Derivatives of indole-3-yl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

 

The invention relates to a derivative of indole-3-yl of the formula

in which

A and b each, independently of one another, represent O, S, NH, NR7, CO, CONH, NHCO or direct connection,

X denotes alkylene containing from 1 to 2 carbon atoms, which may be unsubstituted or monosubstituted R4or R5or a direct link,

R1denotes H, Z or -(CH2)about-Ah,

R2denotes H, R7or-C(O)Z,

R3means other6, -NR6-C(=NR6)-Other6, -C(=NR6)-Other6, -NR6-C(=NR9)-Other6, -C(=NR9)-Other6or Het1,

R4and R5each, independently of one another, represent H, oxo, R7, -(CH2)o-Ar, -C(O)-(CH2)o-Ar, -C(O)-(CH2)o-R7, -C(O)-(CH2)o-Het, Het, other6, NHAr, NH-Het, CONH-R7, CONH-(CH2)o-Ar, CONH-(CH2)o-Het, OR7, OAR, OR6or O-Het,

R6denotes H, -C(O)R7, -C(O)-Ar, -C(O)-Het, R7, COOR7, COO-(CH2)o-Ar, COO-(CH2)o-Het, SO2-Ar, SO2R7or SO2-Het,

R7represents alkyl containing from 1 to 10 carbon atoms, or cycloalkyl containing from 3 to 10 carbon atoms,

R8denotes Hal, NO2CN, Z, -(CH2)o-Ar, COOR1, OR1, CF3, CF 3, SO2R1, Other1N(R1)2, NH-C(O)R1, NHCOOR1, COOH, COOZ, or C(O)R1,

R9denotes CN or NO2,

Z represents alkyl containing from 1 to 6 carbon atoms,

AG represents aryl which may be unsubstituted or monosubstituted or polyamidine R8,

Hal denotes F, Cl, Br or I,

Het denotes a saturated, partially or fully unsaturated monocyclic or bicyclic heterocyclic radical containing from 5 to 10 ring members, which can be 1 or 2 N atom and/or 1 or 2 atoms S or O, and the heterocyclic radical can be monosubstituted or disubstituted R8,

Het1denotes a saturated, partially or fully unsaturated monocyclic or bicyclic heterocyclic radical containing from 5 to 10 ring members and from 1 to 4 N atoms, which may be unsubstituted or monosubstituted or disubstituted by Hal, R7, OR7CN, NHZ, oxo or NO2,

n denotes 0, 1 or 2,

m denotes 0, 1, 2, 3, 4, 5 or 6, and

o denotes 0, 1 or 2,

and their physiologically acceptable salts and solvate.

Some such compounds are disclosed in application WO 99/30713 and WO 94/12478.

The object of the invention consisted in the discovery of new compounds having valuable properties, in particular those that can be applied in the change in the production of medical products.

It was found that the compounds of formula I and their salts, vysokotsenny and possess very valuable pharmacological properties. In particular, they act as integrin inhibitors, these compounds inhibit, in particular, the interaction of receptors α v-, β 3 β 5-integrin with a ligand, such as, for example, linking with vitronectin receptor integrin. Integrins are associated with the membrane heterodimeric glycoproteins consisting of a subunit α and a smaller subunit β . The relative affinity and specificity towards bond formation with the ligand is determined by the recombination of different subunits α and β . The particular effect of the compounds according to this invention exhibit a in the case of integrins α vβ 1, α vβ 3, α vβ 5, α llbβ 3, α vβ 6 and α vβ 8, preferably α vβ 3, α vβ 5 and α llbβ 3. The compounds of this invention are particularly promising inhibitors of receptor α vβ 3 and/or α vβ 5 vitronectin and/or receptor α llbβ 3 fibrinogen. Especially preferred if the compounds according to this invention are inhibitors of receptor α vβ 3 vitronectin.

A significant factor that depends on the activity of integrin inhibitors is the presence of acid is based functional group at a suitable distance from the main centre. The activity and specificity can be adjusted by changing the distance between them and the type of the main centre. Suitable Central template is indole.

α vβ 3 integrin is expressed in many cells, such as endothelial cells, smooth muscle cells of blood vessels such as the aorta, the cells that destroy bone matrix (osteoclasts) or tumor cells.

The action of the compounds according to this invention can be demonstrated, for example, by the method described in J.W.Smith and others in J.Biol. Chem. 1990, 265, 12267-12271.

.Felding-Habermann and D.A.Cheresh in Curr. Opin. Cell. Biol. 1993, 5, 864, described the important role of integrins as receptors adhesion to a wide variety of phenomena and the clinical picture, especially in the context of receptor α vβ 3 vitronectin.

The dependence of the occurrence of angiogenesis from the interaction of vascular integrins with wasnecessary protein matrix was described in ..Brooks, R.A.Clark and Cheresh DA in Science 1994, 264, 569-571.

The ability to inhibit these interactions and, thus, to initiate apoptosis (programmed cell death) angiogenic cells of blood vessels by means of cyclic peptides was described in ..Brooks, A.M.Montgomery, M.Rosenfeld, R.A.Reisfeld, T.Hu, G.Klier and D.A.Cheresh in Cell 1994, 79, 1157-1164. In this work are described, for example, antagonists avp3 or antibodies against avp3, which causes the reduction is of puhala in the initiation of apoptosis.

The fact that the compounds according to this invention prevent the accession of living cells to the corresponding proteins of the matrix and thus prevent the adherence of tumor cells to matrix proteins, can be proven experimentally using the test for adhesion of cells, the methodology of which is described in the work F.Mitjans and others, J.Cell Science 1995, 108, 2825-2838.

P.C.Brooks in J.Clin. Invest. 1995, 96, 1815-1822, described antagonists αvβ3intended for cancer and for the treatment of tumor-induced angiogenic diseases.

These compounds are able to inhibit the binding metalloproteinase with integrins and, thus, to prevent the use of cell enzymatic activity of proteases. As an example, you can specify the ability of the peptide cyclo-RGD to inhibit the binding of MMP-2 (matrix-metalloproteinase 2) receptor αvβ3 vitronectin, which is described in the work P.C.Brooks etc., Cell 1996, 85, 683-693.

The compounds of formula I according to this invention can therefore be used as active ingredients of medicaments, in particular for the treatment of neoplastic diseases, osteoporosis, osteolytic diseases and to inhibit angiogenesis.

The compounds of formula I that inhibit the interaction of integrin receptors with ligands, such as, for example, the R, interaction of fibrinogen to the fibrinogen receptor (glycoprotein llb/llla or α llβ 3)prevent the spread of tumor cells by metastases, and can thus be used as antimetastatic substances during operations to remove tumors or operative surgery. This fact is confirmed by the following observations.

The spread of tumor cells from the local tumor in the vascular system occurs through the formation of microaggregates (microthrombi) as a result of interaction of tumor cells with blood platelets. Under the protection of microaggregates tumor cells are masked and are not recognized by cells of the immune system. Microaggregate can adhere to the walls of blood vessels, which further simplifies the penetration of tumor cells into the tissue. Since the formation of microthrombi contributes to ligand binding to corresponding receptors integrin, for example, α vβ 3 or α llbβ 3, on activated blood platelets, as effective inhibitors of metastasis themselves to apply appropriate antagonists.

In addition to the binding of fibrinogen, fibronectin and factor a background of Villebranda fibrinogen receptor of blood platelets, the compounds of formula I also inhibit the binding of other adhesion proteins, such equitrekking, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent the occurrence of thrombosis platelet cells, and therefore, they can be used for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation and arteriosclerosis.

Inhibitory effect on platelet aggregation can be demonstrated in vitro by the method described by Born (Nature 1962, 4832, 927-929).

The compounds of formula I can be used as active ingredients of drugs in veterinary medicine and medicine, in particular for the prophylaxis and/or treatment of circulatory disorders, thrombosis, myocardial infarction, arteriosclerosis, apoplexy, angina, malignant diseases, such as tumor growth or tumor metastasis, osteolytic diseases such as osteoporosis, pathological angiogenic diseases, such as inflammation, eye diseases, diabetic retinopathy, degeneration stains, myopia, ocular histoplasmosis, restenosis, rheumatoid arthritis, osteoarthritis, glaucoma, diabetic reddening of the iris, ulcerative colitis, Crohn's disease,, atherosclerosis, psoriasis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, acute renal insufficient the tee and for the treatment of wounds as a means of contributing to the healing process.

The compounds of formula I can be used as antimicrobial substances in the operations that use biological materials, implants, catheters or pacemakers. In these cases, they have antiseptic effect. The effectiveness of antimicrobial action can be demonstrated according to the method described .Valentin-Weigund and others in Infection and Immunity, 1988, 2851-2855.

Measure absorption by the body of the active ingredient of the drug is its bioaccumulation.

If the active ingredient of the drug is administered intravenously into the body in the form of an injection solution, its absolute bioaccumulation, i.e. the share of the pharmaceutical substance, which remains unchanged in the circulatory system, i.e. enters the General circulation, is 100%.

During oral appointment of a therapeutically active ingredient, the active ingredient, in General, is the drug in the solid state, and must first be dissolved in order to overcome barriers to the penetration into the body, for example, the gastrointestinal tract, oral mucosa, the mucous membrane of the nose or the skin, in particular, the layers of the cornea, and only after that it can be absorbed by the body. Pharmacokinetic data, i.e. data about byakua the funding, can be obtained by the method described in J.Shaffer and others, J.Pharm. Sciences, 1999, 88, 313-318.

The invention relates to compounds of the formula I in claim 1 and their physiologically acceptable salts and/or solvate how to therapeutically active ingredients.

Consequently, the invention relates to compounds of the formula I in claim 1 and their physiologically acceptable salts and/or solvate as inhibitors α v-integrin.

In addition, the invention relates to compounds of the formula I in claim 1 and their physiologically acceptable salts and/or solvate as antagonists GPllb/llla.

The invention relates to the use of compounds of the formula I in claim 1 and their physiologically acceptable salt and/or solvate for the treatment of diseases.

The compounds of formula I have at least one centre of chirality and, therefore, can occur in a large number stereoisomeric forms. All of these forms (for example, form D and L) and their mixtures (for example, form DL) are included in the invention.

Compounds according to this invention, under Paragraph 1 also cover so-called derivative precursor, i.e. the compounds of formula I modified, for example, alkyl or acyl groups, sugars or oligopeptides, which the body quickly split, and the result is the effective compounds according to this invention.

Cu is IU, can be provided free amino groups or free hydroxyl groups as substituents of the compounds of the formula I with suitable protective groups.

The term solvate of the compounds of formula I indicates the units of the compounds of formula I with molecules of an inert solvent, which are formed as a result of their mutual attraction. The solvate are, for example, mono - or dihydrate, or additional compounds with alcohols, such as methanol or ethanol.

The invention relates to compounds of formula I and their salts and solvate according to Paragraph 1 and to a method for producing compounds of formula I and their salts and solvate, characterized in that

a) a compound of formula I is recovered from one of its functional derivatives by treatment solvolysis or hydrogenolysis agent, or

b) the radical R1, R2, R3, R4, R5and/or R6is converted into another radical R1, R2, R3, R4, R5and/or R6,

using, for example,

i) converting an amino group into guanidinium in the reaction with lidiruyushchim agent,

ii) saponification of the ester,

iii) alkylation or acylation of the amino group,

iv) converting ceanography in amidinopropane,

and/or a base or acid of the formula I is converted into one of its salts.

In the what's above formulas, Z represents alkyl, which may be linear or branched and contains from 1 to 6, preferably 1, 2, 3, 4, 5 or 6, carbon atoms. Z preferably denotes methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, and pentyl, 1-, 2 - or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3 - or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3.3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl.

Z particularly preferably represents methyl or ethyl.

Alkyl containing from 1 to 10 carbon atoms, may be linear or branched and preferably contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Alkyl containing from 1 to 10 carbon atoms, preferably denotes methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, and n-pentyl, 1-, 2 - or 3-methylbutyl, n-hexyl, 1-, 2-, 3 - or 4-methylpentyl, n-heptyl, n-octyl, n-nonyl or n-decyl.

Alkylene containing from 1 to 2 carbon atoms, a denotes a methylene or ethylene, in which at least one bond With-N alkylene can be replaced by connection C-R4or C-R5.

AG represents aryl, which may be unsubstituted or monosubstituted, disubstituted or tizamidine R8and the aryl is a phenyl, naphthyl, antrel or biphenyl. Preferably, AG denotes phenyl naphthyl or biphenyl, each of which can be unsubstituted or monosubstituted, disubstituted or tizamidine R8. Particularly preferably, AG denotes phenyl or biphenyl-4-yl, each of which may be unsubstituted or monosubstituted or polyamidine R8.

Ah, so preferably denotes phenyl, o-, m - or p-were, o-, m - or p-ethylphenyl, o-, m - or p-propylphenyl, o-, m - or p-isopropylphenyl, o-, m - or p-tert-butylphenyl, o-, m - or p-hydroxyphenyl, o-, m - or p-methoxyphenyl, o-, m - or p-ethoxyphenyl, o-, m-, p-triptoreline, o-, m-, p-trifloromethyl, o-, m - or p-forfinal, o-, m - or p-chlorophenyl, o-, m - or p-bromophenyl, o-, m - or p-carboxyphenyl, in addition, preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-differenl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-acid, H-chloro-4-forfinal, 4-chloro-Z-triptoreline, 3-fluoro-4-triptoreline, 4-fluoro-2-hydroxyphenyl, 2,4,6-tryptophanyl, 2-chloro-3,6-differenl, 3-cyano-4-dimethylamino-2-forfinal or biphenyl-4-yl, naphthalene-1-yl, naphthalene-2-yl or 2-, 3-, 4-, 5-, 6-, 7 - or 8-methylnaphthalene-1-yl, 2-, 3-, 4-, 5-, 6-, 7 - or 8-ethylnaphthalene-1-yl, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chloronaphthalene-1-yl, 2-, 3-, 4-, 5-, 6-, 7 - or 8-fornatale-1-yl, 2-, 3-, 4-, 5-, 6-, 7 - or 8 does not depend-1-yl, 2-, 3-, 4-, 5-, 6-, 7 - or 8-GI is roximately-1-yl, 1-, 3-, 4-, 5-, 6-, 7 - or 8-methylnaphthalene-2-yl, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethylnaphthalene-2-yl, 1-, 3-, 4-, 5-, 6-, 7 - or 8-chloronaphthalene-2-yl, 1-, 3-, 4-, 5-, 6-, 7 - or 8-fornatale-2-yl, 1-, 3-, 4-, 5-, 6-, 7 - or 8 does not depend-2-yl, 1-, 3-, 4-, 5-, 6-, 7 - or 8-hydroxynaphthalene-2-yl.

Particularly preferably, AG denotes phenyl, m - or p-trifloromethyl, p-isopropylphenyl, p-forfinal, m-chlorophenyl, m-hydroxyphenyl, p-carboxyphenyl, 2,4 - or 3,5-dichlorophenyl, 4-chloro-3-triptoreline, 2,6-, 3,4 - or 3,5-differenl, Z.-fluoro-4-triptoreline, 2,4,6-tryptophanyl, 2-chloro-3,6-differenl, 3-cyano-4-dimethyl-amino-2-forfinal or biphenyl-4-yl. Even more preferably, when AG denotes p-forfinal.

C(O)Z denotes alkanoyl and is preferably formyl, acetyl, propionyl, butyryl, pentanoyl or hexanoyl.

C(O)-AG denotes aroyl, in which AG corresponds to the above definitions. Particular preference is given to the benzoyl.

COO-(CH2)about-AG denotes arylalkylamines in which -(CH2)about-AG corresponds to the following definitions. Particular preference is given to benzyloxycarbonyl.

Cycloalkyl containing from 3 to 10 carbon atoms, and is, preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Cycloalkyl can, similarly, to represent Monaci the symbolic or bicyclic terpenes, preferably, the p-Menten, menthol, pinan, Bornand or camphor, and these definitions include all known stereoisomeric form, or substituted. In the case of camphor, the definition covers both forms, L-camphor, D-camphor.

-(CH2)about-Ah means, preferably, Ah if=0, or benzyl, phenylethyl or naphthylmethyl, if o=1 or 2. -(CH2)about-Ah means, particularly preferably benzyl, if o=1 or AG when o=0.

Hal denotes F, Cl, Br or I, particularly preferably F, Cl or Br.

Het represents, preferably, a substituted or unsubstituted 2 - or 3-furyl, 2 - or 3-thienyl, 1-, 2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3- or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, in addition, preferably, 1,2,3-triazole-1-, -4 - or-5-yl, 1,2,4-triazole-1-, -4-or-5-yl, 1-or 5-tetrazolyl, 1,2,3-oxadiazol-4 - or-5-yl 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-thiadiazole-3- or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 2-, 3-, 4-, 5 - or 6-2H-dipiradol, 2-, 3 - or 4-4H-dipiradol, 3 - or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6 - or 7 - benzofuran, 2 - 3-, 4-, 5-, 6 - or 7-benzothiazyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-1H-1-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6 - or 7-benzimidazolyl, 2-, 4-, 5-, 6 - or 7-benzoxazolyl, 3-, 4-, 5-, 6 - or 7-benzo-isoxazolyl, 2-, 4-, 5-, 6 - or 7-benzothiazolyl, 4 - or 5-benzol diazoles, 2-, 4-, 5-, 6 - or 7-benzisothiazole, 4-, 5-, 6 - or 7-benzo-2,1,3-oxadiazole, 1-, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinoline, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethenolysis, 1-, 2-, 3-, 4-or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-acridine, 3-, 4-, 5-, 6-, 7-or 8-indolinyl, 2-, 4-, 5-, 6-, 7 - or 8-hintline. Heterocyclic radicals may be partially or fully hydrogenated. Therefore, Het may represent a 2,3-dihydro-2-, -3-, -4 - or-5-furyl, 2,5-dihydro-2-, -3-, -4 - or-5-furyl, tetrahydro-2 - or-3-furyl, 1,3-dioxolane-4-yl, tetrahydro-2 - or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4 - or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4 - or-5-pyrrolyl, 1-, 2 - or 3-pyrrolidinyl, tetrahydro-1-, -2 - or - 3-pyrrolyl, tetrahydro-1-, -2 - or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6 - or-7-1H-indolyl, 2,3-dihydro-1-, -2-, -3-, -4 - or-5-pyrazolyl, tetrahydro-1-, -3 - or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3 - or 4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5 - or-6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3, -4-, -5- or-6-pyridyl, 1-, 2-, 3 - or 4-piperidinyl, 1-, 2-, 3 - or 4-azepane, 2-, 3 - or 4-morpholinyl, tetrahydro-2-, -3 - or-4-pyranyl, 1,4-dioxane, 1,3-dioxane-2-, -4 - or-5-yl, hexahydro-1-, -3 - or-4-pyridazinyl, hexahydro-1-, -2-, -4 - or-5-pyrimidinyl, 1-, 2 - or 3-piperazinil, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7 - or-8-chinoline, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7 - or-8-ethenolysis.

Het denotes preferably, Z is a substituted or unsubstituted morpholine-4-yl, tetrahed operan-4-yl, piperidine-4-yl, indol-2-yl, pyrrol-2-yl, pyridin-4-yl, thiophene-2-yl, thiazol-2-yl or benzothiazol-5-yl. Particularly preferably, Het denotes unsubstituted indol-2-yl, pyrrol-2-yl, pyridin-4-yl, thiophene-2-yl, thiazol-2-yl or benzothiazol-5-yl.

Het1represents preferably a substituted or unsubstituted 1-, 2-or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 3-, 4 - or 5-pyrazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, in addition, preferably 3 - or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-1H-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6 - or 7-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinoline, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethenolysis, 3-, 4-, 5-, 6-, 7 - or 8-indolinyl, 1-, 4-, 5-, 6-, 7 - or 8-phthalazine, 2-, 3-, 5-, 6-, 7 - or 8-honokalani, 2-, 4-, 5-, 6-, 7 - or 8-hintline. Heterocyclic radicals may be partially or fully hydrogenated. Therefore, Het1may represent a 2,3-dihydro-1-, -2-, -3-, -4 - or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4 - or-5-pyrrolyl, 1-, 2 - or 3-pyrrolidinyl, tetrahydro-1-, -2 - or-3-pyrrolyl, tetrahydro-1-, -2 - or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7-1H-indolyl, 2,3-dihydro-1-, -2-, -3-, -4 - or-5-pyrazolyl, tetrahydro-1-, -3 - or-4-pyrazolyl, 1,5-dihydroimidazole-4-one-2 - or-5-yl, 1,4-dihydro-1-, -2-, -3 - or 4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5 - or-6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3, -4-, -5 - or-6-pyridyl, 1-, 2-, 3 - or 4-piperidine is, 1-, 2-, 3 - or 4-azepane, tetrahydro-2-, -3 - or-4-pyranyl, hexahydro-1-, -3 - or-4-pyridazinyl, hexahydro-1-, -2-, -4 - or-5-pyrimidinyl, 1-, 2 - or 3-piperazinil, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7 - or -8-chinoline, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-ethenolysis.

Mentioned heterocyclic rings can also be monosubstituted or disubstituted =O or NHZ.

Het1especially preferably represents 3-nitropyridine-2-yl, 3-aminopyridine-2-yl, 3-(N-acetylamino)pyridin-2-yl, pyridin-2-yl, 1,4,5,6-tetrahydropyridine-2-yl, benzimidazole-2-yl, imidazol-2-yl, 4,5-dihydroimidazole-2-yl, 3,5-dihydroimidazole-4-one-2-yl, pyrimidine-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl.

A and b each, independently of one another, represent O, S, NH, NR7, CO, CONH, NHCO, or a direct bond, where R7corresponds to the following definition. Especially preferably represents NH, CONH, NHCO or direct connection, even more preferably - NH. In a particularly preferably represents O or a direct link most preferably O.

X denotes alkylene containing from 1 to 2 carbon atoms, which may be unsubstituted or monosubstituted R4or R5where R4and R5correspond to the following definitions, or direct connection. X particularly preferably represents a bond or crenel for ewenny methylene. Most preferably, if X denotes a direct link.

m denotes 0, 1, 2, 3, 4, 5 or 6. Particularly preferably, m is 3 or 4. Most preferably, m is 3.

n represents 0,1 or 2. Particularly preferably, n represents 0.

o denotes 0, 1 or 2, preferably 0 or 1, particularly preferably 0.

R1denotes H, Z or -(CH2)about-Ah, where Z and -(CH2)about-AG correspond to the definitions given above, especially preferably, R1denotes N.

R2denotes H, R7or-C(O)Z, where R7corresponds to the following definitions, and Z corresponds to the above definitions. R2particularly preferably denotes H, methyl or acetyl. R2most preferably denotes N.

R3means other6, -NR6-C(=NR6)-Other6, -C(=NR6)-Other6, -NR6-C(=NR9)-Other6, -C(=NR9)-Other6or Het1where R6corresponds to the following definitions and Het1match the definitions given above. R3means is preferably an amino group, guanidinium, NHBoc, -C(=N-Boc)-NHBoc, -NH-C(=N-Boc)-NHBoc, -NBoc-C(=N-Boc)-NH2where Vos denotes tert-butoxycarbonyl, -NH-C(=N-CN)-NR6or-NH-C(=N-NO2)-NR6where R6corresponds to the following definitions, or nitropyridine-2-yl, 3-aminopyridine-2-yl, 3-(N-acetylamino)pyridin-2-yl, pyridin-2-yl, 1,4,5,6-tetrahydropyridine-2-yl, benzimidazole-2-yl, imidazol-2-yl, 4,5-dihydroimidazole-2-yl, 3,5-dihydroimidazole-4-one-2-yl, pyrimidine-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl. R3particularly preferably denotes 1 H-imidazol-2-yl, 4,5-dihydroimidazole-2-yl, 3,5-dihydroimidazole-4-one-2-yl or pyridine-2-yl.

R4and R5each, independently of one another, represent H, oxo, R7, -(CH2)about-Ah, -C(O)-(CH2)about-Ah, -C(O)-(CH2)oR7, -C(O)-(CH2)o-Het, Het, other6, NHAr, NH-Het, CONH-R7, CONH-(CH2)o-Ar, CONH-(CH2)o-Het, OR7, OAr, OR6or O-Het, where AG and Het correspond to the definitions given above, a R6and R7correspond to the following definitions. -C(O)-(CH2)about-AG denotes preferably phenylcarbinol, benzylcarbamoyl or phenylethylamine.

In a-C(O)-(CH2)o-R7, R7corresponds to the following definitions. -C(O)-(CH2)about-R7means preferably acetyl, propionyl, butanoyl, cyclohexylcarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl or cyclohexylcarbonyl. In a-C(O)-(CH2)o-Het, Het corresponds to the above definitions. -C(O)-(CH2)o-Het preferably denotes pyridine-4-ylcarbonyl is, pyridine-4-iletileri or pyridine-4-iletileri.

In CONH-R7, R7corresponds to the following definitions. -CONH-R7means preferably methylaminomethyl, ethylaminomethyl, cyclohexanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl or cyclohexyloxycarbonyl.

CONH-(CH2)oAr preferably denotes phenylenecarbonyl, benzylaminocarbonyl or fenilatilmalonamid.

CONH-(CH2)o-Het preferably denotes pyridine-4-enaminocarbonyl, pyridine-4-ylmethylamino or pyridine-4-iletilmesini.

R4and R5each, independently of one another, denote, preferably H, -(CH2)o-Ar, R7or Het, where o denotes 0 or 1. R4particularly preferably denotes phenyl, 3-trifloromethyl, 4-forfinal, 3-chlorophenyl, 3-hydrofoil, pyridine-4-yl, 3,5-dichlorophenyl, 2,4-dichlorophenyl, cyclohexyl, 4-chloro-3-triptoreline, benzothiadiazole-4-yl, 2,6-differenl, 2-chloro-3,6-differenl, 2,4,6-tryptophanyl or cyclohexyl, R5particularly preferably denotes N.

R6means preferably H, -C(O)R7, -C(O)-Ar, R7, COOR7, COO-(CH2)o-Ar, SO2-Ar, SO2R7or SO2-Het, where AG and Het correspond to the definitions given above, and R7about the means alkyl, containing from 1 to 10 carbon atoms, or cycloalkyl containing from 3 to 10 carbon atoms. R6means preferably N, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl.

R7represents alkyl containing from 1 to 10 carbon atoms, or cycloalkyl containing from 3 to 10 carbon atoms, where the terms alkyl and cycloalkyl correspond to the definitions given above. R7means preferably tert-butyl, 2,2-dimethylpropyl, cyclopropyl or cyclohexyl.

R8denotes Hal, NO2CN, Z, -(CH2)o-Ar, COOR1, OR1, CF3, F3, SO2R1, Other1N(R1)2, NH-C(O)R1, NHCOOR1or C(O)R1where Hal, Z, -(CH2)oAr and R1correspond to the definitions given above.

R9denotes CN or NO2especially predpochtitelno-CN.

Preferred variants of the substituent R3-(CH2)-A-(CH2)m-B-are

Deputy R3-(CH2)n-And-(CH2)m-Is preferably a 5 - or 6-position of the indole ring, especially preferably at the 6-position.

Consequently, the invention relates in particular to compounds of the formula I, in which at least one of providing Utah radicals takes one of the above preferred values. Some preferred groups of compounds can be expressed by the following subformulas from La to li, which correspond to the formula 1 and in which the radicals, if it is not specifically mentioned, shall take the values specified in the formula I, but in which

In la

X denotes a direct bond

In lb

X denotes a direct bond,

R2denotes H,

R5denotes H,

R4means (CH2)about-Ah, and

o denotes 0

In line with an

X denotes a direct bond,

R5denotes H,

R4means (CH2)o-Ar or Het; and

o denotes 0;

In ld

X denotes a direct bond,

R5denotes H,

In denotes Oh,

And denotes NH,

n denotes 0,

m represents 3 or 4,

R3denotes Het1and

R4means (CH2)about-Ah, and

o denotes 0

Le

X denotes a direct bond,

R5denotes H,

B denotes Oh,

And denotes NH,

n denotes 0,

m represents 3 or 4, and

R3denotes Het1

If

X is methylene which may be unsubstituted or substituted Ah,

R2oznachaet N

R5denotes H or AG, and

R4means oxo

Lg

X denotes methylene,

In lh

X denotes methylene,

R4represents H or (CH2)o-Ah,

R5represents H or (CH2)about-Ah,

o denotes 0, and

R2denotes N;

In li

X denotes methylene,

R4represents H or (CH2)about-Ah,

R5represents H or (CH2)about-Ah,

o denotes 0,

In denotes Oh,

And denotes NH,

n denotes 0,

m represents 3 or 4,

R3denotes Het1and

R2denotes N

The compounds of formula 1, Paragraph 1, as well as source materials for their production can also be prepared by methods which are in themselves known and described in literature (for example, in the classic works, such as Houben-Weyl, Methods der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), in strict compliance with the reaction conditions which are known and suitable for carrying out the above reactions. You can also use variants of these reactions, which are in themselves known, but are not described in detail here.

If desired, the starting materials can also be obtained in the same reactor; in this case, they are not separated from react the Onna mixture, but immediately after getting converted into the compounds of formula I in claim 1.

The compounds of formula I can preferably be obtained by release of the compounds of the formula I from one of their functional derivatives by treatment solvolysis or hydrogenolysis agent.

The preferred raw materials for the solvolysis or hydrogenolysis are those which correspond to the formula I, but instead of one or more amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, especially those instead of group H-N have SG1-N, where SG1means aminosidine group, and/or such that instead of atom N hydroxyl groups have hydroxylamino group, for example those which correspond to the formula I, but instead of the group-COOH have the group-COOSG2where SG2means hydroxylamino group.

In the molecule of the original material may also be present several identical or different protected amino and/or hydroxyl groups. If present protective groups differ from each other, they, in many cases, can be removed selectively (as a comparison, see T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2ndEdn., Wiley, New York 1991, or P.J.Kocienski, Protecting Groups, 1stEdn., Georg Thieme Verlag, Stuttgart - ew York, 1994, H.Kunz, H.Waldmann in Comprehensive Organic Synthesis, Vol.6 (Eds. B.M.Trost, I.Fleming, E.Winterfeldt), Pergamon, Oxford, 1991, pp.631-701).

The term "aminosidine group" in the General case, the known and relates to groups which are suitable for protecting (blocking) amino group from chemical reactions. Typical examples of such groups are, in particular, unsubstituted or substituted acyl, aryl, arelaxation or kalkilya group. Because aminosidine group is removed after the target's reaction (or sequence of reactions synthesis), their type and size is irrelevant; however, preference is given to such of them that contain 1-20 carbon atoms. The term "acyl group" in connection with this method should be understood in its broadest sense. It covers acyl group selected from aliphatic, alifaticheskih, alicyclic, aromatic and heterocyclic carboxylic acids and sulfonic acids, as well as, in particular, alkoxycarbonyl, altneratively, aryloxyalkyl and especially alcoxycarbenium group. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl, butyryl; arkanoid, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoic, such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, In the 2-iodoxybenzoic; alkenylacyl, such as allyloxycarbonyl (Aloe), arelaxation, such as CBZ (synonym Z), 4-methoxybenzeneboronic (MOZ), 4-nitrobenzenesulfonyl and 9-fluorenylmethoxycarbonyl (Fmoc); 2-(phenylsulfonyl)-etoxycarbonyl; trimethylsilylacetamide (theos), and arylsulfonyl, such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred aminosidine groups are BOC, Fmoc and Alo, in addition, Z, benzyl and acetyl.

Similarly, the term "hydroxylamine group" in the General case, the known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions. Typical examples of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl group, in addition, also alkyl groups, alkyl-, aryl - and aralkylamines group, as well as O - and O,S-acetals. The nature and size hydroxylamine groups are not that significant, because they are removed when the targeted chemical reaction or sequence of reactions synthesis; preference is given to groups containing 1-20 carbon atoms, especially 1 to 10 carbon atoms. Examples hydroxylamine groups are, including kalkilya groups such as benzyl, 4-methoxybenzyl and 2,4-dimethoxybenzyl, aroline groups such as benzoyl and p-nitrobenzoyl, acyl group is s, such as acetyl and pivaloyl, p-toluensulfonyl, alkyl groups such as methyl and tert-butyl, and allyl, alkylsilane groups, such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) and triethylsilyl, trimethylsilylmethyl, aralkylamines group, such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals, such as isopropylbenzyl, cyclopentylacetyl, cyclohexylethyl, benzylideneacetone, p-methoxybenzylideneamino and o,p-dimethoxybenzaldehyde, acyclic acetals, such as tetrahydropyranyl (Tpd), methoxymethyl (MOM)methoxyethoxymethyl (MEM), benzoyloxymethyl (CMV) and methylthiomethyl (MTM). Especially preferred hydroxylamine groups are benzyl, acetyl, tert-butyl and TBS.

The release of the compounds of the formula I from their functional derivatives is described in the literature on the protective groups used in each case (for example, by T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2ndEdn., Wiley, New York, 1991 or P.J.Kocienski, Protecting Groups, 1stEdn., Georg Thieme Verlag, Stuttgart - New York, 1994). With this purpose you can also use the options mentioned reactions, which are in themselves known, but here is not particularly specified.

The compounds of formula I in which R3=Met1,=O,=NH, n=0 (formula I-1) can preferably be obtained by the following scheme 1 the reaction. S 3and SG4are as defined above, hydroxylamine group. SG5means, as defined above, aminosidine group. The radicals X, R1, R2, R4and R5and the variable m, which are mentioned in the compounds I-1 and II-VI correspond to the definitions given in Paragraph 1.

Reaction scheme 1:

After removal hydroxylamino group SG4of the compounds of formula II with the corresponding known reaction conditions, with a compound of formula III conducting the reaction under conditions similar to the conditions of nucleophilic substitution. Under reaction conditions known for the reaction of Mitsunobu [literature: .Mitsunobu, Synthesis 1981, 1-28], in the next step, conduct the reaction with the compound of the formula V and, respectively, separated aminosidine group SG5. Remove hydroxylamino group SG3results of the free acid of the formula l-1 (R1=N). If this is desirable, hydroxylamino SG3transform in the substituent R1.

The invention also relates to compounds of formula IIA

in which R2, R4and R5take the value specified in Paragraph 1

X denotes a bond,

R10denotes hydro is sirsasana group or H, and

R11means hydroxylamino group or N.

R10means preferably H or alkyl group Z as hydroxylamino group, where Z corresponds to the above definitions.

R11means preferably H or aracelio group, as hydroxylamino group, as described above.

Hydroxyl group OR11preferably is on the 6 position of the indole ring.

The compounds of formula To represent valuable intermediate compounds in the synthesis of the compounds of formula I according to this invention, in which X designates the connection.

Preferred are the following compounds of formula IIA:

ethyl 3-phenyl-3-(6-O-benzyl-indol-3-yl)propionate;

ethyl 3-phenyl-3-(6-hydroxy-indol-3-yl)propionate;

ethyl 3-phenyl-3-(5-O-benzyl-indol-3-yl)propionate;

ethyl 3-phenyl-3-(5-hydroxy-indol-3-yl)propionate;

ethyl 3-(4-were)-3-(6-O-benzyl-indol-3-yl)propionate;

ethyl 3-(4-were)-3-(6-hydroxy-indol-3-yl)propionate;

ethyl 3-(3-were)-3-(6-O-benzyl-indol-3-yl)propionate;

ethyl 3-(3-were)-3-(6-hydroxy-indol-3-yl)propionate;

ethyl 3-(2-were)-3-(6-O-benzyl-indol-3-yl)propionate;

ethyl 3-(2-were)-3-(6-hydroxy-indol-3-yl)propionate;

ethyl 3-[(4-trifluoromethyl)phenyl]-3-(6-O-benzyliden-3-yl)propionate;

ethyl 3-[(4-trifluoromethyl)phenyl]-3-(6-hydroxyindole-3-yl)p is opional;

ethyl 3-(4-methoxyphenyl)-3-(6-O-benzyliden-3-yl)propionate;

ethyl 3-(4-methoxyphenyl)-3-(6-hydroxyindole-3-yl)propionate;

ethyl 3-(4-ethoxyphenyl)-3-(6-O-benzyliden-3-yl)propionate;

ethyl 3-(4-ethoxyphenyl)-3-(6-hydroxyindole-3-yl)propionate;

ethyl 3-(4-chlorophenyl)-3-(6-O-benzyliden-3-yl)propionate;

ethyl 3-(4-chlorophenyl)-3-(6-hydroxyindole-3-yl)propionate;

ethyl 3-(3-chlorophenyl)-3-(6-O-benzyliden-3-yl)propionate;

ethyl 3-(3-chlorophenyl)-3-(6-hydroxyindole-3-yl)propionate;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-pyridin-4-ylpropionic;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-pyridin-4-ylpropionic;

ethyl 3-benzo-1,2,5-thiadiazole-4-yl-3-(6-benzyloxy-1H-indol-3-yl)propionate;

ethyl 3-benzo-1,2,5-thiadiazole-4-yl-3-(6-hydroxy-1H-indol-3-yl)propionate;

ethyl 3-benzo-1,2,5-thiadiazole-5-yl-3-(6-benzyloxy-1H-indol-3-yl)propionate;

ethyl 3-benzo-1,2,5-thiadiazole-5-yl-3-(6-hydroxy-1H-indol-3-yl)propionate;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-naphthalene-1-ylpropionic;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-naphthalene-1-ylpropionic;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-naphthalene-2-ylpropionic;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-naphthalene-2-ylpropionic;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(1H-indol-2-yl)propionate;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(1H-indol-2-yl)propionate;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(thiophene-2-yl)propionate;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(thiophene-2-yl)PR is peanut;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(1H-pyrrol-2-yl)propionate;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(1H-pyrrol-2-yl)propionate;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(thiazol-2-yl)propionate;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(thiazol-2-yl)propionate;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(1H-indol-2-yl)propionate;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(1H-indol-2-yl)propionate;

ethyl 3-biphenyl-4-yl-3-(6-benzyloxy-1H-indol-3-yl)propionate;

ethyl 3-biphenyl-4-yl-3-(6-hydroxy-1H-indol-3-yl)propionate;

ethyl 3-(3-cyano-4-dimethylamino-2-forfinal)-3-(6-benzyloxy-1H-indol-3-yl)propionate;

ethyl 3-(3-cyano-4-dimethylamino-2-forfinal)-3-(6-hydroxy-1H-indol-3-yl)propionate;

ethyl 3-(3-fluoro-4-triptoreline)-3-(6-benzyloxy-1H-indol-3-yl)-propionate;

ethyl 3-(3-fluoro-4-triptoreline)-3-(6-hydroxy-1H-indol-3-yl)-propionate;

ethyl 3-(4-isopropylphenyl)-3-(6-benzyloxy-1H-indol-3-yl)propionate;

ethyl 3-(4-isopropylphenyl)-3-(6-hydroxy-1H-indol-3-yl)propionate;

ethyl 3-cyclohexyl-3-(6-benzyloxy-1H-indol-3-yl)propionate;

ethyl 3-cyclohexyl-3-(6-hydroxy-1H-indol-3-yl)propionate;

ethyl 3-cyclopropyl-3-(6-benzyloxy-1H-indol-3-yl)propionate;

ethyl 3-cyclopropyl-3-(6-hydroxy-1H-indol-3-yl)propionate;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-4,4-dimethyl-pentanoic;

ethyl 3-(6-hydroxy-1H-indol-3-yl)-4,4-dimethyl-pentanoic;

ethyl 3-(6-benzyloxy-1H-indol-3-yl)-5,5-dimethyl-g is xanat or

ethyl 3-(6-hydroxy-1H-indol-3-yl)-5,5-dimethyl-hexanoic.

The compounds of formula IIa as described above, can be prepared according to the method described in Example 1, in accordance with the reaction scheme Ia, where R5denotes N and R11represents hydroxylamino SG4.

The reaction scheme 1A:

Condensation of compounds of formula (1A-I) with aldehyde XI and 2,2-dimethyl-1,3-dioxane-4,6-dione (acid Meldrum) when known for reactions of condensation reaction conditions leads to the formation of compounds of the formula (1A-II). The combination of fission reactions ether/decarboxylation/esterification leads to obtaining the ethyl ester of the formula (1a-III). Hydroxylamino SG4you can delete the software described in the literature methods, which leads to obtaining a free of hydroxyl compounds of the formula On. Cleavage of the ether compounds of the formula (1A-II) or hydroxyl analogues results in a free acid of formula IIA.

The compounds of formula I in which R3=Het1,=O, A=NHCO, n=0 (Formula I-2) can preferably be obtained in accordance with the following reaction scheme 2. SG3, SG4and SG6are as defined above, hydroxylamine group. The radicals X, R1, R2, R4and R5and the variable m is mentioned is in the compounds I-2, II and VII to IX correspond to the definitions given in Paragraph 1.

Reaction scheme 2:

After removal hydroxylamino group SG4of the compounds of formula II with the corresponding known reaction conditions, conduct the reaction with the compound of the formula under conditions similar to the conditions of nucleophilic substitution. After removal hydroxylamino group SG6conducting the reaction of the compound of formula IX under reaction conditions known for reactions of the type peptide mating.

Remove hydroxylamino group SG3results of the free acid of formula 1-2 (R1=N). If this is desirable, hydroxylamino SG3transform in the substituent R1.

The compounds of formula I in which a=Oh, X=bond, R1=N and R5=N (formula 1-3) can preferably be obtained in accordance with the following reaction scheme 3. The radicals R3, R2and R4and the variables A, n and m, which are mentioned in the compounds X-XII, consistent with the definitions provided in Paragraph 1, with the free amino group in R3protected aminosidine groups during synthesis, and the protective group is removed in the last step of the reaction.

Reaction scheme 3:

Condensation of compounds of formula X with the aldehyde XI and 2,2-dimethyl-1,3-dioxane-4,6-dione, under reaction conditions which are known for reactions of condensation leads to the formation of compounds of formula XII. Cleavage of the ester and decarboxylation results in a free acid of formula I-3. If desired, the hydroxyl group is converted into a substituent R1or acid of the formula I-3 is converted into a physiologically acceptable salt. The compounds of formula X is obtained by alkylation of 1H-indole-6-ol with bromide of formula XIII (R3-(CH2)n-A-(CH2)m-Br XIII)referred to in which the radical R3and the variables A, n and m correspond to the definitions given in Paragraph 1.

The compounds of formula I in which R3=Het1, R5=H, X=bond, A=NH,=O and n=0 (formula 1-4) can be obtained, preferably, by the following reaction scheme 4. In the compounds of formula I, as described above, R10denotes SG3and R11denotes SG4(formula IIa-1), where SG3and SG4are as defined above hydroxylamine group. SG5means defined above aminosidine group. The radicals R1, R2and R4and the variable m mentioned in compounds 1-4 and XV-XVIII, correspond to the definitions given in Paragraph 1.

The reaction schema:

After removal hydroxylamino group SG4of the compounds of formula IIa-1 in reaction scheme 4 with the corresponding known reaction conditions, conduct the reaction with the compound of the formula XV with conditions analogous to the reaction of nucleophilic substitution. In the next step, remove aminosidine SG5and carry out the reaction of the free amine with timetravel or chlorine compound of formula XVII. Remove hydroxylamino group SG3results of the free acid of formula 1-4 (R1=N). If this is desirable, hydroxylamino SG3you can convert in the substituent R1.

The compounds of formula I in which R3=-C(=NR6)-Other6or-C(=NR9)-Other6, R5=H, X=bond, A=NH,=O and n=0 (formula I-5) can be obtained, preferably, in accordance with reaction scheme 4.

However, instead of the reaction with compounds of formula XVII (Het1-SMe or Het1-CL), conduct the reaction with the compound of the formula XIX

or with the compound of the formula XX

Me-S-C(=NR6/9)-SMe XX

With the subsequent substitution of an amine of formula XXI

R6NH2XXI.

The radicals R6and R9referred to in compounds 1-4 and XIX-XXI matched what are the signs listed in Paragraph 1.

The compounds of formula X

in which R2, R3, A, n and m correspond to the definitions provided in Paragraph 1, can be obtained in the sequence of reactions for the synthesis according to the reaction scheme 4, by replacing compound IIA-1 hydroxylamine connection indole XXII

where R2corresponds to the designation described in Paragraph 1. After the reaction of hydroxyindole XXII with a compound of formula XV and remove aminosidine group SG5by the method described above can, depending on the substituent R3to carry out the reaction with the compound of the formula XVII or XIX, or with the compound of the formula XX, followed by the reaction with the compound of the formula XXI. Free amino groups in compounds of formula XVII in the process for the synthesis of protected aminosidine groups.

The invention relates also to compounds of the formula X

in which

R2, R3And, n and m correspond to the definitions given in the Paragraph

1, or their salts.

Preferred compounds of formula X are the following:

6-(3-(N-benzylpyridine-2-yl-amino)propoxy)indole;

6-(3-(N-benzylpyridine-2-yl-amino)propoxy)indole hydrobromide;

6-(3-(pyridin-2-yl-amino)propoxy)indole;

6-[3-(4,5-dihydro-1H-imidazol-2-yl-amino)is robaxi]indole or

6-[3-(4,5-dihydro-1H-imidazol-2-yl-amino)butoxy]indole.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene and xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform and dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol and tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) and dioxane; glycol ethers, such as ethylene glycol onomatology and monotropy ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone and butanone; amides, such as ndimethylacetamide, dimethylacetamide and dimethylformamide (DMF); NITRILES, such as acetonitrile; sulfoxidov, such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid and acetic acid; nitro compounds such as nitromethane and nitrobenzene; esters, such as ethyl acetate, and mixtures of the mentioned solvents.

In addition, the radicals R1, R2, R3, R4, R5and/or R6can be converted into other radicals R1, R2, R3, R4, R5and/or R6.

Thus, it is possible to carry out the saponification of ester of the formula I under standard conditions, for example NaOH in dioxane/water, 0-60° C.

The transformation is the use of cyano groups in amidinopropane can be done, for example, by reaction with hydroxylamine and subsequent recovery of N-hydroxyamides hydrogen in the presence of catalysts, such as Pd/C.

To get amicin formula I (R3=-C(=NH)-NH2), a nitrile of the formula I can be supplemented with ammonia. Adducci can be done, preferably, megatape, by methods which are known in themselves, by (a) converting the nitrile in thioamide using H2S and subsequent conversion thioamide in the corresponding S-alkalinization using an alkylating agent, for example CH3l, and the subsequent reaction of tiefer with NH3, the product of which is amidon, b) converting the nitrile into the corresponding imidoyl using alcohol, for example ethanol, in the presence of Hcl and ether, ammonia, or (C) the reaction of the nitrile with bis(trimethyl-silyl)amidon lithium, and subsequent hydrolysis of the product.

The conversion of the amino group in guanidinium can be done using ameerega agent, for example 1-amidino-3,5-dimethylpyrazole (DPFN), which can be applied, in particular, in the form of its nitrate. This transformation is mainly carried out with addition of a base, such as triethylamine or ethyldiethanolamine, in an inert solvent or solvent mixture, for example, water/dioxane, at temperatures of the t, about 0 to 120° C, preferably from 60 to 120° C.

Furthermore, free amino groups can be allievate in the usual way, using the acid chloride or anhydride, or alkilirovanii using unsubstituted or substituted alkylamide, mainly in an inert solvent such as dichloromethane or THF, and/or in the presence of a base such as triethylamine or pyridine, at temperatures from -60 to +30° C.

The basis of the formula I can be converted in an associate salt with the acidic residue with acid, for example in the reaction of equivalent amounts of base and acid in an inert solvent, such as ethanol, followed by evaporation. Suitable for this reaction acids are, in particular, those which yield physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, sulfurous acid, ditionary acid, nitric acid, hydrohalogenation acid, such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic oneonone or politonalnye carboxylic, sulfonic or sulfuric key is lots for example, such as formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, cekanova acid, hexadecanol acid, octadecanoic acid, trimethylhexane acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultancy acid, benzolsulfonat acid, trimethoxybenzoic acid, adamantanecarbonyl acid, p-toluensulfonate acid, glycolic acid, albanova acid, chlorprothixene acid, aspartic acid, glutamic acid, Proline, glykeria acid, palmitic acid, parachlorophenylalanine acid, cyclohexanecarbonyl acid, glucose 1-phosphate, naphthalenamine - and-disulfonate acid or louisanna acid. Salts with physiologically unacceptable acids, for example the picrate, you can apply for isolation and/or purification of the compounds of the formula I. on the other hand, the compounds of formula I can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal, or into the corresponding ammonium salts, p. and care of grounds (for example, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). Suitable salts are, in addition, substituted ammonium salts, for example, dimethyl-, diethyl - and Diisopropylamine salt, monoethanol-, diethanol - and diisopropanolamine salts, cyclohexyl - and dicyclohexylammonium salt, dibenzylethylenediamine salt, in addition, for example, salts with arginine or lysine.

The compounds of formula I contain at least one centre of chirality and can therefore exist in racemic or optically active form. Resulting racemates can be separated into the isomers known mechanical or chemical methods. The diastereomers are preferably obtained from the racemic mixture by reaction with optically active separating agent. Examples of suitable separating agents are optically active acids, such as D and L forms of tartaric acid, diacetylpyridine acid, dibenzoylmethanes acid, Mandelieu acid, malic acid, lactic acid or the various optically active camphorsulfonic acid, such as p-camphorsulfonic acid. Preference is given to the separation of enantiomers using columns filled with optically active separating agent (for example, dinitrobenzonitrile); an example of a suitable e is went mixture is hexane/isopropanol/acetonitrile, for example, in a volume ratio 82:15:3.

Separation of the diastereomers can also be achieved using standard purification methods, such as chromatography or fractional crystallization.

Of course, optically active compounds of formula I can also be obtained by the above methods, by using starting materials which are already optically active.

In addition, the invention relates to pharmaceutical preparations containing at least one compound of the formula I and/or its physiologically acceptable salt or MES prepared, in particular, non-chemical ways. The compounds of formula I can be introduced in these drugs in appropriate doses with at least one solid, liquid and/or semi excipient or auxiliary substance, and, if desired, in combination with one or more other active ingredients.

These drugs can be used as drugs in medicine and veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or local purposes and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkalophile, glycols, glyceroltrinitrate, Latin, carbohydrates such as lactose or starch, magnesium stearate, talc or vaseline. Suitable for oral use are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for local purposes are ointments, creams or powders. The new compounds can also be liofilizirovanny, and received lyophilizate to apply, for example, for the preparation of injection preparations. These preparations can be sterilized and/or may include excipients, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for adjusting osmotic pressure, buffer substances, colorants, odorants and/or a variety of active ingredients, for example one or more vitamins.

Upon appointment by inhalation can be applied aerosols, in which the active ingredient either dissolved or suspended in gas-propellant or mixture of propellants (e.g., CO2or chloroflorocarbons). In these aerosols active ingredient is applied mainly in connoissances is m, in this case, there may be one or more additional physiologically acceptable solvent, such as ethanol. Inhalation solutions can be assigned to the introduction using conventional inhalers.

The compounds of formula I and their physiologically acceptable salts can be used as integrin inhibitors for the treatment of diseases, in particular thrombosis, myocardial infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections.

The compounds of formula I in claim 1 and/or their physiologically acceptable salts can also be applied to pathological processes, which are stored or distributed as a result of angiogenesis, particularly in tumors, restenosis, diabetic retinopathy, diseases diabetic degeneration stains or rheumatoid arthritis.

Substances according to this invention appoint, in General, similar to other known commercially available peptides, but especially similar to the compounds described in applications WO 99/30713 and WO 94/12478, preferably in doses of from about 0.05 to 500 mg, in particular from 0.5 to 100 mg, per dose. Daily dosage is preferably from about 0.01 to 2 mg/kg of body weight. However, the specific dose for each patient depends on many factors, for example, the effectiveness of specific the CSOs used the connection age, body weight, General health, sex, diet, time and mode of appointment, on the excretion rate, combination of drugs and the severity of the particular disease, for the treatment which is applied therapy. Parenteral use are preferred. Indicators of biological activity of compounds 1 are shown in table 1.

Above and below, all temperatures are given in ° C. In the following examples, the term "conventional treatment" means that the organic phase is washed with a saturated solution of NaHCO3if you want water and saturated NaCl solution, to make a separation of the phases, the organic phase is dried over sodium sulfate and evaporated and the product purified by chromatography on silica gel, using preparative liquid chromatography high resolution (HPLC), and/or by crystallization. If required, purified compound is dried by sublimation.

HPLC: eluent A = water + 0,3% TFA, eluent B = acetonitrile/water + 0.3% of TFA in the ratio of 4:1. Rtindicates the time of settling. Rfdenotes the ratio of the assertion.

Primer:

1. 5-[Phenyl(6-O-benzyliden-3-yl)methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione

5 g, 22.4 mmole) of 6-benzyloxyindole with and 2.26 ml (22.4 mmole) of benzaldehyde and of 3.23 g (22.4 mmole) of the acid Meldrum (2,2-dimethyl-1,3-dioxane-4,6-dione) was dissolved in 100 ml anhydrous is of acetonitrile and stirred at 30° In the presence of 129 mg (1.1 mmole) of L-Proline to the completion of the reaction (3 h, TLC monitoring). The mixture allowed to cool to room temperature, the precipitate was filtered with suction and washed with ether. After complete drying was performed to further reaction of the crude product 5-[phenyl(6-O-benzyliden-3-yl)methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione without additional purification.

HPLC: (RP-18, gradient a/b 50:50 → 1:99 in 1 hour, where A = water + 0,3% TFA, B = acetonitrile/water + 0.3% of TFA 4:1) Rt=41,4 min; TLC: Si-60, toluene/acetone 4:1, Rf=0,3;

FAB-MS:(M+1)=456.

2. Ethyl 3-phenyl-3-(6-0-benzyliden-3-yl)propionate

5 g (11 mmol)ofintroduced in 30 ml of anhydrous pyridine together with 300 mg of copper powder and 3 ml of dried ethanol, and the mixture stands were delegirovali under stirring for 3 hours (TLC control). Next, the mixture was filtered through kieselguhr, the solution has boiled away, and the precipitate was transferred to the ethyl acetate. Conducted regular processing and obtained ethyl 3-phenyl-3-(6-O-benzyliden-3-yl)propionate, which was purified by chromatography on silica gel with a mixture of toluene/acetone 20:1 as additionally separated by.

HPLC: (RP-18, gradient a/b 50:50→ 1:99 in 1 hour as above) Rt=54 min; TLC: Si-60, toluene/acetone 4:1, Rf=0,7;

FAB-MS:(M+1)=400.

3. Ethyl 3-phenyl-3-(6-hydroxyindole-3-yl)propionate

3.7 g (9,26 mmole) dissolved in 60 ml of ethanol and was hydrogenosomal for 2.5 hours at room temperature and atmospheric pressure in the presence of 900 mg palladium/10% on charcoal. When the benzil was removed, the catalyst was filtered and washed in a small amount of ethanol, and the solution is boiled away and obtained ethyl 3-phenyl-3-(6-hydroxyindole-3-yl)propionate.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=40,3 min; TLC: Si-60, toluene/acetone 4:1, Rf=0,2;

FAB-MS:(M+1)=310.

4. Ethyl 3-phenyl-3-[6-(3-hydroxypropoxy)indol-3-yl]propionate

1.2 g (3,88 mmole)was delegirovali overnight in 30 ml of acetone together from 0.66 ml (7.6 mmole) of 3-bromo-1-propanol and 2.1 g (15.2 mmole) of potassium carbonate. After cooling, the insoluble precipitate was filtered and the filtrate is boiled away. Crude product can be purified by chromatography on silica gel (gradient additionally separated by toluene/acetone 9:1→ 4:1); as a result, there was obtained ethyl 3-phenyl-3-[6-(3-hydroxypropoxy)indol-3-yl]propionate.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=42,4 min; TLC: Si-60, toluene/acetone 4:1, Rf=0,1;

FAB-MS:(M+1)=368.

5. Ethyl 3-phenyl-3-(6-{3-[(pyridine-2-yl)(2,2,2-trichlorocyanuric)-amino]propoxy}indol-3-yl)propionate

500 mg (1,36 mmole), 550 mg (2,04 mmole) of 2-(2,2,2-trichloro-adoxical is arylamino)pyridine and 907 mg (2,72 mmole) of triphenylphosphine (polymer bound) introduced in 7.5 ml of anhydrous THF, and at room temperature drip for 30 minutes was added a solution of 0.32 ml (2,04 mmole) of diethyl ester of azodicarboxylic acid (diethylazodicarboxylate, DEAD) in 7.5 ml of THF. TLC monitoring showed that after 1.5 hours the conversion was held to the end. The polymer was filtered and the solution washed with a little water, then dried and boiled away. The residue can be cleaned by chromatography on silica gel (gradient additionally separated by toluene/acetone 20:1→ 4:1)to obtain ethyl 3-phenyl-3-(6-{3-[(pyridine-2-yl)(2,2,2-trichlorocyanuric)amino]propoxy}indol-3-yl)propionate.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=56,1 min

TLC: Si-60, toluene/acetone 4:1, Rf=0,5;

FAB-MS:(M+1)=619.

6. Ethyl 3-phenyl-3-{6-[(3-pyridin-2-ylamino)propoxy]indol-3-yl}propionate

275 mg (0.44 mmole)was stirred for 2.5 hours at room temperature with 500 mg of zinc dust, 0.5 ml water and 0.5 ml of acetic acid in 5 ml of THF. When the reaction was held until the end, the zinc was filtered, the solution has boiled away and the residue was purified preparative HPLC on RP-18 (additionally separated by gradient water/acetonitrile 99:1→ 1:99); the result obtained ethyl 3-phenyl-3-{6-[(3-pyridin-2-ylamino)propoxy]indol-3-yl}propionate triptorelin.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=42,8 min;

FAB-MS:(M+1)=444.

7. 3-Phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}prop is about acid

80 mg (0,18 mmole)dissolved in 2 ml of dioxane, and the mixture was stirred overnight at room temperature with 0.9 ml of 1 N NaOH (0.9 mmole). When the cleavage of the ether is passed to the end, the solution was neutralized with a small amount of acetic acid and obtained 3-phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. Using preparative HPLC received 3-phenyl-3-{6-[3-(pyridin-2-yl-amino)propoxy]indol-3-yl}propionic acid triptorelin; TPL 232° (decomp.).

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=34,7 min;

FAB-MS:(M+1)=416.

Primer

1. Ethyl 3-phenyl-3-(6-{3-[(imidazol-2-yl)(2,2,2-trichlorocyanuric)-amino]propoxy}indol-3-yl)propionate

In accordance with Example 1.5, 907 mg (2,72 mmole) of triphenylphosphine (polymer bound) was added to a solution of 500 mg (1,36 mmole), 527 mg (2,04 mmole) and 2-(2,2,2-trichlorocarbanilide)imidazole in 7.5 ml of anhydrous THF, and then at room temperature drip slowly added of 0.32 ml (2,04 mmole) DEAD. The solution was stirred overnight, then was filtered polymer, and washed THF solution with water, dried over MgSO4and boiled away. Crude product was purified preparative HPLC and was obtained ethyl 3-phenyl-3-(6-{3-[(imidazol-2-yl)(2,2,2-trichlorocyanuric)amino]propoxy}indol-3-yl)propionate Tr is fluoroacetate.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=47,5 min;

FAB-MS:(M+1)=608.

2. Ethyl 3-phenyl-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionate

According to Example 1.6, spent the reaction of 185 mg (0,304 mmole)with 400 mg of zinc dust and 0.4 ml of acetic acid in 4 ml of THF, and made the processing of the mixture. Spent purified using preparative HPLC on RP-18, and obtained ethyl 3-phenyl-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionate triptorelin.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=40,9 min;

FAB-MS:(M+1)=433.

3. 3-Phenyl-3-{6-[3-{imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid

25 mg (0,058 mmole)was stirred at 70° C for 36 hours in 1 ml of dioxane together with 0.3 ml of 1 N HCl (0.3 mmole), and received 3-phenyl-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. As a result of preparative HPLC received 3-phenyl-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) R=33,4 min;

FAB-MS:(M+1)=405.

Example 3:

Analogously to Example 1, reaction of 6-benzyloxyindole

4-methylbenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-were)-3-{6-[3-(pyridine-2-ylamino)propoxy]ndol-3-yl}propionic acid. After preparative HPLC: 3-(4-were)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

with 3-methylbenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(3-were)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(3-were)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

2-methylbenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(2-were)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(2-were)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

4-triftormetilfullerenov and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-triptoreline)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-triptoreline)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

with 4-methoxybenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-methoxyphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-methoxyphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]in the ol-3-yl}propionic acid triptorelin;

4-ethoxybenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-ethoxyphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-ethoxyphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

4-chlorobenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-chlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-chlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

with 3-chlorobenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(3-chlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(3-chlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=34,3 min; FAB-MS:(M+1)=450.

pyridine-4-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-pyridin-4-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-pyridin-4-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

HPLC: (RP-18, gradient a/b 99:1→1:99 in 1 hour) R t=20,7 min; FAB-MS:(M+1)=417.

with benzo-1,2,5-thiadiazole-4-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-benzo-1,2,5-thiadiazole-4-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-benzo-1,2,5-thiadiazole-4-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

with naphthalene-1-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-naphthalene-1-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-naphthalene-1-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin og

with naphthalene-2-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-naphthalene-2-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-naphthalene-2-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin.

Example 4:

Analogously to Example 2, reaction of 6-benzyloxyindole

4-methylbenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-were)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-were)-3-{6-[3-(imidazol-2-ylamino)propoxy]and the Dol-3-yl}propionic acid triptorelin;

with 3-methylbenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(3-were)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(3-were)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

2-methylbenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(2-were)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(2-were)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

4-triftormetilfullerenov and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-triptoreline)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-triptoreline)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

with 4-methoxybenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-methoxyphenyl)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-methoxyphenyl)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

4-ethoxybenzaldehyde and then carrying out consequently the particular reactions of synthesis allows to obtain

3-(4-ethoxyphenyl)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-ethoxyphenyl)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

4-chlorobenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-chlorophenyl)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-chlorophenyl)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

4-vorbesuregen and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-forfinal)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(4-forfinal)-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

pyridine-4-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-pyridin-4-yl-3-{6-[3-(imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-pyridin-4-yl-3-{6-[3-(imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

with benzo-1,2,5-thiadiazole-4-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-benzo-1,2,5-thiadiazole-4-yl-3-{6-[3-(imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propio the OIC acid. After preparative HPLC: 3-benzo-1,2,5-thiadiazole-4-yl-3-{6-[3-(imidazol-2-ylamino)propoxy]-1H-indol-3-yl}-propionic acid triptorelin;

with naphthalene-1-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-naphthalene-1-yl-3-{6-[3-(imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-naphthalene-1-yl-3-{6-[3-(imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin or

with naphthalene-2-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-naphthalene-2-yl-3-{6-[3-(imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-naphthalene-2-yl-3-{6-[3-(imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin.

Example 5:

1. Ethyl 3-phenyl-3-[6-(4-hydroxyethoxy)indol-3-yl]propionate

Analogously to Example 1.4, spent the reaction of 1.2 g (3,88 mmole) of ethyl 3-phenyl-3-(6-hydroxyindole-3-yl)propionate from 1.16 g (7.6 mmole) of 4-bromo-1-butanol in the presence of 2.1 g (15.2 mmole) of potassium carbonate in 30 ml of acetone, and the obtained ethyl 3-phenyl-3-[6-(4-hydroxyethoxy)indol-3-yl]propionate.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour as above) Rt=43,4 min;

TLC; Si-60, toluene/acetone 4:1, Rf=0,13;

FAB-MS:(M+1)=382.

2. Ethyl 3-phenyl-3-(6-{4-[(pyridine-2-yl)(2,2,2-trichlorocyanuric)-amino]is ataxi}indol-3-yl)propionate

The reaction of 170 mg (0.45 mmole)with 178 mg (0,66 mmole) of 2-(2,2,2-trichlorocarbanilide)pyridine in the presence of 293 mg (from 0.88 mmole) of triphenylphosphine (polymer bound) and 0,103 ml (0,66 mmole) DEAD in 6 ml of THF, in accordance with Example 1.5, leads, after conventional treatment and chromatography to obtain ethyl 3-phenyl-3-(6-{4-[(pyridine-2-yl)(2,2,2-trichlorocyanuric)amino]butoxy}indol-3-yl)propionate.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour as above) Rt=57,4 min;

TLC: Si-60, toluene/acetone 4:1, Rf=0,47;

FAB-MS:(M+1)=633.

3. Ethyl 3-phenyl-3-{6-[4-(pyridine-2-ylamino)butoxy]indol-3-yl}propionate

Analogously to Example 1.6, remove This with zinc in a mixture of acetic acid/THF leads to the production of ethyl 3-phenyl-3-{6-[4-(pyridine-2-ylamino)butoxy]indol-3-yl}propionate.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour as above) Rt=44,3 min;

FAB-MS:(M+1)=458.

4. 3-Phenyl-3-{6-[4-(pyridine-2-ylamino)butoxy]indol-3-yl}propionic acid

Analogously to Example 1.7, splitting ethyl ester in an alkaline medium by means of 1 N sodium hydroxide solution in dioxane leads to the production of 3-phenyl-3-{6-[4-(pyridine-2-ylamino)butoxy]indol-3-yl}propionic acid. Preparative HPLC allows to obtain 3-phenyl-3-{6-[4-(pyridine-2-ylamino)butoxy]indol-3-yl}propionic acid, trifter zett.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour as above) Rt=36,1 minutes

FAB-MS:(M+1)=430.

Example 6:

1. Analogously to Example 1, the reaction of 5-benzyloxyindole with benzaldehyde and acid Meldrum and the subsequent conduct of the sequence of reactions for the synthesis allows to obtain 3-phenyl-3-{5-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-phenyl-3-{5-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin, TPL 240° (decomp.).

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour as above) Rt=33,5 min;

FAB-MS:(M+1)=416.

2. Analogously to Example 1, the reaction of 5-benzyloxyindole with benzaldehyde and acid Meldrum and the subsequent conduct of the sequence of reactions for the synthesis of 4-bromo-1-butanol allows to obtain 3-phenyl-3-{5-[4-(pyridine-2-ylamino)butoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-phenyl-3-{5-[4-(pyridin-2-yl-amino)butoxy]indol-3-yl}propionic acid triptorelin.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour as above) Rt=35,1 min;

FAB-MS:(M+1)=430.

Example 7:

1. Ethyl 3-phenyl-3-[6-(tert-butoxycarbonylmethyl)indol-3-yl]propionate

The compound ethyl 3-phenyl-3-(6-hydroxyindole-3-yl)propionateobtained according to the method described in Examples 1.1-1.3 (3,23 mmole), was stirred overnight at 60° C ,94 ml (6.4 mmole) of tert-butyl bromoacetate and 1.8 g (13 mmol) of potassium carbonate in 20 ml of acetone. When the reaction was held until the end (TLC control toluene/acetone 4:1), the precipitate was filtered, the solution is boiled away, and the crude product was purified by chromatography on silica gel (eluent toluene/acetone 9:1), which allowed us to obtain ethyl 3-phenyl-3-[6-(tert-butoxycarbonylmethyl)indol-3-yl]propionate.

TLC: Si-60, toluene/acetone 4:1, Rf=0,56;

FAB-MS:(M+1)=424.

2. Ethyl 3-phenyl-3-(6-carboxymethoxy-3-yl)propionate

1 g (a 2.36 mmole)dissolved in 20 ml of dichloromethane and stirred at room temperature for 20 hours with 2 ml triperoxonane acid. Then the solution is boiled away, the residue was purified preparative HPLC on RP-18, and obtained ethyl 3-phenyl-3-(6-carboxymethoxy-3-yl)propionate triptorelin.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=40,72 min;

FAB-MS:(M+1)=368.

3. Ethyl 3-phenyl-3-[6-(pyridine-2-illinoisbusiness)indol-3-yl]-propionate

100 mg or 0.27 mmole)was stirred overnight at room temperature with 51 mg (0.54 mmole) of 2-aminopyridine in the presence of 112 mg (0.35 mmole) of TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate), 11 mg (81 mmol) NOUT (1-hydroxybenzotriazole hydrate) and 90 μl (about 0.82 mmole) 4-methylmorpholine in 5 ml of DMF. When the reaction was held until the end of the reaction solution was poured into 100 ml of water and the extras who were garofali with ethyl acetate. After conventional treatment received ethyl 3-phenyl-3-[6-(pyridine-2-illinoisbusiness)indol-3-yl]propionate.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=40,96 min;

FAB-MS:(M+1)=444.

4. 3-Phenyl-3-[6-(pyridine-2-illinoisbusiness)indol-3-yl]propionic acid

The reaction of 50 mg (113 mcmole)with 0.15 ml of 1 N NaOH in 1 ml of dioxane at room temperature was allowed to get through 24 hours, 3-phenyl-3-[6-(pyridine-2-illinoisbusiness)indol-3-yl]propionic acid. After preparative HPLC: 3-phenyl-3-[6-(pyridine-2-illinoisbusiness)indol-3-yl]-propionic acid triptorelin.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=32,1 min;

FAB-MS:(M+1)=416.

Example 8:

1. Analogously to Example 7.3, spent the reaction of ethyl 3-phenyl-3-(6-carboxymethoxy-3-yl)propionate, 2-aminoimidazole. Saponification of the resulting ester under conditions described in Example 7.4, allowed to obtain 3-phenyl-3-[6-(benzimidazole-2-yl-aminocarboxylate)indol-3-yl]propionic acid. After preparative HPLC: 3-phenyl-3-[6-(benzimidazole-2-illinoisbusiness)indol-3-yl]propionic acid triptorelin.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=35,4 min;

FAB-MS:(M+1)=455.

1. Analogously to Example 7.3, spent the reaction of ethyl 3-phenyl-3-(6-carboxymethoxy-3-yl)propionate, 2-aminobenzimidazole. Washed the of ether under conditions described in Example 7.4, allowed to obtain 3-phenyl-3-[6-(imidazol-2-yl-aminocarboxylate)indol-3-yl]propionic acid. After preparative HPLC: 3-phenyl-3-[6-(imidazol-2-illinoisbusiness)indol-3-yl]propionic acid triptorelin.

HPLC: (RP-18, gradient a/b 99:1→ 1:99 in 1 hour) Rt=29,3 min;

FAB-MS: M+1=(405).

Example 9:

1.6-(3-benzyloxycarbonylamino)indole

10 g (75 mmol) of 6-hydroxyindole and 21.5 g (79 mmol) of 3-benzyloxy-carboalumination dissolved in 150 ml of acetonitrile and stirred at 80° C for 12 hours with 31.1 g (225 mmol) of potassium carbonate. When the reaction was held until the end (TLC control: silica gel Si-60 with toluene/acetone 10:1), the insoluble precipitate was filtered, the solution is boiled away, and the product was purified by chromatography on silica gel with a mixture of toluene/acetone 10:1 as additionally separated by.

HPLC/MS: (Chromolith RP-18, gradient A:b from 80:20→ 0:100 for 3.5 min using A = water + 0.01% of ofTFA, B = acetonitrile) Rt=2,13 min;

TLC: Si-60, toluene/acetone 6:1, Rf=0,31;

FAB-MS:(M+1)=325.

2. 6-(3-Aminopropoxy)indole

15 g (46 mmol) of 22 was dissolved in 100 ml of ethanol and was hydrogenosomal at room temperature (RT) at atmospheric pressure using 2 g of the catalyst of palladium/activated carbon (10%). After 4 hours the catalyst was filtered and the solution is boiled away. rafinirovaniyu product can be used in subsequent reactions without further purification.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=19,1 min;

TLC: Si-60, ethyl acetate/methanol/water 4:3:2, Rf=0,07;

FAB-MS:(M+1)=191.

3. 6-(3-(N-benzylpyridine-2-ylamino)propoxy)indole hydrobromide

3.5 g (an 18.4 mmole)was stirred for 12 hours at RT in a protective gas atmosphere (nitrogen) from 5.2 g (an 18.4 mmole) of N-benzyl-2-chloropyridine hydrobromide in the presence of 11 g (129 mmol) of hydrogencarbonate of sodium in 200 ml of ethanol. When the reaction was held until the end, inorganic salt salt was filtered, and the solution is boiled away under reduced pressure.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=35,6 min;

TLC: Si-60, dichloromethane/methanol 6:1, Rf=0,55;

FAB-MS: M+=438.

4. 3-[(1-(4-forfinal)-2-(4,6-dioxo-2,2-dimethyl-1,3-dioxane-5-yl)ethyl]-6-[3-(N-benzylpyridine-2-ylamino)propoxy]indole hydrobromide

500 mg (1.05 mmole)was stirred for 12 hours at 30° With 110 μl (1.05 mmole) of 4-forventelige, 150 mg (1.05 mmole) of the acid Meldrum (2,2-dimethyl-1,3-dioxane-4,6-dione) and 6 mg (0.05 mmole) of L-Proline in 4 ml of acetonitrile. After evaporation of the solution, the crude product was ground into powder with MTB ether (methyl tert-butyl ether), and the crystalline precipitate was filtered with suction. Further, it can be applied directly to rassal is of the ester and decarboxylation.

HPLC-MS: (Chromolith RP-18, gradient A:b from 80: 20→ 0:100 for 3.5 min, where A = water + 0.01% of TFA, B = acetonitrile), Rt=1,77 min;

M+=608.

5. 3-(4-Forfinal)-3-{6-[3-(N-benzylpyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin

295 mg (0.43 mmole)dissolved in 3.5 ml of DMSO and stirred for 12 hours at 100° With 36 mg of 0.85 mmole) of lithium chloride and 9 ál of water. When the reaction was held until the end (HPLC/MS monitoring), the solution has boiled away, and the residue was purified preparative HPLC on RP-18. After subliminaly drying solution HPLC, received the product as a white amorphous solid phase in the form of triptoreline.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=38,1 min;

FAB-MS: W=524.

6. 3-(4-forfinal)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid

60 mg (94 mcmole)dissolved in 5 ml of acetone and was hydrogenosomal for 10 hours at RT and atmospheric pressure in the presence of 40 mg (0.48 mmole) of hydrogencarbonate sodium and 20 mg of catalyst a palladium/activated carbon (10%). After removal of catalyst by filtration and evaporation of the solution obtained 3-(4-forfinal)-3-{6-[3-(pyridine-2-ylamino)-propoxy]indol-3-yl}propionic acid. Preparative HPLC on RP-18 gives 3-(4-forfinal)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}p is pianoboy acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt= 31,6 min;

FAB-MS: (M+1)= 434.

Example 10:

Analogously to Example 9, reaction of 6-(3-(N-benzylpyridine-2-yl-amino)propoxy)indole hydrobromide

with 3,5-bis(trifluoromethyl)benzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-[3,5-bis(trifluoromethyl)phenyl]-3-{6-[3-(pyridine-2-ylamino)propoxy]-indol-3-yl}propionic acid. After preparative HPLC: 3-[3,5-bis(trifluoromethyl)phenyl]-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=36,5 min;

FAB-MS: (M+1)= 594.

with a 3.5-dichlorobenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(3,5-dichlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid. After preparative HPLC: 3-(3,5-dichlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt= 37,2 min;

FAB-MS:(M+1)=485.

with 4,6-dichlorobenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4,6-dichlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid. After preparative HPLC: 3-(4,6-dichlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic sour the s triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=37,3 min;

FAB-MS:(M+1)=485.

with 4-chloro-5-triftormetilfullerenov and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-chloro-5-triptoreline)-3-{6-[3-(pyridine-2-ylamino)propoxy]-indol-3-yl}propionic acid. After preparative HPLC: 3-(4-chloro-5-triptoreline)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=38,7 min;

FAB-MS:(M+1)=518.

with 3-cyclohexylbenzene and then carrying out the sequence of reactions for the synthesis allows to obtain

3-cyclohexyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-cyclohexyl-3-{6-[3-(pyridin-2-yl-amino)propoxy]indol-3-yl}propionic acid triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=37,2 min;

FAB-MS:(M+1)=422.

with benzo-1,2,5-thiadiazole-5-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-benzo-1,2,5-thiadiazole-5-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-benzo-1,2,5-thiadiazole-5-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=30,7 min;

FAB-MS:(M+1)=474.

with 2,6-debtor what benzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(2,6-differenl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid. After preparative HPLC: 3-(2,6-differenl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=32,6 min; FAB-MS:(M+1)=452.

with 2-chloro-3,6-diferentialglea and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(2-chloro-3,6-differenl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(2-chloro-3,6-differenl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=34,6 min; FAB-MS:(M+1)=486.

with 2,4,6-tripersonality and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(2,4,6-tryptophanyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. After preparative HPLC: 3-(2,4,6-tryptophanyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=33,8 min;

FAB-MS:(M+1)=470.

4-methoxycarbonylbenzyl and then holding

the sequence of reactions for the synthesis allows to obtain

3-(4-ethoxycarbonylphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid. After preparative HPLC: 3-(4-methoxy bonisteel)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin.

Example 11:

1. 6-[3-(Pyridine-2-ylamino)propoxy]indol

6 g (12.9 mmole) 6-(3-(N-benzylpyridine-2-ylamino)propoxy)indole hydrobromide(prepared analogously to Example 9.1-9.3] was dissolved in 300 ml of acetone and was hydrogenosomal for 8 hours at RT and atmospheric pressure in the presence of 2 g of the catalyst of palladium/activated carbon (10%). After the catalyst was filtered, the solution is boiled away, and got a crude product as a white solid phase.

TLC: SI-60, dichloromethane/methanol 6:1, Rf=0,67;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=28,6 min;

FAB-MS:(M+1)=268.

2. 3-[(1-(4-trifloromethyl)-2-(4,6-dioxo-2,2-dimethyl-1,3-dioxane-5-yl)ethyl]-6-[3-(pyridine-2-ylamino)propoxy]indol

350 mg (1.3 mmole)was stirred for 12 hours at RT with 190 μl (1.3 mmole) of 4-triphtalocyaninine, 190 mg (1.3 mmole) of the acid Meldrum and 9 mg (0.07 mmole) of Proline in 5 ml of acetonitrile. When the reaction was held until the end (control HPLC/MS), the solution has boiled away, and the product was used for cleavage of the ester and decarboxylation without additional purification.

HPLC/MS: (Chromolith RP-18, gradient A:b from 80:20→ 0:100 for 3.5 min, where A = water + 0.01% of TFA, B = acetonitrile), Rt=1,71 min;

(M+1)=544.

3. 3-(4-Trifloromethyl)-3-{6-[3-(pyridin-2-yl) - Rev. Ino)propoxy]indol-3-yl}propionic acid triptorelin

In accordance with Example 9.5, 760 mg (1.3 mmole)was stirred for 12 hours at 100° With 4 ml of DMSO with 110 mg of lithium chloride and 29 μl of water. When the reaction was held until the end, the solution is boiled away, and got 3-(4-Trifloromethyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid. Preparative HPLC on RP-18 allowed to obtain 3-(4-trifloromethyl)-3-{6-[3-(pyridine-2-ylamino)-propoxy]indol-3-yl}propionic acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=36,7 min;

FAB-MS:(M+1)=498.

Analogously to Example 11, reaction of 6-[3-(pyridine-2-ylamino)-propoxy]indole

with 3-triftormetilfullerenov and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(3-trifloromethyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]-indol-3-yl}propionic acid. Preparative HPLC allows to obtain 3-(3-trifloromethyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=40,2 min;

FAB-MS:(M+1)=500

Example 12:

1. 6-[3-(4,5-dihydro-1 H-imidazol-2-ylamino)propoxy]indol.

500 mg (2.6 mmole) 6-(3-aminopropoxy)indole[prepared according to Example 9.1] was dissolved in 10 ml of DMF together with 0.97 g (3,9 the mole) of 2-(3,5-dimethylpyrazole)-4,5-dihydroimidazole hydrobromide and 1.7 ml (11.9 mmole) of triethylamine, and the solution was stirred at 60° C for 12 hours. After evaporation of the solution, the crude product was purified preparative HPLC.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=26,7 min;

FAB-MS:(M+1)=259.

2. 3-[(1-(Benzo-1,2,5-thiadiazole-7-yl)-2-(4,6-dioxo-2,2-dimethyl-1,3-dioxane-5-yl)ethyl]-6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-indole

In accordance with Example 11.2, spent the reaction of 100 mg (0,33 mmole)with 53 mg (0,33 mmole) 5-formelement-1,2,5-thiadiazole, 46 m (0,33 mmole) of the acid Meldrum and 2 mg L-Proline in 4 ml of acetonitrile at 30° C. Evaporation leads to the production of sludge, which can be used in subsequent reactions without further purification.

HPLC/MS: (Chromolith RP-18, gradient A:b from 80:20→ 0:100 for 3.5 min, where A = water + 0.01% of TFA, B = acetonitrile) Rt=1.,9 min; (M+1)=549.

2. 3-(Benzo-1,2,5-thiadiazole-7-yl)-3-{6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid

Crude productwas stirred for 12 hours at 100° With 4 ml of DMSO along with 27 mg of lithium chloride and 7 μl of water, and then boiled away and got 3-(benzo-1,2,5-thiadiazole-7-yl)-3-{6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. Purification preparative HPLC allows to obtain 3-(benzo-1,2,5-thiadiazole-7-yl)-3-{6-[3-(45-dihydro-1H-imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=28,1 min;

FAB-MS:(M+1)=465.

Example 13:

Analogously to Example 12, reaction of 6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]indole

4-vorbesuregen and then carrying out the sequence of reactions for the synthesis allows to obtain

3-{6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl}-3-(4-forfinal)propionic acid. Preparative HPLC allows to obtain 3-{6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl}-3-(4-forfinal)propionic acid triptorelin;

with benzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-{6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl}-3-phenylpropionate acid. Preparative HPLC allows to obtain 3-{6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1 H-indol-3-yl}-3-phenylpropionic acid triptorelin;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=29,8 min;

FAB-MS:(M+1)=407.

pyridine-4-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-pyridin-4-yl-3-{6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)-propoxy]-1H-indol-3-yl}propionic acid. Preparative HPLC allows to obtain 3-pyridin-4-yl-3-{6-[3-(3,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin.

Similar what about the Example 12, the reaction of 6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)butoxy]indole, obtained analogously to Example 9.1-9.3 in the reaction with 4-benzyloxycarbonylamino,

with benzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-{6-[4-(4,5-dihydro-1H-imidazol-2-ylamino)butoxy]-1H-indol-3-yl}-3-phenylpropionate acid. Preparative HPLC allows to obtain 3-{6-[4-(4,5-dihydro-1H-imidazol-2-ylamino)butoxy]-1H-indol-3-yl}-3-phenylpropionic acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=30,5 min;

FAB-MS:(M+1)=421.

Example 14:

1. Ethyl 3-phenyl-3-[6-(3-phthalimidopropyl)indol-3-yl]propionate

25 g (81 mmol) of ethyl 3-phenyl-3-(6-hydroxyindole-3-yl)propionate[prepared in accordance with Example 1.1-1.2] was dissolved in 250 ml of acetonitrile together with 30,3 g (113 mmol) of N-(3-bromopropyl)phthalimide of 26.4 g (80,6 mmole) of cesium carbonate and added to 0.67 g (4 mmole) of potassium iodide, then the mixture was delegirovali within 12 hours. The reaction mixture is allowed to cool, was filtered through a layer of kieselguhr, and the filtrate is boiled away. Crude product can be recrystallized from hot ethanol.

TPL: 95° C

TLC: Si-60, toluene/MTB ether 4:1, Rf=0,31,

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rf=to 49.9 min,

FAB-MS:(M+1)=497.

2. Ethyl 3-phenyl-3-[6-3-aminopropoxy)indol-3-yl]propionate hydrochloride

34,6 g (69.7 mmole)dissolved in 350 ml of ethanol and was delegirovali with 5.1 ml (104,5 mmole) of hydrazine hydrate is added until the reaction is completed, which occurred after 2.5 hours. After cooling the solution in an ice bath, usageprice calogeras was filtered, and the solution was acidified using ethanol HCl. New sediment ftlorida hydrochloride was again filtered with suction, and the solution was concentrated to about 100 ml Product crystallizes ethanol solution at 0° in the form of hydrochloride.

TPL: 158° C

TLC: Si-60, dichloromethane/methanol/ammonia 4:1:0,1, Rf=0,33;

FAB-MS:(M+1)=367.

3. 3-Phenyl-3-[6-(3-aminopropoxy)indol-3-yl]propionic acid

1.6 g (4 mmole)dissolved in 10 ml of dioxane and stirred for 2 days at RT with 10 ml of 2N sodium hydroxide solution. When the reaction was held until the end, the solution was neutralized using 2N HCl, and the product was besieged in acetone. Further reaction with this product can be done without additional purification.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=25,8 min; FAB-MS:(M+1)=339.

4. 3-Phenyl-3-[6-(3-guanidinopropionic)indol-3-yl]propionic acid

250 mg (0,74 mmole)was stirred for 12 hours at 60° With 223 mg (1,11 mmole) of 3,5-d is methyl-1-pyrazolopyrimidine nitrate and 0.31 ml (2,22 mmole) of triethylamine in 10 ml of DMF. When the reaction was held until the end (HPLC/MS monitoring), the solution has boiled away, and got 3-phenyl-3-[6-(3-guanidinopropionic)indol-3-yl]propionic acid. Purification using preparative HPLC allows to obtain 3-phenyl-3-[6-(3-guanidinopropionic)indol-3-yl]propionic acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=28,9 min;

FAB-MS:(M+1)=381.

Example 15:

Analogously to Example 14, the reaction of ethyl 3-phenyl-3-(6-hydroxyindole-3-yl)propionateN-(4-bromobutyl)phthalimide and then carrying out the sequence of reactions for the synthesis allows to obtain

3-[6-(4-guanidinoacetic)-1H-indol-3-yl]-3-phenylpropionate acid. Preparative HPLC allows to obtain 3-[6-(4-guanidinate)-1 H-indol-3-yl]-3-phenyl-propionic acid triptorelin,

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=30,6 min;

FAB-MS:(M+1)=395.

Example 16:

3-Phenyl-3-{6-[3-(1,5-dihydroimidazole-4-one-2-ylamino)propoxy]-indol-3-yl}propionic acid

130 mg (0,29 mmole)prepared analogously to Example 14, was stirred for 24 hours at RT with 115 mg (of 0.87 mmole) 2-methylsulfanyl-1,5-dihydroimidazole-4-it and 0.12 ml of 0.87 mmole) of triethylamine in a mixture of 2 ml of ethanol and 1 ml of DMF, and received 3-phenyl-3-{6-[3-(1,5-dihydroimidazole-4-one-2-ylamino)propoxy]indol-3-yl}propionic acid. Cleaning agents the active HPLC on RP-18 gives 3-phenyl-3-{6-[3-(1,5-dihydroimidazole-4-one-2-ylamino)propoxy]indol-3-yl}propionic acid triptorelin.

FAB-MS:(M+1)=421.

Example 17:

Analogously to Example 16, the reaction of 3-(4-forfinal)-3-[6-(3-aminopropoxy)indol-3-yl]propionic acid (prepared analogously to Example 1.1-1.2 and 15) with 2-methylsulfanyl-1,5-dihydroimidazole-4-one and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-forfinal)-3-{6-[3-(4-oxo-4,5-dihydro-1H-imidazol-2-ylamino)-propoxy]-1H-indol-3-yl}propionic acid. Preparative HPLC allows to obtain 3-(4-forfinal)-3-{6-[3-(4-oxo-4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin.

Analogously to Example 16, the reaction of 3-[6-(3-aminopropoxy)-1H-indol-3-yl]-3-pyridin-4-ylpropionic acid (prepared analogously to Example 1.1-1.2 and 15) with 2-methylsulfanyl-1,5-dihydroimidazole-4-one and then carrying out the sequence of reactions for the synthesis allows to obtain

3-{6-[3-(4-oxo-4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl}-3-pyridin-4-ylpropionic acid. Preparative HPLC allows to obtain 3-{6-[3-(4-oxo-4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl}-3-pyridin-4-yl-propionic acid triptorelin.

Analogously to Example 16, the reaction of 3-[6-(3-aminopropoxy)-1H-indol-3-yl]-3-benzo-1,2,5-thiadiazole-5-ylpropionic acid (prepared analogously to Example 1.1-1.2 and 15) with 2-methylsulfanyl-1,5-dihydroimidazole-4-one and then carrying out the sequence of reactions SinTe is and allows you to get

3-benzo-1,2,5-thiadiazole-5-yl-3-{6-[3-(4-oxo-4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. Preparative HPLC allows to obtain 3-benzo-1,2,5-thiadiazole-5-yl-3-{6-[3-(4-oxo-4,5-dihydro-1H-imidazol-2-yl-amino)propoxy]-1H-indol-3-yl}propionic acid triptorelin.

Example 18:

Ethyl 3-phenyl-3-{6-[3-(pyrimidine-2-ylamino)propoxy]indol-3-yl}propionate

1 g (2,48 mmole)prepared in accordance with Example 14.2, dissolved in 30 ml of anhydrous ethanol with 426 mg (3,72 mmole) of 2-chloropyrimidine and 1 ml (7,44 mmole) of triethylamine, and the solution was delegirovali for 20 hours. After evaporation the residue was subjected to chromatography on silica gel (eluent ethyl acetate).

TLC: Si-60, ethyl acetate, Rf=0,42;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=39,0 min;

FAB-MS:(M+1)=445.

Cleavage of the ester by means of sodium hydroxide solution in dioxane at RT was possible to obtain the free acid 3-phenyl-3-{6-[3-(pyrimidine-2-ylamino)propoxy]indol-3-yl}propionic acid.

FAB-MS:(M+1)=417.

Example 19:

Ethyl 3-phenyl-3-{6-[3-(3,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-indol-3-yl}propionate

200 mg (0.45 mmole)dissolved in 10 ml ethanol and was hydrogenosomal for 3 hours at RT and atmospheric pressure in presets the accordance of 0.68 ml (1,35 mmole) of 2N HCl and 60 mg of catalyst a palladium/activated carbon (10%). When the reaction was held until the end, the catalyst was filtered, the solution is boiled away, and the residue was purified preparative HPLC on RP-18.

TLC: Si-60, ethyl acetate/methanol 4:1, Rf=0,08;

HPLC/MS: (Chromolith RP-18, gradient A:b from 80:20→ 0:100 for 3.5 min, where A = water + 0.01% of TFA, B = acetonitrile) Rf=1,39 min; FAB-MS:(M+1)=449.

Ether cleavage of the ethyl ester with sodium hydroxide in dioxane at RT was possible to obtain the free acid 3-phenyl-3-{6-[3-(3,4,5,6-tetrahydropyrimidin-2-yl-amino)propoxy]indol-3-yl}propionic acid.

FAB-MS: M+1=421.

Example 20:

1. Ethyl 3-phenyl-3:{6-[3-(3,4,5,6-tetrahydropyridine-2-yl)aminopropoxy]-indol-3-yl}propionate

In accordance with Example 19, 200 mg of ethyl 3-phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionatewas hydrogenosomal in the presence of 2N hydrochloric acid and the catalyst is palladium/activated carbon (10%), received. FAB-MS: (M+1)=448.

Cleavage of the ester by means of sodium hydroxide solution in dioxane at RT was possible to obtain the free acid 3-phenyl-3-{6-[3-(3,4,5,6-tetrahydropyridine-2-yl)aminopropoxy]-indol-3-yl}propionic acid.

FAB-MS:(M+1)=420.

2. Analogously to Example 9, spent the reaction of the compoundwith 3-hydroxybenzaldehyde, and then, in the sequence of reactions of the synthesis is Lucile methyl 3-(3-hydroxyphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-propionate.

Analogously to Example 19 methyl 3-(3-hydroxyphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionate was hydrogenosomal, and obtained methyl 3-(3-hydroxyphenyl)-3-{6-[3-(3,4,5,6-tetrahydropyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionate.

Cleavage of the ester by means of sodium hydroxide solution in dioxane at RT allows you to obtain the free acid 3-(3-hydroxyphenyl)-3-{6-[3-(3,4,5,6-tetrahydropyridine-2-ylamino)-propoxy]-1H-indol-3-yl}propionic acid.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rf=26,6 min;

FAB-MS:(M+1)=436.

Example 21:

1. 3-Phenyl-3-{6-[3-(thiomethyl-N-cyanoimino)aminopropoxy]indol-3-yl}propionic acid

1 g (2.9 mmole)was stirred for 20 hours at 80° with 1.3 g (8.7 mmole) of dimethyl N-cyanodithioiminocarbonate in 10 ml of DMF. When the reaction was held until the end, the solution is boiled away, and the crude productpurify by chromatography on silica gel using toluene/ethyl acetate 1:1 as additionally separated by.

TLC: Si-60, toluene/methanol 3:1, Rf=0,55;

HPLC/MS: (Chromolith RP-18, gradient A:b from 80:20→ 0:100 for 3.5 min, where A = water + 0.01% of TFA, B = acetonitrile) Rt=1,75 min; M+1=437.

2. Phenyl-3-{6-[3-(N'-methyl-N"-cyanoguanidine)propoxy]indol-3-yl}-propionic acid

100 mg (0,23 mmole)/img> dissolved in 2 ml of DMF, and the solution was stirred for 12 hours at 60° With 1 ml of a solution of methylamine (33% in ethanol). Then the solution is boiled away,and got phenyl-3-{6-[3-(N'-methyl-N"-cyanoguanidine)propoxy]indol-3-yl}propionic acid. Purification preparative HPLC on RP-18 allowed to obtain phenyl-3-{6-[3-(N'-methyl-N"-cyanoguanidine)propoxy]indol-3-yl}propionic acid triptorelin.

TLC: Si-60, dichloromethane/methanol 1:1, Rf=0,53;

HPLC/MS: (Chromolith RP-18, gradient A:b from 80:20→ 0:100 for 3.5 min, where A = water + 0.01% of TFA, B = acetonitrile) Rt=1,49 min; M+1=420.

Example 22:

Analogously to Example 1, reaction of 6-benzyloxyindole

with 1H-indole-2-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(1H-indol-2-yl)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-propionic acid. After preparative HPLC: 3-(1H-indol-2-yl)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

with thiophene-2-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-thiophene-2-yl-propionic acid. After preparative HPLC: 3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-thiophene-2-ylpropionic acid triptorelin;

with 1H-pyrrole-2-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows the floor is'it

3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-(1H-pyrrol-2-yl)-propionic acid. After preparative HPLC: 3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-(1H-pyrrol-2-yl)propionic acid triptorelin;

with thiazole-2-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-thiazol-2-ylpropionic acid. After preparative HPLC: 3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-thiazol-2-ylpropionic acid triptorelin;

with biphenyl-4-carbaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-biphenyl-4-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-propionic acid. After preparative HPLC: 3-biphenyl-4-yl-3-{6-[3-(pyridin-2-yl-amino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

6-dimethylamino-2-fluoro-3-formylbenzoate and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(3-cyano-4-dimethylamino-2-forfinal)-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-(3-cyano-4-dimethylamino-2-forfinal)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

with 3-fluoro-4-triftormetilfullerenov and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(3-ft is R-4-triptoreline)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid. After preparative HPLC: 3-(3-fluoro-4-triptoreline)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

4-isopropylbenzaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-(4-isopropylphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-propionic acid. After preparative HPLC: 3-(4-isopropylphenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-propionic acid triptorelin;

with cyclopropanecarboxaldehyde and then carrying out the sequence of reactions for the synthesis allows to obtain

3-cyclopropyl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-propionic acid. After preparative HPLC: 3-cyclopropyl-3-{6-[3-(pyridin-2-yl-amino)propoxy]-1H-indol-3-yl}propionic acid triptorelin;

with 2,2-dimethylpropanamide and then carrying out the sequence of reactions for the synthesis allows to obtain

4,4-dimethyl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}pentane acid. After preparative HPLC: 4,4-dimethyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indol-3-yl}pentanol acid triptorelin;

with 2,2-dimethylbutylamino and then carrying out the sequence of reactions for the synthesis allows to obtain

5,5-dimethyl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}hexanoic acid. After preparative HPLC: 5,5-dimethyl-3-{6-[3-(pyridine-2-Ilam is but)-propoxy]-1H-indol-3-yl}hexanoic acid triptorelin;

Example 23:

Analogously to Example 1.7, ethyl 4-(2-etoxycarbonyl-1-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}ethyl)benzoate, prepared analogously to Example 1.1-1.6, mixed with dioxane/1N NaOH, and received 4-(2-carboxy-1-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}ethyl)Bentiu acid.

Example 24:

Analogously to Example 18, spent the reaction of the compoundprepared in accordance with Example 14.2, 2-chloro-3-nitropyridine and triethyl-amine, in the received 3-{6-[3-(3-nitropyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-phenylpropionate acid. After preparative HPLC: 3-{6-[3-(3-nitropyridine-2-yl-amino)propoxy]-1H-indol-3-yl}-3-phenylpropionic acid triptorelin.

TLC: Si-60, toluene/methanol 4:1, Rf=0,36;

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=43.5 minutes;

FAB-MS:(M+1)=461.

The restoration of the nitro group by catalytic hydrogenation (palladium/activated carbon, hydrogen, ethanol) allowed to obtain 3-{6-[3-(3-aminopyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-phenylpropionate acid.

After preparative HPLC: 3-{6-[3-(3-aminopyridine-2-ylamino)propoxy]-1H-indol-3-yl}-3-phenylpropionic acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=33,3 min;

FAB-MS:(M+1)=431.

N-Acetylation of amino groups using acetic anhydride is allowed to obtain 3-{6-[3-(3-Aza eliminability-2-ylamino)propoxy]-1H-indol-3-yl}-3-phenylpropionate acid. After preparative HPLC: 3-{6-[3-(3-acetylpiperidine-2-ylamino)propoxy]-1H-indol-3-yl}-3-phenylpropionic acid triptorelin.

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour) Rt=31,7 min;

FAB-MS:(M+1)=473.

Example 25:

1. (3S)-3-Phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid

50 g (0,113 mole) ethyl 3-phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionateprepared in accordance with Example 1, was divided into two enantiomers by using continuous chromatography on modified cellulose substrate (Chiralcel OD-H) in a mixture of isopropanol/n-heptane 30:70. Output: 24.5 g (98% of theoretical) of the active enantiomer S. HPLC: Chiralcel OD-H, i-propanol/n-hepten 30/70, Rt=14,08 minutes

For cleavage of the ether, 24.4 g (55 mmol) of the S enantiomer was dissolved in 100 ml of ethanol and was stirred for 12 hours at 60° With 110 ml (110 mmol) of 1N NaOH. When the reaction was held until the end of the reaction solution allowed to cool and acidified to pH 6 using 1N HCL. The precipitate was filtered with suction, washed with water and then ether MTV and dried, the result is obtained (3S)-3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]indol-3-yl}propionic acid.

TPL: 137°

HPLC: (RP-18, gradient A:b from 99:1→ 1:99 in 1 hour), where A = water + 0,3% TFA, B = acetonitrile/water +0.3% of TFA 4:1) Rt=31,1 min; chiral HPLC: Cirobiotic V, water (+ 1% of triethylamine acetate/methanol 65:35, Rt=to 21.15 minutes

2. (3S)-3-Phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid hydrochloride

2 g (4.8 mmole) of the internal saltdissolved in 5 ml of dioxane and stirred for 2 hours at RT with 20 ml (20 mmol) of 1N HCl.

Then, the solution was subjected to subliminaly drying, and received (3S)-3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]indol-3-yl}propionic acid hydrochloride.

Analysis: calculation: 66,4%, 5,80% N, Of 9.30% N, 7,84% Cl

measurements: 65,9%, 5,91% H, 9,11% N, 7,44% Cl.

3. (3S)-3-Phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid methanesulfonate

2 g (4.8 mmole) of the internal saltdissolved in 5 ml of dioxane and stirred for 2 hours at RT with 310 μl (4.8 mmole) methanesulfonic acid, 5 ml of water. Then the solution is boiled away, and got (3S)-3-phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid methanesulfonate after subliminales drying from a mixture of acetonitrile/water.

Analysis: calculation: 61,04%, 5,71% N, 8,21% N, 6,26% S

measurements: 60,90%, Of 5.99% N, 8,01% N, of 5.92% s

The following examples relate to pharmaceutical preparations:

Example: Injection vials

A solution of 100 g of active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is brought to pH 6.5 using 2N hydrochloric is islote, sterilized by filtration, filled into injection vials, liofilizirovanny in sterile conditions and corked in sterile conditions. Each injection vial contains 5 mg of active ingredient.

Example: Suppositories

A mixture of 20 g of active ingredient of formula 1 fused with 100 g of soya lecithin and 1400 g of cocoa butter, Packed up the forms and allowed to cool. Each suppository contains 20 mg of the active ingredient.

Example: Solution

The solution is prepared from 1 g of the active ingredient of the formula I, 9,38 g NaH2PO4·2H2O, 28,48 g Na2HPO4·Na and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. Brought the pH to 6.8, brought the volume up to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

500 mg of the active ingredient of the formula I mixed with 99.5 g of vaseline under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate were pressed into tablets in the usual manner so that each tablet contained 10 mg of the active ingredient.

Example F: coated Tablets

Tablets were pressed analogously to Example E, then the usual procedure was applied a coating of sucrose, potato starch, talc, t is againt and dye.

Example G: Capsules

2 kg of active ingredient of formula 1 is introduced into hard gelatin capsules in the usual manner so that each capsule contained 20 mg of the active ingredient.

Example N: Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water were sterilized by filtration, was poured into the vials, liofilizirovanny in sterile conditions and corked in sterile conditions. Each ampoule contains 10 mg of active ingredient.

Example I: Aerosol for inhalation

14 g of active ingredient of formula I dissolved in 10 l of isotonic NaCl solution and poured the solution into aerosol containers with a pump dispenser, which are commercially available. The solution can be sprayed into the mouth or nose. One portion of the aerosol (about 0.1 ml) corresponds to a dose of about 0.14 mg

1. Derivatives of indol-3-yl of the formula I

in which a and b each independently of one another represents O, NH, CONH, NHCO or direct connection,

X denotes alkylene containing from 1 to 2 carbon atoms, or a direct link,

R1denotes H, Z or -(CH2)about-Ah,

R2denotes H,

R3means other6, -NR6-C(=NR6)-Other6 , -C(=NR6)-Other6, -NR6-C(=NR6)-Other6, -C(=NR9)-Other6or Het1,

R4and R5each independently of the other represents H, R7, -(CH2)o-Ar, Het, OR6,

R6denotes H,

R7represents alkyl containing from 1 to 10 carbon atoms, or cycloalkyl containing from 3 to 10 carbon atoms,

R8denotes Hal, NO2CN, Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, Other1,

R9denotes CN or NR2,

Z represents alkyl containing from 1 to 6 carbon atoms,

AG represents aryl, which may be unsubstituted or monosubstituted or polyamidine R8,

Hal denotes F, CI, Br, or 1,

Het denotes a saturated, partially or fully unsaturated monocyclic or bicyclic heterocyclic radical containing from 5 to 10 ring members, which contains 1 or 2 N atom and/or 1 S atom, and the heterocyclic radical may be monogamist by phenyl,

Het1denotes a saturated, partially or fully unsaturated monocyclic or bicyclic heterocyclic radical containing from 5 to 10 ring members and from 1 to 4 N atoms, which may be unsubstituted or monosubstituted NHZ, or oxo,

will oboznachaet 0, 1 or 2,

m denotes 0, 1, 2, 3, 4, 5 or 6,

o denotes 0, 1 or 2,

and their physiologically acceptable salt and solvate.

2. The enantiomers of the formula I according to claim 1.

3. The compounds of formula I according to items 1 and 2, characterized in that X represents a direct link.

4. The compounds of formula I according to items 1 to 3, characterized in that

In denotes Oh,

R4means R7, (CH2)about-AG or Het,

o represents 0 or 1,

R5denotes H,

R7represents alkyl containing from 1 to 10 carbon atoms or cycloalkyl containing from 3 to 10 carbon atoms.

5. The compounds of formula I according to claim 1

a) 3-phenyl-3-{6-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-propionic acid;

b) 3-phenyl-3-{6-[4-(pyridine-2-ylamino)butoxy]-1H-indol-3-yl}propionic acid;

c) 3-phenyl-3-{5-[4-(pyridine-2-ylamino)butoxy]-1H-indol-3-yl)propionic acid;

d) 3-phenyl-3-{5-[3-(pyridine-2-ylamino)propoxy]-1H-indol-3-yl}-propionic acid;

e) 3-phenyl-3-[6-(pyridine-2-illinoisbusiness)indol-3-yl]-propionic acid;

f) 3-phenyl-3-[6-(benzimidazole-2-illinoisbusiness)indol-3-yl]propionic acid;

g) 3-phenyl-3-[6-(imidazol-2-illinoisbusiness)indol-3-yl]-propionic acid;

h) 3-{6-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propoxy]-1H-indol-3-yl{3-dryers is proponowa acid;

i) 3-(4-forfinal)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid;

j) 3-(3,5-dichlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}propionic acid;

k) 3-(4-chloro-5-triptoreline)-3-{6-[3-(pyridine-2-ylamino)-propoxy]indol-3-yl}propionic acid;

l) 3-cyclohexyl-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid;

m) 3-pyridin-4-yl-3-;6-{3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid;

n) 3-(3-chlorophenyl)-3-{6-[3-(pyridine-2-ylamino)propoxy]indol-3-yl}-propionic acid;

o) 3-phenyl-3-[6-(3-guanidinopropionic)indol-3-yl]propionic acid;

R) 3-benzo-1,2,5-thiadiazole-5-yl-3-{6-[3-(pyridine-2-ylamino)propoxy]-indol-3-yl}propionic acid;

q) 3-(3-hydroxyphenyl)-3-{6-[3-(3,4,5,6-tetrahydropyridine-2-ylamino)-propoxy]indol-3-yl}propionic acid, or

r) 3-[4-ethoxycarbonylphenyl]-3-{6-[3-(pyridine-2-ylamino)propoxy]-indol-3-yl}propionic acid;

and their physiologically acceptable salt and solvate.

6. Method of producing compounds of the formula I according to claim 1 and their salts and solvate, characterized in that the compound of formula I is recovered from one of its functional derivatives containing one or more of the corresponding amino - and/or hydroxylamine groups, by treatment solvolysis or hydrogenation AG is Tom and/or conversion of a base or acid of the formula I into one of their salts.

7. The compounds of formula I according to claim 1 and their physiologically acceptable salt or solvate as therapeutically active ingredients with Interenergoservis action.

8. The compounds of formula I according to claim 1 and their physiologically acceptable salt or solvate as integrin inhibitors.

9. Pharmaceutical drugs that have Interenergoservis effect, containing at least one compound of formula I according to claim 1 and/or one of its physiologically acceptable salt or solvate.

10. The compounds of formula IIA

in which R2, R4and R5have the meanings given in claim 1,

X denotes a bond,

R10and R11each independently of the other represents H or alkyl containing from 1 to 10 carbon atoms.

11. The compounds of formula X

in which R2, R3, A, n and m have the meanings given in claim 1.



 

Same patents:

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1have the values listed above in their characters except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group

The invention relates to 1-(3-heteroaromatic or prop-2-enyl)-4-benzylpiperidine formula (1), where X Is O, NR1, S, or CH2; Y is CH; Z is CH; Y and Z together may denote C= S; R1, R2and R3is hydrogen, R4- fluorine

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

The invention relates to a group of new compounds - heterocyclic derivatives of glycyl-beta-alanine General formula I

< / BR>
or pharmaceutically acceptable salt of this compound, where

< / BR>
is a 5-8-membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group comprising N and S, and1selected from the group comprising SN, SN2, N, NH, O and S, provided that

< / BR>
is not pyrrolidinium when V represents NH;

A represents a group of the formula

< / BR>
where Y1selected from the group comprising N-R2and R2means hydrogen; R2means hydrogen, R7when not with R2and R8mean hydrogen, alkyl, substituted alkoxy group, or R2together with R7form a 4 to 12-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted by one or more substituents selected from the group comprising hydroxy, C1-C10< / BR>
where R2together with R7form a 5-8-membered ring containing two nitrogen atom a heterocycle, R5means hydrogen, R8means alkyl, optionally substituted by alkoxygroup; or A signifies a group

< / BR>
where R2together with R7form a 5-8-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted hydroxy-group; R8- alkyl, substituted alkoxygroup; V means-N(R6)-; R6is hydrogen; Y and Z denote hydrogen, t = 0, n and R = 1, 2; R means X-R3where X is-O-; R3is hydrogen, alkyl; R1selected from the group including aryl, alkyl, optionally substituted one or more times by halogen, alkyl, HE; monocyclic heterocycle; haloalkyl; R11means hydrogen, or a pharmaceutically acceptable salt of the compounds; pharmaceutical compositions having properties antagonistV3-integrin, as well as to a method of treating diseases mediatedV3-integrin in a mammal

FIELD: organic chemistry, insecticides, chemical technology.

SUBSTANCE: invention describes derivative of 1-aryl-3-cyano-5-heteroarylalkylaminopyrazole of the general formula (1): wherein A means: (A-1) , (A-2) , (A-3) and (A-4) and wherein X represents C-halogen; R1 represents (C1-C4)-alkyl group or halogen-(C1-C4)-alkyl group; A represents any group among (A-1) - (A-4) wherein R4 represents hydrogen atom or (C1-C4)-alkyl group; n = 0, 1 or 2 under condition that R1 represents halogen-(C1-C4)-alkyl group with exception for perhalogenalkyl group when A represents (A-1) and n = 0, and that n doesn't equal 0 when A represents (A-4). Also, invention describes derivative of pyrazole of the formula (2): wherein A means: (A-1) and Y means: (Y-1) , (Y-2) and (Y-3) wherein X, R2, R3 and R4 have values given above; R5 represents hydrogen atom; A represents (A-1); Y means any group among (Y-1) - (Y-3); Z represents halogen atom that are intermediate compounds used for synthesis of the compound (1). Invention describes methods for preparing compounds of the formula (1) and (2) and insecticide comprising compound of the formula (1) as an active component. Insecticide shows high systemic activity, high safety and reduced harmful effect on environment in vicinity areas of its applying.

EFFECT: improved methods for preparing, valuable insecticide properties of compound.

11 cl, 9 tbl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

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, pharmacy.

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

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

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

SUBSTANCE: invention relates to new derivatives of piperazinylalkylthiopyrimidine of the formula (I): wherein R1 represents hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkanoyl or di-(C1-C4-alkyl)-amino-(C1-C4-alkyl); R2 means hydrogen atom or benzyl substituted with 1-3 substitutes taken among the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy-group, di-(C1-C4-alkyl)-amino-group, hydroxyl group and halogen atom; n = 2, 3 or 4, and to its pharmaceutically acceptable acid addition salt. Also, invention describes a method for preparing compounds and pharmaceutical composition based on thereof. Compounds are useful for treatment of diseases arising as result of the central nervous system injury.

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

14 cl, 3 tbl, 26 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

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