Derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinediones, method for their preparing (variants), intermediate compounds and pharmaceutical composition

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

 

The invention relates to new derivatives of hydantoins, thiohydantoins, pyrimidinediones and dioxopyrimidine following General formula I, to processes for their preparation and to their use as medicines. These compounds have high affinity to certain subtypes of somatostatin receptors and are, therefore, valuable pharmacological properties. The invention relates also to containing these compounds, pharmaceutical compositions and to their use for the preparation of drugs intended for the treatment of pathological conditions or diseases that involve one (or more) of somatostatin receptors.

Somatostatin (SST) is a cyclic tetradecapeptide, which was first isolated from the hypothalamus as a substance that inhibits growth hormone (Brazeau P. et al., Science 1973, 179, 77-79). He also acts as neuroparalytic in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995, 16, 427-442). Molecular cloning has allowed to prove that the biological activity of somatostatin directly depends on the family of five membrane-bound receptors.

The diversity of biological functions of somatostatin caused the research to try to identify the relationships between the structure and the efficiency of peptide analogues to the receptor somatostatin, which led to the discovery of the 5 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). Currently actively studied the functional role of these receptors. Affinity to different subtypes of somatostatin receptors was associated with the treatment of the following disorders/diseases. Activation subtypes 2 and 5 was associated with the inhibition of growth hormone (GH) and, more specifically, with the suppression of adenoma secreting growth hormone (acromegaly), and adenomas secreting the hormone TSH. Activation of subtype 2, but not subtype 5, associated with the treatment of adenomas secreting prolactin. Other indications associated with activation of subtypes of somatostatin receptors are restenosis, inhibition of the secretion of insulin and/or glucagon and, in particular, diabetes mellitus, hyperlipidemia, insensitivity to insulin. Syndrome X, angiopathy, proliferative retinopathy, the phenomenon down and nephropathy; inhibition of gastric secretion of acid and, in particular, gastric ulcers, intradermal and pancreatectomy fistula, irritable bowel syndrome, syndrome, Dumping syndrome, watery diarrhea, diarrhea, AIDS-related diarrhea caused by chemotherapy, acute or chronic pancreatitis and secreting gastrointestinal cancer; cancer treatment, such as hepatoma; inhibition of angiogenesis, treatment is the development of inflammatory disorders, such as arthritis, chronic rejection of allografts; angioplasty; prevention of bleeding transplanted vessels and gastrointestinal bleeding. Agonists of somatostatin can also be used to reduce the weight of the patient.

Of pathological disorders associated with somatostatin (J.P. Moreau et al., Life Sciences, 1987, 40, 419; A.G. Harris et al., The European Journal of Medicine, 1993, 2, 97-105), can be, for example, are: acromegalia, hypophyseal adenomas, Cushing disease, gonadotropinum and prolactinoma, secondary catabolic effects of glucocorticoids, insulin-dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, gastroenteropancreatic endocrine tumor with carcinoid syndrome, Utama (VIP - vasoactive intestinal peptide), insulinoma, nesidioblastosis, hyperinsulinemia, glucagonoma, gastrinoma and syndrome Zollinger-Ellison, GRF, as well as acute bleeding varicose veins of the esophagus, gastro-esophageal reflux, gastroduodenal reflux, pancreatitis, skin and pancreatic fistula and also diarrhoea, persistent diarrhoea syndrome acquired immunosuppression, chronic secretory diarrhea, diarrhea caused by irritable bowel syndrome, disorders associated peptide, gastrin releasing, pathology, subject to the intestinal transplants, portal hypertension and bleeding varicose veins in patients with cirrhosis, gastrointestinal bleeding, bleeding gastro-dvenadcatiperstnoy ulcers, Crohn's disease, systemic sclerosis, dumping-syndrome, small intestine, hypotension, scleroderma and medullary thyroid carcinoma, diseases caused by cellular hyperproliferation, such as cancers and, in particular, breast cancer, prostate cancer, thyroid cancer, and pancreatic cancer and colorectal cancer, fibrosis and, in particular, fibrosis of the kidney, liver fibrosis, lung fibrosis, fibrosis of the skin, as well as fibrosis of the Central nervous system, nasal fibrosis and fibrosis caused by chemotherapy, and in other areas of therapy: headaches, including headaches, caused by pituitary tumors, pain, panic attacks, chemotherapy, scarring, renal insufficiency due to stunted growth, obesity and obesity growth retardation, stunted growth of the uterus, skeletal dysplasia, Noonan syndrome, apnea during sleep, graves ' disease, polycystic ovarian disease, false cyst and the pancreatic ascites, leukemia, meningioma, cancer cachexia, inhibition of the pylorus of the stomach, psoriasis, and Alzheimer's disease. You can also mention osteoporosis.

The applicant has found that op is below sledge compounds of General formula I possess affinity and selectivity in respect of somatostatin receptors. Because somatostatin and its peptide analogs often have poor oral bioavailability and poor selectivity (S. Robinson, Drugs of the Future, 1994, 19, 992; Reubi J.C. et al., TIPS, 1995, 16, 110), these compounds representing ones agonists or antagonists of somatostatin, can be successfully used for the treatment of pathological conditions or diseases, such as those listed above, and are involved in one (or more) of somatostatin receptors. These compounds can be advantageously used for the treatment of acromegaly, pituitary adenomas and endocrine gastroenteropancreatic tumors, manifested in the form of carcinoid syndrome.

Compounds of the present invention correspond to General formula I:

in racemic form, in the form of enantiomers or any combination of these forms, in which:

R1 denotes a radical (C1-C12)-alkyl, -(C0-C6)-alkyl-C(O)-OZ1, -(C0-C6)-alkyl-C (O)-NH-(CH2)p-Z2 or possibly substituted aryl; Z1 represents N, radical (C1-C6)-alkyl, - (CH2)p-aryl; Z2 denotes an amino radical, a (C1-C12) -alkylamino, (C3-C8)-cyclooctylamino, N,N-di(C1-C12)-alkylamino, -NH-C(O)-O-(CH2)p-phenyl, -NH-C(O)-O-(CH2)p-(C1-C6)-lkyl, possibly substituted carbocyclic or heterocyclic aryl or possibly substituted non-aromatic heterocyclic radical;

R2 denotes H, (C1-C12)-alkyl or possibly substituted aryl;

R3 denotes H or (CH2)p-Z3;

Z3 denotes a (C1-C12)-alkyl, (C1-C12)-alkenyl, (C3-C8-cycloalkyl, -Y1- (CH2)p-phenyl- (X1)n, -S-(C1-C12)-alkyl, -S-(C1-C12)-alkyl-S-S-(C1-C12) -alkyl, possibly substituted carbocyclic or heterocyclic aryl, and in particular, one of the following radicals:

possibly substituted non-aromatic heterocyclic radical, a radical bis-arylalkyl or giarelli, or the radical:

Y1 represents O, S, NH or is absent;

R4 represents -(CH2)p-Z4;

Z4 denotes amino, (C1-C12)-alkyl, (C3-C8-cycloalkyl, (C1-C12)-alkylamino, N/N-di (C1-C12) -alkylamino, amino-(C3-C6-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6-cycloalkyl-(C1-C6)-alkyl, carbocyclic or heterocyclic aminoaryl, (C1-C12)-alkoxy, (C1-C12)-alkenyl, -N-C(O)O-(C1-C6)-alkyl, possibly substituted ka is bottlesi or heterocyclic aryl, possibly substituted non-aromatic heterocyclic radical, bis-arylalkyl, giarelli or one of the following radicals:

or Z4 denotes a radical N(R6) (R7), where R6 and R7 together with the nitrogen atom to which they are attached, form a 5-7-membered heterocycle;

R5 denotes H, - (CH2)p-C (O)-(CH2)p-Z5, -(CH2)p-Z5, -(CH2)p-OZ5 or - (C0-C6)-alkyl-C(O)-NH-(CH2)p-Z5, Z5 denotes a possibly substituted radical selected from the group comprising the radicals (C1-C12)-alkyl, benzo[b]thiophenyl, phenyl, naphthyl, benzo[b]furanyl, thiophenyl, isoxazolyl, indolyl and

provided that possibly substituted radical or possibly substituted phenyl may be substituted by one or more substituents, each independently preferably selected from the group comprising the radicals Cl, F, Br, I, CF3, NO2HE, NH2CN, N3, -OCF3, (C1-C12)-alkyl, (C1-C12)-alkoxy, -(CH2)p-phenyl-(X1)g, -NH-CO-(C1-C6)-alkyl, -NH-C(O)O-(C1-C6)-alkyl, -S-(C1-C6)-alkyl, -S-phenyl-(X1)q, -O-(CH2) -phenyl-(X1)q, -(CH2)p-C(O)-O-(C1-C6)-alkyl, -(CH2)p-C(O)-(C1-C6-alkyl, -O-(CH2)p-NH2, -O-(CH2)p-NH-(C1-C6)-alkyl, -O-(CH2)p-N-di(C1-C6)-alkyl and -(C0-C12)-alkyl-(X1)q;

X1, if present, is independently selected from the group comprising the radicals H, Cl, F, Br, I, CF3, NO2HE, NH2CN, N3, -OCF3, (C1-C12)-alkyl, (C1-C12)-alkoxy, -S-(C1-C6)-alkyl, -(CH2)p-amino, - (CH2)p-NH-(C1-C6)-alkyl, -(CH2)p-N-di(C1-C6)-alkyl, -(CH2)p-phenyl and -(CH2)p-NH-(C3-C6-cycloalkyl;

R, if present, is independently 0 or an integer from 1 to 6;

q, if present, is independently an integer from 1 to 5;

X denotes O or S;

n is 0 or 1, and, finally,

when n is 0, m is 1, 2 or 3, and when p is 1, m is 0 or 1.

According to one preferred variants of the invention, compounds of General formula I are those in which R5 is N.

Compounds of General formula I may in some cases contain more than one asymmetric center. In this case, the diastereomers, or any mixture of diastereomers are also included in the invention. For example, when compounds of General formula I has two asymmetric centre, the invention includes compounds of General formula I with the config of the walkie-talkies "R,S". "S,R". R,R and S,S', and any mixture with different ratios of the latter.

In the present invention the alkyl radicals may be normal or branched. Under-alkyl, unless specified particularly, refers to a normal or branched alkyl radical containing from 1 to 6 carbon atoms. Under cycloalkyl, if not particularly refined, refers to monocyclic carbon system containing from 3 to 7 carbon atoms. Under alkenyl, if not specified particularly, refers to a normal or branched alkyl radical containing from 1 to 6 carbon atoms and having at least one unsaturation (double bond). Under quinil, if not specified particularly, refers to a normal or branched alkyl radical containing from 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). Under carbocyclic or heterocyclic aryl refers to carbocyclic or heterocyclic system containing at least one aromatic cycle, and this system is called heterocyclic, if at least one of forming the system cycles contains at least one heteroatom (O, N, or S). Under the aryl, if not particularly refined, refers to carbocyclic system containing at least one aromatice the cue cycle. Under halogenation refers to an alkyl radical, in which at least one of the hydrogen atoms (and possibly all of the hydrogen atoms replaced by halogen atom. Under non-aromatic heterocyclic radical is meant heterocyclic system containing a single aromatic cycle, and at least in one of its forming cycles with at least one heteroatom (O, N, or S).

Under radicals, alkylthio, alkoxy, halogenated, halogenoalkane, aminoalkyl, alkylamino, alkenyl, quinil or arylalkyl means, respectively, radicals, alkylthio, alkoxy, halogenated, halogenoalkane, aminoalkyl, alkylamino, alkenyl, quinil or arylalkyl, in which the alkyl radical has the meaning specified above.

Under the radical of N,N-di(C1-C12)-alkylamino refers to a radical of dialkylamino, two alkyl radicals which, which substituents at the nitrogen atom may be independently contain from 1 to 12 carbon atoms.

As a normal or branched alkyl having from 1 to 6 carbon atoms, assumed, in particular, radicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl and isohexyl. As cycloalkyl assumed, in particular, radicals: cyclopropyl, cyclobutyl, cyclopentyl, cyclohe the forces and cycloheptyl. As a carbocyclic or heterocyclic aryl assumed, in particular, radicals: phenyl, naphthyl, pyridyl, furyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofuran, benzothiophene and phthalimides. As a carbocyclic or heterocyclic arylalkyl assumed, in particular, radicals: benzyl, phenylethyl, phenylpropyl, phenylbutyl, intolerance and phthalimidobutyl.

If the chemical structure is attached arrow, the latter indicates the place of attachment. For example:

denotes a radical aminoethyl.

If the depicted arrow intersects bi - or tricyclic group, this arrow indicates that this bi - or tricyclic group may be attached at any of the places of joining in any of its aromatic cycles. For example:

denotes a radical, which is attached at any position in the benzene cycle.

In particular, compounds of General formula I according to the invention may be such that:

R1 denotes a possibly substituted aryl radical;

R2 denotes H or an alkyl radical;

R3 denotes one of the following radicals:

;

R4 denotes one of the following radicals:

R5 denotes H or an alkyl radical.

Compounds of General formula I are, predominately, in which:

R1 denotes a phenyl radical, possibly substituted by a halogen atom, or a radical (C1-C12)-alkyl, (C1-C12)-alkoxy or nitro;

R2 and R5 represent H or alkyl;

R3 denotes H or (CH2)p-Z3;

Z3 denotes a (C1-C12)-alkyl, (C3-C3-cycloalkyl, -Y1-(CH2)p-phenyl-(X1)npossibly substituted carbocyclic or heterocyclic aryl radical, possibly substituted non-aromatic heterocyclic radical, bis-arylalkyl, giarelli or one of the following radicals:

Y1 represents O, S, NH or is absent;

R4 denotes H or (CH2)p-Z4;

Z4 denotes amino, (C3-C8-cycloalkyl, (C1-C12)-alkylamino, N, N-di (C1-C12) -alkylamino, amino-(C3-C6-cycloalkyl, amino (C1-C6)-alkyl (C3-C6-cycloalkyl (C1-C6)-alkyl, carbocyclic or hetero Klionsky aminoaryl, possibly substituted carbocyclic or heterocyclic aryl radical, possibly substituted non-aromatic heterocyclic radical, bis-arylalkyl, giarelli or one of the following radicals:

provided that possibly substituted radical or possibly substituted phenyl may be substituted by one or more substituents, each of which preferably independently from each other selected from the group of radicals, which includes:

Cl, F, Br, I, CF3, NO2HE, NH2CN, N3, -OCF3, (C1-C12)-alkyl, (C1-C12)-alkoxy, -(CH2)p-phenyl-(X1)q, -NH-CO-(C1-C6)-alkyl, -NH-C(O)O-(C1-C6)-alkyl, -S-(C1-C6)-alkyl, -S-phenyl-(X1)q, -O-(CH2)-phenyl-(X1)q, -(CH2)p-C(O)-O-(C1-C6)-alkyl, -(CH2)p-C(O)-(C1-C6)-alkyl, -O-(CH2)p-NH2, -O-(CH2)p-NH-(C1-C6)-alkyl, -O-(CH2)p-N-di(C1-C6)-alkyl) and -(C0-C12)-alkyl-(X1)q;

X1, if present, is independently selected from the group comprising the radicals H, Cl, F, Br, I, CF3, N02HE, NH2CN, N3, -OCF3, (C1-C12)-alkyl, (C1-C12)-alkoxy, -S-(C1-C6)-alkyl, -(CH2)p-amino, -(CH2) p-NH-(C1-C6)-alkyl, -(CH2)p-N-di((C1-C6)-alkyl), -(CH2)p-phenyl and -(CH2)p-NH-(C3-C6-cycloalkyl;

R, if present, is independently 0 or an integer from 1 to 6;

q, if present, is independently an integer from 1 to 5;

X denotes O or S;

n is 0 or 1, and, finally,

when n is 0, m is 1, 2 or 3, and when n is 1, m is 0 or 1.

More preferably, when the compounds of General formula I are those in which:

R1 denotes a phenyl radical, possibly substituted by a halogen atom, or a radical (C1-C12)-alkyl, (C1-C12) -alkoxy or nitro;

R2 and R5 represent H or alkyl;

R3 represents (CH2)p-Z3;

Z3 denotes a (C3-C8-cycloalkyl or possibly substituted radical selected from the radicals: phenyl, naphthyl, furyl, thiophenyl, indolyl, pyrrolyl and benzothiophenes;

R4 represents (CH2)p-Z4;

Z4 denotes amino, (C1-C12)-alkylamino, N,N-di ((C1-C12)-alkyl)amino, or amino (C1-C6)-alkyl(C3-C6-cycloalkyl (C1-C6)-alkyl;

X represents S;

R, if present, independently denotes 0 or an integer from 1 to 6;

m denotes 0, 1 or 2; and, finally, n is 0 or 1.

Even more preferably, when the joint is of the present invention are the compounds:

- following sub-formula (I):

in which:

R'3 represents one of the following radicals:

and R'4 denotes one of the following radicals:

;

- following sub-formula (I)b:

in which:

R'3 represents one of the following radicals:

and R'4 denotes one of the following radicals:

- below under formula (1)with:

in which:

R'3 represents one of the following radicals:

and R'4 denotes one of the following radicals:

In addition, the invention relates to methods of producing the above compounds of General formula I (also suitable to obtain the corresponding compounds of sub-formula (I)a (I)b and (dc).

The above compounds of General formula I, in which n is 0 and X denotes O or S, can be obtained by the interaction in an aprotic solvent compounds to the following General formula II:

in which m, R1, R2, R3 and R5 have the same meanings as in formula I, and the radical O-GP is leaving a protective group, derived from an alcohol, in particular a group, benzyloxy, methoxy or tert-butoxy, isocyanate or isothiocyanato General formula III:

in which R4 and X have the same meanings as in General formula I,

mainly in the presence of a tertiary base for about 1 to 24 hours at temperatures mainly in the range from 20 to 60°C.

The above compounds of General formula I, in which n is 1 and X denotes O or S, can be obtained by the interaction in an aprotic solvent compounds to the following General formula IV:

in which m, R1, R2, R3 and R5 have the same meanings as in formula I, and the radical O-GP is going protection of the Oh group, derived from alcohol, in particular group benzyloxy, methoxy or tert-butoxy, isocyanate or isothiocyanato General formula III:

in which R4 and X have the same meanings as in General formula I,

mainly in the presence of a tertiary base for about 1 to 48 hours at temperatures mainly in the range from 20 to 70°C.

Aprotic solvent in the above processes predominantly polar and may, in particular, to be THF or dichloromethane. The tertiary base may, for example, be triethylamine or N,N-diisopropylethylamine.

The invention also provides new intermediate compounds for the synthesis used to obtain the compounds of General formula I. These compounds, the precursors of compounds of General formula II and IV - meet the General formula V:

in which:

R1, R2, R3 and R5, m and n have the same meanings as in formula I;

and the radical O-GP is leaving a protective group, derived from an alcohol, in particular a group, benzyloxy, methoxy or tert-butoxy.

Preferred intermediate compounds of General formula V are the following connections:

Benzyl ester of (2S)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoic acid;

Benzyl ether of (2R)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoic to the slots;

Benzyl ester of (2S)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butane acid;

Benzyl ether of (2R)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butane acid;

Benzyl ester of (3R)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoic acid;

Benzyl ester of (3S)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoic acid.

The subject invention are the above compounds of General formula I, (I)a (I)b and (1)or their pharmaceutically acceptable salts as a drug. The invention relates also to pharmaceutical compositions containing the above compounds or their pharmaceutically acceptable salts, and to their use for the preparation of drugs intended for the treatment of pathological conditions or diseases that involve one (or more) of somatostatin receptors.

In particular, the above-described compounds of General formula I, (I)a (I)b and (1)or their pharmaceutically acceptable salts can be used for the preparation of drugs intended for the treatment of pathological conditions or diseases related to the group the following pathological conditions or diseases: acromegalia, hypophyseal adenomas, Cushing disease, gonadotropinum and prolactinoma, secondary catabolic effects of glucocorticoids, insulin dependent diabetes, diabetic d is ineptia, diabetic nephropathy syndrome X, the phenomenon down, angiopathy, angioplasty, hypertenion, gigantism, gastroenteropancreatic endocrine tumor with carcinoid syndrome, VI Roma, insulinoma, nesidioblastosis, hyperinsulinemia, glucagonoma, gastrinoma and syndrome Zollinger-Ellison, GRF, as well as acute bleeding varicose veins of the esophagus, ulcers, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, skin and pancreatic fistula and, in addition, diarrhoea, persistent diarrhoea syndrome acquired immunosuppression, chronic secretory diarrhea, diarrhea caused by irritable bowel syndrome, diarrhea caused by chemotherapy, disorders due peptide, gastrin releasing, secondary pathology, caused by intestinal grafts, portal hypertension, and bleeding varicose veins in patients with cirrhosis, gastrointestinal bleeding, bleeding gastro-dvenadcatiperstnoy ulcers, bleeding of the transplanted vessels, Crohn's disease, systemic sclerosis, dumping-syndrome, small intestine, hypotension, scleroderma and medullary thyroid carcinoma, diseases caused by cellular hyperproliferation, such as cancers and, in particular, breast cancer, prostate cancer, thyroid cancer as the drive, as well as pancreatic cancer and colorectal cancer, fibrosis and, in particular, fibrosis of the kidney, liver fibrosis, lung fibrosis, fibrosis of the skin and fibrosis of the Central nervous system, nasal fibrosis and fibrosis caused by chemotherapy, and in other areas of therapy: headaches, including headaches, caused by pituitary tumors, pain, inflammatory disorders such as arthritis, panic attacks, chemotherapy, scarring, renal insufficiency due to stunted growth, obesity and obesity growth retardation, stunted growth of the uterus, skeletal dysplasia syndrome Noonan, apnea during sleep, graves ' disease, polycystic ovarian disease, false cyst and the pancreatic ascites, leukemia, meningioma, cancer cachexia, inhibition of the pylorus of the stomach, psoriasis, chronic rejection of allografts, as well as Alzheimer's disease and, finally, osteoporosis.

Preferably, the above-described compounds of General formula I, (I)a (I)b and (1)or their pharmaceutically acceptable salts can be used for the preparation of drugs intended for the treatment of pathological conditions or diseases from the group of pathological conditions or diseases, which includes acromegalia, hypophyseal adenomas and endocrine gastroenteropancreatic tumors show is already in the form of carcinoid syndrome, and gastrointestinal bleeding.

Under a pharmaceutically acceptable salt refers, in particular, salt adducts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate, or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, pamoate, oxalate and stearate.

In the scope of the present invention also includes (when they are suitable for use) salts formed with bases such as sodium hydroxide or potassium. Other examples of pharmaceutically acceptable salts, you can refer to "Pharmaceutical salts", J.Pharm. Sci. 66:1 (1977).

The pharmaceutical composition may take the form of a solid, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and wax.

Pharmaceutical compositions containing a compound of the invention may also be in liquid form, for example in the form of solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, is also their mixtures in different ratios in the water. As suspensions can be, in particular, suspensions of microparticles slow release containing the active principle (in particular microcapsules of polyacrilamide copolymer (PLGA), see, for example, US patents 3773919, EP 52510 or EP 58481 or patent application PCT WO 98/47489), which make possible the introduction of a daily dose, calculated for the period from several days to several weeks.

The introduction of a medicinal product according to the invention can be carried out by topical, oral, parenteral, intramuscular, etc.

Featured injected dose of a medicinal product according to the invention is from 0.1 mg to 10 g depending on the applied active compounds.

These compounds can be obtained using methods described below.

OBTAINING COMPOUNDS of the INVENTION

OBTAINING DERIVATIVES of IMIDAZOLE

General procedure:

i) Obtaining imidazole group method cyclization

The amino acid is converted into its cesium salt, using cesium carbonate in a polar solvent such as, for example, a mixture of DMF/N2About (1:1) or EtOH/H2O (1:1). Then get ester using a suitable Bratton in a polar aprotic solvent, such as anhydrous DMF. Removed by filtering the resulting cesium bromide and add ACET is tons of ammonium in an aprotic solvent, having a high boiling point, such as xylene or toluene, or in an acidic proton solvent, for example acetic acid. The mixture is refluxed with trap Dean-stark during the time from half an hour to one hour. In the diagram below, PG1 is a protective group, predominantly urethane, such as t-Boc or benzylcarbamoyl, a PG2 is a protective group, mainly benzyl group.

or

ii) N-substitution in the imidazole group:

In some cases, to obtain compounds of General formula I, in which R5 is not H, N-substitution in the imidazole group is carried out using a reaction, which is described below.

The solution obtained in the previous stage intermediate compound, an alkylating agent, such as α-Bratton, α-bromine-containing ester, alkyl - or arilbred, in the presence of organic or inorganic bases (possibly immobilized on a resin, such as polystyrene resin) in an aprotic solvent such as THF, acetonitrile or DMF is heated at a temperature of from 20 to 80°C for from 2 to 48 hours. Getting benzyl ester (2S)-2-[(tert-butoxycarbonyl)-amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoic acid

A solution of Boc-L-Asp-OBn (12 g, 37,1 mmol) and cesium carbonate (6,05 g, 0.5 EQ.) in EtOH/H2O (1:1.7 ml) is stirred for approximately 30 minutes at approximately 20°and then evaporated under reduced pressure and about 40°C.

To the resulting salt dissolved in 130 ml dry DMF, add 25 ml of 2-bromoacetophenone (7,38 g, 1 EQ.) in dry DMF. The mixture is stirred for about 1 hour at about 20°in argon atmosphere, and then evaporated under reduced pressure. Add ethyl acetate (100 ml), after which the mixture is filtered, rinsing CsBr with ethyl acetate, and the filtrate evaporated under reduced pressure.

A solution of the obtained residue and ammonium acetate (58 g, 20 EQ.) in xylene (280 ml) is refluxed for approximately half an hour at approximately 140°C. an Excess of NH4OAc and water is removed by means of traps Dean-stark. The reaction course is monitored by means of thin layer chromatography (TLC, eluent: ethyl acetate/heptane 1:1). After this mixture, the temperature of which was adjusted to approximately 20°With, successively washed with water, saturated solution of NaHCO3to obtain an alkaline pH and then with brine until neutral pH. The organic phase is dried over Na2S04and evaporated under reduced pressure.

Purification of the obtained residue flash chromatography on silica gel (eluent: atilas the tat/heptane 1:1) gives the target compound (8.2 g, 52%).

NMR (1H, 400 MHz, CDCl3): of 7.64-7,14 (m, 11N, N arene.); 5,95 (d, 1H, NHBoc); to 5.21-5,13 (AB, 2H, OCH2Ph, JAB=12 Hz); to 4.73 (m, 1H, CH); 3,30 (m, 2H, CH2); to 1.42 (s, N, (CH3)3C).

SM/CL: calculated molmasse 421/2; m/z = 422,2 (M+H).

Using a procedure similar to that described for benzyl ester (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoic acid, obtained the following compounds:

Stage release

General methods: N-Boc-protected derivatives of imidazole is treated with an organic or inorganic acid, such as triperoxonane acid or hydrogen chloride (aqueous or gaseous) in an aprotic solvent, such as dichloromethane or ethyl acetate at a temperature in the range from 0 to 25°C for 0.5 to 5 hours.

Getting dihydrochloride benzyl ester of (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-aminopropanoic acid

Through a solution of benzyl ester of (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-[(tert-butoxycarbonyl)aminopropanoic acid (5 g) in ethyl acetate (120 ml) at 0°let the stream of dry HCl until TLC (eluent: 100%ethyl acetate) shows complete disappearance of the parent compound. The resulting mixture is then evaporated under reduced pressure. To the obtained solid substance is added diethyl ether and the mixture filtered. The dihydrochloride washed several times with dichloromethane and then diethyl ether and dried under reduced pressure, obtaining 4.6 g of target compound (yield 98%). NMR (1H, 400 MHz, DMSO d6): of 9.21 (user., 2H, NH); 8,03-7,28 (m, N arene., 11N); 5,10 (s, 1H, OCH2Ph); 5,04 (m, 1H, CH); 3,61 (DD, 1H, CH2, 3J=9 Hz, 2J=17,0 Hz); 3,39 (DD, 1H, CH2', 3J=5.5 Hz, 2J=17,0 Hz).

SM/CL: calculated mol. weight 321,2; m/z=322,1 (M+H).

Using a procedure analogous to that described for the dihydrochloride benzyl ester of (3S)-3-(4-phenyl-1H-imidazol-2-yl)aminopropanoic acid, obtained the following compounds:

The REACTION of N-ALKYLATION

General method: to a free amine of formula (a) or (b) operate the aldehyde in a proton or an aprotic solvent, preferably in dichloromethane or tetrahydrofuran, in the course of time from 1 to 15 hours at 20 to 50°C. the Formed Imin then restore using a reducing agent, preferably triacetoxy the reed sodium or cyanoborohydride sodium in the presence or in the absence of acid, such as acetic acid, at a temperature in the range from 20 to 50°during the time from 0.2 to 5 hours. N-alkilirovanie connection allocate the addition of water and extraction with subsequent flash chromatography on silica gel or crystallization.

Getting benzyl ester (2S)-4-(4-phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butane acid

To a solution of benzyl ester of (2S)-2-amino-4-(4-phenyl-1H-imidazol-2-yl)butane acid in free base form (3.6 g, 1 EQ.) in tetrahydrofuran (hereinafter THF, 40 ml) was added thiophene-3-carboxaldehyde (1 ml, 1 EQ.). The mixture is stirred for 15 hours at approximately 20°With and diluted by addition of 50 ml of tetrahydrofuran, then added NaBH(OAc)3(4,73 g, 2 EQ.). After stirring for 1 hour at approximately 20°the reaction is stopped by addition of water (40 ml), then add ethyl acetate (100 ml). After separation of the phases by decantation and extraction, the combined organic phases are washed with brine, dried over Na2SO4and then evaporated under reduced pressure and 40°C. Purification with flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) gives the target compound as a yellow oil (is 3.08 g, yield 66%). NMR (1H, 400 MHz, CDCl3): 7,62? 7.04 baby mortality (m, 15 NM, N arene., NH); is 5.18 (s, 2H, OCH2); a 3.87 at 3.69 (AB, 2H, CH2NH, 2JAB= 13 Hz); 3,38 (DD 1H, CHNH, 3J = 4.5 Hz, 2J = 8.5 Hz); 2,98 (m, CH2CH); is 2.88 (m, 1H, CH2CH); 2,17 (m, 1H, CH2); of 1.97 (m, 1H, CH2). SM/CL: calculated molmasse 431,2; m/z = 432,2 (M+H); m/z = 430,8 (M+H).

Using a procedure similar to that described for benzyl ester (2S)-4-(4-phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butane acid, obtained the following compounds (in two enantiomeric forms):

In the above formulas, R3 denotes one of the following radicals:

RECEIVING HYDANTOINS AND THIOHYDANTOINS

General procedure:

On amine of the formula II in which m, R1, R2, R3 and R5 have the same meanings as in General formula I, and the radical O-GP is leaving a protective group, derived from an alcohol, in particular a group, benzyloxy, methoxy or tert-butoxy apply the isocyanate or isothiocyanato General formula R4-NCX, in which R4 has the same meaning as in General formula I, in the presence or in the absence of tre the ranks of the base, such as triethylamine or N,N-diisopropylethylamine, in an aprotic solvent, mainly tetrahydrofuran or dichloromethane, at a temperature in the range from 20 to about 60°and in the course of from 1 to about 24 hours. Formed as or thiohydantoin can be selected with the output from 60 to 95% or flash chromatography on silica gel or by adding to the reaction mixture nucleophilic reagent to the polymer carrier, such as aminomethylpropanol resin (purchased from the firm Novabiochem) followed by filtration and evaporation of the filtrate.

When R4 denotes a radical having a terminal primary amino group (for example, R4 is aminoethyl, aminopropyl and so on), the reagent is not R4-NCX and the corresponding compound in which the amino group protected with a suitable protecting group, for example group, tert-butoxycarbonyl. Thus, to obtain compounds of General formula I is required by the final stage of release (carried out in normal conditions, for example by treatment with an acid).

Getting some not commercially available isothioscyanates General formula III

These compounds are obtained as follows: on the primary amine of General formula R4-NH2apply a mixture of carbon disulfide and N-cyclohexylcarbodiimide-N-metrolotio Inoi resin in an aprotic solvent, preferably in tetrahydrofuran or dichloromethane, in the course of time from 1 to 18 hours at 20 to 50°C. the resulting isothiocyanate allocate filtering ritterband the glass, followed by evaporation of the filtrate.

Getting 6-isothiocyanato-N,N-dimethyl-1-aminohexyl

To a suspension of N-cyclohexylcarbodiimide-N-methylpredisolone resin (7,8 g, 1.1 EQ.; purchased from the firm Novabiochem; the concentration of 1.95 mmol/g) in anhydrous THF (120 ml) was sequentially added dropwise carbon disulfide (8,3 ml, 10 EQ.) and a solution of N,N-dimethyl-1,6-diaminohexane (2 g, 1 EQ.) in THF (10 ml). The suspension is stirred for 2 hours at approximately 20°and then filtered on ritterband glass. The filtrate is then evaporated to dryness under reduced pressure and 40°receiving a desired isothiocyanate derivative (2.6 g, yield 93%).

NMR1H, 400 MHz, CDCl3that δ): 3,50 (t, 2H), 2,24 (t, 2H), 2,20 (C, 6N), by 1.68 (q, 2H), 1,50 to 1.31 (m, 6N).

Using a procedure similar to that described for 6-isothiocyanato-N,N-dimethyl-1-aminohexyl, received the following connections:

Receipt of (5S)-1-(1H-indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)those who]-2-thioxo-4-imidazolidinone

To a solution of benzyl ester of (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butane acid (93 mg, 1 EQ.) in THF (2 ml) is added 4-nitrophenylacetylene (43 mg, 1.2 EQ.). The mixture is stirred for 2 hours at approximately 20°and diluted with 4 ml of THF, and then add aminomethylpropanol resin (purchased from the firm Novabiochem, concentration of 3.2 mmol/g, 125 mg, 2 EQ.) and then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20°C, then filtered on ritterband glass. The filtrate is evaporated to dryness under reduced pressure and 40°With (to remove excess of triethylamine to the joint process of evaporation with dichloromethane). Purification with flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) gives the target compound (90 mg, yield 84%).

NMR (1H, 400 MHz, CDCl3): 8,24-to 7.09 (m, 17H, H arene., NH); 5,88, with 4.64 (AB, 2H, CH2N, 2JAB= 15 Hz); 3,38 (DD, 1H, CH, 3J = 3.0 Hz, 2J = 8.5 Hz); 2,92 (m, 2H, CH2CH); is 2.74 (m, 1H, CH2); 2,24 (m, 1H, CH2). SM/CL: calculated molmasse 536,2; m/z = 537,1 (M+H).

Using a procedure similar to that described for (5S)-1-(1H-indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-2-thioxo-4-imidazolidinone (except for the final purification with flash chromatography on silica gel, which is not mandatory), received the following connection is the link (in two enantiomeric forms):

In the above formulas, R3 denotes one of the following radicals:

a R4 denotes one of the radicals below:

Receipt of (5S)-1-(1H-indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione

To a solution of benzyl ester of (2S)-2-[ (1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butane acid (23 mg, 1 EQ.) in 2 ml of THF added 3-trifluoromethyl-phenylisocyanate (11 mg, 1.2 EQ.). The mixture is stirred for 2 hours at approximately 20°and diluted with 2 m is THF, then add aminomethylpropanol resin (purchased from the firm Novabiochem, concentration of 3.2 mmol/g, 125 mg, 2 EQ.) and then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20°C, then filtered on ritterband glass. The filtrate is evaporated to dryness under reduced pressure and 40°With (to remove excess of triethylamine to the joint. evaporation with dichloromethane)to give the target compound (25 mg, yield 92%).

NMR (1H, 400 MHz, CDCl3): 7,75-6,99 (m, 17H, H arene., NH); 2,25, of 4.44 (AB, 2H, CH2N, JAB= 15 Hz); of 3.77 (m, 1H, CH); 2,92 (m, 1H, CH2CH); is 2.88 (m, 1H, CH2CH); 2,72 (m, 1H, CH2); 2,17 (m, 1H, CH2).

SM/CL: calculated molmasse 543,2; m/z = 544,2 (M+H).

Using a procedure similar to that described for (5S)-1-(1H-indol-3-ylmethyl)-5-(2-(4-phenyl-1H-imidazol-2-yl)-ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione obtained the following compounds (in two enantiomeric forms):

In the above formulas, R3 denotes one of the following radicals:

and R4 denotes one of the following radicals:

GETTING DIHYDROPYRIMIDINE-2,4-DIONES AND 2-TAXOTERE-4-PYRIMIDINONE

General procedure:

On amine of the formula IV in which m, R1, R2, R3 and R5 have the same meanings as in General formula I, and the radical O-GP is leaving protective g is uppoi, derived from alcohol, in particular group benzyloxy, methoxy or tert-butoxy apply the isocyanate or isothiocyanato General formula R4-NCX in the presence of a tertiary base such as triethylamine or N,N-diisopropylethylamine, in an aprotic solvent, preferably in tetrahydrofuran or dichloromethane, at a temperature in the range from 20 to 70°C for from 1 to 48 hours. The compound obtained can be isolated with yields ranging from 40 to 90% or flash chromatography on silica gel or by adding to the reaction mixture nucleophilic reagent to the polymer carrier, such as aminomethylpropanol resin (purchased from the firm Novabiochem) followed by filtration and evaporation of the filtrate.

When R4 denotes a radical having a terminal primary amino group (for example, R4 is aminoethyl, aminopropyl and so on), the reagent is not R4-NCX and the corresponding compound in which the amino group protected with a suitable protecting group, for example group, tert-butoxycarbonyl. Thus, to obtain compounds of General formula I is required by the final stage of release (carried out in normal conditions, for example by treatment with an acid).

Receipt of (6S)-1-(1H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl)-2-Taxotere-4(1H)-pyrimidinone

To a solution of the benzyl ester of (3S)-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoic acid (90 mg, 1 EQ.) in 2 ml of THF added propalestinian (25 μl, 1.2 EQ.). The mixture is stirred for 15 hours at a temperature close to 40°C, and diluted with 2 ml of THF, and then add aminomethylpropanol resin (purchased from the firm Novabiochem, concentration of 3.2 mmol/g, 125 mg, 2 EQ.). The mixture is stirred for 5 hours at approximately 20°C, then filtered on ritterband glass. The filtrate is evaporated under reduced pressure and 40°C. To the residue was added 1 ml of THF and 1 ml of triethylamine. The mixture is stirred for 15 h at a temperature close to 40°S, and evaporated under reduced pressure. Purification with flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) gives the target compound (72 mg, yield 82%).

NMR (1H, 400 MHz, CDCl3): a mixture of two atropisomers: 8,69-of 6.45 (m, N, N arene., NH); 6.42 per, 4,89 (AB, 1H, CH2I , JAB= 14,5 Hz); 5,78, 5,42 (AB, 1H, CH2I , JAB= 14,5 Hz); 4,99 (m, 1H, CH); to 4.41 is 4.36 (m, 1H, CH2); 4,20-4,11 (m, 1H, CH2); 3,49, 2,94 (AB, 1H, CH2CO, JAB= 16 Hz); 3,28, 2,80 (AB, 1H, CH2CO, JAB= 16 Hz); of 1.52 (m, 1H, CH2); of 1.40 (m, 1H, CH2); 0,76, 0,62 (2m, 3H, CH3).

SM/CL: calculated molmasse 443,2; m/z = 444,2 (M+H).

Using a procedure similar to that described for (6S)-1-(1H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl) -2-Taxotere-4(1H)-pyrimidinone (except for the final purification with flash chromatography on silica gel, which n is required), received the following compounds (in two enantiomeric forms):

In the above formula, R3 represents one of the following radicals:

a R4 denotes one of the following radicals:

;

Receipt of (6S)-1- (1H-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H-imidazol-2-yl)dihydro-2,4 (1H,3H)-pyrimidinedione

To a solution of benzyl ester of (3S)-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoic acid (100 mg, 1 EQ.) in THF (2 ml) is added 4-methoxyphenylazo the Anat (40 μl, 1.2 EQ.). The mixture is stirred for 5 hours at a temperature close to 20°C, and diluted with 2 ml of THF, and then add aminomethylpropanol resin (purchased from the firm Novabiochem, concentration of 3.2 mmol/g, 138 mg, 2 EQ.). The mixture is stirred for 3 hours at a temperature close to 20°C, then filtered on ritterband glass. The filtrate is evaporated to dryness under reduced pressure and 40°C. To the residue add 2 ml THF and 2 ml of triethylamine. The mixture is refluxed for 24 h, then evaporated under reduced pressure. Purification of the residue with flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) gives the target compound (80 mg, yield 74%).

NMR (1H, 400 MHz, CDCl3): a mixture of two atropisomers: 9,67-8,96 (2s, 1H, NH); 8,49 (s, 1H, NH); 5,15, 4,36 (AB, 1H, CH2I , JAB= 15 Hz); 5.08 to, 4,69 (AB, 1H, CH2I , JAB= 15 Hz); 4,67, 4,57 (2m, 1H, CH); and 3.72 (s, 3H, och3); 3,29-and 2.79 (m, 2H, CH2WITH).

SM/CL: calculated molmasse 491,2; m/z = 492,3 (M+H).

Using a procedure similar to that described for (6S)-1-(1H-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H-imidazol-2-yl)dihydro-2,4(1H,3H)-pyrimidinedione (except for the final purification with flash chromatography on silica gel, which is not mandatory), obtained the following compounds (in two enantiomeric forms):

The above is ormula R3 denotes one of the following radicals:

;

a R4 denotes one of the following radicals:

EXAMPLES

In the who's following table summarizes the examples, obtained using the methods described above. These examples are presented as illustrations of the above procedures and in any case should not be construed as limiting the scope of the invention.

The analytical methods used to characterize

connections

The compounds obtained okharakterizovali using retention time (tr) and mass spectrometry (MH+).

a) Mass spectrometry

For carrying out mass spectrometry used a simple four-pole mass spectrometer (Micromass, model Platform)equipped with a source of electrocapillary, with a resolution of 0.8 Yes up to 50% of the minimum value.

Calibration is conducted on a monthly basis within the mass range from 80 to 1000 Yes using a calibration mixture of sodium iodide and rubidium iodide, dissolved in a mixture of isopropyl alcohol/water (1/1 by volume).

b) high performance liquid chromatography (HPLC)

For liquid chromatography system was used HPLC NR (Hewlett-Packard), including degasser on line, four-way pump, tube furnace and a UV detector with strap and diodes.

There were used different elution conditions, as it follows from the examples:

Conditions (i):

Eluent: water + 0,04% triperoxonane acid

In acetonitrile

T (min)A(%) In(%)
01000
11000
83070
103070

Flow rate: 1.1 ml/min

Injected volume: 5 ál

Column: Uptisphere ODS 3 µm 33·4,6 mm i.d.

Temperature: 40°

Conditions (ii):

Eluent: water + 0,04% triperoxonane acid

In acetonitrile

T (min)A(%)In(%)
09010
61585
101585

Flow rate: 1 ml/min

Injected volume: 5 ál

Column: Uptisphere ODS 3 µm 50·4,6 mm i.d.

Temperature: 40°

The elution conditions (i) were used to okharakterizovanie products of examples 1-479, 560-572 and 733-1040. Conditions (ii), in turn, were used for sample 480-559, 573-732 and 1041-1234. UV detection in all examples is performed at a wavelength of 220 nm.

PHARMACOLOGICAL properties of the COMPOUNDS of the INVENTION

Compounds of the present invention have been tested and can be tested for their affinity for different n is tipam of somatostatin receptors using the procedures described below.

Study of the AFFINITY FOR SUBTYPES of SOMATOSTATIN RECEPTORS PERSON

The affinity of the compounds of the invention to subtypes of somatostatin receptors 1-5 (respectively sst1sst2sst3sst4and sst5) is determined by measuring the inhibition of the connection (125I-Tyr11] SRIF-14 transfitsirovannykh cells Cho-K1.

Gene receptor sst1somatostatin man was prolongirovanne in the form of a genomic fragment. Segment > PST -XmnI 1.5 KB containing 100 base pairs retranscribing section 5', and at 1.17 KB site coding in General, and 230 base pairs of retranscribing region 3', modify by adding a linker Bg1II. The resulting DNA fragment subcloning belongs pCMV-81 BamHI site, forming plasmid expression in mammals (provided by Dr. Graeme Bell, University of Chicago). Line of cloned cells, stably expressing the receptor sst1receive by transfection in cells Cho-K1 (ATS) using the calcium phosphate method of coprecipitation. The plasmid pRSV-neo (ATS) include as a marker for selection. Line of cloned cells were selected in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), cloned in a circle and multiplied in culture.

Gene receptor sst2somatostatin person identified as genomic DNA fragment with a size of 1.7 KB BamHI-Hindlll and subclavian the th in the plasmid vector pGEM3Z (Promega), was provided by Dr. G.Bell (University of Chicago). The expression vector mammalian cell is constructed to implement a fragment of BamHI-Hindlll of 1.7 KB in sites of restriction endonucleases that are compatible with the plasmid pCMV5. Line of cloned cells obtained by transfection in cells Cho-K1 using the calcium phosphate method of coprecipitation. The plasmid pRSV-neo include as a marker for selection.

The sst receptor3allocate as genomic fragment, and a complete coding sequence contained in the fragment BamHI-Hindlll of 2.4 KB. Expressing plasmid in mammalian pCMV-h3 design implement a fragment of the NcoI-HindIII 2 KB EcoR1 site of the vector pCMV after inoculation endings and add EcoR1 linkers. Line of cloned cells, stably expressing the receptor sst3receive by transfection in cells Cho-K1 (ATS) using the calcium phosphate method of coprecipitation. The plasmid pRSV-neo (ATS) include as a marker for selection. Line of cloned cells were selected in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), cloned in a circle and multiplied in culture.

Plasmid expression of sst receptor4man, pCMV-HX, was provided by Dr. Graeme Bell (University of Chicago). This vector contains a fragment of the genome that encodes the receptor for sst4man, $ 1.4 KB NheI-NheI and 456 base pairs of netrance the dummy area 5' and 200 base pairs retranscribing section 3', cloned into the XbaI sites/EcoR1 plasmids pCMV-HX. Line of cloned cells, stably expressing the receptor sst4obtained by transfection in cells Cho-K1 (ATS) method phosphatecalcium coprecipitate. The plasmid pRSV-neo (ATS) include as a marker for selection. Line of cloned cells were selected in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), cloned in a circle and multiplied in culture.

The gene corresponding to the receptor sst5man, obtained by PCR using genomic clone λ as a probe, was delivered by Dr. Graeme Bell (University of Chicago). The resulting fragment of 1.2 KB contains 21 a couple of retranscribing section 5', fully coded site and 55 base pairs of retranscribing section 3'. The clone is implanted into the EcoR1 site of the plasmid pBSSK(+). Embedded fragment isolated in the form of a fragment HindIII-XbaI and 1.2 KB for sublimirovanny in expressing the vector in mammals, pCVM5. Line of cloned cells, stably expressing the receptor sst4receive by transfection in cells Cho-K1 (ATS) using the calcium phosphate method of coprecipitation. The plasmid pRSV-neo (ATS) include as a marker for selection. Line of cloned cells were selected in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), cloned in a circle and multiplied in culture.

Cells Cho-K1 stably expressing one of the receptors sst human cultured in medium RPMI 1640, containing 10% of fetal calf serum and 0.4 mg/ml geneticin. Cells are harvested using 0.5 mm EDTA and centrifuged at a speed of 500 g for 5 min at approximately 4°With. Centrifugal re-suspended in 50 mm Tris buffer pH 7.4 and centrifuged twice at a speed of 500 g for about 5 min at about 4°C. the Cells are lysed by the action of ultrasound and centrifuged at 39000 g for about 10 min at 4°With. Centrifugal re-suspended in the same buffer medium and centrifuged at 50000 g for 10 min at approximately 4°and membrane obtained in centrifugate stored at -80°C.

Tests on competitive inhibition of [125I-Tyr11] SRIF-14 is conducted in pairs with polypropylene plates with 96 wells. Cell membranes (10 μg protein in the well) are incubated with [125I-Tyr11] SRIF-14 (0,05 nm) for approximately 60 minutes at a temperature of about 37°With 50 mm HEPES buffer (pH 7.4)containing 0.2% serum albumin bull, 5 mm MgCl2, 200 KIU/ml Trasylol/ 0.02 mg/ml bacitracin and 0.02 mg/ml phenylmethylsulfonyl.

Associated [125I-Tyr11] SRIF-14 is separated from the free [125I-Tyr11]SRIF-14 by immediate filtration through filter plates of glass fiber GF/C Unifilter, Packard), pre-soaked in 0.1% polyethylenimine with and is using Filtermate 196 (Packard). The filters are washed with 50 mm HEPES buffer at approximately 0-4°C for approximately 4 seconds and measure the radioactivity using a counter (Packard Top Count).

Specific communication receive by subtracting nonspecific relationship (defined in the presence of 0.1 μm SRIF-14) from the total due. Data on the relationship analyzed by nonlinear regression analysis using the computer and determine values of the constants of inhibition (Ki).

Determination of agonist or antagonist nature of the compounds of the present invention is produced using the following test.

Functional test: inhibition of intracellular production of cyclic AMP (the ADR methods):

Cells Cho-K1 expressing subtypes of somatostatin receptors person (SRIF-14) were cultured on plates with 24 wells in medium RPMI 1640 with 10% fetal calf serum and 0.4 mg/ml geneticin. Wednesday replaces one day before the experiment.

Cells in 105cells 1 well washed twice 0/5 ml of new medium RPMI containing 0.2% serum albumin bull with the addition of 0.5 mm 3-isobutyl-1-methylxanthines (IBMX) and incubated for approximately 5 minutes at approximately 37°C.

The production of cyclic AMP stimulated by addition of 1 mm of Forskolin (FSK) for 15-30 minutes at approximately 37°C.

Inhibit the Mering effect of the compounds, are agonists of somatostatin, measured with the simultaneous addition of FSK (1 μm), SRIF-14 (10-12-10-6M) and test compounds (10-10-10-5M).

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

Reaction medium was removed and added to 200 ml of 0.1 G. of HCl. The number of the ADR methods measured by radioimmunoassay test Kit FlashPlate SMP991A, New England Nuclear). The results:

Tests conducted according to the above protocols, allowed us to prove that certain in this application, the compounds of General formula I possess a good affinity to at least one of the subtypes of somatostatin receptors, because the inhibition constant Ki for hundreds of tested compounds (and in particular for the compounds presented in the following tables I and II) less than 1 mm.

1. The compound of General formula I

in racemic form, in the form of enantiomers or in any comb the Nations of these forms,

in which R1 denotes phenyl,

R2 denotes H,

R3 denotes H or (CH2)p-Z3 or one of the following radicals:

Z3 denotes a (C3-C8-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl, and carbocyclic aryl selected from phenyl, naphthyl and fluorenyl and it can be substituted by one or more substituents,each of which, preferably,is independently selected from the group consisting of radicals Cl,F,Br,CF3,NO2CN, -OCF3,(C1-C12)-alkyl, (C1-C12)-alkoxy,-(CH2)p-phenyl-(XI)q-NH-CO-(C1-C6)-alkyl,-O-(CH2)p-phenyl-(XI)q and (C0-C12)-alkyl-(XI)q;

XI in each case independently selected from the group consisting of radicals of N -(CH2)R-N-di-((C1-C6)-alkyl);

and heterocyclic aryl selected from indolyl,teinila,thiazolyl,carbazolyl or radicals of the formula

and may be substituted by one or more substituents,each of which, preferably,is independently selected from the group consisting of radicals of NO2, (C1-C12)-alkyl, -(CH2)p-C(O)- (C1-C6)-alkyl;

or the radical

R4 represents (CH2)p-Z4 or;

Z4 denotes amino, (C1-C12) -alkyl, (C3-C8-cycloalkyl, cyclohexyl, substituted-CH2-NH-C(O)O-(C1-C6) -alkyl, the radical (C1-C12) -alkylamino, N,N-di(C1-C12)-alkylamino, amino- (C1-C6) -alkyl- (C3-C6-cycloalkyl- (C1-C6) -alkyl, (C1-C12)-alkoxy, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6) -alkyl, possibly substituted carbocyclic or heterocyclic aryl,

and carbocyclic aryl is phenyl and may be substituted by one or more substituents,each of which ,preferably,is independently selected from the group of radicals Cl,F,Br,CF3,NO2, NH2CN, N3,-OCF3,(C1-C12)-alkyl, (C1-C12)-alkoxy, -NH-C(O)O-(C1-C6) -alkyl, -CH2-NH-C(O)O-(C1-C6)-alkyl, -S-(C1-C6) -alkyl, O-(CH2)p-phenyl-(XI)q, -(CH2)R-C(O)-O-(C1-C6) -alkyl, -(CH2)R-C(O)-(C1-C6) -alkyl, (C0-C12)-alkyl-(XI)q;

XI in each case independently selected from the group consisting of the radicals H, (C1-C12) -alkoxy, -(CH2)R-amino and -(CH2)R-N-di-((C1-C6)-alkyl);

and g is teracycline aryl selected from Shrila or one of the radicals

or tetrahydrofuryl;

or Z4 denotes a radical N(R6)(R7), where R6 and R7 together with the nitrogen atom to which they are attached, form morpholinyl a heterocycle;

R5 denotes H,

R, if present, is independently 0 or an integer from 1 to 6;

q, if present, is independently an integer from 1 to 5;

X represents 0 or S;

n is 0 or 1, and, finally,

when n is 0, m is 1, 2 or 3, and when n is 1, m is 0 or 1,

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, characterized in that

R3 denotes one of the radicals

R4 denotes one of the radicals

provided that when the radical R4 includes the nitrogen atom, this nitrogen atom is associated with one or more hydrogen atoms in the case of mandated the tel is not specified.

3. The compound according to claim 1, characterized in that

R3 represents -(CH2)-Z3

Z3 denotes a (C3-C8-cycloalkyl or possibly substituted radical selected from phenyl, naphthyl,tanila and indolyl;

R4 represents -(CH2)-Z4,

Z4 denotes amino, (C1-C12) -alkylamino, N,N-di(C1-C12)-alkylamino or amino-(C1-C6)-alkyl(C3-C6-cycloalkyl-(C1-C6)-alkyl;

X represents S;

M is 0,1 or 2, and, finally,

n is 0 or 1.

4. The compound according to claim 3, characterized in that it is a combination of podhorany (1)

(Ia)

in which

R'3 represents one of the radicals

and R4 denotes one of the radicals

provides podhorany (1)b

(I)b

in which

R'3 represents one of the radicals

and R4 denotes Odie is from radical

provides podhorany (I)

(I)

in which

R'3 represents one of the radicals

and R4 denotes one of the radicals

5. The connection according to one of claims 1 to 4 or a pharmaceutically acceptable salt of this compound for the preparation of drugs intended for the treatment of pathological conditions or diseases that involve one (or more) of somatostatin receptors.

6. The method of obtaining compounds of General formula I under item 1, in which n is 0, wherein the compound of General formula II

where m, R1, R2, R3 and R5 have the same meaning as in

the formula I according to claim 1, and a radical ABOUT-GP is leaving a protective group, derived from an alcohol, in particular a group, benzyloxy, methoxy or tert-butoxy, expose isocyanate or isothiocyanate General formula III

R4-N=C=X, (III)

in which R4 and X have the same meanings as in General formula I according to claim 1,

in an aprotic solvent preferably in the presence of a tertiary base for about 1 to 24 hours at a temperature of preimushestvenno from 20 to 70° C.

7. The method of obtaining compounds of General formula I on p. 1,in which n is 1, characterized in that the compound of General formula IV

in which m, R1, R2, R3 and R5 have the same meanings as in formula I according to claim 1, and the radical O-GP is leaving a protective group, derived from an alcohol, in particular a group, benzyloxy, methoxy or tert-butoxy, expose isocyanate or isothiocyanate General formula III

R4-N=C=X (III)

in which R4 and X have the same meanings as in General formula I according to claim 1,

in an aprotic solvent preferably in the presence of a tertiary base for about 1 to 48 hours at a temperature mainly from 20 to 70°C.

8. The compound of General formula V

(V)

in which R1, R2, R3 and R5, m and n have the same meanings as in formula I

claim 1, and the radical O-GP is leaving a protective group, derived from an alcohol, in particular a group, benzyloxy, methoxy or tert-butoxy, as intermediate compounds in the synthesis of compounds of General formula(I).

Caetanina of claim 8,representing

Benzyl ester of (2S)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoic acid;

Benzyl ether of (2R)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoic acid;

Benzyl e is Il (2S)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butane acid; or

Benzyl ether of (2R)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butane acid

or pharmaceutically acceptable salt of these compounds.

10. The connection according to one of claims 1 to 4 or a pharmaceutically acceptable salt of this compound with affinity to somatostatin receptors, to obtain drugs.

11. Pharmaceutical composition having affinity to somatostatin receptors, containing as active principle a compound according to one of claims 1 to 4 or a pharmaceutically acceptable salt of the compound.



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

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

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

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