4-aminopiperidine derivatives, methods for their preparing, compounds, pharmaceutical composition

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

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

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

14 cl, 4 tbl, 778 ex

 

The object of this application are new derivatives of 4-aminopiperidine and methods for their preparation by synthesis in the liquid and solid phase. These products have a good affinity for certain sub-types of somatostatin receptors, especially suitable for the treatment of pathological conditions and diseases caused by one (or more) receptors somatostatin.

Somatostatin (SST) is cyclic tetradecapeptide, which was first isolated from the hypothalamus as a substance inhibiting the growth hormone (Brazeau P. et al., 11111,, Science 1973, 179, 77-79). He also acts as a neurotransmitter in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995, 16, 427-442). The molecular cloning has established that the biological activity of somatostatin is directly dependent on the family of five membrane-bound receptors.

The diversity of biological functions of somatostatin served as the basis for research aimed at the identification of the relationship between structure and activity of the peptide analogues acting on the receptor somatostatin, which was opened 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 under active study of the functions of these receptors. Affinity for R the EIT subtypes of somatostatin receptors determines the possibility of treating the following disorders/diseases. Activation subtypes 2 and 5 suppresses the growth hormone (GH), in particular, adenoma secreting GH (acromegaly), and adenomas secreting the hormone TSH. Activation of subtype 2, not affecting the subtype 5, allows to treat adenoma secreting prolactin. Other indications for treatment by activation of different subtypes of somatostatin receptors are recurrence of stenosis, suppressing the secretion of insulin and/or glucagon, in particular diabetes mellitus, hyperlipidemia, insulin resistance, syndrome X, angiopathy, proliferative retinopathy, the phenomenon down and nephropathy; inhibition of gastric secretion, in particular, peptic ulcers, intestinal and pancreatic fistulas, mucous colitis, dumping syndrome, watery stools, diarrhea, AIDS-related diarrhea caused by chemotherapy, acute or chronic pancreatitis and tumors of the gastrointestinal tract; cancer, such as hepatoma; development blood vessels, inflammatory diseases such as arthritis; chronic rejection of allografts; vascular reconstruction; prevention of bleeding from the transplanted blood vessels and the gastrointestinal tract. Agonists of somatostatin can also be used to reduce the body weight of the patient.

Among pathological disorders caused by somatostatin (J.P. Moreau et al., Life Science 1987, 40, 419; A.G. Harris et al., The European Journalof Medicine, 1993, 2, 97-105), it can be noted, for example, acromegaly, a pituitary adenoma, Cushing disease, gonadotropinum and prolactinoma, catabolic side effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrine tumors of the gastrointestinal tract and pancreas, including carcinoid syndrome, VI, insulinoma, nesidioblastosis, hyperinsulinemia, glucagonoma, ulcerative adenoma of the pancreas and the syndrome of Zollinger-Ellison, GRFoy as acute variceal bleeding, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, small bowel and pancreatic fistula; diarrhea, refractory diarrhea caused by acquired immunodeficiency syndrome, chronic secretory diarrhea, diarrhea caused by mucous colitis, disorders caused gastrointerologist peptide, secondary pathology of intestinal grafts, portal hypertension, as variceal bleeding in subjects suffering from cirrhosis, gastrointestinal bleeding, bleeding from stomach ulcers, Crohn's disease, multiple sclerosis, dumping syndrome, the syndrome of the irritable intestine, hypotension, scleroderma, and carcinoma of the thyroid gland, diseases caused by hyperproliferating to etok, such as malignant tumors, in particular breast cancer, prostate cancer, thyroid cancer, and pancreatic cancer and cancer of the colon, fibrosis, in particular the kidney fibrosis, liver fibrosis, lung fibrosis, fibrosis of the skin, fibrosis of the Central nervous system, fibrosis of the nasopharynx and fibrosis caused by chemotherapy, and other diseases, such as severe headaches, including severe headaches caused by tumors of the pituitary gland, pain, anxiety, chemotherapy, scarring, failure of kidney function due to delays in the development, obesity and developmental delay associated with obesity, delayed development of the uterus, skeletal dysplasia syndromes Noonan, seizures, sleep apnea, a disease greivsa, polycystic ovarian disease, false cyst and the pancreatic ascites, leukemia, meningioma, a tumor cachexia, pyloric stenosis, psoriasis, and Alzheimer's disease. These diseases also include osteoporosis.

The authors of the present invention have found that the connection to the following General formula have affinity and selectivity in respect of somatostatin receptors. Because somatostatin and peptide analogues are often characterized by poor bioavailability after oral administration and low selectivity (Robinson S., Dugs of the Future, 1994, 19, 992; Reubi J.C. et al., TIPS, 1995, 16, 110), the compounds of the present invention, which ones agonists or antagonists of somatostatin, can be used effectively for the treatment of the above mentioned pathological conditions or diseases caused by one (or more) somatostatin receptors. These compounds can preferably be used for the treatment of acromegaly, pituitary adenomas and endocrine tumors of the gastrointestinal tract and pancreas, including carcinoid syndrome.

Thus, an object of the present invention are compounds of General formula

in racemic, enantiomeric form or all combinations of these forms,

where R1means (C1-C6)alkyl linear or branched chain, alkenyl, quinil, the radical -(CH2)m-Y-Z11or -(CH2)m-Z12in which

Z11means optionally substituted C1-C6)alkyl or aryl;

Z12means cyano, cyclohexenyl, biphenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7)heteroseksualci, optionally substituted aryl or optionally substituted heteroaryl;

or Z12means a radical of the formula

or R1oznacza the t radical of the formula

R2means a radical of the formula-C(Y)NHX1-C(O)X2or SO2X3;

R3means a hydrogen atom, optionally substituted alkyl, alkenyl, quinil, optionally substituted aralkyl, optionally substituted heteroarylboronic radical or a radical of the formula-C(Y)-NHX1, -(CH2)n-C(O)X2, SO2X3or

X1means (C1-C15)alkyl linear or branched chain, alkenyl, quinil, the radical -(CH2)m-Y-Z21or -(CH2)pZ22in which

Z21means (C1-C6)alkyl;

Z22means cyclohexenyl, indanyl, biphenyl, (C3-C7)cycloalkyl, (C3-C7) heteroseksualci, mono - or dialkylamino, -C(O)-O-alkyl, optionally substituted aryl or heteroaryl

or Z22means a radical of the formula

X2means (C1-C10)alkyl radical with a linear or branched chain, alkanniny radical, optionally substituted phenyl radical (phenyl radical may be optionally substituted), alkynylaryl radical or a radical of the formula -(CH2)m-W-(CH2)q-Z23or -(CH2)p-U-Z24in which

Z23about the means optionally substituted C 1-C6)alkyl or aryl;

Z24means alkyl, cyclohexenyl, biphenyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)heteroseksualci, cyano, amino, mono - or dialkylamino, optionally substituted aryl or heteroaryl;

or Z24means a radical of the formula

or X2means the following radical:

where the protective group (PG) is H or tert-butyloxycarbonyl;

X3means (C1-C10)alkyl radical with a linear or branched chain, alkanniny radical, optionally substituted phenyl radical (phenyl radical may be optionally substituted), CF3or -(CH2)pZ25where

Z25means optionally substituted aryl or heteroaryl;

or X3means a radical of the formula

optionally substituted by one or more identical or different halogen-containing radicals;

Y represents an oxygen atom or sulfur;

W denotes an oxygen atom or sulfur or SO2;

U represents a covalent bond or an oxygen atom;

n is an integer from 0 to 4;

m is an integer from 1 to 6;

p is an integer from 0 to 6;

q is an integer from 0 to 2

or their additive salts with pharmaceutically acceptable mineral or organic acids, with the exception of compounds of General formula I, where R1means alkyl, alkenyl or benzyl, R2means optionally substituted benzyloxy and R3means aralkyl.

A separate object of the present invention are described above, the products of General formula I, characterized in that

i) Deputy or deputies, substitute aryl radicals represented by Z11and Z12and heteroaryl, presents Z12independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, -CF3, -OCF3, phenyl, phenoxy, aminosulfonyl;

ii) the Deputy or deputies, replacement heterologously radical represented by Z12independently selected from hydroxy and alkyl radicals;

iii) the Deputy or deputies, substitute aryl and heteroaryl radicals represented by Z22independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, aminosulfonyl, piperidinemethanol, mono - or dialkylamino, -C(O)-O-alkyl, -C(O)-alkyl or phenyl, phenoxy, phenylthio, benzyloxy and phenyl radical may be substituted;

iv) the Deputy or deputies, replacement ariline the radicals, presents Z23and Z24cycloalkyl or heteroaryl, presents Z24independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, CF3, OCF3, OCHF2SCF3, nitro, cyano, azido, hydroxy, -C(O)O-alkyl, -O-C(O)-alkyl, -NH-C(O)-alkyl, alkylsulfonyl, mono - or dialkylamino, amino, aminoalkyl, pyrrolyl, pyrrolidinyl or phenyl, phenoxy, phenylthio, benzyl, benzyloxy, and the aryl radical may be optionally substituted by one or more alkyl, CF3or halogenation;

v) the Deputy or deputies, substitute aryl or heteroaryl radicals represented by Z25independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, OCF3, nitro, cyano, -NH-C(O)-alkyl, alkylsulfonyl, amino, mono - and dialkylamino, phenyl, pyridine;

vi) Deputy, substitute the alkyl radical represented by R3is cineradiogram;

vii) the Deputy or deputies, replacement Uralkaliy radical represented by R3independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, OCF3, OCHF2SCF3, SCHF2, nitro, cyano, -C(O)O-alkyl, alkylsulfonyl, thiadiazolyl or phenyl, phenoxy, and the phenyl radical may be optionally substituted by one the or more halogenation;

viii) Deputy or deputies, replacement heteroarylboronic radical represented by R3independently chosen from radicals comprising fluorine, chlorine, bromine or nitro.

In the above definitions of "halogen" means fluorine, chlorine, bromine or iodine, preferably chlorine, fluorine or bromine. "Alkyl" (except where otherwise stated) preferably denotes an alkyl radical with a linear or branched chain having 1-6 carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, second-botilony and tert-boutigny, pentelenyi or amily, isopentenyl, neopentylene, sexily or isohexyl radicals. From alkyl radicals containing 1 to 15 carbon atoms, in addition to the above Akilov may also be called heptylene, aktalnye, monilinia, decile, modelline, tradeline or pentadecyl radicals.

"Alkenyl" except where otherwise indicated, means an alkyl radical with a linear or branched chain having 1 to 6 carbon atoms and at least one unsaturation (double bond), such as, for example, vinyl, allyl, propenyl, butenyl or pentenyl. "Quinil" except where otherwise indicated, means an alkyl radical with a linear or branched chain having 1 to 6 carbon atoms and at least one double not asiannet (triple bond), such as, for example, ethinyl, propargyl, butynyl or pentenyl.

The term "cycloalkyl" means monocyclic carbon system having 3-7 carbon atoms and preferably cyclopropyl, cyclobutyl, cyclopentene or tsiklogeksilnogo ring. "Heteroseksualci" means a saturated cycloalkyl having 2-7 carbon atoms and at least one heteroatom. Specified organic radical can contain several identical or different heteroatoms. The heteroatoms are preferably selected from oxygen, sulfur or nitrogen. As examples of geterotsiklicheskie can lead pyrolidine, pyrrolidinone, imidazolidinone, pyrazolidinone, isothiazolinone, thiazolidinone, isoxazolidinone, piperidino, pieperazinove or morpholino ring.

CNS radicals, such as, for example, methoxy, ethoxy, propyloxy or isopropylacetate, in addition, include secondary or tertiary, butoxy, pentyloxy with a linear chain, meet the above alkyl radicals. The term "lower alkylthio" preferably means the radicals in which the alkyl moiety has the above values, for example methylthio, ethylthio. The term "alkylsulfonyl" means preferably radicals in which the alkyl moiety has the above values.

"Aryl" means an aromatic radical, having the second one or more condensed rings, such as, for example, phenyl or nattily radical. "Heteroaryl" means an aromatic radical having one or more condensed rings, and at least one ring contains one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen. As an example, the heteroaryl radical can lead thienyl, purely, pyrrolidinyl, imide solely, personilnya, isothiazolinones, diazolidinyl, isoxazolidine, oxazolidine, triazolinones, peredelnyj, personilnya, pyrimidinyl, ginally, ethinally, khinoksalinona, sensationally, benzofuranyl, indolinyl, benzoxadiazole radicals.

The terms "mono - and dialkylamino" preferably mean the radicals in which the alkyl radicals have the above values, such as, for example, methylamino, ethylamino, dimethylamino, diethylamino or (methyl)(ethyl)amino.

The symbolcorresponds to the place of attachment of the radical. If the radical is not specified the place of connection, that means used to attach one of the locations present in the radical for the specified connection.

A separate object of the present invention are the above compounds of General formula I, in which

R1means (C1-C6)alkylpyridine with a linear or branched chain, the radical -(CH2)m-Y-Z11or -(CH2)mZ12where

Z11means (C1-C6)alkyl;

Z12means biphenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7)heteroseksualci, aryl or heteroaryl, optionally substituted by one or more substituents chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy,

or Z12means

Y represents an oxygen atom;

or R1means a radical of the formula

R2means a radical of the formula-C(Y)NHX1, -C(O)X2or SO2X3where

X1means (C1-C15)alkyl radical with a linear or branched chain, or -(CH2)pZ22in which

Z22means cyclohexenyl, biphenyl, (C3-C7)cycloalkyl, (C3-C7)heteroseksualci, mono - or dialkylamino, -C(O)-O-alkyl, aryl or heteroaryl, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinemethanol, -C(O)-O-alkyl, -C(O)-alkyl or phenyl,

or Z22means a radical of the formula

<> X2means (C1-C10)alkyl radical with a linear or branched chain, quinil, a radical of the formula -(CH2)m-W-(CH2)q-Z23or -(CH2)p-U-Z24in which

W means SO2;

U represents a covalent bond;

Z23means aryl radical;

Z24means cyclohexenyl, biphenyl, (C3-C7)cycloalkyl, optionally substituted aminoalkyl, aryl or heteroaryl radical, optionally substituted by one or more radicals selected from the group comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, -CF3, -OCF3SCF3, hydroxy, -C(O)-O-alkyl, mono - or dialkylamino, amino,

or Z24means a radical of the formula

or X2means

X3means a radical -(CH2)pZ25where Z25is aryl radical, optionally substituted by one or more identical or different radicals selected from alkoxy and CF3;

R3means a hydrogen atom, optionally substituted alkyl, alkanniny, heteroarylboronic radical or a radical of the formula-C(Y)-NHX1, -C(O)X2or SO2X3where

X1means a radical -(CH2)pZ22in which

Z2 means aryl radical, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, phenoxy;

X2means the vinyl radical, substituted phenyl, and the phenyl radical in turn optionally substituted by one or more halogen, or a radical -(CH2)p-U-Z24where

Z24means alkyl, (C3-C7)cycloalkyl, (C3-C7)heteroseksualci, biphenyl, amino, mono - or dialkylamino, aryl or heteroaryl, optionally substituted by one or more radicals selected from the group comprising alkoxy, bromine, chlorine, fluorine, hydroxy, CF3, nitro, amino, mono - and dialkylamino, pyrrolyl;

or X2means a radical of the formula

X3means (C1-C10)alkyl radical with a linear or branched chain, the vinyl radical, a substituted phenyl radical (phenyl radical may be optionally substituted), CF3or -(CH2)pZ25where

Z25means aryl or heteroaryl, optionally substituted by one or more substituents, independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, -NH-C(O)-alkyl, mono -, and e is alkylamino.

R1preferably means (C1-C6) alkyl radical with a linear or branched chain, the radical -(CH2)m-Y-Z11or -(CH2)m-Z12in which

Z11means (C1-C6)alkyl;

Z12means naphthyl, morpholino, biphenyl, pyrrolidinyl, replaced by oxyradicals, or phenyl, piperazinilnom, pyridinoline and indolizinyl radicals, which are optionally substituted by one or more substituents, independently selected from radicals comprising bromine, fluorine, chlorine, alkyl, alkoxy, -CF3, -OCF3,

or Z12means

Y represents an oxygen atom;

or R1means the radical following formula:

R2preferably means a radical of the formula-C(Y)NHX1-C(O)X2or SO2X3where

X1means (C1-C10)alkyl linear or branched chain or a radical -(CH2)pZ22in which

Z22means cyclohexyl, cyclohexenyl, biphenyl, morpholino, piperidino, mono - or dialkylamino, -C(O)-O-alkyl or phenyl, naphthyl or furyl, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, CF3 , OCF3, nitro, cyano, azido, piperidinemethanol, -C(O)-O-alkyl, -C(O)-alkyl or phenyl,

or Z22means a radical of the formula

X2means alkyl, quinil, the radical -(CH2)m-W-(CH2)q-Z23or -(CH2)pZ24in which

W means SO2;

Z23means phenyl radical;

Z24means cyclohexenyl, biphenyl, cyclohexyl, optionally substituted by aminoalkyl, or phenyl, nattily, benzothiazolyl, thienyl or indolinyl radical, optionally substituted by one or more radicals selected from the group comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, -CF3, -OCF3SCF3, hydroxy, -O-C(O)-alkyl, -NH-C(O)-alkyl, mono - or dialkylamino, amino, or

Z24means a radical of the formula

or X2means

X3means a radical -(CH2)pZ25in which Z25is a phenyl radical, optionally substituted by one or more identical or different radicals selected from alkoxy and CF3.

R3preferably means hydrogen atom, alkyl, alkanniny or furylmethyl radical, substituted by one or more nitroreductase, or RA is hiccuping formula-C(Y)-NHX 1-C(O)X2or SO2X3where

X1means a radical -(CH2)pZ22in which

Z22means phenyl or nattily radical, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, phenoxy;

X2means the vinyl radical, substituted phenyl radical, which is in turn substituted by one or more halogen, or a radical -(CH2)p-U-Z24where

Z24means alkyl, cyclohexyl, tetrahydrofuryl, biphenyl, amino, mono - or dialkylamino, and phenyl, indolyl, thienyl, pyridinyl, sensational and furyl, optionally substituted by one or more radicals selected from the group comprising alkoxy, bromine, chlorine, fluorine, amino, mono - and dialkylamino, nitro, hydroxy, pyrrolyl;

or X2means a radical of the formula

X3means (C1-C10)alkyl radical with a linear or branched chain, the vinyl radical, substituted phenyl, CF3or the radical -(CH2)pZ25in which

Z25means phenyl, nattily, thienyl, personilnya or diazolidinyl radical, optionally substituted by one or more substituents, regardless what about chosen from radicals, comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, -NH-C(O)-alkyl, mono - and dialkylamino;

In the most preferred case, R1means a radical -(CH2)mZ12in which m=2 and Z12means biphenyl or indolinyl radical, substituted by one or more substituents, independently selected from alkyl and CNS radicals.

In the most preferred case, R2means radicals of the formula-C(Y)NHX1and-S(O)X2in which

Y represents S;

X1means phenyl radical, optionally substituted by one or more azithramycine;

X2means -(CH2)pZ24where

p is 1, 2 or 3;

Z24means cyclohexyl, phenyl or sensational, optionally substituted by one or more radicals selected from fluorine, chlorine, bromine, iodine or-CF3.

In the most preferred case, R3means a hydrogen atom or a methyl radical.

Compounds according to this invention can be obtained in the solid or liquid phase.

A) Synthesis in the liquid phase using N-substituted piperidone

A1) Reductive amination

The specified synthesis is carried out according to the following scheme:

where R is methyl or Boc and R1has given the s above values.

The General method consists in the following: N-substituted piperidin subjected to reductive aminating (Abdel-Magid, A.F.; Maryanoff, C.A.; Carson, K.G., Tetrahedron Lett. 1990, 31, 5595-5598; Abdel-Magid, A.F.; Carson, K.G.; Harris, B.D.; Maryanoff, C.A.; Shah, R.D., J. Org. Chem. 1996, 61, 3849-3862) in anhydrous chlorinated solvents such as dichloroethane, in the presence of a primary amine (1.1 to 1.5 EQ.), reductant, such as triacetoxyborohydride sodium (1.1 to 1.5 EQ.) and acetic acid (10 wt.% in the calculation of the N-substituted piperidone). The reaction mixture is stirred for 1-4 hours at room temperature. In some cases, add the soda solution (0.1 M solution) and the mixture is stirred for 20-90 minutes. If the soda solution is not added, the reaction mixture was washed with a saturated solution of sodium bicarbonate, sodium chloride, dried over magnesium sulfate, filtered and concentrated. The desired product was then purified on a flash chromatography on silica gel.

The method of obtaining 1

tert-Butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate (C25H34N2O2M=394,56)

3,3-Diphenylpropylamine (5.8 g, 27.5 mmol), triacetoxyborohydride sodium (6,36 g, 30 mmol) and 0.5 ml of acetic acid are added to 5 g (25 mmol) of N-Boc-piperidone in 100 ml of anhydrous dichloroethane. The turbid yellow solution was stirred at room temperature for 1 hour. Then add 50 ml of races the thief soda (0.1 M solution) and the mixture is stirred for 30 minutes. The organic phase is washed with a saturated solution of sodium bicarbonate, sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 10 g of yellow solid. Specified, the solid is purified on a flash chromatography on silica gel, elwira a mixture of heptane/ethyl acetate (4/1, 3/1, 2/1 and 1/1) and then pure ethyl acetate. The fractions are concentrated under vacuum, thus obtaining 5.6 g (yield 57%) of pale yellow solid.

NMR1H (CD3OD, 400 MHz) δ: 7,27 (m, 8H); 7,16 (m, 2H); 4 (DD, J=6.4 and 14 Hz, 3H); 2,73 (m, 2H); to 2.55 (m, 3H); 2.26 and (kV, J=7,6 Hz, 2H); 1,78 (d, J=12 Hz, 2H); 1,45 (s, N); 1,15 (arcs, J=4.4 and of 12.8 Hz, 2H). MS/LC: m/z=395,2 (M+H).

In this way receive a series of 4-aminotoluene-1-piperidino below other groups of R1:

A2A) Introduction of functional groups in piperidine

A2A) Synthesis of ureas and thioureas

Urea and thiourea synthesized by a method described in the literature (Kaldor, S.W.; Siegel, M.G.; Fritz, J.E.; Dressman, B.A.; Hahn, P.J. Tetrahedron Lett 1996, 37, 7193-7196; Kaldor, S.W.; Fritz, J.E.; Tang, J.; McKinney, E.R., Bioorg. Med. Chem. Lett. 1996, 6, 3041-3044; Booth, J.; Hodges, J.C. J. Am. Chem. Soc. 1997, 119, 4882-4886; Flynn, D.L.; Crich, J.Z.; Devraj, R.V.; Hockerman, S.L.; Parlow, J.J.; South, M. S.; Woodard, S.; J. Am. Chem. Soc. 1997, 119, 4874-4881), in accordance with the following scheme:

where R is methyl or Vos, X1and Y have the above values. It should be noted that in tomslake, when R means the First, thus obtained compound is the final product corresponding to the formula I according to the present invention, which can also be used as intermediate compounds in the synthesis process.

The General method consists in the following: isocyanate or isothiocyanate (1,1-1.5 EQ.) add to 4-aminosilane-1-piperidine in an aprotic solvent, such as dichloromethane, tetrahydrofuran or dimethylformamide, and the mixture is stirred for a period of time from 45 minutes to 18 hours at room temperature. Add aminomethyl resin (Novabiochem, of 1.33 mmol/g, 0.2 to 1 EQ.) and the mixture is stirred for a period of time from 45 minutes to 18 hours. In some cases, add a basic ion-exchange resin, such as IRA-68 (Gayo, L.M.; Suto, M.J. Tetrahedron Lett. 1997, 38, 513-516). The resin is filtered and the filtrate concentrated. The resulting product can be cleaned in other ways, using cartridges with silica gel and basic alumina (500 mg, Interchim).

Example A2A

tert-Butyl 4-((3,3-diphenylpropyl)-[[3-(trifluoromethyl)aniline]carbonyl}amino)-1-piperidinecarboxylate (C33H38F3N3About3M=581,68)

246 mg (1,32 mmol) 3-(trifluoromethyl)phenylisocyanate added to a solution of tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate (470 mg, 1.2 mmol) in 5 ml dichloro the Ana. The solution is stirred for 45 minutes, add aminomethyl resin (180 mg, 0.36 mmol) and the reaction mixture is again placed in a rotary shaker for 45 minutes. The resin is filtered and washed with dichloromethane. The filtrate was concentrated in vacuo, while receiving 610 mg (yield 87%) of a white foam.

NMR1H (CD3OD, 400 MHz): δ 7,71 (s, 1H); EUR 7.57 (d, 1H); the 7.43 (t, 1H); 7,26 (m, 10H); to 7.15 (m, 1H); to 4.1 (m, 3H); of 3.97 (DD, J=7.6 and 10 Hz, 1H); 3,17 (m, 2H); to 2.75 (m, 2H); 2,35 (m, 2H); 1,65 (d, J=12 Hz, 2H); 1,46 (C N, tert-bucilina group); of 1.39 (DD, J=2,4 and 10.8 Hz, 2H); of 1.29 (s, 1H). MS/LC: m/z=582 (M+H).

Below are group X1used for the synthesis of ureas (Y=Oh) as described above, which correspond to the groups of R1described in paragraph A1:

Below are group X1used for the synthesis of thioureas (Y=S) described above, which correspond to the groups of R1described in paragraph A1:

A2b) Synthesis of amides from carboxylic acids

Synthesis of amides from carboxylic acids is carried out in accordance with the following reaction scheme:

where R is methyl or Boc and X2has the above values. It should be noted that in the case when R is Boc, the thus obtained compound is the final product corresponding to the formula I according to the present invention, which can also be used as intermediate compounds in the synthesis process.

The General method consists in the following: carboxylic acid (1,1-2.5 equiv.) dissolved in an anhydrous aprotic solvent such as dichloromethane, dimethylformamide or tetrahydrofuran, activate 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide associated with the resin (P-EDC, Novabiochem, 2,33 mmol/g, 1.3 to 3 EQ.) (Desai, M.C.; Stephens Stramiello, L.M. Tetrahedron Lett. 1993, 34, 7685-7688). The resulting mixture was stirred for 5-30 minutes at room temperature. Then add 4-aminotoluene-1-piperidine, pre-dissolved in an anhydrous aprotic solvent such as dichloromethane, dimethylformamide or tetrahydrofuran and the reaction mixture was stirred at room temperature for 1-18 hours. In some cases, add a basic ion-exchange resin (IRA-68, SAX) and the mixture is again stirred at room temperature for 1-18 hours. The resin is filtered through a Frit, a cartridge with a basic ion exchange resin (IRA-68, SAX) or cartridge with aluminum oxide (500 mg, Interchim).

Example 2b

tert-Butyl 4-{(3,4-dimethoxyphenyl who yl)[2-(1H-indol-3-yl)acetyl]amino}-1-piperidinecarboxylate (C 35H41H3About3M=551,74)

512 mg (1.12 mmol, 1.4 EQ.) resin P-EDC subjected to preliminary swelling in dichloromethane. Add 2-(1H-indol-3-yl)acetic acid (153 mg, 0,875 mmol, 1.1 EQ.) and the mixture is stirred for 10 minutes. Add tert-butyl-4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate (292 mg, 0.8 mmol) in tetrahydrofuran and the reaction mixture was stirred over night. Add 2 spatula basic ion-exchange resin IRA-68 and the reaction mixture is again stirred overnight. The resin is filtered and the filtrate was concentrated in vacuo, while receiving 250 mg (yield 86%) of a pale yellow foam.

NMR1H (CD3OD, 400 MHz) δ: 7,63 (d, J=8 Hz, 1H); 7,44 (d, J=8 Hz, 1H); of 7.36 (d, J=8 Hz, 1H); 7,26 (d, J=8 Hz, 1H); to 7.2 (m, 6N); 7,13 (m, 3H); and 7.1 (m, 2H); of 6.68 (s, 1H); 4-3,75 (m, 4H); the 3.65 (s, 1H); 3,2 (m, 1H); 3 (m, 1H); to 2.75 (m, 1H); and 2.26 (m, 3H); 1,6 (m, 2H); of 1.44 (s, N); of 1.13 (m, 2H). MS/LC: m/z=552,4 (M+H).

In this way synthesize a series of amides. Below is a possible radicals X2:

where the protective group (PG) is H or tert-butyloxycarbonyl.

A3) Synthesis of 4-aminobenzamidine of piperidino

4-Aminobenzamidine piperidine according to this invention are synthesized, treating acid of the above N-Boc-compound in accordance with the following reaction scheme:

General method: a protective group of the above ureas, thioureas and amides can be removed in acidic environments in two ways. In accordance with the first method, the compound is dissolved in dichloromethane and add triperoxonane acid (5-20 equiv.) and in accordance with the second method uses a diluted solution of hydrochloric acid in solvents such as ethyl acetate, dioxane or diethyl ether (5-20 equiv.). The reaction mixture is stirred for 1-4 hours at room temperature. In some cases, add dichloromethane and the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated under vacuum, thus obtaining the free base.

Example A3

N-(3,3-Diphenylpropyl)-N-(4-piperidinyl)-N'-[3-(trifluoromethyl) phenyl] urea (C28H30F3N3Oh, M=481,57)

1.6 ml (21 mmol, 20 EQ.) triperoxonane acid are added to a solution of tert-butyl 4-((3,3-diphenylpropyl){[3-(trifluoromethyl)aniline]carbonyl}amino)-1-piperidinecarboxylate (600 mg, 1.04 mmol) in dichloromethane. The reaction mixture is stirred for 90 minutes and concentrate. Add dichloromethane and org the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo, while receiving 490 mg (yield 98%) of a white foam.

NMR1H (CD3OD, 400 MHz) δ: 7,7 (s, 1H); at 7.55 (d, 1H); 7,44 (t, 1H); 7,28 (m, N); to 7.18 (m, 2H); of 4.05 (m, 2H); 3,26 (m, 2H); 3,11 (d, J=10,8 Hz, 2H); 2,7 (dt, J=2, 4 and 12.4 Hz, 2H); 2,38 (kV, J=8 Hz, 2H); 1,76 (d, J=10 Hz, 2H); 1,63 (arcs, J=4 and 12.4 Hz, 2H). MS/LC: m/z=RUB 482.2 (M+H).

In this way synthesize a number of 4-aminopiperidine. Possible radicals R1X1and X2illustrated above in paragraphs A1 and A2.

C) Synthesis of 4-aminopiperidine in the solid phase

4-Aminopiperidine synthesized in the solid phase, using as the starting material resin Wong.

B1) obtaining the resin

B1a) Obtaining a pair of nitrophenylarsonic resin Wong

The specified synthesis is carried out in accordance with the following reaction scheme:

The specified resin obtained from the resin Wong (company Bachem or Novabiochem) with the degree of filling more than 0.89 mmol/g by the method described in the literature (Bunin, VA The Combinatorial Index, Academic Press, 1998, p. 62-63; Dressman, VA; Spangle, L.A.; Kaldor, S.W. Tetrahedron Lett. 1996, 37, 937-940; Hauske, J.R.; Dorff, P. Tetrahedron Lett., 1995, 36, 1589-1592; Cao, J.; Cuny, G.D.; Hauske, J.R. Molecular Diversity 1998, 3, 173-179): N-methylmorpholine or pyridine and 4-nitrophenylphosphate successively added to the resin Wong, subjected to preliminary swelling in dichloromethane or tetrahydrofuran at room temperature. CME is ü stirred over night. The resin is washed with tetrahydrofuran, diethyl ether and dichloromethane and then dried in vacuum at 50°With during the night.

B1b) Obtaining piperidinecarbonitrile resin

The specified synthesis is carried out according to the following scheme:

The triethylamine (1 EQ.) and molecular sieve are added to gidratirovannom piperidineacetic dissolved in dimethylformamide. The mixture is heated to dissolve the ketone. The resulting solution is added to the pair-nitrophenylarsonic resin Wong (of 0.05 equiv.) which is subjected to preliminary swelling in dimethylformamide. The mixture is stirred for 24-72 hours at room temperature, the resin is filtered and then washed several times with dimethylformamide, tetrahydrofuran, diethyl ether and dichloromethane.

The method of obtaining 2

2.5 g of para-nitrophenylphosphate resin Wong (the degree of filling 0.88 mmol/g, 2.2 mmol) is subjected to preliminary swelling in 100 ml of dimethylformamide. Simultaneously, 6.7 g (44 mmol, 20 EQ.) hydrated piperidinedione, of 4.45 g (44 mmol, 20 EQ.) of triethylamine and three spatula molecular sieve is heated in 100 ml of dimethylformamide to dissolve. Warm yellowish solution is poured into the resin and the mixture is stirred for 40 hours at room temperature. The resin is filtered and washed the Ute dimethylformamide, the tetrahydrofuran, diethyl ether and dichloromethane (three times each solvent) and then dried in vacuum. Obtain 2.4 g of a pale yellow resin with a degree of filling of 0.88 mmol/g, calculated after performing elemental analysis of nitrogen.

B2) Reductive amination of solid media

Reductive amination is carried out in accordance with the following scheme:

The General method consists in the following: primary amine (5-10 EQ.) add to ketone resin, subjected to preliminary swelling in triethylorthoformate (TMOF), after which the mixture is treated with ultrasound. Then add the complex with borane pyridine (8 M, 5-10 EQ.) and the mixture is stirred for 12-72 hours. The resin was filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and then dried in vacuum (Pelter, A.; Rosser, R. J. Chem. Soc. Perkin Trans I, 1984, 717-720; Bomann, M.D.; Guch, I.C.; DiMare, M. J. Org. Chem. 1995, 60, 5995-5996; Khan, N.M.; Arumugam, V.; Balasubramanian, S. Tetrahedron Lett. 1996, 37, 4819-4822).

The method of obtaining 3

300 mg (degree of filling 0.88 mmol/g, 0.27 mmol) ketone resin is subjected to preliminary swelling in TMOF. Then add 4-bromophenethylamine (540 mg, 420 μl, 2.7 mmol, 10 EQ.) and complex with borane pyridine (8 M, 338 μl, 2.7 mmol, 10 EQ.). The mixture is stirred for 56 hours at room te is the temperature. The resin was filtered, successively washed with dichloromethane, dimethylformamide, tetrahydrofuran and dichloromethane and then dried in vacuum. Thus obtain 340 mg of a pale yellow resin with a degree of filling of 0.81 mmol/g, calculated after performing elemental analysis of nitrogen.

B3) Introduction of functional groups

VA) Introduction of functional groups with isocyanates or isothioscyanates

A functional group is introduced according to the following scheme:

The General method is as follows: the resin-based "secondary amine" is subjected to preliminary swelling in a solvent such as dichloromethane or dimethylformamide, and add isocyanate or isothiocyanate (3-10 equiv.). The mixture is stirred for 1-24 hours at room temperature. Then the resin was filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and dried in vacuum. Resin otscheplaut in the presence of equimolar mixture of dichloromethane and triperoxonane acid, stirring the mixture over a period of time from 30 minutes to 4 hours. The resin was washed with dichloromethane and the filtrate concentrated in vacuo. In some cases, the filtrate is again dissolved in dichloromethane and absoluut a saturated solution of sodium carbonate. The organic phase is evaporated in vacuum, obtaining t is thus free base.

Example VA

N-(4-Bromophenetole)-N-(4-piperidinyl)-N'-[4-(trifluoromethyl)phenyl]urea (C21H23BrF3N3Oh, M=470,3)

55 mg (50 μmol) of the resin (see method of obtaining 3) is subjected to preliminary swelling in anhydrous dichloromethane. Then add 4-Cryptosporidium (28 mg, 150 μmol, 3 EQ.) and the resulting mixture is stirred over night. The resin was filtered, washed with tetrahydrofuran, dimethylformamide, tetrahydrofuran and dichloromethane and then dried in vacuum. The mixture is stirred for 1.5 hours in the presence of 800 ál of equimolar mixture of dichloromethane and triperoxonane acid. The resin is filtered and washed with dichloromethane, the filtrate is concentrated and again dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, thus receiving 6 mg of a brown oil (yield 25%).

NMR1H (CD3OD, 400 MHz) δ: 7,53 (m, 4H); 7,44 (d, J=6,8 Hz, 2H); 7,21 (d, J=8,4 Hz, 2H); to 4.1 (m, 1H); of 3.53 (t, J=7.2 Hz, 2H); 3,12 (d, J=12,8 Hz, 2H); 2,89 (t, J=8 Hz, 2H); to 2.7 (m, 2H); at 1.73 (m, 4H). MS/LC: m/z=472,2 (M+H).

In this way synthesize a series of ureas (Y=O) and thioureas (Y=S). Below is a possible radicals R1:

Possible radicals X1 illustrated above in paragraph A.

3b) Introduction of functional groups by means of sulphonylchloride

A functional group is introduced according to the following scheme:

General method: a resin-based "secondary amine" is subjected to preliminary swelling in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then add sulphonylchloride (5-10 EQ.) and triethylamine (6-12 EQ.) and the mixture is stirred for 12-24 hours at room temperature. The resin was filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and dried in vacuum. Then the resin is stirred for 1-4 hours in the presence of equimolar mixture of dichloromethane and triperoxonane acid. The resin was washed with dichloromethane and the filtrate concentrated in vacuo. In some cases, the filtrate is again dissolved in dichloromethane and absoluut a saturated solution of sodium carbonate. The organic phase is evaporated in vacuum, thus obtaining the free base.

Example 3b

N-(4-Bromophenetole)-4-methoxy-N-(4-piperidinyl)vinylsulfonate (C20H25BrN2O3S, M=453,4)

55 mg (50 μmol) of the resin (see method of obtaining 3) is subjected to preliminary swelling in anhydrous dichloromethane. Then add treat the Lamin (42 μl, 300 μmol, 6 EQ.) and 4-methoxybenzenesulfonamide (51,5 mg, 250 μmol, 5 EQ.) and the resulting mixture is stirred over night. The resin was filtered, washed with tetrahydrofuran, dimethylformamide, tetrahydrofuran and dichloromethane and then dried in vacuum. The above reaction is performed again until a full replacement. Add 800 ál of equimolar mixture of dichloromethane and triperoxonane acid and stir the mixture for 1.5 hours at room temperature. The resin is filtered and washed with dichloromethane. The filtrate is concentrated and again diluted with dichloromethane and washed with saturated sodium bicarbonate solution. So get 14 mg brown oil (yield 63%).

NMR1H (CD3CD, 400 MHz) δ: 7,8 (DD, J=2.8 and 10 Hz, 2H); 7,44 (DD, J=1,2 and 6.8 Hz, 2H); 7,17 (d, J=8,4 Hz, 2H); 7,07 (DD, J=3.2 and 10 Hz, 2H); a 3.87 (s, 3H, och3); and 3.72 (m, 1H); 3,3 (m, 2H); 3.04 from (d, J=12,8 Hz, 2H); 2,92 (t, J=8,4 Hz, 2H); 2,6 (t, J=12,4 Hz, 2H); was 1.58 (m, 2H); 1,47 (userd, J=10 Hz, 2H). MS/LC: m/z=455 (M+H).

In this way synthesize a number of sulfonamides. Possible radicals R1illustrated above in paragraphs a and VA. Below is a possible radicals X3:

Vs) Introduction of functional groups with anhydrides of acids

A functional group is introduced according to the following scheme:

General method: a resin-based "secondary amine" is subjected to preliminary swelling in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then add the acid chloride of acid (5-10 EQ.) and triethylamine (6-12 EQ.) and the mixture is stirred for 12-24 hours at room temperature. The resin was filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and dried in vacuum. Then the resin is stirred for 1-4 hours in the presence of equimolar mixture of dichloromethane and triperoxonane acid. The resin was washed with dichloromethane and the filtrate concentrated in vacuo. In some cases, the filtrate is again dissolved in dichloromethane and absoluut a saturated solution of sodium carbonate. The organic phase is evaporated in vacuum, thus obtaining the free base.

Example Vs

N-(4-Bromophenetole)-N-(4-piperidinyl)-2-thiophencarboxylic (C18H21BrN2OS, M=to 393.3)

55 mg (50 μmol) of the resin (see method of obtaining 3) is subjected to preliminary swelling in anhydrous tetrahydrofuran. Then add triethylamine (42 μl, 300 μmol, 6 EQ.) and 2-thiophenecarboxylate (37 mg, 250 μmol, 5 EQ.) and the resulting mixture is stirred over night. The resin was filtered, washed with tetrahydrofuran, dimethylformamide, tetrahydrofuran by dichloromethane and dried in vacuum. Add 800 ál of equimolar mixture of dichloromethane and triperoxonane acid and stir the mixture for 1.5 hours at room temperature. The resin is filtered and washed with dichloromethane. The filtrate is concentrated and again diluted with dichloromethane and washed with saturated sodium bicarbonate solution, while receiving 10 mg of a brown oil (yield 50%).

NMR1H (CD3OD, 400 MHz) δ: to 7.64 (DD, J=0.8 and 4,8gts, 1H); 7,44 (d, J=8,4 Hz, 2H); of 7.36 (d, J=3.6 Hz, 1H); 7,14 (m, 3H); 4,11 (m, 1H); 3,61 (t, J=8 Hz, 2H); to 3.09 (d, J=12 Hz, 2H); 2,92 (m, 2H); to 2.54 (m, 2H); to 1.82 (m, 2H); 1,7 (m, 2H). MS/LC: m/z=393,1 (M+H).

In this way receive a number of amides. Possible groups R1illustrated above in paragraphs a and B3. Below is a group X2.

B3d) Introduction of functional groups by means of carboxylic acids

Functional groups introduced by the method described in the literature (Kobayashi, S.; Aoki, Y., J. Comb. Chem. 1999, 1, 371-372), in accordance with the following scheme:

General method: a resin-based "secondary amine" is subjected to preliminary swelling in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then add the carboxylic acid is the (3-5 equiv.) hexaphosphate benzotriazol-1-electroparadise (Rubor, 3-5 EQ.) and diisopropylethylamine (6-10 EQ.) and the mixture is stirred for 24 hours at room temperature. The resin was filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and dried in vacuum. Then the resin is stirred for 1-4 hours in the presence of equimolar mixture of dichloromethane and triperoxonane acid. The resin was washed with dichloromethane and the filtrate concentrated in vacuo. In some cases, the filtrate is again dissolved in dichloromethane and absoluut a saturated solution of sodium carbonate. The organic phase is evaporated in vacuum, thus obtaining the free base.

Example B3d

N-[2-(4-Bromophenyl)ethyl]-N-(4-piperidinyl)ndimethylacetamide (C15H21BrN2Oh, M=325,25)

55 mg (50 μmol) of the resin (see method of obtaining 3) is subjected to preliminary swelling in anhydrous dimethylformamide. Then add acetic acid (8,8 mg, 150 μmol, 3 EQ.), Rover (76 mg, 150 μmol, 3 EQ.) and diisopropylethylamine (38 mg, 300 μmol, 6 EQ.) and the resulting mixture is stirred over night. The resin was filtered, washed with dimethylformamide, tetrahydrofuran and dichloromethane and dried in vacuum. Add 800 ál of equimolar mixture of dichloromethane and triperoxonane acid and stirred the mixture is for 1.5 hours at room temperature. The resin is filtered and washed with dichloromethane. The filtrate is concentrated and again diluted with dichloromethane and washed with saturated sodium bicarbonate solution, thus obtaining 11 mg brown oil (yield 68%).

NMR1H (CD3OD, 400 MHz) δ: 7,44 (m, 2H); 7,20 (m, 2H); of 4.05 (m, 1H); to 3.45 (m, 2H); 3,10 (m, 2H); and 2.83 (m, 2H); of 2.64 (m, 2H); 2.13 and (s, 3H); at 1.73 (m, 4H). MS/LC: m/z=325,2 (M+H).

In this way synthesize a series of amides. Possible groups R1illustrated above in paragraphs a and VA. Group X3presented above in paragraph A.

(C) the background of functional groups in piperidinol part of the solution

C1) Receiving piperidine with R3= C(Y)NHX1

The specified synthesis is carried out according to the following scheme:

General method: isocyanate or isothiocyanate (1,1-1.5 EQ.) add to the piperidine in the form of a free base, diluted with dichloromethane. The mixture is stirred for 1-18 hours at room temperature. Add aminomethyl resin (0.2 to 1 EQ.) and the mixture is again stirred for 2-18 hours. In some cases, add ion-exchange resin, such as IRA68 or SAX. The resin is filtered and the filtrate concentrated. In some cases, the product is dissolved in dichloromethane or ethyl acetate and filtered through a cartridge with silica gel and basic alumina (550 mg, Interchim).

An example is 1

4-((3,3-Diphenylpropyl){[3-(trifluoromethyl)aniline]carbonyl}amino)-N-phenyl-1-piperazinecarboxamide (C35H35F3N4O2M=600,68)

N-(3,3-Diphenylpropyl)-N-(4-piperidinyl)-N'-[3-(trifluoromethyl)phenyl] urea (24 mg, 0.05 mmol) is dissolved in dichloromethane. Add phenylisocyanate (9 mg, of 0.075 mmol, 1.5 EQ.) and the mixture is stirred for 2.5 hours. Add aminomethyl resin (0.02 mmol) and the reaction mixture is again stirred overnight. The resin was filtered, washed with dichloromethane and the filtrate concentrated. The oil obtained is passed through the cartridge with silica gel, elwira equimolar mixture of heptane and ethyl acetate, and concentrated, while receiving 12 mg (yield 40%) of a yellow oil.

NMR1H (CD3OD, 400 MHz) δ: 7,72 (s, 1H); 7,58 (d, 1H); 7,44 (m, 1H); 7,38 (m, 2H); 7,29 (m, N); for 7.12 (m, 2H); 7,07 (m, 1H); 4,2 (d, J=12,4 Hz, 3H); is 3.21 (t, J=8 Hz, 2H); 2,9 (t, J=12,4 Hz, 2H); 2,38 (kV, J=8 Hz, 2H); 1,73 (d, J=10 Hz, 2H); 1,54 (arcs, J=3.6 and 12 Hz, 2H). MS/LC: m/z=601,4 (M+H).

In this way synthesize a series of ureas (Y=O) and thioureas (Y=S). Possible groups R1X1and X2illustrated above, respectively, in paragraphs (a and VA), and (a and Vs).

C2) Introduction of functional groups by means of carboxylic acids

A functional group is introduced according to the following scheme:

General method: smo is the P-EDC (1.3 to 3 EQ.) subjected to preliminary swelling in anhydrous dichloromethane. Carboxylic acid (1,1-2.5 EQ.) dissolved in anhydrous solvent such as dichloromethane, dimethylformamide or tetrahydrofuran, and added to the resin. The mixture is stirred for 5-30 minutes at room temperature. Then to the mixture is added 4-aminodiphenyl piperidine in the form of the free base, dissolved in anhydrous solvent such as dichloromethane, dimethylformamide or tetrahydrofuran, and the mixture was stirred for 1-18 hours at room temperature. In some cases, add ion-exchange resin, such as IRA68 or SAX, and the mixture is again stirred at room temperature for 1-18 hours. The resin is filtered through a Frit, cartridge ion exchange resin SAX (500 mg, Interchim) or cartridge with basic aluminum oxide (500 mg, Interchim).

Example C2

N-(1-Acetyl-4-piperidinyl)-N-(3,3-diphenylpropyl)-N'-[3-(trifluoromethyl) phenyl] urea (C30H32F3H3O2M=523,60)

117 mg (175 mmol, 3.5 EQ.) resin P-EDC subjected to preliminary swelling in 1.5 ml of anhydrous dichloromethane. Add acetic acid (7.5 mg, 125 μmol, 2.5 EQ.) and the mixture is stirred for 10 minutes. Then add N-3,3-diphenylpropyl)-N-(4-piperidinyl)-N'-[3-(trifluoromethyl)phenyl]urea (24.3 mg, 50 μmol) and the mixture is stirred over night. The resin is filtered and the filtrate concentrated. the received oil is passed through the cartridge with silica gel, elwira equimolar mixture of heptane and ethyl acetate, and concentrated, while receiving 16 mg (yield 62%) of a white foam.

NMR1H (CD3OD, 400 MHz) δ: 7,71 (s, 1H); 7,58 (d, J=8,4 Hz, 1H); the 7.43 (t, J=8 Hz, 1H); 7,28 (m, N); 7,17 (m, 2H); 4,56 (DD, J=2 and 11.2 Hz, 1H); to 4.17 (m, 1H); 3.96 points (t, J=7,6 Hz, 1H); 3,88 (d, J=12 Hz, 1H); 3,19 (kV, J=4 and 8 Hz, 2H); 3,1 (t, J=12 Hz, 1H); of 2.58 (t, J=12 Hz, 1H); is 2.37 (m, 2H); to 2.06 (s, 3H, CH3); 1,72 (t, J=14,4 Hz, 2H); 1,43 (arcs, J=4 and 12.4 Hz, 2H). MS/LC: m/z=524,3 (M+H).

In this way synthesize a series of amides. Possible groups R1X1and X2illustrated respectively in points (a and VA), and (a and Vs).

C3) Introduction of functional groups by means of sulphonylchloride

A functional group is introduced according to the following scheme:

General method: morpholinomethyl resin (Novabiochem, 2-3 EQ.) subjected to preliminary swelling in anhydrous solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Add sulphonylchloride (1,1-2 equiv.) dissolved in anhydrous solvents such as dichloromethane, dimethylformamide or tetrahydrofuran, and then add 4-aminodiphenyl piperidine. The mixture is stirred for 16-48 hours. Add aminomethyl resin (0.1 to 1.5 EQ.) and the reaction mixture was stirred over night. In some cases, add ion-exchange resin, such as IRA68 or SAX, and semipermissive at room temperature for 1-18 hours. The resin is filtered through a Frit, cartridge ion exchange resin SAX (500 mg, Interchim) or cartridge with basic aluminum oxide (500 mg, Interchim).

Example C3

N-(3,3-Diphenylpropyl)-N-{1-[(4-methoxyphenyl)sulfonyl]-4-piperidinyl}-N'-[3-(trifluoromethyl)phenyl]urea (C35H36F3N3O4S, M=651,75)

27,5 mg (100 μmol, 2 EQ.) morpholinomethyl resin is subjected to preliminary swelling in anhydrous tetrahydrofuran, and then add 4-methoxyphenylalanine (15,5 mg of 0.075 mmol, 1.5 EQ.) and N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N'-[3-(trifluoromethyl)phenyl]urea (24.3 mg, 0.05 mmol). The mixture is stirred over night. Add aminomethyl resin (20 mg) and ion-exchange resin SAX and the mixture is stirred over night. The resin is filtered and washed with dichloromethane. The oil obtained after evaporation of the mixture, is passed through the cartridge with silica gel (500 mg, Interchim), elwira with ethyl acetate, and concentrated, while receiving 18 mg (yield 56%) of a white solid.

NMR1H (CD3OD, 400 MHz) δ: 7,71 (d, J=9,2 Hz, 2H); the 7.65 (s, 1H); 7,51 (d, 1H); 7,41 (t, J=7,6 Hz, 1H); 7,29 (m, N); 7,20 (m, 2H); 7,11 (DD, J=1.6 and 6.8 Hz, 2H); 3,88 (s, 3H, och3); of 3.77 (d, J=12,4 Hz, 2H); and 3.16 (t, J=8 Hz, 2H); 2,33 (m, 4H); 1,71 (d, J=10 Hz, 2H); 1,62 (arcs, J=4 and 12 Hz, 2H); 1,3 (m, 2H). MS/LC: m/z=652,4 (M+H).

In this way synthesize a number of sulfonamides. Possible groups R1X1 , X2and X3illustrated respectively in points (a and VA), And (a and Vs) and 3b.

D) Synthesis trisemester of piperidinol in the solid phase

The specified synthesis carried out using as the starting material vinylsulfonate resin (Kroll, F.E.K.; Morphy, R.; Rees, D.; Gani, D. Tetrahedron Lett. 1997, 38, 8573-8576; Brown, A.R. J. Comb. Chem. 1999, 1, 283-285), in accordance with the following schema.

D1) Receiving resin

Tar receive in accordance with the following scheme:

The triethylamine (1 EQ.) add to gidratirovannom piperidinedione, diluted with dimethylformamide. The mixture is heated to dissolve the ketone. The resulting solution was added to vinylsulfonate resin is 0.05 equiv.) subject to a preliminary swelling in dimethylformamide. The resin is stirred for 24-72 hours at room temperature, filtered and washed several times with dimethylformamide, tetrahydrofuran, diethyl ether and dichloromethane.

The method of obtaining 4

1.5 g vinylsulfonate resin (Novabiochem, the degree of filling 1 mmol/g, 1.5 mmol) is subjected to preliminary swelling in 50 ml of dimethylformamide. Simultaneously, 2.3 g (15 mmol, 10 EQ.) hydrated piperidinedione and 1.8 g (15 mmol, 10 EQ.) of triethylamine are heated in 100 ml of dimethylformamide to dissolve. Warm yellowish solution was poured in, see the Lu and the mixture is stirred for 24 hours at room temperature. The resin was filtered, washed with dimethylformamide, tetrahydrofuran, diethyl ether and dichloromethane (three times each solvent) and dried in vacuum. Obtain 1.7 g of pale yellow resin with a degree of filling of 1 mmol/g, calculated after performing elemental analysis of nitrogen.

D2) Reductive amination of solid media

Reductive amination on a solid medium to perform the method described in the literature (Pelter, A.; Rosser, R.; J. Chem. Soc. Perkin Trans I, 1984, 717-720; Bomann, M.D.; Guch, I.c.; DiMare, M.; J. Org. Chem. 1995, 60, 5995-5996; Khan, N.M.; Arumugan, V.; Balasubramanian, S.; Tetrahedron Lett. 1996, 37, 4819-4822), in accordance with the following scheme:

General method: primary amine (5-10 EQ.) add to ketone resin, subjected to preliminary swelling in triethylorthoformate (TMOF), after which the mixture is treated with ultrasound. Then add the complex with borane pyridine (8 M, 5-10 EQ.) and the mixture is stirred for 12-72 hours. The resin was filtered, washed with solvents such as dichloromethane, dimethylformamide, methanol and tetrahydrofuran, and dried in vacuum.

The method of obtaining 5

1 g (degree of filling 1 mmol/g, 1 mmol) ketone resin is subjected to preliminary swelling in TMOF. Then add 2-(1-methyl-1H-indol-3-yl)ethylamine (1.01 g, 10 mmol, 10 EQ.) and complex with borane pyridine (8 M 1,25 is l, 10 mmol, 10 EQ.). The mixture is stirred for 48 hours at room temperature. The resin was filtered, successively washed with dichloromethane, dimethylformamide, methanol, tetrahydrofuran and dichloromethane and dried in vacuum. So get of 1.05 g of a pale yellow resin with a degree of filling of 0.91 mmol/g, vacilando after performing elemental analysis of nitrogen.

D3) Introduction of functional groups into the secondary amine

D3a) Introduction of functional groups with isocyanates

General method: a resin-based "secondary amine" is subjected to preliminary swelling in a solvent such as dichloromethane or dimethylformamide, and added the isocyanate (3-10 equiv.). The mixture is stirred for 1-24 hours at room temperature. Then the resin was filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and dried in vacuum.

The method of obtaining 6

55 mg (50 μmol) of the resin (see method of obtaining 5) is subjected to preliminary swelling in anhydrous dichloromethane. Then add 4-Cryptosporidium (28 mg, 150 μmol, 3 EQ.) and the resulting mixture is stirred for 2 hours at room temperature. The resin was filtered, washed with tetrahydrofuran, dimethylformamide, tetrahydrofuran and dichloromethane and sushi is t in vacuum.

D3b) Introduction of functional groups by means of sulphonylchloride

This method of introducing functional groups similar to the method described in paragraph 3b.

D3c) Introduction of functional groups with anhydrides of acids

This method of introducing functional groups similar to the method described in paragraph Vs.

D3d) Introduction of functional groups by means of carboxylic acids

This method of introducing functional groups similar to the method described in paragraph B3d.

D4) stage off

Described below stage removal suitable for all the above methods of introducing functional groups into the secondary amine:

General method: disubstituted resin is subjected to swelling in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran, then add the halide R3X, in which R3has the above meaning and X denotes a halogen atom (5 equiv.) and the mixture is stirred overnight at a temperature of from 20 to 60°C. the Resin is filtered, washed with solvents such as dimethylformamide, tetrahydrofuran, methanol and dichloromethane, and dried in vacuum. The resin is again subjected to swelling in dichloromethane and add basic ion-exchange resin (Ouyang, X.; Armstrong, R.W.; Murphy, M.M. J. Org. Chem. 1998, 63, 1027-1032). The resulting mixture was stirred for 48 h the owls at room temperature. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo.

Example D4

N-[2-(1-Methyl-1H-indol-3-yl)ethyl]-N-(1-methyl-4-piperidinyl)-N'-[4-(trifluoromethyl)phenyl]urea (C25H29F3N4Oh, M=458,5)

55 mg (50 μmol) of urea resins subjected to swelling in dimethylformamide, add 35 mg (250 μmol, 5 EQ.) iodomethane and the mixture is stirred for 18 hours at room temperature. The resin was filtered, washed with dimethylformamide, tetrahydrofuran, methanol and dichloromethane and dried in vacuum. The resin is again subjected to swelling in dichloromethane, then add about 100 mg of ion exchange resin IRA68 and the mixture is stirred for 48 hours. The resin was filtered, washed with dichloromethane and the filtrate is concentrated, while receiving 18 mg (yield 78%) of colorless oil.

NMR1H (CD3OD, 400 MHz) δ: the 7.65 (m, 2H); 7,40 (m, 2H); 7,31 (m, 1H); 7,20 (m, 1H); 7,10 (m, 1H); 7,06 (m, 2H); Android 4.04 (m, 1H); 3,68 (s, 3H); of 3.60 (t, 2H); 3.04 from (t, 2H); 2,44 (m, 2H); to 2.29 (s, 3H); and 2.14 (m, 2H); at 1.91 (m, 2H); to 1.76 (m, 2H). MS/LC: m/z=459,3 (M+H).

Below is a group R3that can be used for the synthesis of trisemester 4-aminopiperidines as described above, in the presence of groups of R1, X1, X2and X3illustrated above in paragraphs a and b:

The object of this invention is also a method of obtaining the above-described compounds of formula I of the present invention in solid or liquid phase.

A separate object of the present invention is a method of obtaining in the liquid phase of the above described compounds of formula I, characterized in that it includes reductive amination of the following N-substituted piperidone

where R is methyl or Boc radical, in the presence of an amine of formula R1NH3in which R1has the above values, which gives the compound of formula 1

after which the compound of formula (1) is subjected to interaction:

A) with the compound of the formula X1NC(Y), where X1and Y have the above values, that gives compound of formula (2)

the compound of the formula (2) represents the corresponding compound of formula (I)in which R3means Me or Boc, and when R3means Boc, this compound can be treated with acid, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom;

thus obtained compound of formula (I) may be subjected interaction is the influence with the compound of the formula X 1NC(Y), X2CO2N or X3SO2Cl, in which X1, Y X2and X3have the above values, the result of which receive a corresponding compound of formula I, in which R2means a radical of the formula-C(Y)NHX1and R3accordingly, means the radical-C(Y)NHX1-C(O)X2or SO2X3;

In) or with the compound of the formula X2CO2H, in which X2has the above values, that gives compound of formula (3)

the compound of the formula (3) represents the corresponding compound of formula (I)in which R3means Me or Boc, and when R3means Boc, this compound can be treated with acid, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom,

thus obtained compound of formula (I) may be subjected to interaction with the compound of the formula X1NC(Y), X2CO2N or X3SO2Cl, in which X1, Y X2and X3have the above values, the result of which receive a corresponding compound of formula I, in which R2means a radical of the formula-C(O)X2and R3accordingly, means the radical-C(Y)NHX1, -C(O)X2or SO2X3.

A separate object of the present from which retene is also a way of getting in the solid phase of the above described compounds of formula I, characterized in that it includes

reductive amination of ketone resin

in the presence of an amine of formula R1NH2in which R1has the above values, that gives compound of formula (4)

after which the compound of the formula (4) is subjected to interaction:

A) with the compound of the formula X1NC(Y), where X1and Y have the above values, that gives compound of formula (5)

subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom;

B) with the compound of the formula X3SO2Cl, in which X3has the above values, that gives compound of formula (6)

subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom;

C) with the compound of the formula X2CO2Cl, in which X2has the above values, that gives compound of formula (7)

subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom;

D) or compound forms of the crystals of X 2CO2H, in which X3has the above values, that gives compound of formula (7), followed by cleavage of the resin, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom.

And finally, a separate object of the present invention is a method for solid phase described above, compounds of the formula I, characterized in that it includes:

reductive amination of ketone resin

in the presence of an amine of formula R1NH2in which R1has the above values, that gives compound of formula (8)

after which the compound of formula (8) is subjected to interaction:

A) with the compound of the formula X1NC (O), in which X1has the above values, that gives compound of formula (9)

thus obtained compound (9) is subjected to interaction with the compound of the formula R3X, in which R3has the above meaning and X is Br or I, with subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I);

B) with the compound of the formula X3SO2Cl, in which X3has the above values, that gives compound of formula (10)

thus obtained compound (10) is subjected to interaction with the compound of the formula R3X, in which R3has the above meaning and X is Br or I, with subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I);

C) with the compound of the formula X2CO2Cl, in which X2has the above values, that gives compound of formula (11)

thus obtained compound (11) is subjected to interaction with the compound of the formula R3X, in which R3has the above meaning and X is Br or I, with subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I);

D) or with the compound of the formula X2CO2H, in which X2has the above values, that gives compound of formula (11);

thus obtained compound (11) is subjected to interaction with the compound of the formula R3X, in which R3has the above meaning and X is Br or I, with subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I).

The compounds of formula I of the present invention possess useful pharmacological properties. It is established that the compounds of formula I of the present invention are characterized by high is Kim affinity to one or more somatostatin receptors. These compounds can be used as selective or non-selective ones agonists or antagonists of somatostatin.

Therefore, compounds of the present invention can be used in different medicinal purposes. They can be used effectively for the treatment of the above mentioned pathological conditions or diseases caused by one (or more) receptors somatostatin.

Pharmacological properties of the compounds according to this invention will be illustrated below in the experimental part.

The object of the invention under the present application are also described above products of formula I, salt additive products of formula I with pharmaceutically acceptable mineral or organic acids and pharmaceutical compositions containing as active ingredient at least one of the above drug in combination with a pharmaceutically acceptable carrier.

The pharmaceutical composition can be obtained in the form of a solid, for example powders, granules, tablets, gelatin capsules or suppositories. Acceptable solid carriers are, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

Some of the above compounds of General formula I are presented in the patent application DE 2751138. In this patent application in Germany described compounds which are antagonists of dopamine and endogenous or exogenous dopaminergic funds and stimulate serotoninergicheskie mechanism, and this activity differs from the activity of the compounds of the present invention.

In addition, an object of the present invention is the use of compounds of General formula Ia

in racemic, enantiomeric form or all combinations of these forms, where

R1ameans (C1-C16)alkyl linear or branched chain, alkenyl, quinil, the radical -(CH2)m-Y-Z11or -(CH2)mZ12to what PR

Z11means optionally substituted C1-C6)alkyl or aryl;

Z12means cyano, cyclohexenyl, biphenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7)heteroseksualci, optionally substituted aryl or optionally substituted heteroaryl;

or Z12means a radical of the formula

or R1ameans a radical of the formula

R2ameans a radical of the formula-C(Y)NHX1, -C(O)X2or SO2X3;

R3Ameans a hydrogen atom, optionally substituted alkyl, alkenyl, quinil, optionally substituted aralkyl, optionally substituted heteroarylboronic radical or a radical of the formula-C(Y)NHX1, -(CH2)n-C(O)X2or SO2X3or

X1means (C1-C15)alkyl linear or branched chain, alkenyl, quinil, the radical -(CH2)m-Y-Z21or -(CH2)pZ22in which

Z21means (C1-C6)alkyl;

Z22means cyclohexenyl, indanyl, biphenyl, (C3-C7) cycloalkyl, (C3-C7)heteroseksualci, mono - or dialkylamino, -C(O)-O-alkyl or optionally substituted aryl or heteroaryl;

or Z22oz achet a radical of the formula

X2means (C1-C10)alkyl radical with a linear or branched chain, alkanniny radical, optionally substituted phenyl radical (phenyl radical may be optionally substituted), alkynylaryl radical or a radical of the formula -(CH2)m-W-(CH3)q-Z23or -(CH2)p-U-Z24in which

Z23means optionally substituted C1-C6)alkyl or aryl;

Z24means alkyl, cyclohexenyl, biphenyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7) heteroseksualci, cyano, amino, mono - or dialkylamino, optionally substituted aryl or heteroaryl

or Z24means a radical of the formula

or X2means the following radical:

where the protective group (PG) is H or tert-butyloxycarbonyl;

X3means (C1-C10)alkyl radical with a linear or branched chain, alkanniny radical, optionally substituted phenyl radical (phenyl radical may be optionally substituted), CF3or -(CH2)pZ25where

Z25means optionally substituted aryl or heteroaryl;

or X3means adical formula

optionally substituted by one or more identical or different halogen-containing radicals;

Y represents an oxygen atom or sulfur;

W denotes an oxygen atom or sulfur or SO2;

U represents a covalent bond or an oxygen atom;

n is an integer from 0 to 4;

m is an integer from 1 to 6;

p is an integer from 0 to 6;

q is an integer from 0 to 2,

or their additive salts with pharmaceutically acceptable mineral or organic acids for the manufacture of medicinal products intended for the treatment of pathological conditions or diseases caused by one (or more) receptors somatostatin.

A separate object of this invention is the use of the above described products of General formula Ia, wherein

i) Deputy or deputies, substitute aryl radicals represented by Z11and Z12and heteroaryl, presents Z12independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, -CF3, -OCF3, phenyl, phenoxy, aminosulfonyl;

ii) the Deputy or deputies, replacement heterologously radical represented by Z12independently selected from hydroxy and alkyl radicals;

iii) the Deputy or zamestitel, replacement aryl and heteroaryl radicals represented by Z22independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, aminosulfonyl, piperidinemethanol, mono - or dialkylamino, -C(O)-O-alkyl, -C(O)-alkyl or phenyl, phenoxy, phenylthio, benzyloxy and phenyl radical may be substituted;

iv) the Deputy or deputies, substitute aryl radicals represented by Z23and Z24cycloalkyl or heteroaryl, presents Z24independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, CF3, OCF3, OCHF2SCF3, nitro, cyano, azido, hydroxy, -C(O)O-alkyl, -O-C(O)-alkyl, -NH-C(O)-alkyl, alkylsulfonyl, mono - or dialkylamino, amino, aminoalkyl, pyrrolyl, pyrrolidinyl or phenyl, phenoxy, phenylthio, benzyl, benzyloxy, and the aryl radical may be optionally substituted by one or more alkyl, CF3or halogenation;

v) the Deputy or deputies, substitute aryl and heteroaryl radicals represented by Z25independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, OCF3, nitro, cyano, -NH-C(O)-alkyl, alkylsulfonyl, amino, mono - and dialkylamino, phenyl, pyridine;

vi) Deputy surrogate alkyl radical, presents R3is cineradiogram;

vii) the Deputy or deputies, replacement Uralkaliy radical represented by R3independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, OCF3, OCHF2SCF3, SCHF2, nitro, cyano, -C(O)O-alkyl, alkylsulfonyl, thiadiazolyl or phenyl, phenoxy, and the phenyl radical may be optionally substituted by one or more halogenation;

viii) Deputy or deputies, replacement heteroarylboronic radical represented by R3independently chosen from radicals comprising fluorine, chlorine, bromine or nitro.

A separate object of the present invention is the use of compounds of the above General formula Ia, in which R1ameans (C1-C6)alkyl radical with a linear or branched chain, the radical -(CH2)m-Y-Z11or -(CH2)mZ12in which

Z11means (C1-C6)alkyl;

Z12means biphenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7)heteroseksualci, aryl or heteroaryl, optionally substituted by one or more substituents chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy,

or Z12means

Y represents an oxygen atom;

or R1ameans a radical of the formula

A separate object of the present invention is the use of the above compounds of General formula Ia, in which R2ameans a radical of the formula-C(Y)NHX1-C(O)X2or SO2X3where

X1means (C1-C15)alkyl radical with a linear or branched chain or a radical -(CH2)pZ22in which

Z22means cyclohexenyl, biphenyl, (C3-C7)cycloalkyl, (C3-C7)heteroseksualci, mono - or dialkylamino, -C(O)-O-alkyl, aryl or heteroaryl, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinemethanol, -C(O)-O-alkyl, -C(O)-alkyl or phenyl,

or Z22means a radical of the formula

X2means (C1-C10)alkyl linear or branched chain, quinil, the radical -(CH2)m-W-(CH2)q-Z23or -(CH2)p-U-Z24in which

W means SO2;

U represents a covalent bond;

Z23means aryl radical;

Z24means cyclohexenyl, biphenyl, (the 3-C7)cycloalkyl, optionally substituted aminoalkyl, aryl or heteroaryl radical, optionally substituted by one or more radicals selected from the group comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, -CF3, -OCF3SCF3, hydroxy, -C(O)-O-alkyl, mono - or dialkylamino, amino,

or Z24means a radical of the formula

or X2means

X3means a radical -(CH2)pZ25where Z25means aryl radical, optionally substituted by one or more identical or different radicals selected from alkoxy and CF3.

A separate object of the present invention is the use of the above compounds of General formula Ia, in which R3Ameans a hydrogen atom, optionally substituted alkyl, alkanniny, heteroarylboronic radical or a radical of the formula-C(Y)-NHX1, -C(O)X2or SO2X3where

X1means a radical -(CH2)pZ22in which

Z22means aryl radical, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, phenoxy;

X2means vinyl radika is, substituted phenyl, and the phenyl radical in turn optionally substituted by one or more halogen, or a radical -(CH2)p-U-Z24where

Z24means alkyl, (C3-C7)cycloalkyl, (C3-C7)heteroseksualci, biphenyl, amino, mono - or dialkylamino, aryl or heteroaryl, optionally substituted by one or more radicals selected from the group comprising alkoxy, bromine, chlorine, fluorine, hydroxy, CF3, nitro, amino, mono - and dialkylamino, pyrrolyl;

or X2means a radical of the formula

X3means (C1-C10)alkyl radical with a linear or branched chain, the vinyl radical, a substituted phenyl radical (phenyl radical may be optionally substituted), CF3or -(CH2)pZ25where

Z25means aryl or heteroaryl, optionally substituted by one or more substituents, independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, -NH-C(O)-alkyl, mono - and dialkylamino.

R1apreferably means (C1-C6)alkyl radical with a linear or branched chain, the radical -(CH2)m-Y-Z11or -(CH2)m-Z12in which

Z11means (C1-C6 )alkyl,

Z12means naphthyl, morpholino, biphenyl, pyrrolidinyl, replaced by oxyradicals, or phenyl, piperazinilnom, pyridinoline and indolizinyl radicals, which are optionally substituted by one or more substituents, independently selected from radicals comprising bromine, fluorine, chlorine, alkyl, alkoxy, -CF3, -OCF3,

or Z12means

Y represents an oxygen atom;

or R1ameans the radical following formula:

R2Apreferably means a radical of the formula-C(Y)NHX1-C(O)X2or SO2X3where

X1means (C1-C10)alkyl linear or branched chain or a radical -(CH2)pZ22in which

Z22means cyclohexyl, cyclohexenyl, biphenyl, morpholino, piperidino, mono - or dialkylamino, -C(O)-O-alkyl, or phenyl, naphthyl or furyl, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinemethanol, -C(O)-O-alkyl, -C(O)-alkyl or phenyl,

or Z22means a radical of the formula

X2means alkyl, quinil, the radical -(CH2)m -W-(CH2)q-Z23or -(CH2)pZ24in which

W means SO2;

Z23means phenyl radical;

Z24means cyclohexenyl, biphenyl, cyclohexyl, optionally substituted by aminoalkyl, or phenyl, nattily, benzothiazolyl, thienyl or indolinyl radical, optionally substituted by one or more radicals selected from the group comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, -CF3, -OCF3SCF3, hydroxy, -O-C(O)-alkyl, -NH-C(O)-alkyl, mono - or dialkylamino, amino,

or Z24means a radical of the formula

or X2means

X3means a radical -(CH2)pZ25in which Z25is a phenyl radical, optionally substituted by one or more identical or different radicals selected from alkoxy and CF3.

R3Apreferably means hydrogen atom, alkyl, alkanniny or furylmethyl radical, substituted by one or more nitroreductase, or a radical of the formula-C(Y)-NHX1-C(O)X2or SO2X2where

X1means a radical -(CH2)pZ22in which

Z22means phenyl or nattily radical, optionally substituted one and the multiple radicals, independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, phenoxy;

X2means the vinyl radical, substituted phenyl radical, which is in turn substituted by one or more halogen, or a radical -(CH2)p-U-Z24where

Z24means alkyl, cyclohexyl, tetrahydrofuryl, biphenyl, amino, mono - or dialkylamino, or phenyl, indolyl, thienyl, pyridinyl, sensational and furyl, optionally substituted by one or more radicals selected from the group comprising alkoxy, bromine, chlorine, fluorine, amino, mono - and dialkylamino, nitro, hydroxy, pyrrolyl;

or X2means a radical of the formula

X3means (C1-C10)alkyl radical with a linear or branched chain, the vinyl radical, substituted phenyl, CF3or the radical -(CH2)pZ25in which

Z25means phenyl, nattily, thienyl, personilnya or diazolidinyl radical, optionally substituted by one or more substituents, independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, -NH-C(O)-alkyl, mono - and dialkylamino;

In the most preferred case, R1ameans a radical -(CH2)mZ12in which m=2 Z 12means biphenyl or indolinyl radical, substituted by one or more substituents, independently selected from alkyl and CNS radicals.

In the most preferred case, R2ameans radicals of the formula-C(Y)NHX1and-S(O)X2in which

Y represents S;

X1means phenyl radical, optionally substituted by one or more azithramycine;

X2means -(CH2)pZ24where

p is 1, 2 or 3;

Z24means cyclohexyl, phenyl or sensational, optionally substituted by one or more radicals selected from fluorine, chlorine, bromine, iodine or-CF3.

In the most preferred case, R3Ameans a hydrogen atom or a methyl radical.

All technical and scientific terms used in the description of the present invention have the meanings known to specialists in this field. In addition, all patents (or patent applications) and other bibliographic data included in this description of the invention as references.

Experimental part

Other compounds of the present invention, obtained in the ways described in examples a, b, C and D, shown in the table below.

Compounds were characterized by retention time (rt), expressed in minutes, and the molecular peak (M+H+),specific mass spectroscopy (MS).

Mass spectroscopy performed using a single-beam mass spectrometer nuclear quadrupole resonance (model platform Micromass)equipped with electrospray source with a resolution of 0.8 Da at 50% reduction. Below are the conditions of chromatography for sample 1-778.

The chromatography conditions C1 and C2

Eluent: water + 0.02% of triperoxonane acid; b: acetonitrile.

T (min)A(%)In(%)
01000
11000
101585
121585

Conditions of chromatography C1Conditions of chromatography C2
Volume flow: 1.1 ml/minVolume flow: 1.1 ml/min
Volume of sample: 5 álVolume of sample: 20 ál
Temperature: 40°Temperature: 40°
Wavelength (% UV): 210 nmWavelength (% UV): 210 nm
Column: Uptisphere ODS 3 µm,

33×4.6 mm (inner diameter)
Column: Kromasyil ODS 3.5 µm

50×4.6 mm (inner diameter)

Usl is via chromatography C3

Eluent: water + 0.02% of triperoxonane acid; b: acetonitrile

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

Volumetric flow rate of 1 ml/min

The volume of the sample 5 ál

Column: Uptisphere ODS 3 µm, 50×4.6 mm inner diameter

Temperature 40°

Wavelength (% UV) 220 nm

Below are the conditions of chromatography giving examples:

ExamplesConditions
1-29C2
30-263C1
264-425C3
426-456C2
457-503C3
504-586C1
587-778C3

The examples serve only to illustrate the methods described above and do not limit the scope of the present invention.

Pharmacological research

Compounds of the present invention are tested for their affinity to different subtypes of somatostatin receptors of the methods described below.

Study of the affinity for subtypes of somatostatin receptors person

The affinity of the compounds according to this invention to the subtypes of somatostatin receptors 1-5 (respectively sst1sst2sst3sst4and sst5) is determined by measuring the inhibition of binding of [125I-Tyr11] SRIF-14 transfected cells Chinese hamster ovary Cho-K1.

Gene receptor sst 1somatostatin human clone in the form of a genomic fragment. Segment > PST -XmnI length of 1.5 KBP containing 100 BP retranscribing 5'-terminal region, all 1,17 KBP coding region and 230 BP retranscribing 3'-terminal region, modifying, adding a BglII linker. The obtained DNA fragment subcloning in the BamHI site of the plasmid pCMV-81, receiving expressing plasmid in mammals (provided by Dr. Graham bell, the University of Chicago). The cloned cell line, stably expressing the receptor sst1get the transfection of cells Cho-K1 (ATSS)by coprecipitation calcium phosphate. The plasmid pRSV-neo (ATS) is used as selectivity marker. The cloned cell line selectyou in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), followed by cloning ring molecules and reproduction in culture.

Gene receptor sst2somatostatin person allocated in the form of a genomic DNA fragment BamHI-HindIII length of 1.7 T. P.O. and subcloned in the plasmid vector pGEM3Z (Promega), provided by Dr. G. bell (University of Chicago). To create expressing vector in mammalian cells fragment BamHI-HindIII length of 1.7 KBP introducing the restriction sites endonuclease compatible with the plasmid pCMV5. The cloned cell line is produced by transfection of cells Cho-K1, performing copresida is of calcium phosphate. The plasmid pRSV-neo used as selectivity token.

The sst receptor3isolated in the form of a genomic fragment, with a complete coding sequence is located in the fragment NcoI-HindIII length of 2.4 KBP To create expressing plasmids in mammalian cells pCMV-h3 fragment BamHI-HindIII length of 2.0 KBP inserted into the EcoR1 site of the vector pCMV after modification of the ends and add EcoR1 linkers. The cloned cell line, stably expressing the receptor sst3get the transfection of cells Cho-K1 (ATCC), while coprecipitation calcium phosphate. The plasmid pRSV-neo (ATCC) used as selectivity marker. The cloned cell line selectyou in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), followed by cloning ring molecules and reproduction in culture.

Expressing plasmid receptor sst4man pCMV-HX provided by Dr. Graham bell (University of Chicago). The specified vector containing the genomic fragment encoding the receptor of human sst4 NheI-Nhel a length of 1.4 KBP containing 456 BP retranscribing 5'-terminal region and 200 BP retranscribing 3'-terminal region, which is cloned in the XbaI sites/EcoR1 plasmids PCMV-HX. The cloned cell line, stably expressing the receptor sst4get the transfection of cells Cho-K1 (ATCC), while coprecipitation fosfato the calcium. The plasmid pRSV-neo (ATCC) used as selectivity marker. The cloned cell line selectyou in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), followed by cloning ring molecules and reproduction in culture.

The gene corresponding to the receptor sst5person polymerase reaction chain (PCR) using genomic λ clone as a probe, provided by Dr. Graham bell (University of Chicago). Obtained using a PCR fragment with a length of 1.2 KBP contains 21 a couple of reasons retranscribing 5'-terminal region, the entire coding region and 55 acting retranscribing 3'-terminal region. The resulting clone is introduced into the EcoR1 site of the plasmid pBSSK(+). The insert is isolated in the form of a fragment HindIII-Xbal length 1.2 KBP to sublimirovanny in expressing vector mammals pCVM5. The cloned cell line stably expressing the receptor sst5get the transfection of cells Cho-K1 (ATSS)by coprecipitation calcium phosphate. The plasmid pRSV-neo (ATS) is used as selectivity marker. The cloned cell line selectyou in medium RPMI 1640 containing 0.5 mg/ml G416 (Gibco), followed by cloning ring molecules and reproduction in culture.

Cells Cho-K1, stably expressing one of the receptors sst human cultured in medium RPMI 1640 containing 10% FET is optimum calf serum and 0.4 mg/ml geneticin. Cells are harvested using EDTA in the amount of 0.5 mm and centrifuged with an acceleration of 500 g for about 5 minutes at a temperature of about 4°C. the Precipitate is again suspended in 50 mm Tris buffer at pH 7.4 and centrifuged twice with an acceleration of 500 g for 5 minutes at a temperature of about 4°C. the Cells are lysed by ultrasound and centrifuged with acceleration 39000 g for approximately 10 minutes at 4°C. the Precipitate is again suspended in the same buffer and centrifuged with acceleration 50000 g for about 10 minutes at a temperature of about 4°and the cell membrane obtained in the sediment stored at -80°C.

Tested by competitive inhibition of the binding with [125I-Tyr11] SRIF-14 is carried out using duplicate samples on a 96-well polypropylene plates. Cell membranes (10 μg protein/well) are incubated with [125I-Tyr11]SRIF-14 (0,05 nm) for about 60 minutes at a temperature of about 37°With 50 mm HEPES buffer (pH 7.4)containing 0.2% bovine serum albumin (BSA), 5 mm MgCl3, 200 u/ml of drug, 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 filtered through filter plates of glass fiber GF/C Unifilter, Packard), pre-soaked in 0.1% polyethylenimine (P.E.I.), using filtering devices is Filtermate 196 (Packard). The filters are washed with 50 mm HEPES buffer at a temperature of about 0-4°C for about 4 seconds and the counter determine their radioactivity (Packard Top Count).

To determine specific binding from the total value binding subtract the amount of nonspecific binding (determined in the presence of 0.1 μm SRIF-14). Data related to linking, analyzing in a computer by the method of nonlinear regression (MDL) and determine the values of the constants of inhibition (Ki).

Agonist or antagonist nature of the compounds according to the present invention is determined using the following test.

Functional test: inhibition of the production of intracellular camp

Cells Cho-K1 expressing subtypes of somatostatin receptors person (SRIF-14), cultured in 24-hole tablets in medium RPMI 1640 containing 10% fetal calf serum and 0.4 mg/ml geneticin. Environment change on the day preceding the beginning of the experiment.

Cells in 105cells/well washed twice with 0.5 ml of fresh RPMI medium with 0.2% BSA containing 0.5 mm 3-isobutyl-1-methylxanthines (IBMX), and incubated for approximately 5 minutes at a temperature of about 37°C.

The production of cyclic adenosine monophosphate (AMP) stimulated by adding 1 mm of Forskolin (FSK) for 15-30 minutes at a temperature of about 37°C.

Inhibit the abuser action of somatostatin connection-agonist measure producing simultaneous addition of FSK (1 μm), SRIF-14 (from 10-12up to 10-6M) and test compounds (10-10up to 10-5M).

Antagonistic action of the compounds measured, producing simultaneous addition of FSK (1 μm), SRIF-14 (from 1 to 10 nm) and test compound (10-10up to 10-5M).

Reaction medium was removed and added to 200 ml of 0.1 n HCl solution. The amount of camp was measured using a radioimmunoassay test (set FlashPlate SMP001A, New England Nuclear).

Results

Tests made by the methods described above show that the products of General formula (I)presented in this application, have good affinity to at least one of the subtypes of somatostatin receptors, and the inhibition constant Kibelow micromolar values for some of the tested compounds.

The pharmaceutical composition

By the way, is common in pharmacology, preparing a composition for injection having the following composition:

to 10 ml
Active substance (compound of the invention)50 mg
Povidone20 mg
Sodium citrate200 mg
Propylene glycol6 ml
Ethanol (96%)0,52 ml
Water for injection

1. Derivatives of 4-aminopiperidine General formula

in racemic, enantiomeric form or all combinations of these forms, where

R1means (C1-C6)alkyl, the radical -(CH2)m-Y-Z11or the radical -(CH2)m-Z12in which

Z11means (C1-C6)alkyl;

Z12means biphenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7)heteroseksualci having 1 or 2 heteroatoms, where the heteroatoms are nitrogen or oxygen, optionally substituted phenyl, naphthyl, optionally substituted (C5-C9) heteroaryl, where the heteroatom represented by nitrogen;

or Z12means

,

Y represents an oxygen atom, or

R1means a radical of the formula

R2means a radical of the formula-C(Y)NHX1-C(O)X2or SO2X3,

where

X1means (C1-C8)alkyl or -(CH2)pZ22in which

Z22means cyclohexenyl, biphenyl, (C3-C7)cycloalkyl, (C3-C7) heteroseksualci having 1 or 2 heteroatoms, where the heteroatoms are what I nitrogen or oxygen, mono - or dialkylamino, -C(O)-O-alkyl, optionally substituted phenyl, naphthyl or optionally substituted heteroaryl having 1 or 2 heteroatoms, where the heteroatoms is nitrogen or oxygen;

or Z22means a radical of the formula

Y represents an oxygen atom or sulfur;

X2means (C1-C10)alkyl, (C2-C8)quinil, a radical of the formula -(CH2)m-W-(CH2)q-Z23or -(CH2)p-U-Z24where

W means SO2;

U represents a covalent bond;

Z23means phenyl;

Z24means optionally substituted C3-C7)cycloalkyl, optionally substituted phenyl, naphthyl, optionally substituted heteroaryl having 1 or 2 heteroatoms, where the heteroatoms are nitrogen or sulfur;

or Z24means a radical of the formula

or X2means

where the protective group (PG) is H or tertbutyloxycarbonyl;

X3means a radical -(CH2)pZ25where

Z25means optionally substituted phenyl;

R3means a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl, neoba is consequently substituted heteroaromatic or a radical of the formula-C(Y)-NHX 1, -(CH2)n-C(O)X2or SO2X3where X1means a radical -(CH2)pZ22in which Z22means optionally substituted C6-C10)aryl; X2means (C1-C10)alkyl or (C2-C10)alkenyl, vinyl, substituted phenyl, in which phenyl optionally substituted by one or more halogen atoms, a radical of the formula -(CH2)m-W-(CH2)q-Z23or -(CH2)p-U-Z24where W means SO2; U represents a covalent bond or an oxygen atom; Z23means aryl; Z24means alkyl, (C3-C7) cycloalkyl, (C3-C7) heteroseksualci, biphenyl, amino, mono - or dialkylamino, optionally substituted aryl or optionally substituted heteroaryl; or X2means a radical of the formula

X3means (C1-C10) alkyl, vinyl, substituted phenyl (the phenyl may be optionally substituted), CF3or -(CH2)pZ25where Z25means optionally substituted C6-C10) aryl or optionally substituted C3-C6) heteroaryl having 1 or 2 heteroatoms selected from sulfur, oxygen and nitrogen;

n is equal to R and is an integer from 0 to 4;

m is an integer from 1 to 6;/p>

p is an integer from 0 to 6;

q is an integer from 0 to 2;

or their additive salts with pharmaceutically acceptable mineral or organic acids.

2. Compounds of General formula I according to claim 1, characterized in that

i) Deputy or deputies, substitute aryl, presents Z12and heteroaryl, presents Z12independently selected from fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, -CF3, -OCF3, phenyl, phenoxy, aminosulfonyl;

ii) the Deputy or deputies, replacement heterologously radical represented by Z12independently selected from hydroxy and alkyl radicals;

iii) the Deputy or deputies, substitute aryl and heteroaryl radicals represented by Z22independently selected from fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkoxy, alkylthio, CF3, ORS, nitro, cyano, azido, aminosulfonyl, piperidinemethanol, mono - or dialkylamino, -C(O)-O-alkyl, -C(O)-alkyl or phenyl, phenoxy, phenylthio, benzyloxy and phenyl radical may be substituted;

iv) the Deputy or deputies, substitute aryl radicals represented by Z23and Z24cycloalkyl or heteroaryl, presents Z24independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, al the sludge, alkoxy, alkylthio, CF3, OCF3, OCHF2SCF3, nitro, cyano, azido, hydroxy, -C(O)O-alkyl, -O-C(O)-alkyl, -NH-C(O)-alkyl, alkylsulfonyl, mono - or dialkylamino, amino, aminoalkyl, pyrrolyl, pyrrolidinyl or phenyl, phenoxy, phenylthio, benzyl, benzyloxy, and the aryl radical may be optionally substituted by one or more alkyl, CF3or halogenation;

v) the Deputy or deputies, substitute aryl or heteroaryl radicals represented by Z25independently chosen from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, OCF3, nitro, cyano, -NH-C(O)-alkyl, alkylsulfonyl, amino, mono - and dialkylamino, phenyl, pyridine;

vi) the Deputy or deputies, replacement heteroarylboronic radical represented by R3independently chosen from radicals comprising fluorine, chlorine, bromine or nitro.

3. Compounds of General formula I according to claim 1 or 2, in which the radical R1

Z12means biphenyl, (C3-C7)cycloalkyl, optionally substituted (C3-C7)heteroseksualci or phenyl or heteroaryl, optionally substituted by one or more substituents, independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy;

or Z12means

in the radical R2

Z22means cyclohexenyl, biphenyl, (C3-C7)cycloalkyl, (C3-C7)heteroseksualci, mono - or dialkylamino, -C(O)-O-alkyl, phenyl or heteroaryl, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinemethanol, -C(O)-O-alkyl, -C(O)-alkyl or phenyl;

or Z22means a radical of the formula

b

Z24means cyclohexenyl, biphenyl, (C3-C7)cycloalkyl, optionally substituted aminoalkyl, or phenyl or heteroaryl radical, optionally substituted by one or more radicals selected from the group comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, -CF3, -OCF3SCF3, hydroxy, -C(O)-O-alkyl, mono - or dialkylamino, amino;

or Z24means a radical of the formula

Z25means phenyl radical, optionally substituted by one or more identical or different radicals selected from alkoxy and CF3;

In the radical R3

Z22means aryl radical, optionally substituted by one or a few is Kimi radicals, independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, phenoxy;

X2means the vinyl radical, substituted phenyl, and the phenyl radical, in turn, optionally substituted by one or more halogen, or a radical -(CH2)p-U-Z24where

Z24means alkyl, (C3-C7)cycloalkyl, (C3-C7)heteroseksualci, biphenyl, amino, mono - or dialkylamino, aryl or heteroaryl, optionally substituted by one or more radicals selected from the group comprising alkoxy, bromine, chlorine, fluorine, hydroxy, CF3, nitro, amino, mono - and dialkylamino, pyrrolyl;

or X2means a radical of the formula

Z25means phenyl, naphthyl or heteroaryl, optionally substituted by one or more substituents, independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, -NH-C(O)-alkyl, mono - and dialkylamino.

4. Compounds of General formula I according to any one of the preceding paragraphs, in which R1means (C1-C6)alkyl radical with a linear or branched chain, the radical -(CH2)m-Y-Z11or -(CH2)m-Z12where

Z11means (C1-C6)Ala is l;

Z12means naphthyl, morpholino, biphenyl, pyrrolidinyl, replaced by oxyradicals, or phenyl, piperazinilnom, pyridinoline and indolizinyl radicals, which are optionally substituted by one or more substituents, independently selected from radicals comprising bromine, fluorine, chlorine, alkyl, alkoxy, -CF3, -OCF3;

or Z12means

Y represents an oxygen atom;

or R1means the radical following formula:

5. Compounds of General formula I according to any one of the preceding paragraphs, in which R2means a radical of the formula-C(Y)NHX1, -C(O)X2or SO2X3where

X1means (C1-C10)alkyl linear or branched chain or a radical -(CH2)pZ22in which

Z22means cyclohexyl, cyclohexenyl, biphenyl, morpholino, piperidino, mono - or dialkylamino, -C(O)-O-alkyl or phenyl, naphthyl or furyl, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylthio, CF3, -OCF3, nitro, cyano, azido, piperidinemethanol, -C(O)-O-alkyl, -C(O)-alkyl or phenyl;

or Z22means a radical of the formula

< num="686">

X2means alkyl, quinil, the radical -(CH2)m-W-(CH2)q-Z23or -(CH2)pZ24in which

W means SO2;

Z23means phenyl radical;

Z24means cyclohexenyl, biphenyl, cyclohexyl, optionally substituted by aminoalkyl, or phenyl, nattily, benzothiazolyl, thienyl or indolinyl radical, optionally substituted by one or more radicals selected from the group comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, -CF3, -OCF3, -SCF3, hydroxy, -O-C(O)-alkyl, -NH-C(O)-alkyl, mono - or dialkylamino, amino;

or

Z24means a radical of the formula

or X2means

X3means a radical -(CH2)pZ25in which Z25is a phenyl radical, optionally substituted by one or more identical or different radicals selected from alkoxy and CF3.

6. Compounds of General formula I according to any one of the preceding paragraphs, in which R3means a hydrogen atom, alkyl, alkanniny or furylmethyl radical, substituted by one or more nitroreductase, or a radical of the formula-C(Y)-HX 1-C(O)X2or SO2X3where

X1means a radical -(CH2)pZ22in which

Z22means phenyl or nattily radical, optionally substituted by one or more radicals independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, phenoxy;

X2means the vinyl radical, substituted phenyl radical, which, in turn, optionally substituted by one or more halogen, or a radical -(CH2)p-U-Z24where

Z24means alkyl, cyclohexyl, tetrahydrofuryl, biphenyl, amino, mono - or dialkylamino or phenyl, indolyl, thienyl, pyridinyl, sensational and furyl, optionally substituted by one or more radicals selected from the group comprising alkoxy, bromine, chlorine, fluorine, amino, mono - and dialkylamino, nitro, hydroxy, pyrrolyl;

or X2means a radical of the formula

X3means (C1-C10)alkyl radical with a linear or branched chain, the vinyl radical, substituted phenyl, CF3or the radical -(CH2)pZ25in which

Z25means phenyl, nattily, thienyl, personilnya or diazolidinyl radical, not necessarily alseny one or more substituents, independently selected from radicals comprising fluorine, chlorine, bromine, iodine, alkyl, alkoxy, CF3, nitro, -NH-C(O)-alkyl, mono - and dialkylamino.

7. Compounds of General formula I according to any one of the preceding paragraphs, in which R1means a radical -(CH2)mZ12where m=2 and Z12means biphenyl or indolinyl radical, substituted by one or more substituents, independently selected from alkyl and CNS radicals.

8. Compounds of General formula I according to any one of the preceding paragraphs, in which R2means radicals of the formula-C(Y)-NHX1and-S(O)X2where

Y represents S;

X1means phenyl radical, optionally substituted by one or more azithramycine;

X2means -(CH2)pZ24where p is 1, 2 or 3;

Z24means cyclohexyl, phenyl or sensational, optionally substituted by one or more radicals selected from fluorine, chlorine, bromine, iodine or-CF3.

9. Compounds of General formula I according to any one of the preceding paragraphs, in which R3means a hydrogen atom or a methyl radical.

10. The method of obtaining in the liquid phase compounds of the formula I according to claim 1, characterized in that it includes: reductive amination of the following N-substituted piperidone

where R is methyl or Boc radical, in the presence of an amine of formula R1NH2in which R1matter specified in claim 1 that gives compound of formula 1

after which the compound of formula (1) is subjected to interaction:

A) with the compound of the formula X1NC(Y), where X1and Y have the meanings indicated in claim 1, which gives the compound of formula (2)

the compound of the formula (2) represents the corresponding compound of formula (I)in which R3means Me or Boc, and when R3means Boc, treatment of this compound with acid to obtain the corresponding compound of formula (I)in which R3means a hydrogen atom;

thus obtained compound of formula (I) are then subjected to interaction with the compound of the formula X1NC(Y), X2CO2N or X3SO2Cl, in which X1, Y X2and X3have the meanings indicated in claim 1, in result of which receive a corresponding compound of formula I, in which R2means a radical of the formula-C(Y)NHX1and R3accordingly, means the radical-C(Y)NHX1, -C(O)X2or SO2X3;

In) or with the compound of the formula X2CO2H, in which X2matter specified in claim 1, Yes the t compound of the formula (3)

the compound of the formula (3) represents the corresponding compound of formula (I)in which R3means Me or Boc, and when R3means Boc, treatment of this compound with acid to obtain the corresponding compound of formula (I)in which R3means a hydrogen atom,

thus obtained compound of formula (I) are then subjected to interaction with the compound of the formula X1NC(Y), X2CO2N or X2SO2Cl, in which X1, Y X2and X3have the meanings indicated in claim 1, in result of which receive a corresponding compound of formula I, in which R2means a radical of the formula-C(O)X2and R3accordingly, means the radical-C(Y)NHX1-C(O)X2or SO2X3.

11. A method of obtaining a solid phase compounds of the formula I according to claim 1, characterized in that it includes

reductive amination of ketone resin

in the presence of an amine of formula R1NH2in which R1matter specified in claim 1 that gives compound of formula (4)

after which the compound of the formula (4) is subjected to interaction

A) with the compound of the formula X1NC(Y), where X1and Y have the meanings at Azania in claim 1, that gives compound of formula (5)

subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom;

B) or with the compound of the formula X3SO2Cl, in which X3matter specified in claim 1 that gives compound of formula (6)

subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom;

C) or with the compound of the formula X2CO2Cl, in which X2matter specified in claim 1 that gives compound of formula (7)

subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom;

D) or with the compound of the formula X2CO2H, in which X2matter specified in claim 1 that gives compound of formula (7), followed by cleavage of the resin, resulting receive a corresponding compound of formula (I)in which R3means a hydrogen atom.

12. A method of obtaining a solid phase compounds of the formula I according to claim 1, characterized in that it includes

restoration of aminirovanie the ketone resin

in the presence of an amine of formula R1NH2in which R1matter specified in claim 1 that gives compound of formula (8)

after which the compound of formula (8) is subjected to interaction

A) with the compound of the formula X1NC(O), in which X1matter specified in claim 1 that gives compound of formula (9)

thus obtained compound (9) is subjected to interaction with the compound of the formula R3X, in which R3matter specified in claim 1, and X is Br or I, with subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I);

B) or with the compound of the formula X2SO2Cl, in which X3matter specified in claim 1 that gives compound of formula (10)

thus obtained compound (10) is subjected to interaction with the compound of the formula R3X, in which R3matter specified in claim 1, and X is Br or I, with subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I);

C) or with the compound of the formula X2CO2Cl, in which X2matter referred to in paragraph 1, what gives with the Association of the formula (11)

thus obtained compound (11) is subjected to interaction with the compound of the formula R3X, in which R3matter specified in claim 1, and X is Br or I, with subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I);

D) or with the compound of the formula X2CO2H, in which X2matter specified in claim 1 that gives compound of formula (11);

thus obtained compound (11) is subjected to interaction with the compound of the formula R3X, in which R3matter specified in claim 1, and X is Br or I, with subsequent cleavage of the resin, resulting receive a corresponding compound of formula (I).

13. The compounds of formula I according to claims 1-9, as well as additive salts of these compounds of formula I with pharmaceutically acceptable mineral or organic acids having activity on the inhibition of the production of intracellular camp.

14. Pharmaceutical composition for inhibiting the production of intracellular camp, containing as active ingredient at least one drug in item 13 in combination with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 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, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, pesticides, agriculture.

SUBSTANCE: invention relates to compounds that elicit high pesticide activity and can be used in control of pests of domestic and agricultural animals. Indicated compounds show the formula (I):

wherein R1 means halogen atom, (C1-C6)-halogenalkyl; R2 means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkylene-phenyl; X1 means nitrogen atom (N); X2 means group C(CN); X3 means oxygen atom (O); Q means CH; R3 and R4 mean independently of one another hydrogen atom (H) or in common with carbon atom with which they are bound form (C3-C7)-cycloalkyl ring; R5 means a substitute taken among group including (C1-C6)-halogenalkyl, halogen atom being if m above 1 then substitutes R5 can be similar or different; m = 1, 2 or 3; n = 0 or 1. Also, invention describes a method for their preparing and method for control of pests.

EFFECT: valuable pesticide properties of compounds.

7 cl, 3 tbl, 14 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.

SUBSTANCE: method relates to new method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I . Claimed compound is high effective drug and is used in medicine as myorelaxant of central action. Claimed method includes condensation of N,N-dimethyldichloromethyleneammonium chloride with 5-chloro-4-amino-1,1,3-benzothiadiazole in organic solvent followed by treatment of formed alpha-chloroformamidine of formula R-N=C(Cl)N(CH3)2, wherein R is 5-chloro-2,1,3-benzothiazol-4-yl, with ethylenediamine. Formed intermediate of formula R-N=C(NH-CH2-CH2-NH2)N(CH3)2 is treated with hydrochloric acid, heated in organic solvent and 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I is isolated.

EFFECT: simplified method for preparation of target compound directly in hydrochloride form.

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

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

25 cl, 6 tbl

FIELD: organic chemistry of natural compounds, medicine.

SUBSTANCE: invention relates to new taxanes with carbonate substitute at C7 of the general formula (I) given in the invention description wherein R2 means benzoyloxy group; R7 means -COO; R9 means -CO; R10 means -OH; R14 means hydrogen atom (H); X3 means (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom; X5 means -COX10, -COOX10 wherein X10 means (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom, and Ac means acetyl. Proposed compounds possess an anti-tumor activity.

EFFECT: valuable medicinal properties of compounds.

61 cl, 1 tbl, 5 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to derivatives of taxane of the general formula (I):

wherein R2 means acyloxy-group; R7 means hydroxy-group; R9 means keto-group; R10 means carbonate; R14 means hydrogen atom; X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted optionally with nitro-group or 5-6-membered heteroaromatic group comprising heteroatoms taken among oxygen (O), nitrogen (N) or sulfur (S) atoms; X5 means -C(O)X10, -C(O)OX10 or -CONHX10 wherein X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl, furyl, pyridyl or thienyl; Ac means acetyl. Also, invention describes a pharmaceutical composition based on taxanes and a method for inhibition of a tumor growth.

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

98 cl, 6 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, agriculture.

SUBSTANCE: invention relates to novel trifluoromethylpyrrole carboxamides of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C4)-alkyl; R2 means (C1-C4)-alkyl, (C1-C4)-halogenalkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, cyano-group or (C1-C6)-alkylcarbonyl; A means the group of the formula:

, or wherein R3 means (C1-C6)-alkyl, (C1-C6)-halogenalkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl, (C1-C4)-alkyl-(C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, (C1-C4)-alkyl-(C4-C7)-cycloalkenyl, phenyl, naphthyl or phenoxy-group, or substituted phenyl, or substituted phenoxy-group wherein substituted represent 1-3 groups taken independently among an order comprising halogen atom, (C1-C4)_alkyl, (C1-C4)-alkoxy-, cyano-group, (C1-C4)-alkylcarbonyl, (C1-C4)-halogenalkyl, (C1-C4)-halogenalkoxy-, methylenedioxy-, difluoromethylenedioxy-group or phenyl; R4 means hydrogen, halogen atom or (C1-C4)-alkyl; each among R5, R6 and R7 means (C1-C6)-alkyl. Compounds of the formula (I) are used for control of phytopathogen organisms or for prophylaxis in damaging cultured plants by these organisms.

EFFECT: valuable properties of compounds.

10 cl, 3 tbl, 1 sch, 12 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, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new taxanes of the general formula (I)

wherein R2 means benzoyloxy-group; R7 means hydroxyl (OH); R9 means keto-group; R10 means R10aCOO-; R10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-6-membered heteroaromatic group wherein heteroatom represents oxygen atom (O), sulfur atom (S) or nitrogen atom (N); R14 means hydrogen atom (H); X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted possibly with nitro-group (-NO2), 5-6-membered heteroaromatic group wherein heteroatom represents O, S or N; X5 means -COX10, -COOX10; X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heteroaromatic group wherein heteroatom represents O, S, N; Ac means acetyl. Compounds of the formula (I) elicit antitumor activity.

EFFECT: valuable medicinal properties of compounds.

68 cl, 1 tbl, 6 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention relates to substituted thienocycloalk(ene)ylamino-1,3,5-triazines of the general formula (I): wherein R1 means hydrogen atom; R2 means hydrogen atom, formyl or alkylcarbonyl, group N(R1R2) denoting dialkylaminoalkylideneamine; R3 means unsubstituted or halogen-substituted alkyl; Z means one of the following thienocycloalkyl groups: and wherein A1, A2 and A3 mean alkylene. Also, invention describes a method for synthesis of indicated compounds and intermediate compounds used in the synthesis. Compounds can be used as herbicides.

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

8 cl, 4 tbl, 5 ex

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

SUBSTANCE: invention relates to new derivatives of 1-aziridino-1-hydroxyiminomethyl of the general formula (I):

wherein R means a single bond or organic radical that can bind aziridinoxime groups by a covalent bond and taken among the group including saturated or unsaturated alkanes with normal or branched chain and comprising up to 6 carbon atoms, substituted azino-group -(R')C=N-N=C(R'') wherein R' and R'' represent independently of one another hydrogen atom or lower alkyl, heterocyclic compounds comprising from 3 to 6 atoms in ring and up to 4 heteroatoms taken among -N- and -O-, and aromatic compounds comprising up to 8 atoms in ring; R1 and R2 mean independently of one another -H, -COOH, -COOCH3, -COOC2H5 or -CONH2; n means a whole number 2 or 3; with exception the compound wherein R represents a single bond and R1 and R2 are both hydrogen atom, and also with exception the compound wherein R represents a single bond and one of substitutes is hydrogen atom among the group R1 and R2. Also, invention describes a method for their preparing and medicinal preparations comprising these compounds that possess an antitumor effect.

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

7 cl, 3 tbl, 19 ex

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