C1-C12)alkylamino, -CH di(C1-C12)alkoxy or phenyl;

each R5and R8independently selected from the group consisting of H, (C1-C12)alkyl, -(CH2)m-Y1-(CH2)m-phenyl-(X1)n, (C3-C12)cycloalkyl, (C3-C12)cycloalkenyl, -(CH2)m-S-(C1-C12)alkyl, (C1-C12)alkyl-S-S-(C1-C12)alkyl, -(CH2)m-(C1-C12)alkenyl and optionally substituted group selected from phenyl, furanyl, thiophene, pyrrolyl, pyridinyl and(C1-C4)alkyl-provided that R5and R8both are not H;

or R5and R8taken together with the carbon atom to which they are bound, form a

, Spiro(C4-C12)cycloalkyl,or;

Y1represents O, S, NH or a bond;

A represents a bond, -CO-, -C(O)O-, -C(O)NH-, -C(S)NH - or-SO2-;

B is a bond or - (CH2)q- where q is an integer from 1 to 6;

J3is H, (C1-C6)alkyl, the optional is up> independently selected from the group consisting of (C1-C6)alkyl and optionally substituted phenyl, or R9and R10taken together with the nitrogen atom to which they are linked, form a ring having 5-8 members including the nitrogen to which R9and R10attached, where one member of the ring may be optionally an oxygen atom or NR11where R11is (C1-C6)alkyl, -C(O)-(C1-C6)alkyl, -C(O)-N(V1V2), -C(S)-N(V1V2or optionally substituted phenyl-(C0-C6)alkyl-, where V1and V2each independently represents H, (C1-C6)alkyl or optionally substituted phenyl -(C0-C6)alkyl;

R6represents H or SO2is phenyl;

R7represents H, Cl, F, Br, I, CF3, NO2HE SO2NH2CN, N3,-OCF3, (C1-C12)alkoxy, -(CH2)m-phenyl-(X1)n, -NH-CO-(C1-C6)alkyl, -S-(C1-C12)alkyl, -S-phenyl-(X1)n, -O-(CH2)m-phenyl-(X1)n, -(CH2)m-C(O)-O-(C1-C6)alkyl, -(CH2)m-C(O)-(C1-C6)alkyl, -O-(CH2)m-NH2, -O-(CH2)m-NH-(C1-C6)neobyazatelno substituted group or optionally substituted phenyl optionally substituted by one or more substituents, each of which is independently selected from the group consisting of Cl, F, Br, I, CF3, NO2HE SO2NH2CN, N3, -F3, -(C1-C12)alkoxy, -(CH2)m-phenyl-(X1)n, -NH-CO-(C1-C6)alkyl, -S-(C1-C12)alkyl, -S-phenyl-(Xl)n, -O-(CH2)m-phenyl-(X1)n, -(CH2)m-C(O)-O-(C1-C6)alkyl, -(CH2)m-C(O)-(C1-C6)alkyl, -O-(CH2)m-NH2, -O-(CH2)m-NH-(C1-C6)alkyl, -O-(CH2)mN-di-((C1-C6)alkyl) and -(C0-C12)alkyl-(X1)n;

X1in each case, independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2HE-CF3, -F3, (C1-C12)alkyl, (C1-C12)alkoxy, -S-(C1-C6)alkyl, -(CH2)m-amino, -(CH2)m-NH-(C1-C6)alkyl, -(CH2)m-N-di(C1-C6)alkyl, -(CH2)m-phenyl and -(CH2)m-NH-(C3-C6)cycloalkyl;

m in each case independently represents 0 or an integer from 1 to 6 and

n in each case independently represents an integer from 1 to 5.

A preferred group of compounds predstavljaet H or methyl;

R4represents H or methyl;

R5represents H, methyl, ethyl, butyl, pentyl or hexyl;

R8represents ethyl, butyl, pentyl, hexyl or cyclohexyl

or R5and R8taken together with the carbon atom to which they are bound, form spirocyclohexane, spirochetal, spiroadamantane,,or,

where a represents a bond or-C(O)O-; b is a bond, -(CH2)- or -(CH2)2-;

J3represents H or phenyl, and

R7represents H, Me, F, Cl, HE, -O-methyl or-O-CH2is phenyl.

A more preferred group of compounds of formula (IIA) are compounds in which

R3, R4and R7each represents hydrogen, R5and R8together representand imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8together representand imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8together representand imidazole together representand imidazolyl is R-configuration, or its hydrochloric salt;

R3is methyl, R4and R7each represents hydrogen, R5and R8each represents n-butyl and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8together representand imidazolyl is R-configuration or its hydrochloric salt;

R3and R4each represents hydrogen, R7is 6-O-CH2-phenyl, R5and R8each represents n-butyl and imidazolyl represents a racemic mixture of S - and R-configurations;

R3, R4and R7each represents hydrogen, R5and R8together representand imidazolyl is R-configuration, or its hydrochloric salt;

R3, R4and R7each represents hydrogen, R5and R8together representand imidazolyl is R-configuration;

R3and R7each represents hydrogen, R4is methyl, R5and R8each represents n-butyl and imidazolyl is R-configuration which is every n-pentyl and imidazolyl represents a racemic mixture of S - and R-configurations;

R3, R4and R7each represents hydrogen, R5and R8each represents n-hexyl and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5is hydrogen, R8represents hexyl in the S-configuration and imidazolyl is R-configuration, or fumaric salt;

R3, R4and R7each represents hydrogen, R5and R8each represents n-butyl and imidazolyl is R-configuration, or fumaric salt;

R3and R7each represents hydrogen, R5and R8together representand imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents n-butyl and imidazolyl is S-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents ethyl and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents n-pentyl and imidazolyl is R-configuration;

R3, R4and R7each represents bodoro the

R3and R4each represents hydrogen, R7is 6-methyl, R5and R8each represents n-butyl and imidazolyl represents a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 7-fluoro, R5and R8each represents n-butyl and imidazolyl represents a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 6-methoxy, R5and R8each represents n-butyl and imidazolyl represents a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 6-hydroxy, R5and R8each represents n-butyl and imidazolyl represents a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 6-fluoro, R5and R8each represents n-butyl and imidazolyl represents a racemic mixture of S - and R-configurations or hydrochloric (or cleaners containing hydrochloride) salt;

R3and R4each represents hydrogen, R7is 8-methyl, R5and R8each represents n-butyl and imidazolyl is racemizes the5and R8each represents n-pentyl and imidazolyl represents a racemic mixture of S - and R-configurations or

R3and R4each represents hydrogen, R7is 6-chloro, R5and R8each represents n-butyl and imidazolyl represents a racemic mixture of S - and R-configurations;

Even more preferred group of compounds of formula (IIA) are compounds selected from the group consisting of compounds in which

R3, R4and R7each represents hydrogen, R5represents hydrogen, and R8represents hexyl in the S-configuration and imidazolyl is R-configuration or fumaric salt;

R3, R4and R7each represents hydrogen, R5and R8each represents n-butyl and imidazolyl is R-configuration or fumaric salt;

R3, R4and R7each represents hydrogen, R5and R8together representand imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents n-butyl and imidazolyl is S-configuration;

R3, R4and R7each represents the R4and R7each represents hydrogen, R5and R8each represents n-pentyl and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5is methyl, R8is cyclohexyl and imidazolyl is R-configuration;

R3and R4each represents hydrogen, R7is 6-methyl, R5and R8each represents n-butyl and imidazolyl is a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 7-fluoro, R5and R8each represents n-butyl and imidazolyl is a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 6-methoxy, R5and R8each represents n-butyl and imidazolyl is a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 6-hydroxy, R5and R8each represents n-butyl and imidazolyl is a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 6-fluoro, R5or its hydrochloric salt;

R3and R4each represents hydrogen, R7is 8-methyl, R5and R8each represents n-butyl and imidazolyl is a racemic mixture of S - and R-configurations;

R3and R4each represents hydrogen, R7is 6-methyl, R5and R8each represents n-pentyl and imidazolyl is a racemic mixture of S - and R-configurations and

R3and R4each represents hydrogen, R7is 6-chloro, R5and R8each represent n-butyl and imidazolyl is a racemic mixture of S - and R-configurations.

According to another aspect of the present invention relates to pharmaceutical compositions containing one or more compounds of the formula (I) or formula (II) or its pharmaceutically acceptable salt, as defined above, and pharmaceutically acceptable carrier.

In another aspect the present invention relates to a method for achieving the agonistic effect of one or more subtypes somatostatinoma receptors from the individual in need thereof, which provides for the introduction of a specified individual, the compounds of formula (I) or (II) or its pharmaceutically acceptable salt, about what tinosa; Crohn's disease; systemic sclerosis; external and internal pseudocysts and ascites pancreatic cancer; apudomy (VIP-ohms); nesidioblastosis; hyperinsulinism; gastronomy; syndrome Zollinger-Ellison; diarrhea; diarrhea associated with AIDS; diarrhea associated with chemotherapy; scleroderma; irritable bowel syndrome; pancreatitis, obstruction of the small intestine; gastroesophageal reflux; gastro-duodenal reflux; Cushing's syndrome; gonadotropinum; hyperparathyroidism; graves disease; diabetic neuropathy; Paget's disease; polycystic ovaries; cancer; cancer cachexia; hypotension; hypotension, emerging after a meal; panic attacks; GR-secreting adenomas and TSH-secreting pituitary adenomas in an individual in need of such treatment, which provides for the introduction of this individual compounds of the formula (I) or (II) or its pharmaceutically acceptable salt.

Detailed description of the invention

Every expert knows that some of the substituents listed in the present invention may have low chemical stability in contact with each other or with heteroatoms in the joints. Such compounds with reduced chemical stabili, including methods of synthesis of compounds, known to experts-chemists. Some of the methods of manufacture of compounds of formula (I) and (II) are provided as additional aspects of the present invention and are illustrated in the following reaction schemes and examples.

All references and patents mentioned in this description included in this description for details.

In the above structural formulas and throughout this application, the following terms have the specified values, if it is not specifically mentioned.

Have in mind that the alkyl groups include alkyl groups specified length, either straight or branched configuration. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl etc.

When "C0-alkyl" is used herein, it means a single covalent bond.

Alkoxygroup defined above, include alkoxygroup specified length, either straight or branched configuration. Examples of such alkoxygroup are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary, butoxy, pentox, isopentane, hexose, isohexane etc.

alkyl" includes monocyclohexyl (for example, cyclopentyloxy, tsiklogeksilnogo and so on), bicycloalkyl (for example, bicyclo[2.2.1]hepta-2,5-diene, etc.,) or tricyclohexyl group (for example, adamantly and so on) with the specified number of carbon atoms known in the art, and need not have a double or triple bond.

The term "aryl" means an aromatic ring, known to specialists in this field, which can be monocyclic, bicyclic or tricyclic, such as phenyl, naphthyl, indenyl, azulene and anthracene.

The term "heterocycle" means a monocyclic, bicyclic or tricyclic system having one or more heteroatoms, such as oxygen, nitrogen and/or sulfur. Ring system may be aromatic, for example, pyridine, indole, quinoline, pyrimidine, thiophene (also known as Teenel), furan, benzothiophene, tetrazol, dihydroindol, indazole, N-formylindole, benzimidazole, thiazole and thiadiazole. Ring system may be non-aromatic, such as pyrrolidine, piperidine, morpholine, etc.,

The following definitions, which are presented in the claims:

"R9and R10taken together with the nitrogen to which they are linked, form a ring having 5-8 members including the nitrogen atom, to which Orada or NR11where R11is (C1-C6)alkyl, -C(O)-(C1-C6)alkyl, -C(O)-NH2-C(O)-NH-(C1-C6)alkyl, -C(O)-N((C1-C6)alkyl)2, -C(S)-NH2- (S)-NH-(C1-C6)alkyl, -C(S)-N(C1-C6)alkyl)2or optionally substituted phenyl-(C0-C6)alkyl" means that the result are the following types of fragments:

where R11defined above, and arc mean carbon ring members (however, the symmetry of the arcs does not mean that they must have the same number of carbon atoms).

Every specialist-chemist obviously understands that some combinations heteroaromatic substituents listed in this invention, identify the connections that will be less stable under physiological conditions. Accordingly, such compounds are less preferred.

If used here, the chemical structure is radiating the arrow, the arrow indicates the site of attachment. For example, the structure ofmeans pentelow group. When the arrow passes through the cyclic fragment, this arrow means that the cyclic fragment or group is achet, which phenyl may be attached at the ortho-, meta - or para-position relative to group X. If the arrow passes through bicyclic or tricyclic fragment, the arrow indicates that the bicyclic or tricyclic ring may be attached at any of the sites available joining in any of the rings, for examplemeans that indole is connected or through a phenyl ring part, or through a nitrogen-containing part of the ring.

In the definition of formula (II) in which R5and R8taken together with the carbon atom to which they are connected, means, for example,* in the ring means a carbon atom, which is associated with R5and R8forming thus spirochetemia.

Compounds of the present invention, with the following core structurenumbered in accordance with the following schema.

The term "treatment" means any treatment of conditions in mammals, especially humans, and includes.

(i) preventing a disease in an individual who has a predisposition to the disease, but in whom the disease is not yet diagnosed;

(ii) the inhibition of this status is.

The term "individual" means a recipient of the compounds of the present invention, preferably a mammal, most preferably a human.

The term "pathological condition which can be cured by the introduction of the blocker of sodium channels" means any and all painful conditions known in this field, mainly as a disease, which can favorably be cured by blockers of sodium channels, and those States in respect of which found that they can be cured by a specific blocker of sodium channels of the present invention, i.e. compounds of formula (I) or (II). Such pathological conditions include, but are not limited to, for example, peripheral neuropathy, such as trigeminal neuralgia, posttherapeutic neuralgia, diabetic neuropathy, glossopharyngeal neuralgia, lumbar and cervical radiculopathy, reflex sympathetic dystrophy and causalgia, and neuropathy, which is a consequence of metastatic infiltration, morbid obesity, and burn pain; painful condition associated with diseases of the Central nervous system after impact, damage to the thalamus and multiple sclerosis.

The term "terapeutiche is my salt sufficient for treatment is indicated, when administered to a mammal in need of such treatment. A therapeutically effective amount varies depending on the specific individual and the disease condition being treated, the severity of the disease and the method of administration, and can be defined in the usual way an expert in this field. The term "therapeutically effective amount" is fully included in the number of connections that you enter during the implementation of the method of the present invention, or when the specified connection is a component of a pharmaceutical composition of the present invention.

Compounds of the present invention have at least one asymmetric centre, marked with an asterisk in the structural formula (I) and (II) above. Depending on the nature of the various substituents in the molecule may be present and other asymmetric centers. Each such asymmetric center will produce two optical isomers, and all of these optical isomers, as separated, pure or partially purified optical isomers, racemic mixture, or diastereomer mixture, included in the scope of the present invention.

Compounds of the present invented the salt, obtained using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, acetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methansulfonate, etc. in Addition, some compounds containing acidic functional group, such as carboxy, can be allocated in the form of their inorganic salts, in which the counterion may be selected from sodium, potassium, lithium, calcium, magnesium, etc. and organic bases.

Pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of formula (I) or (II) and its introduction into contact with about 1 equivalent of a suitable acid corresponding to the desired salt. Processing and isolation of the salts is well known to specialists in this field.

As is known in the technique, agonists and antagonists of the somatostatin useful for treating a variety of medical conditions and diseases, such as inhibition of proliferation N. pylori; acromegaly; restenosis; Crohn's disease; systemic sclerosis; external and internal pseudocysts and ascites pancreatic cancer; anupadaka; nesidioblastosis; hyperinsulinemia; gastrinoma; syndrome Zollinger-Ellison; dia who s intestines; pancreatitis; obstruction of the small intestine; gastroesophageal reflux; gastro-duodenal reflux, and in the treatment of endocrinological diseases and/or conditions such as Cushing's syndrome; gonadotropinum; hyperparathyroidism; graves disease; diabetic neuropathy; Paget's disease, polycystic ovary; in the treatment of various types of cancer such as thyroid cancer, hepatoma, leukemia, meningioma, and conditions associated with cancer, such as cancer cachexia; in the treatment of conditions such as hypotension, such as orthostatic hypotension and hypotension after eating and panic attacks; GR-secreting adenomas (acromegaly) and S-secreting adenomas. Activation of the receptor type 2, but not subtype 5 is associated with the treatment of prolactin-secreting adenomas. Other indications associated with activation of receptors somatostatinoma subtypes, is the inhibition of insulin and/or glucagon, in particular diabetes mellitus; hyperlipidemia; insulin resistance; syndrome X, angiopathy; proliferative retinopathy; the phenomenon of "dawn" and nephropathy; inhibition of gastric juice, and more particularly peptic ulcers, skin, intestinal, skin and pancreatic fistulas, demi-intestinal hormones; the inhibition of angiogenesis, treatment of inflammatory diseases such as arthritis; chronic allograft rejection; violations caused by angioplasty; prevention of bleeding in the transplantation of blood vessels and gastrointestinal bleeding. Agonists of somatostatin can also be used to reduce the body weight of the patient. Accordingly, the compounds of the present invention are useful for the methods above.

Accordingly the scope of the present invention is included a pharmaceutical composition comprising as an active ingredient, at least one of the compounds of formula (I) or (II) in combination with a pharmaceutically acceptable carrier.

The compounds of this invention can be administered orally, parenterally (for example, by intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), vnutripuzarno, vaginal, rectal, sublingual, or local introduction, or they can be combined with a pharmaceutically acceptable carrier for receiving a metered dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, p is artnum pharmaceutically acceptable carrier, such as sucrose, lactose or starch. Such dosage forms can also include, as is common practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, these dosage forms may also include tabularasa agents. In addition, tablets and pills can be prepared with InterCasino coverings.

Liquid dosage forms for oral administration are pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents commonly used in this field, such as water. Besides such inert diluents, compositions can also include adjuvants such as wetting agents, emulsifying and suspendresume agents, sweeteners, perfuming and flavouring agents.

In accordance with the present invention the preparations for parenteral administration include sterile aqueous or anhydrous solutions, suspensions or emulsions. Examples anhydrous solvents or media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and injectable, organic the guys, wetting agents, emulsifying and dispersing agents. They can be sterilized, for example, by filtration through a filter that retains bacteria, by incorporating in the composition of sterilizing agents, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile environment for injection immediately before use.

Compositions for rectal or vaginal injection are preferably suppositories, which, besides the active substance, may contain excipients such as cocoa butter or wax for suppositories.

Compositions for intranasal or sublingual introduction also prepared using standard fillers are well known in the art.

In addition, the compound of this invention of formula (I) or (II) may be in the form of a composition with a slow release, such as those described in the following patents. In U.S. patent No. 5672659 described the prolonged release composition containing a biologically active agent, or a complex of the polyester. In U.S. patent No. 5595760 Noah to form a gel. In the application U.S. No. 08/929363, filed September 9, 1997, described the prolonged release composition containing a biologically active agent and chitosan. In the application U.S. No. 08/740778, filed November 1, 1996, described the prolonged release composition containing a biologically active agent and a cyclodextrin. In the application U.S. No. 09/015394, filed January 29, 1998, describes the prolonged release composition containing a biologically active agent. The description of the above patents and applications are included in the present description for details.

Basically, an effective dose of a compound of the present invention of formula (I) or (II) in the compositions of the present invention may vary, however, it is necessary that the amount of active ingredient was so, to get a suitable dosage form. The selected dosage depends upon the desired therapeutic effect, the route of administration and duration of treatment, and all of these factors are within the knowledge of an average person skilled in the art. The usual dose for administration to humans and other animals, for example mammals, is in the range from 0.0001 to 100 mg/kg of body weight per day.

The preferred dosage is 0.01-10.0 mg/kg of body weight per day, which may centuries analyzed for their ability to communicate with somatostatinomas receptor in accordance with the following tests.

Research associate somatostatinoma receptors man

The affinity of compounds in relation to somatostatinomas receptors human subtypes 1-5 (sst1sst2sst3sst4and sst5respectively) is determined by measuring the degree of inhibition of binding of [125ITyr11]SRIF-14 transfitsirovannykh cells Cho-K1.

The gene of the human receptor sst1cloned as a genomic fragment. 1,5, etc., ad-stI-HMP-fragment containing 100 p. N. 5’-noncoding region, 1,17, etc., N. the entire coding region and 230 p. N. 3’-noncoding region was modified by adding a BglII-linker. The obtained DNA fragment was subcloned into the BamHI-site of pCMV-81 for producing plasmids expressing in mammalian cells (provided by Dr.Graeme Bell, Univ. Chicago). Clonal cell line stably expressing the receptor sst1was obtained by transfection of cells Cho-K1 (ATS) method coprecipitation using calcium phosphate (1). The plasmid pRSV-neo (ATCC) was included as a selective marker. Clonal cell lines were selected in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), were subjected to cyclic cloning and multiplied in culture.

Gene receptor somatostatin vector pGEM3Z (Promega), was kindly provided by Dr. G. Bell (University of Chicago). Expressing in a mammalian cell vector cell designed by embedding 1,7, etc., n-BamH1-HindII fragment into compatible restriction sites in the plasmid pCMV5. Clonal cell line was obtained by transfection of cells Cho-K1 method coprecipitation using calcium phosphate. The plasmid pRSV-neo was included as a selective marker.

Gene sst3the man was identified as genomic fragment, and a complete coding sequence was 2.4, etc., ad-AMN-HindIII fragment. Expressing in mammalian cells plasmid, pCMV-h3, designed by embedding 2,0, etc., ad-NI-HindIII fragment into the EcoRI site of the vector pCMV after modification of the ends and add EcoR1-linkers. Clonal cell line stably expressing the receptor sst3, was obtained by transfection of cells Cho-K1 (ATS) method coprecipitation using calcium phosphate. The plasmid pRSV-neo (ATS) was included as a selective marker. Clonal cell lines were selected in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), were subjected to cyclic cloning and multiplied in culture.

A plasmid expressing the human receptor sst4, pCMV-HX was predelovalci sst4, 456 p. N. 5’-netransliruemoi area and 200 p. N. 3’-netransliruemoi region cloned in bI/ER1 sites pCMV-HX. Clonal cell line stably expressing the receptor sst4was obtained by transfection into cells Cho-K1 (ATS) method coprecipitation using calcium phosphate. The plasmid pRSV-neo (ATS) was included as a selective marker. Clonal cell line were selected in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), were subjected to cyclic cloning and multiplied in culture.

The gene of the human receptor somatostatin sst5was obtained using a genomic cloneas the matrix and courtesy of Dr.Graeme Bell (University of Chicago). The obtained 1,2, etc., N.-PCR fragment, containing 21 p. N. 5’-untranslated region, the entire coding region and 55 p. N. 3’-noncoding region. This clone was built into the EcoR1 site of the plasmid pBSSK(+). This insert was identified as 1,2, etc., ad-HindIII-XbaI fragment for sublimirovanny in expressing in mammalian cells the vector pCMV5. Clonal cell line stably expressing the receptor sst5, was obtained by transfection of cells Cho-K1 (ATS) method coprecipitation using calcium phosphate. The plasmid pRSV-neo least the g/ml G418 (Gibco), subjected to cyclic cloning and multiplied in culture.

Cells Cho-K1, stably expressing one of the human sst receptors were cultured in medium RPMI 1640 containing 10% fetal calf serum and 0.4 mg/ml geneticin. Cells were collected using 0.5 mm EDTA and centrifuged at 500 g for approximately 5 minutes at about 4C. the Precipitate resuspendable in 50 mm Tris, pH 7.4, and centrifuged twice at 500 g for about 5 minutes at about 4C. the Cells were subjected to lysis by treatment with ultrasound and centrifuged at 39000 g for about 10 minutes at aboutC. the Precipitate resuspendable in the same buffer and centrifuged at 50000 g for approximately 10 minutes at about 4With the membrane in the obtained precipitate was stored at -80C.

Experiments on the inhibition of competitive binding with [125I-Tyr11]SRIF-14 conducted in the triple duplicate in polypropylene 96-well plates. Cell membranes (10 μg protein/well) were incubated with [125I-Tyr11]SRIF-14 (0,05 nm) to about 60 minutes at about 37With 50 mm HEPES (pH 7.4), 0.2% BSA, 5 mm MgCl2, 200 KIE/ml of the Drug, the t free by immediate filtration through glass fiber filter tablet CF/C (Unifilter, Packard), pre-soaked in 0.1% polyethylenimine (PAYS) using the collector cells Filtermate 196 (Packard). Filters were washed in 50 mm HEPES at 0-4With about 4 seconds and analyzed for radioactivity using a counter Packard Top Count.

Specific binding was obtained by subtracting nonspecific binding (determined in the presence of 0.1 μm SRIF-14) from the total binding. Data binding was analyzed on the computer by the method of nonlinear regression analysis (MDL) and determined the size of the inhibition constants (Ki).

In order to determine whether the connection of the present invention is an agonist or antagonist, conducted the following analysis.

Functional analysis: inhibition of intracellular products cGMP.

Cells Cho-K1 expressing somatostatin receptors person (SRIF-14), were sown in 24-hole plates to the cultivation of tissues in medium RPMI-1640 with 10% FCS and 0.4 mg/ml geneticin. The day before the experiment the medium was replaced.

Cells at a concentration of 105cells/well twice washed with 0.5 ml of fresh RPMI with 0.2% BSA, to which was added 0.5 mm (1) 3-isobutyl-1-methylxanthines (IBMX), and incubated for approximately 5 minutes at about 37C.

Agonistic effect of the compounds was measured by simultaneous addition of FSK (1 μm), SRIF-14 (10-12M -10-6M) and test compounds (10-10M -10-5M).

The antagonistic effect of the compounds was measured by simultaneous addition of FSK (1 μm), SRIF-14 (1012-10-6nm) and test compound (10-10M - 10-5M).

The reaction medium was removed and added to 200 ml of 0.1 N. Hcl. The content of camp was measured by radioimmunoassay method (Kit FlashPlate SMP001A, New England Nuclear).

Compounds of the present invention can be tested for blocking activity against sodium channels. Compounds of the present invention associated with susceptible to veratridine sodium channel. The procedure of binding, see for example, J. B. Brown, Journal of Neuroscience 6, 2064-2070 (1986), the contents of which are incorporated into this description by reference. These compounds block the induced veratridine release of glutamate in the preparations of slices of rat hippocampus. This experiment was carried out in accordance with a modification of the method described by M. J. Leach et al., in the works Epilepsia 27, 490-497 (1986), and Stroke 24, 1063-1067 (1993), using exogenous glutamate.

Compounds of this izaberete the

Tetrahydro--carboline

The General procedure. Amine of the formula (a) is treated with aldehyde in proton or an aprotic solvent in the presence of acid or without, preferably in chloroform with TFA, at a temperature of about 20-80With approximately 5-72 hours. The resulting carbolin (obtained as a mixture of diastereomers) can be selected or water treatment with subsequent flash chromatography on silica gel or by adding to the reaction mixture of the nucleophile on the polymer carrier (for gripping an excess of aldehyde), such as aminomethylenemalonate resin, followed by filtration, and then the rapid purification of the resulting residue on a layer of silica gel (using a cartridge with silica Alltech and collector Alltech).

Example 1

Diastereomer a mixture of 1,2,3,4-tetrahydro-1-(4-methoxyphenyl)-3(S)-(4-phenyl-1H-imidazol-2-yl)-N-pyrido[3,4-d]indole in C1

To 2-[1(S)-amino-2-(3-indolyl)ethyl]-4-phenyl-1H-imidazole (100 mg, 1 EQ.) in a solution of chloroform (0.8 ml) are successively added n-anisaldehyde (80 ml, 2 EQ.) and TFA (256 ml, 10 EQ.). After about 2 days of stirring at temperature). Then add aminomethylpropanol resin (Novabiochem, loading=1.2 mmol/g, 550 mg, 2 EQ.) and the mixture is stirred overnight at about 20With, and then filtered. Then the filtrate is concentrated under reduced pressure and purified by rapid filtration on a layer of silica gel cartridge with silica Alltech) using ethyl acetate as eluent, resulting in a gain tetrahydro--carbolin in the form of a mixture of diastereoisomers (65:35) (yield=78%).

NMR (1H, 400 MHz, CDCl3): 12,2 (m, 1H, NH), to 7.77-6,83 (m, 15 NM, N arene. NH), of 5.29, 5,17 (2s, 1H, H1), was 4.42 (m, 1H, H3), 3,82, of 3.78 (2s, 3H, och3), to 3.49 (m, 1H, H4), 3,17 (m, 1H, H4), 1,90 (s, 1H, NH). LC/MS: calculated mol. weight (Mw)=420,51, m/z=421,05 (M+N), m/z=419,07 (M-N).

Examples 2-1303

The following compounds receive similarly to the procedure described in Example 1, using appropriate starting materials, which can be obtained from commercial sources or can be synthesized by methods known in the art, or methods described in this application. Each combination of R2and R5below, were or can be synthesized, therefore, the number of Examples is calculated by multiplying (c="https://img.russianpatents.com/img_data/80/807403.gif">

R5:

N-SUBSTITUTED, TETRAHYDRO-CARBOLINE

The General procedure. The compound of formula (b) can react with isocyanates, isothioscyanates, N-succinimidylester, acylchlorides or activated carboxylic acid in an aprotic solvent at 20-70C for 2-18 hours. Derived can be isolated by evaporation of the mixture followed by flash chromatography on silica gel or by adding to the mixture of the nucleophile on the polymer carrier, such as aminomethyl - Il>=(CH2)nNHBoc) appropriate connections without protection (R4=(CH2)nNH2) can be obtained by treating the N-protected compounds in acidic conditions (DHM/TFA, 10%).

Example 1304

Diastereomer a mixture of 1,2,3,4-tetrahydro-1-(4-methoxyphenyl)-2-[(phenylamino)carbonyl]-3(S)-(4-phenyl-1H-imidazol-2-yl)-N-pyrido[3,4-b]indole when C1

To a solution of diastereomer a mixture of 1,2,3,4-tetrahydro-1-(4-methoxyphenyl)-3(S)-(4-phenyl-1H-imidazol-2-yl)-N-pyrido[3,4-b]indole (50 mg) in chloroform (700 ml) is added benzylsuccinic. The mixture is stirred overnight at a temperature of about 20C, and then diluted with chloroform (2 ml).

Add aminomethylpropanol resin (Novabiochem, loading=1.2 mmol/g, 198 mg, 2 EQ.). After shaking for approximately 15 hours at a temperature of about 20The mixture is filtered and the filtrate concentrated under reduced pressure to obtain the target compound (60 mg, yield 92%).

NMR (1H, 400 MHz, CDCl3): 9,2-6,7 (m, 22N, arene. H, NH), and 6.25 (m, 1H, H1), 5,80 (m, 1H, H3), to 4.52-4,32 (m, 2H, CH2PH), 3,81 of 3.28 (m, 5H, co3H4N4). LC/MS: calculated mol. weight (Mw)=553,56, m/z=554,2 (M+H).

Examples 1305-1332

Nigel stuudy raw materials, which can be obtained from commercial sources or can be synthesized by methods known in the art, or methods described in this application. Each combination of R4and R5below, were or can be synthesized, therefore, the number of Examples is calculated by multiplying (R4(9 substituents)) (R5(3 Deputy))=27.

-carboline

General procedure: Tetrahydro--carbolin formula (C) are oxidized to the corresponding fully aromatic-carbolines, which with the use of palladium-on-coal or DDH (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in an aprotic solvent such as toluene or xylene, chromic acid proton solvent, KMPO4in THF or manganese dioxide in an aprotic solvent, preferably chloroform, at 20-80From within 2-48 hours.

Example 1333

1-Butyl-3-(4-phenyl-1H-imidazol-2-yl)-N-pyrido[3,4-b]indole

A mixture of 1,2,3,4-tetrahydro-1-butyl-3 is t at a temperature of approximately 40With about 3 hours. The mixture is cooled to about 20C and filtered through a layer of celite®. The filtrate is concentrated under reduced pressure to obtain a fully aromatic-carboline with quantitative yield (97 mg).

NMR (1H, 400 MHz, Dl3): 10,8 (s, 1H, NH), 8,77-7,25 (m, 1H, arene.H, NH), of 3.07 (t, 2H,3J=8 Hz, CH2), of 1.85 (m, 2H, CH2), 2,42 (m, 2H, CH2), of 0.91 (t, 3H),3J=8 Hz, CH3). LC/MS: calculated Mw=366,46, m/z=367,19 (M+N), m/z=479,15 (M+TFA).

Examples 1334-1336

The following compounds can be obtained by the method described in Example 1333, using the appropriate starting materials, which can be obtained from commercial sources or can be synthesized by methods known in the art, or methods described in this application.

Examples 1337-1493

The following compounds can be obtained by the method described in Example 1333, using the appropriate starting materials, which can be obtained from commercial sources or can be synthesized by methods known in the art, or methods described in this "https://img.russianpatents.com/img_data/80/807432.gif">

0

Example 1494

Hydrochloride (1R)-1-(4,5-dimethyl-1,3-oxazol-2-yl)-2-(1H-indol-3-yl)-1-ethanamine

A solution of tert-butyl{1R)-1-(4,5-dimethyl-1,3-oxazol-2-yl)-2-(1H-indol-3-yl)ethylcarbamate (3 g, 8.4 mmol) in 1 N. a mixture of HCl/AcOEt (80 ml) was stirred at room temperature for approximately 2.5 hours. The mixture is concentrated under reduced pressure, add diethyl ether (100 ml) and the white precipitate collected by filtration, and then washed with diethyl ether to obtain hydrochloric salt of the desired product (2.4 g). Melting point 172-174C.

Hydrochloride, (3R)-1,1-dibutil-3-(4,5-dimethyl-1,3-oxazol-2-yl)-2,3,4,9-tetrahydro-1H--carboline

To a solution of hydrochloride (1R)-l-(4,5-dimethyl-1,3-oxazol-2-yl)-2-(lH-indol-3-yl)-1-ethanamine (1.2 g, 3.6 mmol) in isopropanol (20 ml) add 5-nonanone (3.1 ml, 20 mmol} and the mixture Institute. To the residue is added water (20 ml), then the solution Panso3(10%) to achieve a neutral pH, and then ethyl acetate (315 ml). After decanting and extracting the combined organic extracts washed with water (20 ml) and dried over MgSO4. The solvent is evaporated under reduced pressure to obtain oil, which was purified column chromatography on silica gel using as eluent a mixture of ethyl acetate/heptane, 7:3. The oil obtained is dissolved in ethyl acetate (15 ml) and slowly add a solution of Hcl in ethyl acetate (1 BC) at about 20With sediment. The resulting suspension is stirred for a few minutes, after which the precipitate is collected by filtration, washed with diethyl ether and dried to obtain 0.14 g of the desired product in the form of a hydrochloric salt. Melting point 128-134C.

Example 1495

Hydrochloride, (3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1’-benzoylamino[1H-carbolin-1,4’-piperidine]

To a solution of hydrochloride (1R)-2-(lH-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine (1 g, to 2.65 mmol) in isopropanol (15 ml) is added N-benzoyl-4-piperidone (2.64 g, 13 )://img.russianpatents.com/chr/176.gif">C. the Solvent is removed under reduced pressure. The residue is treated with dichloromethane (30 ml) and stirred for about 30 minutes at about 20C. the precipitate is collected by filtration, washed with dichloromethane and diethyl ether and dried to obtain 1.2 g of the desired product in the form of a hydrochloric salt. Melting point 240-244C.

Example 1496

(3R)-3-(4-Phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1’-(tert-butoxycarbonyl)Spiro[1H--carbolin-1,4’-piperidine]

To a solution of hydrochloride (1R)-2-(lH-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine (14 g, 35 mmol) in isopropanol (210 ml) was added 1-tert-butoxycarbonyl-4-piperidone (35 g, 170 mmol) and the mixture heated under reflux for about 2 hours. The solvent is evaporated under reduced pressure. To the residue is added water (150 ml) and then 10% solution Panso3to obtain a neutral pH and extracted with ethyl acetate (450 ml). The combined organic extracts washed with water (250 ml) and dried over MgSO4. The solvent is removed under reduced pressure to obtain oil, which solidifies after you add obtain 13.5 g of the desired product. Melting point 118-120C.

Example 1497

(3R)-3-(4-Phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydrofuro-[1H--carbolin-1,4’-piperidine

A solution of (3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1’-(tert-butoxycarbonyl)Spiro[1H--carbolin-1,4’-piperidine] (13.5 g, 28 mmol) in ethyl acetate (400 ml) is cooled to about 0C in an ice bath and treated with a stream of anhydrous gaseous Hcl for two hours. The solvent is removed under reduced pressure to obtain a semi-solid substance. After trituration with acetone receive a white solid, which was collected by filtration and washed with acetone and diethyl ether. Hydrochloric salt is converted into the free base using a 10% solution Panso3and the aqueous layer was extracted with ethyl acetate (350 ml). The combined organic extracts washed with water (250 ml), dried (MgSO4), filtered and evaporated to obtain 10 g of the desired product. Melting point >250C.

Example 1498

Hydrochloride (1R)-2-(1-benzothiophen-3-yl)-1-(4~phenyl-1H-imidazol-2-yl)-1-etail)ethylcarbamate (4 g, 9.5 mmol) in 70 ml of 1 N. a mixture of HCl/AcOEt heated to about 50C for one hour. The mixture of concentrate and add diethyl ether (50 ml). The obtained white precipitate is collected by filtration and washed with diethyl ether to obtain hydrochloric salt of the desired product (3 g). Melting point 190-192C.

(3R)-3-(4-Phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1’-[N-(3-pyridinyl)carbothioamide]Spiro[1H--carbolin-1,4’-piperidine]

To a solution of (3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydrofuro[lH-carbolin-1,4’-piperidine] (0,38 g, 10 mmol) in dichloromethane (5 ml) is added 3-predilatation (0,136 g, 10 mmol). The mixture is stirred for about 30 minutes at about 20C and the precipitate is collected by filtration and washed with dichloromethane and diethyl ether obtaining of 0.38 g of the desired product. Melting point 234-236C.

Example 1499

(3R)-1,1-Dibutil-3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro[1]benzothieno[2,3-C]pyridine

To a solution of (1R)-2-(1-benzothiophen-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine (1 g, 2.5 mmol) in n-buta is ritel removed under reduced pressure. To the residue is added water (15 ml) and then 10% solution of NaHCO3to achieve a neutral pH and extracted with ethyl acetate (320 ml). The combined organic extracts washed with water (210 ml), dried over gSO4filter. The solvent is evaporated under reduced pressure to obtain oil, which was purified column chromatography on silica gel using a mixture of ethyl acetate/heptane, 1:1, as eluent. After removal of the solvent to the residue add diisopropyl ether. The obtained white precipitate is filtered off and washed with diisopropyl ether to obtain 0.1 g of the target product. Melting point 198-200C.

Example 1500

Fumarate (3R)-1,1-dibutil-3-(4-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1H--carboline

The mixture (10 g, 33 mmol) of hydrochloride (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine, n-butanol (150 ml) and 5-nonanone (23,44 g, 165 mmol) is heated under reflux for about 4 hours, and then remove 10 ml of n-butanol using the apparatus of Dean-stark. After heating under reflux for a further 2 hours the mixture degreeprecision between ethyl acetate (100 ml) and 10% solution Panso3(50 ml). After decanting, the organic layer washed with 10% solution Panso3(50 ml) and water, and then dried over MgSO4. After evaporation of the solvent receive a brown residue, which was purified flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate, 9:1). Pure fractions are collected and concentrated, and after washing diisopropyl ether obtain 3.6 g of the target compound in the form of free base. Melting point 160-162C.

The free base (1.3 g, 3 mmol) dissolved in acetone (5 ml). Added fumaric acid (448 mg, 3 mmol). The mixture is heated to about 50With obtaining a solution. After settling in for the night formed white crystals. Then add diethyl ether (20 ml) and dried connection (1,05 g) is collected by filtration. Melting point 168-170C.

Example 1501

(3R)-3-(4-Phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-Spiro-[1H--carbolin-1,1-cycloheptyl]

To (1R)-2-(lH-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine (0.75 g, 2.5 mmol) is added 20 ml of 1,2-dichloroethane, triperoxonane acid (2 ml, 25 mmol) and Cyclopentanone (560 mg, 5 mmol). A mixture of load, the acetic acid (1 ml) and Cyclopentanone (560 mg) and heating under reflux continued for approximately 4 hours. The solvent is removed under reduced pressure. To the residue is added 20 ml of ethyl acetate and 10% solution Panso3. After decanting, the organic layer washed with water and dried over gSO4. After evaporation of the solvent to obtain the residue, which is purified flash chromatography on silica gel (eluent: a mixture of heptane/ethyl acetate, 3:7). Pure fractions are collected and concentrated to obtain 80 mg of the target compound. Melting point 208-210C.

Example 1502

(3R)-3-(4-Phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1’-[3-(4-were)-1-propionyl]Spiro[1H--carbolin-1,4’-piperidine]

To 20 ml of anhydrous tetrahydrofuran add the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (192 mg, 1 mmol) and triethylamine (of 0.14 ml, 1 mmol). The mixture is stirred for about 15 minutes, and then add (3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydrofuro[1H-carbolin-1,4’-piperidine] (383 mg, 1 mmol) and 3-(4-were)propionic acid (164 mg, 1 mmol). The reaction mixture is heated to approximately 40C and stirred overnight at this temperature. The solvent is removed under reduced pressure. The residue is partitioned between the th and dried over gSO4. After evaporation of the solvent to obtain the residue, which is purified flash chromatography on silica gel (eluent: a mixture of ethyl acetate/dichloromethane, 1:1). Pure fractions are collected and concentrated. White solid was washed with diethyl ether and collected by filtration to obtain 100 mg of the target compound. Melting point 180-182C.

Example 1503

(3R)-3-(4-Phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1’-[N-(4-triptoreline)carboxamide]Spiro[1H--carbolin-1,4’-piperidine]

To a solution of (383 mg, 1 mmol) (3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydrofuro[1H-carbolin-1,4’-piperidine] in dichloromethane add 4-triftormetilfullerenov (187 mg, 1 mmol). The mixture is stirred for approximately one hour and diluted with 20 ml diethyl ether. Pale cream precipitate is collected by filtration and washed with diethyl ether to obtain 140 mg of the target product. Melting point 222-224C.

Example 1504

tert-Butyl(1R)-2-amino-1-(1H-indol-3-ylmethyl)-2-oxoethylidene

In the reactor under a pressure of 200 pounds per square inch (14,06 kg/cm2) add methyl(2R)-2-[(tre stirred at about 85C for approximately 24 hours. After cooling, the solution is evaporated and the residue is precipitated by the addition of diisopropyl ether. Filtration gave of 5.4 g of the desired product as a white powder. Melting point 142-143C.

tert-Butyl(1R)-2-amino-1-(1H-indol-3-ylmethyl)-2-thioacetimidate

To a solution (5 g, 160 mmol) of tert-butyl(1R)-2-amino-1-(1H-indol-3-ylmethyl)-2-oxoethylidene in 85 ml of 1,2-dimethoxyethane added to 5.2 g (62 mmol) of NaHCO3and then the P2S5(7,3 g, 32 mmol) over about 45 minutes. The mixture is stirred overnight and the solvent is evaporated. The residue is suspended in ethyl acetate and washed with water, 10% solution Panso3and again with water. After drying over MgSO4the organic layer is concentrated and the crude product is precipitated by adding a mixture of isopentane/diisopropyl ether 1:1. Filtration gave 4.3 g of the desired product in the form of a cream powder. MS: 320,2 (MN+). TLC: Rf=0,7 (CH2Cl2/MeOH, 90:10).

tert-Butyl(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)ethylcarbamate

A mixture of tert-butyl(1R)-2-amino-1-(lH-indol-3-ylmethyl)-2-thioacetimidate (2.24 g, 7 mmol) andC for about 10 minutes and after cooling, add ethyl acetate (50 ml) and water (25 ml). The organic layer is decanted, washed with 10% solution Panso3, water and dried over MgSO4. Evaporation of the solvent to obtain the residue, which is purified flash chromatography on silica gel (eluent: a mixture of dichloromethane/ethyl acetate, 95:5). Pure fractions are collected and concentrated to obtain 1.1 g of the desired product in the form of a cream powder. MS: 420,2 (MN+). TLC: Rf=0,7 (SiO2CH2Cl2/EtOAc, 95:5).

Hydrochloride (1R)-2-(lH-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)-1-ethanamine

To tert-butyl(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)ethylcarbamate (1.2 g, 2,85 mmol) is added ethyl acetate (10 ml) and 20 ml of 1 n solution of Hcl in ethyl acetate. The solution is stirred for about 2 hours at about 20And then about 2 hours at about 50C. the Crystals which formed upon cooling is collected by filtration and washed with diethyl ether, obtaining 1 g of the desired product as an orange powder. Melting point 170-172C.

(3R)-1,1-Dibutil-3-(4-phenyl-1,3-thiazol-2-yl)-2,3,4,9-tetrahydro-1H--carbolin

3. After decanting, the organic layer washed with water and dried over MgSO4. After evaporation of the solvent to obtain the residue, which is purified flash chromatography on silica gel (eluent: a mixture of dichloromethane/ethyl acetate, 97:3). Pure fractions are collected and concentrated. The residue is dissolved in diethyl ether and add 1 ad (n=normal) Hcl in ethyl acetate. The resulting hydrochloride is collected by filtration and washed with diethyl ether to obtain 85 mg of the desired product as an orange powder. Melting point 134-136C.

Preparative example 1

tert-Butyl(1R)-2-(1-benzothiophen-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate

To a solution of Boc-D-3-benzothiazolinone (5 g, 15 mmol) in absolute ethanol (60 ml) and water (20 ml) is added cesium carbonate (2.4 g, 7.5 mmol) and the mixture plinii, giving a white powder, which is dissolved in dimethylformamide (100 ml) and treated with 2-bromoacetophenone (3 g, 15 mmol). After stirring overnight at about 20With the solvent concentrated under reduced pressure. The residue is treated with ethyl acetate (100 ml) and the thus obtained residue (CsBr) is filtered off, washed with ethyl acetate and the filtrate concentrated under reduced pressure, obtaining a light brown solid. The solid is dissolved in xylene (100 ml), add ammonium acetate (23 g, 300 mmol) and the mixture heated under reflux for approximately two hours. After cooling to about 20With added water (50 ml) and ethyl acetate (100 ml). The organic layer is decanted and washed with water (50 ml), 10% solution Panso3(250 ml), brine (50 ml) and dried over MgSO4. The solvent is evaporated under reduced pressure. To the residue add neopentane (60 ml), and then it is filtered, receiving 4 g of target compound in the form of a white powder. Melting point 116-120C.

Preparative example 2

tert-Butyl(1R)-1-(4,5-dimethyl-1,3-oxazol-2-yl)-2-(1H-indol-3-yl)ethylcarbamate

With and concentrate under reduced pressure to obtain a white powder which is dissolved in dimethylformamide (100 ml) and treated with 3-bromo-2-butanone (3,56 ml, 34 mmol). After stirring for approximately two hours at about 20The solvent is removed under reduced pressure to obtain a suspension, which is treated with ethyl acetate. The precipitate (CsBr) is filtered off and the filtrate is evaporated to form oil which is dissolved in xylene (400 ml). Then add ammonium acetate (52 g, 680 mmol) and the mixture heated under reflux for about 45 minutes. After cooling to about 20With added water (150 ml) and ethyl acetate (100 ml). After decanting, the organic layer washed with water (100 ml), 10% Panso3(2100 ml) and brine (100 ml) and then dried over gSO4and the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of ethyl acetate/heptane, 1:1, as eluent, obtaining 3 g of the target product as a white powder. Melting point: 138-140C.

Neither nasirovna, and specified retention time in HPLC (in minutes and mass spectral data for each connection.

Mass spectra were obtained on a one-dimensional quadrupole mass spectrometer with electrodisco (Micromass, Platform model, the resolution of 0.8 Da. Monthly calibration between 80 and 1000 Da was carried out using a solution of sodium iodide and rubidium in a mixture of isopropanol/water (1/1 by vol.).

Time HPLC retention was determined by HPLC-system: NR (Hewlett-Packard) equipped with photodiode UV-detector.

HPLC-conditions are presented below, and the conditions used for each of the compounds of the following tables is indicated in the column headers.

The condition a

Solvents: A: Water+0.02% of triperoxonane acid

In: Acetonitrile

Flow rate: 1.1 ml/min

Volume of injection: 5 ál.

Column: Uptisphere ODS 3 µm 33* wew.dia. 4,6 mm

Temperature: 40C.

Wavelength: 220 nm.

Condition And used for HPLC analysis of compounds in Tables of Compounds of formulas 2, 3 and 4.

The condition In

Solvents: A: Water+0,04% triperoxonane acid

In: Acetonitrile

Flow rate: 1.1 ml/min

Volume of injection: 5 ál.

Column: Uptisphere ODS 3 µm 33* wew.ø the analysis of the compounds in the Tables of Compounds of formula 1.

The condition

Solvents: A: Water+0,04% triperoxonane acid

In: Acetonitrile

Flow rate: 1.1 ml/min

Volume of injection: 5 ál.

Column: Uptisphere ODS 3 µm 33* wew.dia. 4,6 mm

Temperature: 40C.

Wavelength: 250 nm.

The condition used for HPLC analysis of compounds in the Table of Compounds of formula 5.

Claims

1.-karbolinovye compounds of General formula (I)

their racemic and diastereomeric mixtures and optical isomers, pharmaceutically acceptable salt,

where---- represents an optional bond;

X represents N or N-R4where X is N, when there are both optional connection, and X is NR4when these links were missing;

R1is N;

R2is (C1-C12)alkyl, (C0-C6)alkyl-C(O)-NH-(CH2)mZ3or optionally substituted C1-C6)alkyl, (C1-C6)alkoxy or nitro-group is phenyl;

Z3is (C6H6)2SN-(diphenylmethylene), N,N-di-(C1-C12)-alkylamino, imidazolyl, pyridi the>With6)alkyl, piperazinil, substituted (C1-C6)alkyl;

R3is N;

R4represents H or-C(=Y) N(X1X2), where Y is O;

X2represents -(CH2)m-Y1-X3where X3represents unsubstituted phenyl;

R5is (C1-C12)alkyl, -(CH2)m-Y1-(CH2)m-phenyl-(X1)n, (C3-C12)cycloalkyl, -(CH2)m-S-(C1-C12)alkyl, (C1-C12)-alkyl-S-S-(C1-C12)alkyl, -(CH2)m-(C2-C12)alkenyl, phenyl, unsubstituted or substituted (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, halogen, nitro, phenyl, (C1-C6)alkylthio, amino, cyano, CF3, -O-CF3di(C1-C6)alkylamino(C1-C6)alkoxy, (C1-C6)alkylcarboxylic or;

unsubstituted or substituted by a nitro-group;

Y1means-On or connection;

R6and R7represent H;

X1is hydrogen;

m represents an integer of 0-2;

n represents an integer of 0-5.

2. Connection on p. 1, in which X PR is up> where m in the definition of R2is 1 or 2; Z3is imidazolyl, pyridinyl, morpholino or N,N-diethylamino;

R5represents propyl, n-butyl, n-pentyl, -(CH2)-O-(CH2)phenyl, 2-nitro-3-OMe-phenyl, p-tert-VI-phenyl,

m-OMe-phenyl, o-OMe-phenyl, p-nitrophenyl,

-(CH2)2-S-Me, cyclohexyl, m-Br-phenyl, n-S-Me-phenyl,

p-N,N-dimethylaminophenyl, m-or were

R6is N;

R7is N.

3. Connection on p. 1, in which X represents NH; R1represents H; R2represents phenyl; R5represents propyl, n-butyl, n-pentyl, n-heptyl, isobutyl, neopentyl, cyclopropyl, cyclohexyl, - (CH2)2-S-Me, phenyl, - (CH2)-O-(CH2)-phenyl, 2-nitro-3-OMe-phenyl, p-tert-VI-phenyl, o-OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, 3,4,5-tri-OMe-phenyl, p-butoxyphenyl, 3 ethoxy-4-methoxyphenyl, o-nitrophenyl, p-nitrophenyl, p-F3-phenyl, o-CF3-phenyl, 3-F-4-OMe-phenyl, o-F-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, 2,4-di-CL-phenyl, 3,4-di-CL-phenyl, p-(3-(N,N-dimethylamino)-propoxy)phenyl, - (CH2)2-S-Me, cyclohexyl, n-(Me-CO-NH)-phenyl, p-tert-VI-phenyl, p-OH-phenyl, p-(S-Me)-phenyl, p-(S-tert-VI)phenyl, p-N,N-dimethylaminophenyl, m-were,

3 represents H;

R7is N.

4. Connection on p. 1, in which X represents NH; R1represents H; R2is p-OMe-phenyl or p-nitrophenyl; R5represents n-butyl, n-pentyl, n-hexyl, isobutyl, cyclohexyl, - (CH2)2-S-Me, phenyl, m-OMe-phenyl, 2-nitro-3-OMe-phenyl, p-nitrophenyl, p-tert-VI-phenyl, p-thiomethyl-phenyl, m-Br-phenyl, 2-ome-4-dimethylaminophenyl, n-(3-(N,N-dimethylamino)propoxy)phenyl, p-dimethylaminophenyl, 3-nitro-4-CL-phenyl, --(CH2)-O-(CH2)phenyl or

R6and R7represent N.

5. The compound of General formula (II)

where J1represents N-R6or S;

J2represents N-R1, O or S;

X represents N-R4;

R1is N;

R2represents unsubstituted phenyl;

R3and R4represent H;

R5and R8each independently represents a C1-C12)alkyl, or R5and R8taken together with the carbon atom to which they are attached, form a Spiro(C4-C12-cycloalkyl or fragment

where a represents a bond, -CO-, -C(O)O-, -C(O)NH - or-C(S)NH-;

B is a bond or -(CH2)config or substituted (C1-C6)alkyl or CF3or an unsubstituted pyridinylmethyl;

R6and R7is N;

6. Connection on p. 5, having the formula (IIA):

in which R3is N;

R4is N;

R5represents H, methyl, ethyl, butyl, pentyl or hexyl;

R8represents ethyl, butyl, pentyl, hexyl;

or R5and R8taken together with the carbon atom to which they are bound, form spirocyclohexane, spirochetal,

where a represents a bond or-C(O)O-;

B is a bond, -(CH2)- or -(CH2)2-;

J3represents H or phenyl;

R7is N.

7. Connection on p. 6, in which R3, R4and R7each represents hydrogen, R5and R8together represent

and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8together represent

and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8together represent, R4and R7each represents hydrogen, R5and R8together represent

and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents n-hexyl, and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5is hydrogen, R8represents hexyl in the S-configuration, and imidazolyl is R-configuration, or fumaric salt;

R3, R4and R7each represents hydrogen, R5and R8each represents n-butyl, and imidazolyl is R-configuration, or fumaric salt;

R3, R4and R7each represents hydrogen, R5and R8together represent

and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents n-butyl, and imidazolyl is S-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents ethyl, and imidazolyl is R-configuration;

R3, R4and RR-configuration;

8. Connection on p. 7, in which these compounds are selected from the group consisting of compounds in which R3, R4and R7each represents hydrogen, R5and R8each represents n-butyl, and imidazolyl is R-configuration, or fumaric salt;

R3, R4and R7each represents hydrogen, R5and R8together represent

and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents n-butyl, and imidazolyl is S-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents ethyl, and imidazolyl is R-configuration;

R3, R4and R7each represents hydrogen, R5and R8each represents n-pentyl, and imidazolyl is R-configuration.

9. Pharmaceutical composition having activity against the binding of one or more types of subtypes of somatostatin, including a connection on p. 1 or 5 or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

10. The way to achieve the agonistic effect which provides for the introduction of a specified individual connections under item 1 or 5 or its pharmaceutically acceptable salt.

11. The way to achieve the antagonistic effect of one or more receptors somatostatinomas subtype in an individual in need thereof, which provides for the introduction of a specified individual connections under item 1 or 5 or its pharmaceutically acceptable salt.

12. A method of binding one or more receptors somatostatinomas subtype in an individual in need thereof, which provides for the introduction of this individual connections under item 1 or 5 or its pharmaceutically acceptable salt.

 

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