Method of producing isothiazole derivatives

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of producing compounds with formula I and to their pharmaceutical salts. In formulae I, II, IV, V: R1 or R2 represent H, -(CH2)t(5-member heterocyclic compound), where t equals 4 and where the heterocyclic compound contains one nitrogen atom as the heteroatom, R3 is -(CH2)t(C6-C10aryl), where t equals 1. The given R3 groups are optionally substituted with 3 R4 groups. Each R4 is independently chosen from halogen. R8 is C1-C10alkyl, R9 is C1-C10alkyl, and n equals 2.

EFFECT: treatment of hyper-proliferative diseases using new intermediate compounds with formulae II, IV, V.

15 cl, 2 dwg, 11 ex

 

BACKGROUND of the INVENTION

This invention relates to methods for derivatives isothiazole suitable for the treatment of hyperproliferative diseases, such as malignant tumors in mammals. It is known that polypeptide growth factors, such as growth factor vascular endothelial (VEGF), which has high affinity to the receptor of man, containing the domain with the kinase insert (KDR), or to the receptor fetal liver kinase 1 (FLK-1) mice, associated with proliferation of endothelial cells, and more specifically, with vasculogenesis and angiogenesis. The present invention relates to a method for producing compounds capable of binding with the receptor KDR/FLK-1 or its modulation. The connection can be used for treating disorders associated with vasculogenesis or angiogenesis, such as diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and cancer of the ovary, breast, lung, pancreas, prostate, colon and epidermoid cancer.

This invention also relates to methods of producing intermediates which can be converted into the above derivative isothiazole and to the resulting intermediate compounds. Methods of obtaining derivatives isothiazole and their intermediate compounds described in international patent is ublications WO 99/62890, published December 9, 1999 and U.S. patent No. 6235764; 6380214 and 6548526, issued may 22, 2001, 30 April 2002 and 15 April 2003, respectively. Methods of obtaining 3-aloxiprin isothiazole as herbicides are described in U.S. patent No. 4059433, issued November 22, 1977. Methods of obtaining 5-amino-3-hydroxy(alkoxy,-amino)isothiazol described in Chemische Berichte (1964), 97(11), 3106-17.

The invention

The present invention relates to a method for obtaining compounds of formula I

or its pharmaceutically acceptable salt, procarcinogen tools, hydrate or MES; where

R1represents H, C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, -C(O)(C1-C10alkyl), -(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compound), -C(O)(CH2)t(C6-C10aryl), or-C(O)(CH2)t(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R1not necessarily related to Csub> 6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); and the above group, R1except H, are optionally substituted by 1 to 3 groups of R4;

R2selected from the list of substituents provided in the definition of R1, -SO2(CH2)t(C6-C10aryl), -SO2(CH2)t(4-10 membered heterocyclic compounds) and-OR5where t is an integer in the range from 0 to 5; and the above group, R2optionally substituted by 1 to 3 groups of R4;

or R1and R2you can take together with the nitrogen to which they are attached, to form a 4-10-membered saturated monocyclic or polycyclic ring or a 5-10 membered heteroaryl ring, where these saturated and heteroaryl rings, in addition to the nitrogen attached to R1and R2not necessarily , include 1 or 2 heteroatoms selected from O, S and-N(R6)-where indicated-N(R6)- does not necessarily represent =N - or-N=, where R1and R2taken together with the above heteroaryl group, where the specified saturated ring optionally may be partially unsaturated through the om include 1 or 2 double bonds in the carbon-carbon and these saturated and heteroaryl rings, including the group R6specified-N(R6)-, optionally substituted by 1 to 3 groups of R4;

R3represents H, C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, -(CH2)t(C6-C10aryl) or -(CH2)t(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R3not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); the group -(CH2)t- the above groups, R3optional include a double or triple bond carbon-carbon, t is an integer from 2 to 5 and the groups of R3optionally substituted by 1-5 groups R4;

each R4independently selected from halogen, C1-C10of alkyl, C2-C10alkenyl, C2-C10the quinil, nitro, trifloromethyl, triptoreline, azido-OR 5, -NR6C(O)OR5, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -S(O)jR7where j is an integer in the interval from 0 to 2, -NR5(CR6R7)tOR6, -(CH2)t(C6-C10aryl), -SO2(CH2)t(C6-C10aryl), -S(CH2)t(C6-C10aryl), -O(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compounds) and -(CR6R7)mOR6where m is an integer from 1 to 5 and t is an integer from 0 to 5; where this alkyl group optionally contains 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R4not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); and alkyl, aryl and heterocyclic groups of the above groups R4optionally substituted by 1-3 substituents, independently selected from the who and Jethro, trifloromethyl, triptoreline, azido, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -(CR6R7)mOR6where m is an integer from 1 to 5, -OR5and the substituents listed in the definition of R5;

each R5independently selected from H, C1-C10of alkyl, -(CH2)t(C6-C10aryl) and -(CH2)t(4-10 membered heterocyclic compounds), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R5not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; and the above substituents R5except H, are optionally substituted by 1-3 substituents, independently selected from nitro, trifloromethyl, triptoreline, azido, -NR6C(O)R7, -C(O)NR6R7, -NR6R7, hydroxy, C1-C6alkyl and C1-C6alkoxy; and

each R6and R7independently represents H or C1- 6alkyl;

comprising the reaction of compounds of formula II

where R8represents H, C1-C10alkyl, -C(O)(C1-C10alkyl), -C(O)(C6-C10aryl), -C(O)(4-10 membered heterocyclic compound), -(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compound), -C(O)O(C1-C10alkyl); -C(O)O(C6-C10aryl), -C(O)O(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where these aryl and heterocyclic groups, R8not necessarily related to C6-C10aryl group; and the above aryl and heterocyclic groups, R8optionally substituted with 1-2 substituents independently selected from halogen, trifloromethyl, C1-C6alkoxy, C1-C6the alkyl and nitro group; and R1, R2, R3, R4, R5, R6and R7are as defined above for the compounds of formula I, with a source of ammonia in a solvent to obtain compounds of formula I. the Reaction is preferably carried out at a temperature from about -50°C to about 150°C and pressures from about atmospheric pressure to about 200 psi, more preferably at a temperature of from about 50� C to about 70°C, from about 10 to about 40 psi, and even more preferably from about 30°C to about 50°C and about 45 to about 80 psi. The source of ammonia is preferably an anhydrous ammonia, but for the successful implementation of the invention, the source of ammonia is not important. Other non-limiting sources of ammonia include ammonium hydroxide, liquid ammonia, ammonium chloride, sodium amide and formamide.

The reaction is preferably carried out in the presence of a solvent, such as C1-C4alcohols (e.g. methanol, ethanol, propanol, 2-propanol), bipolar aprotic solvents (e.g. dimethylsulfoxide, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidinone), ethers (e.g. tetrahydrofuran, diisopropyl ether, methyl-tert-butyl ether, dioxane, 2-methyltetrahydrofuran), water or a mixture of at least two of them. Especially preferred tetrahydrofuran and methanol or mixtures thereof.

One of the embodiments of the present invention relates to such methods m and compounds, where R2represents H, and R1represents a C1-C10alkyl, optionally substituted by 1 or 2 substituents, independently selected from-NR5R6, -NR5(CR6 7)tOR6and -(CH2)t(4-10 membered heterocyclic compounds), where t is an integer from 0 to 5. In another embodiment, R1selected from propyl, butyl, pentile and exile and optionally may be substituted by dimethylamino, hydroxy, pyrrolidinyl, morpholino and ethyl-(2-hydroxyethyl)amino, and R2represents H.

In another embodiment, R2represents H, and R1represents -(CH2)t(4-10 membered heterocyclic compound), where t is an integer from 0 to 5 specified heterocyclic group optionally associated with C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10-membered heterocyclic group, and R1including any related part of the specified group R1may be substituted by 1 or 2 substituents, independently selected from C1-C4the alkyl, hydroxy and hydroxymethyl.

In another embodiment, R2represents H, 4-10-membered heterocyclic group group R1when the variable t group R1is in the range from 2 to 5, may be any of morpholino, pyrrolidinyl, imidazolyl, piperazinil, piperidinyl and 2,5-diazabicyclo[2,2,1]hept-2-yl, and R1neobyazatelnostyu hydroxy, the hydroxymethyl and stands.

One of the embodiments of the present invention relates to such methods and compounds where R3represents -(CH2)t(C6-C10aryl), where t is an integer from 1 to 3, and R3optionally substituted by 1-4 groups R4. In another embodiment, R3represents benzyl, optionally substituted by 1-4 halogen substituents.

In a preferred embodiment, the present invention relates to such methods and compounds where R2represents H, R1represents -(CH2)4-1-pyrrolidin, R3represents a 2,6-debtor-4-bromobenzyl, and R8represents methyl. Preferably, in this embodiment, the compound of formula II is subjected to interaction with anhydrous ammonia in methanol at a temperature of from 50°C to 70°C at a pressure of from 10 to 40 psi. In this embodiment, even more preferably, the compound of formula II is subjected to interaction with anhydrous ammonia in methanol and tetrahydrofuran at a temperature of from 30°C to 50°C at a pressure of from 45 to 80 psi.

Another variant of implementation of the present invention relates to such methods, where the compound of formula I selected from the group consisting of am is Yes 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido}isothiazol-4-carboxylic acid;

amide 5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-(3-{4-[ethyl-(2-hydroxyethyl)amino]butyl}ureido)isothiazol-4-carboxylic acid;

amide 3-(2-fluoro-4-methylbenzylamino)-5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,5-debtor-4-methylbenzylamino)-5-(3-4-[4-(2-hydroxyethyl)piperazine-1-yl]butyl}ureido)isothiazol-4-carboxylic acid;

amide 3-(2,5-debtor-4-methylbenzylamino)-5-[3-(6-dimethylaminomethyl)ureido]isothiazol-4-carboxylic acid;

amide 3-(2-fluoro-4-methylbenzylamino)-5-[3-(5-isopropylaminomethyl)ureido]isothiazol-4-carboxylic acid;

salts of hydrochloric acid amide 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-{3-[(1-(methylpyrrolidine-2-yl)ethyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-[3-{4-[4-(2-hydroxyethyl)piperazine-1-yl]butyl}ureido)isothiazol-karbonovoi acid;

amide 3-(4-chloro-2,6-deferasirox)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)pentyl)ureido}isothiazol-4-carboxylic acid;

amide 3-(2,5-debtor-4-methylbenzylamino)-5-{3-[4-(3,4-dihydroxypyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-{3-[4-(3,4-dihydroxypyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,5-debtor-4-methylbenzylamino)-5-{3-[4-(2-hydroxyethylpyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-{3-[4-(2-hydroxyethylpyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,5-debtor-4-methylbenzylamino)-5-{3-[4-(3-hydroxypyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(4-hydroxy-5-piperidine-1-alpental)ureido]isothiazol-4-carboxylic acid;

amide 3-(2,5-debtor-4-methylbenzylamino)-5-{3-[4-(3-hydroxy-5-piperidine-1-alpental)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-{3-[4-(2-hydroxyethylpiperazine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,5-debtor-4-methylbenzylamino)-5-(3-{4-[ethyl-(2-hydroxyethyl)amino]butyl}ureido)isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-[-(5-hydroxy-6-piperidine-1-yl)hexyl)ureido}isothiazol-4-carboxylic acid;

amide 3-(4-bromo-2,3,6-triptoreline)-5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-{3-[3-(4-methylpiperazin-1-ylpropyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(3-hydroxy-5-pyrrolidin-1-alpental)ureido]isothiazol-4-carboxylic acid;

amide 5-[3-(4-pyrrolidin-1-libutil)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(3-hydroxy-5-pyrrolidin-1-alpental)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-{3-[3-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)propyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,3,6-triptoreline)-5-{3-[3-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)propyl]ureido}isothiazol-4-carboxylic acid amide;

amide 3-(4-chloro-2,3,6-triptoreline)-5-{3-[2-(1-methylpyrrolidine-2-yl)ethyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,3,6-triptoreline)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,3,6-triptoreline)-5-{3-[4-(2-hydroxyethylpyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

amide 5-{3-[2-(1-methylpyrrolidine-2-yl)ethyl]ureido}-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(4-dimethylaminomethyl)ureido]3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(3-dimethylaminopropyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(3-hydroxy-5-isopropylaminomethyl)ureido]-3-(2)3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(3-isopropylaminomethyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-{3-[4-(4-methylpiperazin-1-yl)butyl]ureido}-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-(3-{4-[4-(2-hydroxyethyl)piperazine-1-yl]butyl}ureido)-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(3-pyrrolidin-1-ylpropyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(4-hydroxy-5-piperidine-1-alpental)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-[3-(4-imidazol-1-libutil)ureido]isothiazol-4-carboxylic acid;

amide 5-(3-{4-[ethyl-(2-hydroxyethyl)amino]butyl}ureido)-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 3-(4-chloro-(2,3,6-triptoreline)-5-{3-[4-(2-hydroxyethylpiperazine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,3,6-triptoreline)-5-[3-(3-hydroxy-5-pyrrolidin-1-alpental)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-bromo-2,6-deferasirox)-5-{3-[3-(4-methylpiperazin-1-yl)p is filing]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-{3-[2-(1-methylpyrrolidine-2-yl)ethyl]ureido}isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(4-dimethylaminomethyl)ureido}isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(3-dimethylaminopropyl)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-bromo-2,3,6-triptoreline)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,3,6-triptoreline)-5-[3-(4-imidazol-1-libutil)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,3,6-deferasirox)-5-(3-{3-[ethyl-(2-hydroxyethyl)amino]propyl}ureido)isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,3,6-triptoreline)-5-(3-{3-[ethyl-(2-hydroxyethyl)amino]propyl}ureido)isothiazol-4-carboxylic acid;

amide 5-[3-(3-methylaminopropyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(3-aminopropyl)-3-methylurea]-3-(2,3)6 trifter-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 5-[3-(4-diethylaminomethyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

amide 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(3-pyrrolidin-1-ylpropyl)ureido]isothiazol-4-carboxylic acid;

amide 3-(3-chloro-2,6-debtor-4-methylbenzylamino)-5-[3-(4-dimethylaminomethyl)ureido]isothiazol-4-carboxylic acid;

amide 5-(3-{4-[bis-(2-Ki is axetil)amino]butyl}ureido)-3-(2,6-debtor-4-methylbenzoate)isothiazol-4-carboxylic acid;

and pharmaceutically acceptable salts, prodrugs, the hydrates and the solvate of such compounds.

In a particularly preferred embodiment, the present invention relates to such methods, where the compound of formula I is an amide 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil]ureido}isothiazol-4-carboxylic acid and its pharmaceutically acceptable salts, proletarienne tools, hydrate and solvate.

The present invention also relates to a method for obtaining compounds of formula II

or its pharmaceutically acceptable salt;

R1, R2, R3, R4, R5, R6, R7and R8are as defined above for formula I; includes (1) the reaction of compounds of formula IV

where R3, R4, R5, R6, R7and R8are as defined above for formula II, with the source of the carbonyl, with the addition of a base or without him, and then adding the compounds of formula III

HNR1R2III

where R1and R2are as defined above for formula II in a solvent to obtain compounds of formula II or (2) the reaction of compounds of formula III with a source of carbonyl, with the addition of a base or without it; and then it is time to relax is of the compounds of formula IV in a solvent to obtain compounds of formula II.

Source carbonyl may be any suitable source of carbonyl, well-known experts in this field. In one embodiment, the implementation of the source of carbonyl represented by the formula

R OCOX'

where R' represents a C1-C4alkyl or C6-C10aryl, and X' represents a leaving group such as chlorine. Alternatively, other non-limiting examples of suitable sources of carbonyl include 1,1'-carbonyldiimidazole, di-tert-BUTYLCARBAMATE in the presence of 4-dimethylaminopyridine and phosgene or its equivalents, such as diphosgene or triphosgene.

The reaction can be conducted at a temperature from about -78°C to about 100°C, and preferably from about 15°C to about 25°C.

In response, you can use any suitable base, known to specialists in this field. Non-limiting examples of suitable bases include tertiary amines (e.g. triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine), carbonates of alkali metals and hydrogen carbonates of alkali metals.

The reaction may occur in any suitable solvent known to specialists in this field. Preferably, the reaction is carried out in the presence of a halogenated hydrocarbon solvent such as dichloro is h or chloroform; simple ether, such as tetrahydrofuran, diisopropyl ether, methyl-tert-butyl ester and 2-methyltetrahydrofuran; bipolar aprotic solvent such as dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidinone and dimethylacetamide, and mixtures thereof.

In a preferred embodiment, the compound of formula IV is treated with triphosgene and triethylamine in dichloromethane at a temperature from about -78°C to about 20°C, then add the compound of formula III, preferably the compound of formula III, where R1represents H, and R2represents -(CH2)4-1-pyrrolidino, obtaining the compounds of formula II.

In a more preferred embodiment, the present invention relates to such methods, where the compound of formula II represents a methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid.

In a more preferred embodiment, the compound of formula III, where R1represents H, and R2represents -(CH2)4-1-pyrrolidin treated with 1,1'-carbonyl diimidazol in tetrahydrofuran at a temperature from about -10°C to about 10°C with the product, which is added to the compound of formula IV in dimethyl sulfoxide is the potassium carbonate at a temperature of from about 15° C to about 25°C, to obtain the compounds of formula II, which preferably is a methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid.

Another variant of implementation of the present invention relates to such methods, where the compound of formula II selected from the group consisting of methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido}isothiazol-4-carboxylic acid;

methyl ester 5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-(3-{4-[ethyl-(2-hydroxyethyl)amino]butyl}ureido)isothiazol-4-carboxylic acid;

methyl ester 3-(2-fluoro-4-methylbenzylamino)-5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,5-debtor-4-methylbenzylamino)-5-(3-4-[4-(2-hydroxyethyl)piperazine-1-yl]butyl}ureido)isothiazol-4-carboxylic acid;

methyl ester of 3-(2,5-debtor-4-methylbenzylamino)-5-[3-(6-dimethylaminomethyl)ureido]isothiazol-4-carboxylic acid;

methyl ester 3-(2-fluoro-4-methylbenzylamino)-5-[3-(5-isopropylaminomethyl)ureido]isothiazol-4-carboxylic acid;

salts of hydrochloric acid methyl ester 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido}isothiazol the-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-{3-[(1-(methylpyrrolidine-2-yl)ethyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-[3-{4-[4-(2-hydroxyethyl)piperazine-1-yl]butyl}ureido)isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)pentyl)ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,5-debtor-4-methylbenzylamino)-5-{3-[4-(3,4-dihydroxypyrrolidine-1-yl]butyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-{3-[4-(3,4-dihydroxypyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,5-debtor-4-methylbenzylamino)-5-{3-[4-(2-hydroxyethylpyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-{3-[4-(2-hydroxyethylpyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,5-debtor-4-methylbenzylamino)-5-{3-[4-(3-guide oxopyrrolidin-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil]ureido}isothiazol-4 - carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(4-hydroxy-5-piperidine-1-alpental)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(2,5-debtor-4-methylbenzylamino)-5-{3-[4-(3-hydroxy-5-piperidine-1-alpental)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-{3-[4-(2-hydroxyethylpiperazine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,5-debtor-4-methylbenzylamino)-5-(3-{4-[ethyl-(2-hydroxyethyl)amino]butyl}ureido)isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-[3-(5-hydroxy-6-piperidine-1-yl)hexyl)ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-bromo-2,3,6-triptoreline)-5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-{3-[3-(4-methylpiperazin-1-ylpropyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(3-hydroxy-5-pyrrolidin-1-alpental)ureido]isothiazol-4'-carboxylic acid;

methyl ester 5-[3-(4-pyrrolidin-1-libutil)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(3-hydroxy-5-pyrrolidin-1-alpental)ureido]-3-(2,3,-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-{3-[3-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)propyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,3,6-triptoreline)-5-{3-[3-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)propyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,3,6-triptoreline)-5-{3-[2-(1-methylpyrrolidine-2-yl)ethyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,3,6-triptoreline)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,3,6-triptoreline)-5-{3-[4-(2-hydroxyethylpyrrolidine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

methyl ester 5-{3-[2-(1-methylpyrrolidine-2-yl)ethyl]ureido}-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(4-dimethylaminomethyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(3-dimethylaminopropyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(3-hydroxy-5-isopropylaminomethyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(3-isopropylaminomethyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-{3-[4-(4-methylpiperazin-1-yl)butyl]wreid the}-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-(3-{4-[4-(2-hydroxyethyl)piperazine-1-yl]butyl}ureido,)-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(3-pyrrolidin-1-ylpropyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(4-hydroxy-5-piperidine-1-alpental)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-[3-(4-imidazol-1-libutil)ureido]isothiazol-4-carboxylic acid;

methyl ester 5-(3-{4-[ethyl-(2-hydroxyethyl)amino]butyl}ureido)-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-(2,3,6-triptoreline)-5-{3-[4-(2-hydroxyethylpiperazine-1-yl)butyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,3,6-triptoreline)-5-[3-(3-hydroxy-5-pyrrolidin-1-alpental)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(4-bromo-2,6-deferasirox)-5-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-{3-[2-(1-methylpyrrolidine-2-yl)ethyl]ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(4-dimethylaminomethyl)ureido}isothiazol-4-carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(3-dimethylamino who drank)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(4-bromo-2,3,6-triptoreline)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,3,6-triptoreline)-5-[3-(4-imidazol-1-libutil)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,3,6-deferasirox)-5-(3-{3-[ethyl-(2-hydroxyethyl)amino]propyl}ureido)isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,3,6-triptoreline)-5-(3-{3-[ethyl-(2-hydroxyethyl)amino]propyl}ureido)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(3-methylaminopropyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(3-aminopropyl)-3-methylurea]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester 5-[3-(4-diethylaminomethyl)ureido]-3-(2,3,6-Cryptor-4-methylbenzoate)isothiazol-4-carboxylic acid;

methyl ester of 3-(2,6-debtor-4-methylbenzylamino)-5-[3-(3-pyrrolidin-1-ylpropyl)ureido]isothiazol-4-carboxylic acid;

methyl ester 3-(3-chloro-2,6-debtor-4-methylbenzylamino)-5-[3-(4-dimethylaminomethyl)ureido]isothiazol-4-carboxylic acid;

methyl ester 5-(3-{4-[bis-(2-hydroxyethyl)amino]butyl}ureido)-3-(2,6-debtor-4-methylbenzoate)isothiazol-4-carboxylic acid;

and their pharmaceutically acceptable salts.

The present invention also relates to a method of obtaining the unity formula IV

or its pharmaceutically acceptable salts; where R3, R4, R5, R6, R7and R8are as defined above;

comprising the reaction of compounds of formula V

where

R3, R4, R5, R6, R7and R8are as defined above; R9represents a C1-C10alkyl, C6-C10aryl, 4-10 membered heterocyclic compound, where these aryl and heterocyclic groups, R9not necessarily related to C6-C10aryl group; and the above aryl and heterocyclic groups, R9optionally independently substituted with 1-2 substituents independently selected from halogen, trifloromethyl, C1-C6alkoxy, C1-C6the alkyl and nitro group; and

n represents 0, 1 or 2;

with a source of ammonia in a solvent to obtain compounds of formula IV. The reaction is preferably carried out at a temperature from about -50°C to about 150°C and pressures from about atmospheric pressure to about 200 psi, more preferably at a temperature of from about 20°C to about 60°C is from about atmospheric pressure to about 50 psi, is even more preferably at a temperature of from about 40°C to about 50°C and approximately 45-55 psi. The source of ammonia is preferably an anhydrous ammonia, but for the successful implementation of the invention, the source of ammonia is not important. Other non-limiting sources of ammonia include ammonium hydroxide and liquid ammonia.

The reaction is preferably carried out in the presence of a solvent, such as water, C1-C4alcohols (e.g. methanol, ethanol, propanol, isopropanol), ethers (e.g. tetrahydrofuran, diisopropyl ether, methyl-tert-butyl ether, dioxane, 2-methyltetrahydrofuran) and bipolar aprotic solvents (e.g. dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidinone and dimethylacetamide).

One of the embodiments of the present invention relates to such methods, where the compound of formula V is subjected to the interaction of the source of ammonia in a solvent to obtain compounds of formula IV where R3represents -(CH2)t(C6-C10aryl), where t is an integer from 1 to 3 and R3optionally substituted by 1-4 groups R4. In another embodiment, R3represents benzyl, optionally substituted by 1-4 halogen substituents.

In a preferred embodiment, the OS is implement the present invention relates to such methods where the compound of formula V is subjected to interaction with a source of ammonia in a solvent to obtain compounds of formula IV, where R3represents a 2,6-debtor-4-bromobenzyl, R8represents methyl, R9represents methyl; and n represents 2. Preferably, in this embodiment, the compound of formula V is subjected to interaction with anhydrous ammonia in methanol or dimethylsulfoxide at a temperature of from 20°C to 60°C at a pressure of from atmospheric pressure to 50 psi. Even more preferably, in this embodiment, the compound of formula V is subjected to interaction with anhydrous ammonia in tetrahydrofuran and preferably approximately at a temperature of from 40°C to about 50°C at a pressure of from 45 to 55 psi.

In a particularly preferred embodiment, the present invention relates to such methods, where the compound of formula IV represents a methyl ester of 5-amino-3-(4-bromo-2,6-deferasirox)isothiazol-4-carboxylic acid.

The present invention also relates to a method for obtaining compounds of formula V

or its pharmaceutically acceptable salt;

R3, R4, R5, R6, R7, R8and R9are as defined above; and

n PR is dstanley a 0, 1 or 2;

comprising the reaction of compounds of formula VII

where n, R8and R9are as defined above, with a compound of formula VI

R3XVI

where R3is as defined above and X represents halogen, such as chlorine, bromine or iodine; hydroxyl; ester C1-C4alkylsulfonate; ester arylsulfonate, such as toilet, nosrat, besylate or brasilit; or imidate, such as trichlorethylene in the presence of acid, base or reagents, Mitsunobu R'3P and R"OC(O)N=NC(O)OR", where each R' and R" independently represents a C1-C4alkyl or C6-C10aryl, and where these alkyl and aryl groups R' and R" optionally substituted by 1 to 3 groups of R10;

R10represents a C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, nitro, trifluoromethyl, triptoreline, -OR5, -NR6C(O)OR5, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -S(O)jR7where j is an integer in the interval from 0 to 2, -NR5(CR6R7)tOR6, -(CH2)t(C6-C10aryl), -SO2(CH2)t(C6-C10aryl), -S(CH2)t(C6-C10 aryl), -O(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compound) and -(CR6R7)mOR6where m is an integer from 1 to 5 and t is an integer in the range from 0 to 5; where the specified C1-C10the alkyl group optionally contains 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where specified -(CH2)t(C6-C10aryl), -SO2(CH2)t(C6-C10aryl), -S(CH2)t(C6-C10aryl), -O(CH2)t(C6-C10aryl) and -(CH2)t(4-10 membered heterocyclic) group is not necessarily associated with C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); and alkyl, aryl and heterocyclic groups of the above groups R10optionally substituted by 1-3 substituents, independently selected from nitro, trifloromethyl, triptoreline, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -(CR6 R7)mOR6where m is an integer from 1 to 5, -OR5and the substituents listed in the definition of R5where R5, R6and R7are as defined above, with the proviso that R5, R6and R7cannot represent H, in a solvent to obtain compounds of formula V. When X is a halogen or ester sulfonate, as a rule, use the base. Non-limiting examples of suitable bases include carbonates of alkali metals, hydroxides of alkali metals, carbonates of alkaline earth metals, hydroxides of alkaline earth metals, C1-C4alkoxides of alkali metals, hydrides of alkali metals and Quaternary amines, such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene ("DBU) and 1,5-diazabicyclo[4,3,0]non-5-ene ("DBN"). When X is imidate, as a rule, use acid. Non-limiting examples include inorganic acids such as hydrochloric acid and sulfuric acid, acid Bronsted, such as triperoxonane acid or a Lewis acid such as trimethylsilyltrifluoromethane, chlorides of transition metals (e.g., SnCl4, TiCl4), apirat BF3and triflate lanthanides (for example, Sc(OTf)3and Ln(OTf)3). When X represents hydroc the sludge, preferably use reagents, Mitsunobu R'3P and R"OC(O)OR". Preferred reagents are, where R' represents a C1-C4alkyl or C1-C4aryl, and R" represents a C1-C4alkyl or C1-C4aryl. Preferred reagents, where R' represents a phenyl, and R" is ethyl or isopropyl.

The reaction can be conducted at a temperature of from about -20°C to about 100°C, and preferably from about 15°C to about 35°C.

The reaction is preferably carried out in the presence of a solvent. Preferably, when X is a halogen, sulfonate or hydroxyl solvent is a halogenated hydrocarbon solvent such as dichloromethane or chloroform, a simple ether, such as tetrahydrofuran, diisopropyl ether, methyl-tert-butyl ether, dioxane or 2-methyltetrahydrofuran or bipolar aprotic solvent, such as dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidinone or dimethylacetamide. Preferably, when X is imidate, the solvent is a polar solvent, such as nitromethane, acetonitrile or 2,2,2-triptorelin or halogenated hydrocarbon solvent, such as dichloromethane or chlorof the RM.

The preferred implementation of the present invention relates to such methods, where the compound of formula VII is subjected to interaction with the compound of the formula VI in which X represents an ester arylsulfonate, bipolar aprotic solvent with a base in the form of a carbonate of an alkali metal to obtain the compounds of formula V. Especially preferably, when R3represents a 2,6-debtor-4-bromobenzyl; X represents an ester of p-toluensulfonate; R8represents methyl; R9represents methyl; n is 2; a base in the form of carbonate of alkali metal is potassium carbonate; and the solvent is a sulfoxide. This preferred reaction can be conducted at a temperature of from about 15°C to about 35°C.

In a particularly preferred embodiment, the present invention relates to such methods, where the compound of formula V is a methyl ester of 3-(4-bromo-2,6-deferasirox)-5-methanesulfonamido-4-carboxylic acid.

The invention also relates to compounds of formula IIa, IVa, or Va, suitable for obtaining derivatives isothiazole formula I, in turn, is suitable for binding and modulation of receptor KDR/FLK-1.

The present invention otnositsa to the compound of formula IIa

or its pharmaceutically acceptable salt;

R1represents H, C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, -C(O)(C1-C10alkyl), -(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compound), -C(O)(CH2)t(C6-C10aryl), or-C(O)(CH2)t(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R1not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); and the above group, R1except H, are optionally substituted by 1 to 3 groups of R4;

R2selected from the list of substituents provided in the definition of R1, -SO2(CH2)t(C6-C10aryl), -SO2(CH2)t(4-10 membered heterocyclic connection is drop-and-OR 5where t is an integer in the range from 0 to 5; and the above group, R2optionally substituted by 1 to 3 groups of R4;

or R1and R2you can take together with the nitrogen to which they are attached, to form a 4-10-membered saturated monocyclic or polycyclic ring or a 5-10 membered heteroaryl ring, where these saturated and heteroaryl rings, in addition to the nitrogen attached to R1and R2not necessarily , include 1 or 2 heteroatoms selected from O, S and-N(R6)-where indicated-N(R6)- does not necessarily represent =N - or-N=, where R1and R2taken together with the above heteroaryl group, where the specified saturated ring optionally may be partially unsaturated by including 1 or 2 double bonds in the carbon-carbon and these saturated and heteroaryl rings, including the group R6specified-N(R6)-, optionally substituted by 1 to 3 groups of R4;

R3represents H, C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, -(CH2)t(C6-C10aryl) or -(CH2)t(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup, is selected from O, S, and-N(R6)-, with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R3not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); the group -(CH2)t- the above groups, R3optional include a double or triple bond carbon-carbon, t is an integer from 2 to 5 and the groups of R3optionally substituted by 1-5 groups R4;

each R4independently selected from halogen, C1-C10of alkyl, C2-C10alkenyl, C2-C10the quinil, nitro, trifloromethyl, triptoreline, azido, -OR5, -NR6C(O)OR5, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -S(O)jR7where j is an integer in the interval from 0 to 2, -NR5(CR6R7)tOR6, -(CH2)t(C6-C10aryl), -SO2(CH2)t(C6-C10aryl), -S(CH2)t(C6-C10aryl), -O(CH2)t(C6-C10aryl), -(CH )t(4-10 membered heterocyclic compound) and -(CR6R7)mOR6where m is an integer from 1 to 5 and t is an integer from 0 to 5; where this alkyl group optionally contains 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R4not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); and alkyl, aryl and heteroaryl groups of the above groups R4optionally substituted by 1-3 substituents, independently selected from nitro, trifloromethyl, triptoreline, azido, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -(CR6R7)mOR6where m is an integer from 1 to 5, -OR5and the substituents listed in the definition of R5;

each R5independently selected from H, C1-C10of alkyl, -(CH2)t(C6-C10aryl) and -(CH2)t(4-10-membered heterocyclic the who connection) where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that 2 of the O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R5not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; and the above substituents R5except H, are optionally substituted by 1-3 substituents, independently selected from nitro, trifloromethyl, triptoreline, azido, -NR6C(O)R7, -C(O)NR6R7, -NR6R7, hydroxy, C1-C6alkyl and C1-C6alkoxy;

each R6and R7independently represents H or C1-C6alkyl; and

R8represents H, C1-C10alkyl, -C(O)(C1-C10alkyl), -C(O)(C6-C10aryl), -C(O)(4-10 membered heterocyclic compound), -(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compound), -C(O)O(C1-C10alkyl); -C(O)O(C6-C10aryl), -C(O)O(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where these aryl and heterocyclic groups which R 8not necessarily related to C6-C10aryl group; and the above aryl and heterocyclic groups, R8optionally substituted with 1-2 substituents independently selected from halogen, trifloromethyl, C1-C6alkoxy, C1-C6the alkyl and nitro group with the proviso that R8is not ethyl when R1represents H, R2is pyrrolidin-1-rbutil and R3represents a C1-C3alkyl.

One of the embodiments of the present invention relates to compounds of formula IIa, where R2represents H, and R1represents a C1-C10alkyl, optionally substituted by 1 or 2 substituents, independently selected from-NR5R6, -NR5(CR6R7)tOR6and -(CH2)t(4-10 membered heterocyclic compounds), where t is an integer in the range from 0 to 5. In another embodiment, R1selected from propyl, butyl, pentile and exile and optionally may be substituted by dimethylamino, hydroxy, pyrrolidinyl, morpholino and ethyl-(2-hydroxyethyl)amine, and R2represents H.

In another embodiment, the present invention relates to compounds of formula IIa, where R2represents H, and R1the stand is made by a -(CH 2)t(4-10 membered heterocyclic compound), where t is an integer from 0 to 5 specified heterocyclic group optionally associated with C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10-membered heterocyclic group, and R1including any related part of the specified group R1may be substituted by 1 or 2 substituents, independently selected from C1-C4the alkyl, hydroxy and hydroxymethyl. Preferably, in this embodiment, 4-10-membered heterocyclic compound of R1selected from one of morpholino, pyrrolidinyl, imidazolyl, piperazinil, piperidinyl and 2,5-diazabicyclo[2,2,1]hept-2-yl, and R1optionally substituted by hydroxy, hydroxymethyl and stands, and the variable t group R1is in the range from 2 to 5.

One of the embodiments of the present invention relates to compounds of formula IIa, where R3represents -(CH2)t(C6-C10aryl), where t is an integer from 1 to 3, and R3optionally substituted by 1-4 groups R4. Preferably, in this embodiment, R3represents benzyl, optionally substituted by 1-4 halogen substituents.

In a preferred embodiment, assests the deposits present invention relates to compounds of formula IIa, where R2represents H, R1represents -(CH2)4-1-pyrrolidin, R3represents a 2,6-debtor-4-bromobenzyl, and R8represents methyl.

Another variant of implementation of the present invention relates to compounds of formula IVa

or its pharmaceutically acceptable salt;

R3represents H, C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, -(CH2)t(C6-C10aryl) or -(CH2)t(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R3not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); the group -(CH2)t- the above groups, R3optional include a double or triple bond carbon-carbon, t is a t the white number from 2 to 5 and the groups of R 3optionally substituted by 1-5 groups R4;

each R4independently selected from halogen, C1-C10of alkyl, C2-C10alkenyl, C2-C10the quinil, nitro, trifloromethyl, triptoreline, azido, -OR5, -NR8C(O)OR5, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -S(O)jR7where j is an integer in the interval from 0 to 2, -NR5(CR6R7)tOR6, -(CH2)t(C6-C10aryl), -SO2(CH2)t(C6-C10aryl), -S(CH2)t(C6-C10aryl), -O(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compounds) and -(CR6R7)mOR6where m is an integer from 1 to 5 and t is an integer from 0 to 5; where this alkyl group optionally contains 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R4not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 atom operadas the above heterocyclic groups optionally substituted by oxopropoxy (=O); and alkyl, aryl and heteroaryl groups of the above groups R4optionally substituted by 1-3 substituents, independently selected from nitro, trifloromethyl, triptoreline, azido, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -(CR6R7)mOR6where m is an integer from 1 to 5, -OR5and the substituents listed in the definition of R5;

each R5independently selected from H, C1-C10of alkyl, -(CH2)t(C6-C10aryl) and -(CH2)t(4-10 membered heterocyclic compounds), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R5not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; and the above substituents R5except H, are optionally substituted by 1-3 substituents, independently selected from nitro, trifloromethyl, triptoreline, azido, -NR6C(O)R7, -C(O)NR6R7, -NR6 R7, hydroxy, C1-C6the alkyl and C1-C6alkoxy;

each R6and R7independently represents H or C1-C6alkyl; and

R8represents H, C1-C10alkyl, -C(O)(C1-C10alkyl), -C(O)(C6-C10aryl), -C(O)(4-10 membered heterocyclic compound), -(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compound), -C(O)O(C1-C10alkyl); -C(O)O(C6-C10aryl), -C(O)O(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where these aryl and heterocyclic groups, R8not necessarily related to C6-C10aryl group; and the above aryl and heterocyclic groups, R8optionally substituted with 1-2 substituents independently selected from halogen, trifloromethyl, C1-C6alkoxy, C1-C6the alkyl and nitro group with the proviso that R8is not ethyl when R3represents a C1-C3alkyl.

In a preferred compound of formula IVa, R3represents -(CH2)t(C6-C10aryl), where t is an integer from 1 to 3, and R3optionally substituted by 1-4 groups R4and more preferably R3represents benzyl, substituted 14 halogen substituents.

In a preferred embodiment, the present invention relates to compounds of formula IVa wherein R3represents a 2,6-debtor-4-bromobenzyl, and R8represents methyl.

Another variant of implementation of the present invention relates to compounds of formula Va

or its pharmaceutically acceptable salt;

R3represents a C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, -(CH2)t(C6-C10aryl) or -(CH2)t(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R3not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); the group -(CH2)t- the above groups, R3optional include a double or triple bond carbon-carbon t presented yet an integer from 2 to 5, and the above group, R3optionally substituted by 1-5 groups R4;

each R4independently selected from halogen, C1-C10of alkyl, C2-C10alkenyl, C2-C10the quinil, nitro, trifloromethyl, triptoreline, azido, -OR5, -NR6C(O)OR5, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -S(O)jR7where j is an integer in the interval from 0 to 2, -NR5(CR6R7)tOR6, -(CH2)t(C6-C10aryl), -SO2(CH2)t(C6-C10aryl), -S(CH2)t(C6-C10aryl), -O(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compounds) and -(CR6R7)mOR6where m is an integer from 1 to 5 and t is an integer in the range from 0 to 5; where this alkyl group optionally contains 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R4not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10-membered, heterocycle eskay group; where 1 or 2 carbon atoms in the above-mentioned heterocyclic groups optionally substituted by oxopropoxy (=O); and alkyl, aryl and heterocyclic groups of the above groups R4optionally substituted by 1-3 substituents, independently selected from nitro, trifloromethyl, triptoreline, azido, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -(CR6R7)mOR6where m is an integer from 1 to 5, -OR5and the substituents listed in the definition of R5;

each R5independently selected from H, C1-C10of alkyl, -(CH2)t(C6-C10aryl) and -(CH2)t(4-10 membered heterocyclic compounds), where t is an integer from 0 to 5; where this alkyl group optionally includes 1 or 2 heterogroup selected from O, S and-N(R6)- with the proviso that two O atom, two atoms, S or O atom and S atom are not directly connected with each other; where these aryl and heterocyclic groups, R5not necessarily related to C6-C10aryl group, a C5-C8saturated cyclic group, or a 4-10 membered heterocyclic group; and the above substituents R5except H, are optionally substituted by 1-3 substituents, independently researched the Simo selected from nitro, trifloromethyl, triptoreline, azido, -NR6C(O)R7, -C(O)NR6R7, -NR6R7, hydroxy, C1-C6the alkyl and C1-C6alkoxy;

each R6and R7independently represents H or C1-C6alkyl;

R8represents H, C1-C10alkyl, -C(O)(C1-C10alkyl), -C(O)(C6-C10aryl), -C(O)(4-10 membered heterocyclic compound), -(CH2)t(C6-C10aryl), -(CH2)t(4-10 membered heterocyclic compound), -C(O)O(C1-C10alkyl); -C(O)O(C6-C10aryl), -C(O)O(4-10 membered heterocyclic compound), where t is an integer from 0 to 5; where these aryl and heterocyclic groups, R8not necessarily related to C6-C10aryl group; and the above aryl and heterocyclic groups, R8optionally substituted with 1-2 substituents independently selected from halogen, trifloromethyl, C1-C6alkoxy, C1-C6the alkyl and nitro groups;

R9represents a C1-C10alkyl, C6-C10aryl, 4-10 membered heterocyclic compound, the aryl and heterocyclic groups, R9not necessarily related to C6-C10aryl group; and the above aryl and heterocyclic groups, R9optional independent is isimo substituted by 1-2 substituents, independently selected from halogen, trifloromethyl, C1-C6alkoxy, C1-C6the alkyl and nitro group; and

n represents 1 or 2.

In a preferred compound of formula Va, R3represents -(CH2)t(C6-C10aryl), where t is an integer from 1 to 3 and R3optionally substituted by 1-4 groups R4and more preferably R3represents benzyl, optionally substituted by 1-4 halogen substituents, even more preferably R8and R9represent methyl.

In an even more preferred embodiment, the present invention relates to compounds of formula Va, where n is 2, R3represents a 2,6-debtor-4-bromobenzyl, R8represents methyl and R9represents methyl.

In one of the embodiments, the compound of formula I, as defined earlier, get through the reaction of compounds of formula IIa with a source of ammonia in the solvent.

In another embodiment, the compound of formula II, as defined earlier, get through the reaction of compounds of formula IVa with a source of carbonyl-added basis, or without it, and then add the compounds of formula III, as defined previously, in a solvent, or alternatively, through the reactions the compound of formula III, source carbonyl-added basis, or without it, and then add the compounds of formula IVa in a solvent to obtain compounds of formula II.

In another embodiment, the compound of formula IV, as defined earlier, get through the reaction of compounds of formula Va with a source of ammonia in the solvent.

Unless otherwise specified, in this invention, the term "halogen" includes fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine and bromine.

As used herein, the term "alkyl", unless otherwise indicated, includes saturated monovalent hydrocarbon radical with unbranched, cyclic or branched structures. It is clear that for cyclic molecules for the specified alkyl group required at least three carbon atoms.

As used herein, the term "alkenyl", unless otherwise indicated, includes monovalent hydrocarbon radicals, at least one double bond carbon-carbon bonds, as well as with unbranched, cyclic or branched structures, as indicated above in the definition of "alkyl".

As used herein, the term "quinil", unless otherwise indicated, includes monovalent hydrocarbon radicals, at least one triple the ligature carbon-carbon and with unbranched, cyclic or branched structures, as indicated above in the definition of "alkyl".

As used herein, the term "alkoxy", unless otherwise indicated, includes O-alkyl groups, where "alkyl" is as defined above.

As used herein, the term "aryl", unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon with the removal of one hydrogen atom, such as phenyl or naphthyl.

As used herein, the term "heteroaryl", unless otherwise indicated, includes an organic radical formed by removal of one hydrogen atom from a carbon atom in the heteroaromatic ring hydrocarbon containing one or more heteroatoms independently selected from O, S, and N. Heteroaryl group must consist of at least 5 atoms in their ring system and is optionally independently substituted 0-2 atoms, halogen, trifluoromethyl, C1-C6alkoxy, C1-C6the alkyl or nitro groups.

As used herein, the term "4-10-membered heterocyclic compound", unless otherwise indicated, includes aromatic or nonaromatic heterocyclic group containing one or more heteroatoms, where each selected from O, S Is N, where the ring system each heterocyclic group consists of 4 to 10 atoms. Ring system non-aromatic heterocyclic groups include groups consisting of only 4 atoms of the ring system of aromatic heterocyclic groups must consist of at least 5 atoms. An example of a 4-membered heterocyclic group is azetidinol (formed from azetidine). Example 5-membered heterocyclic group is thiazolyl, and example 10-membered heterocyclic group is chinoline. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothieno, tetrahydropyranyl, tetrahydropyranyl, piperidino, morpholino, thiomorpholine, dioxane, piperazinil, azetidine, oxetane, titanyl, homopiperazine, oxetanyl, tepanil, oxazepines, diazepines, thiazepines, 1,2,3,6-tetrahydropyridine, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, dithienyl, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolidine, imidazoline, imidazolidinyl, 3-azabicyclo[3,1,0]hexenyl, 3-azabicyclo[4,1,0]heptenyl,3H-indolyl and finalizing. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetraza the sludge, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolin, pyrrolyl, chinoline, ethenolysis, indolyl, benzimidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properidine. The above group formed of the above compounds can be contacted with C or N, where possible. For example, a group formed from pyrrole can be a pyrrol-1-yl (associated with N) and pyrrol-3-yl (associated with C).

As used herein, the term "saturated cyclic group", unless otherwise indicated, includes non-aromatic, fully saturated, cyclic molecule, where alkyl is as defined above.

As used herein, the phrase "pharmaceutically acceptable salt(s)", unless otherwise indicated, includes salts of acidic or basic groups that may be represented in the compounds according to the invention. Compounds according to the invention, which in its basic nature, can form a wide variety of salts with various inorganic and organic acids. Acids which can be used to obtain farmaceuticas is acceptable acid additive salts of such basic compounds of the invention are acids, which form non-toxic acid additive salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride salt, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, Pantothenate, bitartrate, ascorbate, succinate, maleate, getitemat, fumarate, gluconate, glucuronate, saharat, format, benzoate, glutamate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-aftout)].

Compounds according to the invention, which are inherently acid, can form basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or salts of alkaline earth metals, especially sodium and potassium salts.

As used herein, the term "MES" includes the connection according to the invention or its salt, optionally containing a stoichiometric or non-stoichiometric amount of solvent bound non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and/or suitable for topical application in humans.

As used herein, the term "hydrate" refers to the connection izobreteniya its salts, optionally containing a stoichiometric or non-stoichiometric amount of water bound non-covalent intermolecular forces.

Some compounds of the present invention may contain centers of asymmetry and therefore exist in different enantiomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds according to the invention or their mixtures. Compounds according to the invention can also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.

The present invention also relates to labeled isotopes compounds and their pharmaceutically acceptable salts, which are identical to the compounds described by formulas I, II, IIa, IV, IVa, V, Va, except for the fact that one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number that is widespread in nature. Examples of isotopes that can be introduced into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N18O,17O,35S18F and36Cl, respectively. Compounds of the present invention, their proletarienne tools and pharmaceutically acceptable the haunted salts of these compounds or the above proletarienne funds which contain the aforementioned isotopes and/or other isotopes of other atoms are included in the scope of this invention. Some labeled isotopes of the compounds of the present invention, for example, which are introduced radioactive isotopes, such as3H and14C, suitable for analysis of tissue distribution of a drug and/or substrate. Particularly preferred isotopes tritium, i.e3H, and carbon-14, i.e14C, because of their easy access and instability. In addition, the replacement of heavier isotopes such as deuterium, i.e2H, can provide some therapeutic benefits, leading to greater metabolic stability, for example, increased time-life isin vivoor lower the required dose, and thus, in some circumstances, it may be preferred. Labeled with isotopes of the compounds of formula I according to this invention and their proletarienne means, as a rule, get through the procedures described in the schemes and/or examples and ways to get below replace isotope-labeled reagent on the reagent labeled with an easily accessible isotope.

The compounds of formula I with free amino groups, aminopropane, hydroxy groups or carboxyl groups can be converted into proletarienne funds. Proletarienne the resources include connections where with a free amino group, a hydroxy-group or carboxyl group of the compounds of formula I, amide or ether bond covalently linked amino acid residue or a polypeptide chain of two or more (e.g. two, three or four) amino acid residues. Amino acid residues include as non-limiting examples of the 20 naturally occurring amino acids, usually indicated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demazin, isodesmosine, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminomethane acid, citrulline, homocysteine, homoserine, ornithine and methanesulfonic.

Also covered additional types proletarienne funds. For example, of the free carboxyl groups can be used to form derivatives in the form of amides or esters with alkilani. Amide and ester groups can include groups, as non-limiting examples of which includes a functional group of simple ether, amine and carboxylic acid. Of the free hydroxy groups can be used to form derivatives with the use of groups, including as non-limiting examples hemisuccinate, phosphate esters, diethylaminoacetate and phosphorylethanolamine, as described in D. Fleisher, R. Bong, B. H. Stewart, Advanced Drug Delivery Reviews (1996) 19, 115. She is also included urethane proletarienne means of hydroxy - and amino-groups in the form of carbonate proletarienne funds and sulfate esters of hydroxy groups. Also involved in the formation of derivatives of hydroxy groups in the form (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group can be a complex alkyl ether optionally substituted by groups that include as non-limiting examples of functional groups of simple ether, amine and carboxylic acid, or where the acyl group is an ester of the amino acids as described above. Proletarienne tools of this type are described in R.P. Robinson et al., J. Medicinal Chemistry (1996) 39, 10.

Each of the patents, patent applications, published international applications and scientific publications to which reference is made in this patent application, incorporated herein by reference in full.

Detailed description of the invention

The compounds of formula I are suitable as means for binding and modulation of receptor KDR/FLK-1 and, therefore, suitable as treatment of hyperproliferative diseases, such as malignant tumors in mammals.

The method according to the present invention in the first aspect relates to the production of derivatives isothiazole formula I. the compounds of formula I can be obtained in accordance with the following scheme of reactions and discussion. Unless stated otherwise, R1, R2, R3, R4, R5, R6, R7, R , R9and R10the reaction scheme and discussion that follows are as defined above.

SCHEME 1

On the basis of scheme 1 above, the compound of the formula I can be obtained by processing complex diapir of malonate (XIII) the basis or carbon and sulfur (reaction a), followed by treatment with alkylating agent with obtaining (alkyl)sulfonylating anion (XI) (reaction b). Amination of (alkyl)sulfonylating anion electrophilic aminimum means leads to the formation of 5-(alkyl)sulfanilamide (VIII) (reaction c). Oxidation isothiazole (VIII) oxidant in a suitable solvent leads to the formation or 5-(alkyl)sulfonylation, when n=2; or 5-(alkyl)sulfanilamide, when n=1 (VII) (reaction d). Alternatively, isothiazol, VIII, can be protected with a suitable protecting group (ZG) to obtain the compounds of General formula X (reaction e), which can then be treated with an oxidant in a suitable solvent to obtain compounds of General formula IX (reaction f). Then with compounds of General formula IX can be removed protection with obtaining the compounds 5-(alkyl)sulfonyl (or sulfinil) isothiazole, VII. This mechanism is illustrated in scheme 2 below.

SCHEME 2

Returning to figure 1, the 5-(alkyl)sulfonyl/sulfenylation VII is treated with a compound of General formula R3X (VI), as a rule, in basic terms, getting isothiazole (V) now alkoxygroup in position three (3) isothiazole (reaction h). The reaction is particularly and unexpectedly effective when the compound VI is toilet and conditions include the base in a bipolar aprotic solvent. The reaction under these conditions occurs with unusually high selectivity O:N, where the alkylation takes place on the hydroxyl group, and not the nitrogen atom isothiazol rings. In suitable conditions, the selectivity O:N is approximately the ratio of the selectivity of O:N 35:1.

In the literature reported the alkylation of a variety of substituted 3-hydroxybenzothiazole. In all cases, the observed mixture of O - and N-alkyl products using a wide variety of electrophiles (alkylhalogenide, alkyl sulphates, diazomethane), solvents (water, acetone, DMSO, DMF, MeCN, DME) and bases (NaOH, K2CO3, Li2CO3Ag2CO3). For example, in Tetrahedron, 1970, (26), 2497-2506 reported on a comprehensive study of the alkylation of 3-hydroxybenzothiazole:

Additional references demonstrating reactions alkylated what I 3-hydroxybenzothiazole with low selectivity O:N include the following:

Stage alkylation (reaction h) in the method according to the present invention takes place with very high selectivity O:N, namely, approximately 35:1 for the conditions described in the experimental method of the seventh example (7), discussed below, which is much higher than the ratio of selectivity, published in the cited herein of the references.

Returning again to figure 1, alkoxycarbonyl isothiazol (V) is treated with a source of ammonia in a suitable solvent, converting the molecule sulfonyl/sulfinil in five (5) position isothiazole in the primary amine (IV) (reaction i). The compound of General formula IV can be subjected to interaction with a secondary amine and a source of carbonyl, with the added base or without it, in a suitable solvent to obtain compounds of General formula II, replacing the primary amine ureidopropionic in five (5) position isothiazole. The second treatment source of ammonia converts the ester of alkyl amide in obtaining compounds of General formula I.

Source materials used in scheme I, can be easily purchased in the sale or easily obtained well-known in the field of methods.

In each of the reactions discussed or illustrated in the diagrams, pressure, unless otherwise indicated, it is not important. Typically, a suitable pressure is from about 0.5 atmospheres to about 5 atmospheres, and in fact, for convenience, preferably ambient pressure, i.e. approximately 1 atmosphere.

Given below are examples and methods of obtaining additionally illustrate and provide examples of the compounds of the present invention, methods of making such compounds and methods of the present invention. It should be understood that the scope of the present invention is not limited to the scope of the following examples and ways to get. The following examples of molecules with one centre of chirality, if not indicated otherwise, are present in the form of racemic mixtures. Molecules with two or more centers of chirality, if not stated otherwise, are in the form of a racemic mixture of diastereomers. Individual enantiomers/diastereomers can be well-known to specialists in this field means.

The present invention is illustrated in the following examples. However, it should be understood that the invention is not limited to the specific details of the following examples.

EXAMPLE 1

Getting 2,2-bis-methoxycarbonyl-1-methylsulfonylmethane anion

In the chemical reactor was placed acetonitrile (240 ml, 6 volumes) followed by the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (2.1 equivalents, 96.8 g). The mixture was cooled to 5°C in the atmosphere is the monk. Within 10-15 minutes added diethylmalonate (1.0 equivalent, 40,0. The mixture was stirred for 30-45 minutes at 5°C. for 10-15 minutes added sulphur carbon (1.0 equivalent, 23.1 g), and then the mixture was stirred for 60-70 minutes at 5°C. for 10-15 minutes added dimethylsulfate (1.05 equivalent to 40.1 g), and then the mixture was stirred at 5°C for 16 hours. In conclusion, a mixture containing 2,2-bis-methoxycarbonyl-1-methylsulfonylmethane anion was heated to 25°C within 30 minutes and kept at 25°C for 1-2 hours.

EXAMPLE 2

Obtain methyl ester of 3-hydroxy-5-methylsulfonylamino-4-carboxylic acid

In a separate chemical reactor were placed water (280 ml, 7 volumes) and sodium bicarbonate (1.5 equivalent, of 38.2 g). A mixture of water/sodium bicarbonate was cooled to 5°C in nitrogen atmosphere. Within 5 minutes was added hydroxylamine-O-sulfonic acid (1.2 equivalent, 41,1 g) and the mixture was stirred for 15-30 minutes. For 60-70 minutes was added a solution of 2,2-bis-methoxycarbonyl-1-methylsulfonylmethane anion/acetonitrile in example 1. The mixture was heated to 25°C for 1 hour, then kept for 16 hours at 25°C. most of the acetonitrile was removed by distillation in vacuum (130 Torr, 50°C). The residue was cooled to the room for the Noah temperature, acidified to pH ≈1 by addition of 37% hydrochloric acid (32 ml). The solid phase was granulated for 16 hours at 25°C. the Suspension was filtered and the filtrate was washed with water 3×100 ml), once with 200 ml of ethyl acetate:hexane 1:3 (V/V) and once with 100 ml of ethyl acetate:hexane 1:3 (V/V). The wet residue (50.5 g) was dried in a vacuum drying for 16 hours to obtain methyl ester of 3-hydroxy-5-methylsulfonylamino-4-carboxylic acid, with the formation of 45.4 grams (yield 73%).1H NMR (DMSO-d6) δ 11,92 (s, 1H); 3,74 (s, 3H); 2,53 (s, 3H). MS: (API-ES, pos) 206 (M+H)+the ground.

EXAMPLE 3

Obtaining methyl ester 3-methoxycarbonylamino-5-methylsulfonylamino-4-carboxylic acid

Methyl ester of 3-hydroxy-5-methylsulfonylamino-4-carboxylic acid (1.00 equivalent, 10.0 g) and dichloromethane (100 ml, 10 volumes) was placed in a flask and kept at 25°C in nitrogen atmosphere. Was added triethylamine (1.0 equivalent, of 6.78 ml, 4,88 g). Formed an orange solution, which was cooled to 0°C. for 3 minutes was added methylchloroform (1.0 equivalent, 3,74 ml, 4,56 g). The mixture was stirred at 25°C for 2 hours, then washed with water (50 ml, 5 volumes), then with saturated saline solution (50 ml, 5 volumes). The solvent was replaced with acetonitrile (100 ml, 10 volumes) to give a yellowish-brown ot the art, contains methyl ether 3-methoxycarbonylamino-5-methylsulfonylamino-4-carboxylic acid.

EXAMPLE 4

Obtaining methyl ester 5-methanesulfonyl-3-methoxycarbonylmethyl-4-carboxylic acid

A suspension of methyl ester of 3-methoxycarbonylamino-5-methylsulfonylamino-4-carboxylic acid was cooled to 0°and added additional connection gidroperit (2.8 equivalent, 12.8 g). Within 20 minutes drip anhydride was added triperoxonane acid (2.8 equivalent of 19.2 ml, 28.4 g). The mixture was stirred at 0°C for 45 minutes and extinguished hydrosulfite sodium (2.0 equivalent, 10.0 g)in water (90 ml, 9 volumes) and was stirred at 25°C. most of the acetonitrile was removed in vacuo, and then the aqueous residue was extracted once with 100 ml and once with 50 ml of dichloromethane to obtain methyl ester 5-methanesulfonyl-3-methoxycarbonylmethyl-4-carboxylic acid.

EXAMPLE 5

Obtain methyl ester of 3-hydroxy-5-methanesulfonamido-4-carboxylic acid

Extracts methyl ester 5-methanesulfonyl-3-methoxycarbonylmethyl-4-carboxylic acid/dichloromethane were combined, then was replaced with methanol (150 ml, 15 volumes). Solution was added 98% sulfuric acid (50 ml, 5 volumes) in water (100 ml, 10 the volume of the MOU) and the mixture was heated at 65° C for 6 hours. Over time foamy suspension became a clear solution with a certain amount of white solids. The mixture was cooled to 25°C and was stirred for 16 hours. Most of the methanol was removed in vacuum. The aqueous residue was extracted once with 100 ml of dichloromethane, then twice with 50 ml dichloromethane. Combined in dichloromethane extracts were dried over anhydrous magnesium sulfate and filtered. Dichloromethane was replaced with hexane (100 ml, 10 volumes) and was stirred at 25°C before the formation of the solid phase. The solid phase was filtered, the filtrate was washed with hexane and dried to obtain 9.2 grams methyl ester 3-hydroxy-5-methanesulfonamido-4-carboxylic acid (yield 80%).1H NMR (DMSO-d6) δ 13,07 (s, 1H] a 3.83 (s, 3H); 3,55 (s, 3H). MS (API-ES, pos): 238 (M+H)+; 206 (M-MeO)+, base.

EXAMPLE 6

Getting 4-bromo-2,6-differenziava ester toluene-4-sulfonic acid

In a flask under nitrogen atmosphere were placed (4-bromo-2,6-differenl)methanol (1.10 equivalent to 19.1 g) in dichloromethane (185 ml, 10 volumes) was added anhydride p-toluensulfonate acid (1.1 equivalent of 28.9 g). The mixture was cooled to 0°C for 20 minutes drip was added triethylamine (1.2 equivalent of 13.0 ml, for 9.47 g). The mixture was heated to 25°C and was stirred for one hour. The mixture is then momentarily from Yali 185 ml of 1 N hydrochloric acid, then once 92,5 ml of 1 N hydrochloric acid. The organic layer containing 4-bromo-2,6-differentialy ester toluene-4-sulfonic acid, concentrated to approximately 55-60 ml

EXAMPLE 7

Obtain methyl ester of 3-(4-bromo-2,6-deferasirox)-5-methanesulfonamido-4-carboxylic acid

In a separate vessel was placed methyl ester of 3-hydroxy-5-methanesulfonamido-4-carboxylic acid (1.00 equivalent of 18.5 g) in dimethyl sulfoxide (185 ml, 10 volumes) was added potassium carbonate (1.0 equivalent, 10.8 g). To a suspension of methyl ester of 3-hydroxy-5-methanesulfonamido-4-carboxylic acid/potassium carbonate/dimethyl sulfoxide of example 6 for 1 hour drip solution was added 4-bromo-2,6-differentialy ester toluene-4-sulfonic acid/dichloromethane. The mixture was stirred at 25°C for 16.5 hours. Added dichloromethane (185 ml, 10 volumes), then water (185 ml, 10 volumes) and the layers were separated. The organic layer was dried over magnesium sulfate and filtered. Dichloromethane was removed in vacuo to obtain an orange paste. Orange paste was diluted with 10 volumes of 1:1 EtOAc:hexane (V/V) and suspended in 25°C for 16 hours. The mixture was filtered, the filtrate was washed 55-60 ml 1:1 EtOAc:hexane (V/V) and dried to obtain 24.22 to g of methyl ester of 3-(4-bromo-2,6-deferasirox)-5-means lonelysoul-4-carboxylic acid (yield 70%). 1H NMR (DMSO-d6) δ EUR 7.57 (m, 2H); 5,46 (s, 2H); of 3.80 (s, 3H); of 3.57 (s, 3H). MS (API-ES, pos): 442/444 (M+H)+; 205/207 (ion 1,5-debtor-3-postroeniya), base.

EXAMPLE 8

Obtain methyl ester of 5-amino-3-(4-bromo-2,6-deferasirox)isothiazol-4-carboxylic acid

In a 1 l autoclave was placed methyl ester 3-(4-bromo-2,6-deferasirox)-5-methanesulfonamido-4-carboxylic acid (1.00 equivalent of 28.0 g) in tetrahydrofuran (840 ml, 30 volumes). The vessel had created a vacuum, heated to 50°C, then placed in gaseous anhydrous ammonia under pressure of 45 psi. The mixture was stirred at 600 rpm for 3 days, then 1000 rpm for an additional 21 hours. The mixture was cooled to 25°C, purified nitrogen, and then the tetrahydrofuran was removed in a rotary evaparator. To the precipitate was added a solution of 60:40 acetonitrile/water (V/V) (240 ml, 10 volumes relative to theoretical mass of product). The suspension was heated to 70°C for 1 hour, then stirred at 25°C during the night. The precipitate was filtered and the filtrate washed with 60:40 acetonitrile/water (V/V) (40 ml). The solid phase was dried in vacuum to obtain 21,55 g of methyl ester of 5-amino-3-(4-bromo-2,6-deferasirox)isothiazol-4-carboxylic acid (yield 90%).1H NMR (DMSO-d6) δ 7,87 (s, 2H); 7,52 (m, 2H); of 5.26 (s, 2H); of 3.60 (s, 3H). MS: (API-ES, pos) 379/381 (M+H)+; 205/207 (IO is 1,5-debtor-3-postroeniya), base.

EXAMPLE 9

Receive (4-pyrrolidin-1-libutil)amide imidazol-1-carboxylic acid

In a flask under nitrogen atmosphere were placed 4-pyrrolidin-1-ibutramine (1.3 equivalent of 10.1 g) in tetrahydrofuran (105 ml, 5 volumes). The mixture was cooled to 0°C and was added 1,1'-carbonyldiimidazole (1.3 equivalent, 11.6 g). The mixture was stirred at 0°C for 20 minutes, then was heated up to 20°C for 10 minutes and kept at 20°C for 30 minutes.

EXAMPLE 10

Obtain methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid

To a mixture of (4-pyrrolidin-1-libutil)amide imidazol-1-carboxylic acid/tetrahydrofuran was added dimethylsulfoxide (105 ml, 5 volumes), the tetrahydrofuran was removed by distillation in vacuum. The mixture was cooled to 20°C, then added the methyl ester of 5-amino-3-(4-bromo-2,6-deferasirox)isothiazol-4-carboxylic acid (1.00 equivalent, 21,0 g), followed by the addition of potassium carbonate (2.0 equivalent of 15.2 g). The mixture was stirred at 20°C for 21.5 hours. Added ethyl acetate (210 ml, 10 volumes), then water (210 ml, 10 volumes). The suspension was stirred at 20°C for 3-4 hours. The solid phase was filtered, and the filtrate was washed with ethyl acetate (63,0 ml, 3 volume). The solid phase is dried under vacuum for 17 hours to obtain 27,36 g of methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid (yield 90%). 1H NMR (DMSO-d6) δ 10,38 (s, 1H); 8,11 (m, 1H); rate of 7.54 (m, 2H); and 5.30 (s, 2H); 3,70 (s, 3H); of 3.12 (m, 2H); 2,48 (m, 6H); and 1.63 (m, 4H); of 1.44 (m, 4H). MS (API-ES, pos): 547/549 (M+H)+the ground.

EXAMPLE 11

Getting amide 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid

In a 1 liter autoclave suspended methyl ester 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid (1.00 equivalent to 27.0 g) in methanol (270 ml, 10 volumes) and tetrahydrofuran (270 ml, 10 volumes). The mixture was cooled to 0°C and stirred at 600 rpm was Carefully made gaseous anhydrous ammonia, maintaining the temperature below 10°C. After reaching the constant pressure of approximately 10 psi, the mixture was heated to 40°C. the Pressure was increased to approximately 45 psi. Pressure was brought to 50 psi and stirred at 600 rpm at 40°C for 90 hours. The mixing speed was brought up to 1000 rpm and was stirred for additional 24 hours. The ammonia was removed in vacuum and the mixture was cooled to 20°C and removed from the reactor. The mixture was filtered to remove insoluble solid phase (non-product). The filtrate was diluted with 2-propanol (270 ml, 10 volumes) and at atmospheric pressure evaporated tetrahydrofuran and methanol. To omnitele was added 2-propanol (135 ml, 5 volumes), then the mixture is evaporated to approximately 250 ml total volume. The suspension was cooled to 20°C and was stirred for 18 hours. The solid phase was filtered and then dried in vacuum to obtain 19.9 g of amide 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid (yield 76%).1H NMR (DMSO-d6) δ 10,98 (s, 1H); 8,18 (m, 1H); at 7.55 (m, 3H); to 6.80 (s, 1H); 5,41 (s, 2H); is 3.08 (m, 2H); 2,47 (m, 6H); of 1.62 (m, 4H); to 1.42 (m, 4H). MS (API-ES, pos) 532/534 (M+H)+the ground.

1. The method of obtaining the compounds of formula I

or its pharmaceutically acceptable salt, where

R1or R2represent H, -(CH2)t(5-membered heterocyclic compound), where t is a 4 and where the heterocyclic compound contains one nitrogen atom as heteroatom;

R3represents -(CH2)t(C6-C10aryl), where t represents 1; where the groups of R3optionally substituted 3 groups of R4;

each R4independently selected from halogen;

comprising the reaction of compounds of formula II

where R8represents a C1-C10alkyl, with a source of ammonia in a solvent to obtain compounds of formula I.

2. Spasibo to claim 1, where the compound of formula I selected from the group consisting of:

amide 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido}isothiazol-4-carboxylic acid;

salts of hydrochloric acid amide 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

amide 3-(4-chloro-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

and pharmaceutically acceptable salts.

3. The method of obtaining the compounds of formula II

or its pharmaceutically acceptable salt, where

R1or R2represent H, -(CH2)t(5-membered heterocyclic compound), where t is a 4 and where the heterocyclic compound contains one nitrogen atom as heteroatom;

R3represents -(CH2)t(C6-C10aryl), where t represents 1; where the groups of R3optionally substituted 3 groups of R4;

each R4independently selected from halogen;

R8represents a C1-C10alkyl;

includes (1) the reaction of compounds of formula IV

where R3, R4and R8are as defined above for formula I, source carbonyl, with the added base or without him, and then adding the compounds of formula III

where R1and R2are as defined above for formula II in a solvent to obtain compounds of formula II or (2) the reaction of compounds of formula III with a source of carbonyl, with the added base or without it; and then adding the compounds of formula IV in a solvent to obtain compounds of formula II.

4. The method according to claim 3, where the compound of formula II selected from the group consisting of:

methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

salts of hydrochloric acid methyl ester 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

methyl ester of 3-(4-chloro-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid;

and their pharmaceutically acceptable salts.

5. The method according to claim 4, where the compound of formula II represents a methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid.

6. The method of obtaining the compounds of formula IV

or its pharmaceutically acceptable salt;

R3the stand is made by a -(CH 2)t(C6-C10aryl), where t represents 1; where the groups of R3optionally substituted 3 groups of R4;

each R4independently selected from halogen;

R8represents a C1-C10alkyl;

comprising the reaction of compounds of formula V

where R3, R4and R8are as defined above;

R9represents a C1-C10alkyl,

n represents 2, with a source of ammonia in a solvent to obtain compounds of formula IV.

7. The method according to claim 6 where the compound of formula IV represents a methyl ester of 5-amino-3-(4-bromo-2,6-deferasirox)isothiazol-4-carboxylic acid.

8. The method of obtaining the compounds of formula V

or its pharmaceutically acceptable salt;

R3represents -(CH2)t(C6-C10aryl), where t represents 1; where the groups of R3optionally substituted 3 groups of R4;

each R4independently selected from halogen;

R8represents a C1-C10alkyl;

R9represents a C1-C10alkyl, and

n represents 2;

including himself the reaction of the compound of formula VII

where n, R8and R9are as defined above, with a compound of formula VI

R3X VI

where R3is the same as defined above, and X represents toil in the presence of a base in a bipolar aprotic solvent, to obtain the compounds of formula V.

9. The method of claim 8 where the compound of formula V is a methyl ester of 3-(4-bromo-2,6-deferasirox)-5-methanesulfonamido-4-carboxylic acid.

10. The compound of formula IIa

or its pharmaceutically acceptable salt, where

R1or R2represent H, -(CH2)t(5-membered heterocyclic compound), where t is a 4 and where the heterocyclic compound contains one nitrogen atom as heteroatom;

R3represents -(CH2)t(C6-C10aryl), where t represents 1; where the groups of R3optionally substituted 3 groups of R4;

each R4independently selected from halogen;

R8represents a C1-C10alkyl.

11. The compound of formula IIa of claim 10, which represents a methyl ester of 3-(4-bromo-2,6-deferasirox)-5-[3-(4-pyrrolidin-1-libutil)ureido]isothiazol-4-carboxylic acid is.

12. The compound of formula IVa

or its pharmaceutically acceptable salt;

R3represents -(CH2)t(C6-C10aryl), where t represents 1; where the groups of R3optionally substituted 3 groups of R4;

each R4independently selected from halogen;

R8represents a C1-C10alkyl.

13. The compound of formula IVa indicated in paragraph 12, which represents a methyl ester of 5-amino-3-(4-bromo-2,6-deferasirox)isothiazol-4-carboxylic acid.

14. The compound of formula Va

or its pharmaceutically acceptable salt;

R3represents -(CH2)t(C6-C10aryl), where t represents 1; where the groups of R3optionally substituted 3 groups of R4;

each R4independently selected from halogen;

R8represents a C1-C10alkyl,

R9represents a C1-C10alkyl,

and n represents 2.

15. The compound of formula Va by 14, which represents a methyl ester of 3-(4-bromo-2,6-deferasirox)-5-methanesulfonamido-4-carboxylic acid.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and pharmaceutically acceptable salts. Claimed compounds have modulation effect on CB cannabinoid receptor. In the general formula (I) , R and R1 are the same or different and are phenyl optionally substituted by 1-3 substitutes Y, where Y is substitute selected out of group including chlorine, iodine, bromine, fluorine, on condition that X is not a sub-group (ii); or one of R and R1 radicals is phenyl group, while the other radical is formed or linear C2-8-alkyl group or benzyl group; X is one of the sub-groups (i) or (ii). Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim.

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of treatment, alleviation and/or prevention of neurological state, particularly neurodegenerative disorders, involving administration of effective quantity of compound with formula I: . Also invention concerns application of compound of the formula I as neurotherapeutical, neuroprotective or antimyloid agent, pharmaceutical or veterinary composition for treatment, alleviation and/or prevention of neurological states, and compounds of the formula I on the following additional terms: (b) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not ethyl or methyl; (c) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not hydrogen or ethyl; (d) if R3, R and R' are H, and R2 is NR11R12, then both R11 and R12 are not hydrogen; (e) if R3, R and R' are H, and R2 is COR6, then R6 is not H, OH or CH2Cl; (f) if R3, R and R' are H, and R2 is not CH3 or CH2Cl; (g) if R3, R and R' are H, and R2 is HCNN R9R10, then both R9 and R10 are not H.

EFFECT: efficient treatment, alleviation and prevention of neurological state.

24 cl, 14 tbl, 21 ex, 14 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) , where R1 is phenyl optionally substituted by halogen, cyano, C1-4alkyl or C1-4haloalkyl; R2 is hydrogen, C1-6alkyl or C3-6cycloalkyl; and R3 is a group with NH or OH and calculated or measured pKa from 1.0 to 8.0, selected out of: 2-oxo-thiazol-5-yl with C1-4fluoroalkyl, optionally substituted phenyl group, optionally substituted heterocyclyl group or CH2S(O)2(C1-4alkyl) group in position 4; 2-oxo-oxazol-5-yl with C1-4fluoroalkyl or CH2S(O)2(C1-4alkyl) in position 4; 1H-1,2,3-triazol-4-yl with C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, S-R4 (where R4 is C1-4alkyl, C1-4fluoroalkyl or C3-6cycloalkyl), NHS(O)2(C1-4alkyl), N(C1-4alkyl)S(O)2(C1-4alkyl), phenyl group, heterocyclyl group or CH2S(O)2C1-4alkyl) group in position 5; 4-oxo-1H-1,4-dihydropyridine-3-yl with C1-4fluoroalkyl in position 2; 2,6-dioxo-1H-1,2,3,6-tetrahydropyrimidine-4-yl with C1-4alkyl, C3-6cycloalkyl or CH2(C1-3fluoroalkyl) in position 3 and optionally substituted in one or more other ring positions; 6-oxo-1H-1,6-dihydropyridine-3-yl with C1-4fluoroalkyl, cyano or phenyl in position 2 and/or in position 5 and optionally substituted in one or more other ring positions; 6-oxo-1H-1,6-dihydropyridine-3-yl with CH2CO2H at ring nitrogen atom and optionally substituted in one or more other ring positions; 2H-tetrazol-5-yl; CO2H, CH2CO2H or OCH2CO2H group at optionally substituted phenyl, optionally substituted CH2O phenyl or optionally substituted naphtyl ring or optionally substituted acylated dihydroisoquinolinyl ring; or group NHS(O)2(C1-4alkyl) at optionally substituted aromatic heterocyclic ring; or their tautomer where possible; in indicated positions where heterocyclyl ring in R3 can be optionally substituted, it can be optionally substituted by fluoro, chloro, bromo, C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, S-R4 (where R4 is C1-4alkyl, C1-4fluoroalkyl or C3-6cycloalkyl), cyano, S(O)2(C1-4alkyl); in indicated positions where phenyl or naphtyl ring in R3 can be optionally substituted, it can be optionally substituted by halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, OCF3, SCF3, nitro, S(C1-4alkyl), S(O)(C1-4alkyl), S(O)2(C1-4alkyl), S(O)2NH(C1-4alkyl), S(O)2N(C1-4alkyl)2, NHC(O)(C1-4alkyl) or NHS(O)2(C1-4alkyl); or its pharmaceutically acceptable salts. Also invention concerns compounds of formula (I), method of obtaining compounds of any of claims 1-12, as well as pharmaceutical composition.

EFFECT: obtaining novel bioactive compounds with chemokine receptor activity modulation effect.

16 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula I: , where L represents radical , in which R1 represents H, C1-4alkyl; n represents 0 or 1; or L represents radical , in which R1 represents H, C1-4alkyl; m equals 1; R represents H, halogen, C1-C4alkyl or C1-C4-alkoxy; Z represents a bond, -C(O)NH-, O or S; p is an integer from 1 to 5; Q represents a bond with the condition that, Z is not a bond, when p equals 1; or represents O, S or -C(O)NR6-, where R6 represents H, C1-4alkyl or C3-6cycloalkyl; or W and R6 together with a nitrogen atom, to which they are bonded, form or or Q represents -NR6-, or in the condition that, p is not equal to 1; W represents , , , , ,

, , ,

, , ,

, , , ,

, , , ,

, , , ,

, , , , ,

, , , , , and

.

EFFECT: obtaining compounds with agonistic activity towards PPAR receptors, which enables them to be used in pharmaceutical compositions and methods of treating conditions, mediated by these receptors.

12 cl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1 and their pharmaceutically acceptable salts as inhibitors of post-proline aminopepdidases, as well as to pharmaceutical composition based on them and application for manufacturing such composition, and to method of inhibition with their application. Compounds can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose. In general formula 1 ,

either G1 represents -CH2-X2-(CH2)a-G3, and G2 represents H, or G2 represents -CH2-(CH2)a-G3, and G1 represents H; G3 is selected from group according to general formula 2 ,

group according to general formula 3

and group according to general formula 4 ;

a is 0, 1 or 2; b is 1 or 2; X1 is selected from CH2, S, CF2, CHF and O; X2 is selected from CH2; X3, X4 and X5 are selected from N; X6 is selected from NH; X7 is selected from NH; R1 is selected from H and CN; R2 represents H; R3 is selected from H, Cl, OH, NH2, NH-C1-C10alkyl and N(C1-C10alkyl)2; R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, OH, NO2; R9 represents H; R10, R11, R12, R13 and R14 are independently selected from H, Cl and CF3; R15 and R16 are independently selected from H, C1-C10alkyl, C1-C10alkenyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, quinoline, naphtyl and -CH2-L-R17; R17 is selected from C1-C10alkyl, phenyl, naphtyl, quinolinyl and indolyl; L is selected from covalent bond, CH=CH and -C6H4-; on condition that when R15 and R16 both represent H, and b is 1, then X1 does not represent S or CH2.

EFFECT: obtaining compounds that can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose.

58 cl, 10 tbl, 1705 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to compounds of formula where one of R6, R7 or R8 means , and X, Y, substitutes of R1-R13 and n are as it is defined in item 1 of formula of invention, and to all their enantiomers, to pharmaceutically acceptable salts and/or esters.

EFFECT: production of compounds for treatment and/or prevention of diseases modulated by PPARδ and/or PPARα agonists.

26 cl, 1 tbl, 35 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to methods of obtaining rosiglytasone, rosiglytasone, obtained by said methods, and its pharmacological compositions and methods of treatment using it.

EFFECT: obtaining of new crystalline modifications of rosiglytasone, which have useful biological properties.

58 cl, 4 dwg, 2 tbl, 9 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new Amida isothiazolinones acid of the formula I, where R is selected from formula (a), (b), (C), (d), (i) and (f), in which R1means cyano, phenyl, cyclopentyl, cyclohexyl, cycloheptyl, R2means- (CH3)3, -CH(C2H5)2, -CH2-S-R3and so on, R3represents alkyl with 1-5 carbon atoms or phenyl, optionally, from mono - to tizamidine the same or different residues selected from the group comprising fluorine, chlorine, bromine and alkyl with 1-4 carbon atoms, R10means fluorine, chlorine, bromine, methyl, etc., n means an integer from 0 to 3 provided that when n represents 2 or 3, R10means the same or different residues

The invention relates to new derivatives isothiazolinones acid of the formula I, where R stands for a group-OR1or-SR2in which R1means alkyl with 1-6 carbon atoms, a substituted once residues selected from the group comprising halogenoalkanes with 1-6 carbon atoms and 1 to 5 halogen atoms, dialkylamino with 1-6 carbon atoms in each alkyl part, phenylalkyl with 1-4 carbon atoms in the CNS parts and pyrrolidinyloxyl with 1-4 carbon atoms in the CNS part, and twice by hydroxyl, or so, m and n is 2, R3means phenyl, R4means alkyl with 1-4 carbon atoms, R2means alkyl with 1-6 carbon atoms, or R2means phenylalkyl with 1-2 carbon atoms in the alkyl part, with the phenyl portion may be substituted with halogen

FIELD: medicine.

SUBSTANCE: method includes application of individually chosen hypohigh-calorie diet, the dosed out physical activities and introduction of Pyoglitazone 30 mg once a day and Valsartane 80 mg, 1 time at the same time of the day. The combined application of a hypohigh-calorie diet, physical activities and Pyoglitazone and Valsartane preparations in the specified dosages allows normalising activity of protein C within three months at patients with metabolic syndrome.

EFFECT: optimisation of activity of protein C at patients with metabolic syndrome.

1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: method includes application of the hypohigh-calorie diet, the dosed out loads and introduction of Pyoglitazone 30 mg once a day, Irbersartane 150 mg, 1 time in the same time and Lerkanidipine - 10 mg in the morning. The combined application of a diet, physical activities and the given preparations allows normalising fibrinosis level in blood plasma during 3 months.

EFFECT: optimisation of fibrinosis level at metabolic syndrome.

1 ex

FIELD: chemical-pharmaceutical industry.

SUBSTANCE: invention refers to pharmaceutical combination including (a) alkylating agent and (b) epothilone derivative of formula where A represents O or NRN, where RN represents hydrogen or lower alkyl, R represents hydrogen or lower alkyl and Z represents O or bonding.

EFFECT: it can be useful for proliferative disease treatment, especially tumour disease, and proliferative action is greater in comparison with maximum action which can be reached with each component separately.

8 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of cyclohexan-1,4-diamine of the general formula (I): possessing binding property with ORLI receptors and showing homology to opioid μ-, κ- and δ-receptors. Compounds can be used for preparing drugs possessing analgesic effect. In the formula (I) R1 and R2 mean independently of one another (C1-C8)-alkyl, or residues R1 and R2 form in common a ring and mean -CH2-CH2NR6CH2CH2 or -(CH2)3-6 wherein R means (C1-C8)-alkyl; R3 means phenyl, naphthyl or 5-membered sulfur-containing heteroaryl wherein each of them is unsubstituted or monosubstituted with halogen atom, or unsubstituted phenyl added through saturated unsubstituted (C1-C4)-alkyl group; R4 means hydrogen atom (H), saturated (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen (O) or sulfur (S) atom; R means H or (C1-C8)-alkyl either unsubstituted phenyl or phenyl substituted with halogen atom; R5 means (C3-C8)-cycloalkyl, adamantyl, aryl or 5-membered heteroaryl comprising 1-3 heteroatoms chosen from nitrogen, oxygen or sulfur and condensed with one or two benzene rings and wherein each of them is unsubstituted or monosubstituted with a substitute chosen from halogen atom, lower alkyl, lower alkoxy, hydroxy or benzyloxy; or -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12 wherein Y means O or H2; R11 means H, saturated, linear or branched (C1-C7)-alkyl, saturated or unsaturated, linear or branched, mono- or multisubstituted either unsubstituted -C(O)O-(C1-C6)-alkyl; R12 means phenyl or 5-membered heteroaryl comprising 1-3 heteroatoms chosen from nitrogen, oxygen or sulfur condensed with one or two benzene rings each of them is unsubstituted or mono- or multisubstituted and wherein in values R11 and R12 substituted of alkyl, phenyl or heteroaryl are chosen from halogen atom, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or benzyloxy; or R4 and R5 form in common 5-membered nitrogen-containing heterocycle that represents unsaturated, monosubstituted lower alkoxycarbonyl-lower alkyl, halogen atom, or it is unsubstituted and condensed with benzene ring under condition that if R means substituted or unsubstituted phenyl and at least one R1 or R2 means (C1-C8)-alkyl then R4 can't mean alkyl, and R3 and R5 can't form in common heterocycle, or if R3 means unsubstituted phenyl and R1 and R2 mean in common -(CH2)5 then R4 means H or (C1-C8)-alkyl; Y means O, and R5 doesn't mean (C1-C6)-alkyl. Also, invention relates to a method for synthesis of compounds of the formula (I) and a drug.

EFFECT: valuable medicinal properties of compounds.

40 cl, 1 tbl, 94 ex

FIELD: medicine, dermatology, pharmacy.

SUBSTANCE: invention relates to drugs and concerns to pharmaceutical compositions used in treatment of inflammatory skin states and mucosa. Agents comprise proanthocyanidins, glycyrrhetinic acid and telmestein as active components in a mixture with suitable carrier. Inflammatory disease is chosen from atopic dermatitis, allergic contact dermatitis, seborrhea dermatitis, radiation dermatitis, xerosis, psoriasis, atopia and inflammatory states of vaginal, rectal, buccal and ophthalmic mucosae.

EFFECT: valuable medicinal properties of pharmaceutical compositions, enhanced effectiveness of treatment.

17 cl, 4 dwg, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carboxylic acid represented by the general formula (I): , their pharmaceutically acceptable salts or esters wherein values Y, L, X, T, Z, M, R1, W and are given in the invention claim. Proposed compounds possess insulin-sensitizing effect and they are double agonists with respect to PPARα and γ, and triple agonists with respect to PPARα, β(δ) and γ. Except for, the invention relates to a medicinal agent and pharmaceutical compositions based on the claimed derivatives of carboxylic acid, to methods for prophylaxis or treatment of diseases, and to using derivatives carboxylic acid for preparing a medicinal agent.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

56 cl, 2 tbl, 609 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with describing the efficient quantity of, at least, one heterocyclic compound of formula (I) or its salts, moreover, the compound of formula (I) should be chosen out of (i) the compounds of formula (III) or their salts, in which Z, Z' indicate O, X indicates S (thiazolidine dionic group), G indicates O or S; at least, one out of R2 and R3 indicates CF3, OR0 or COOR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C10-C10-alkyl, (ii) compounds (VI) or their salts: in which Z, Z' and G independently indicate O or S, at least, one out of R2 and R3 indicates hydrogen, CN, CF3, NO2, OR0, COOR0 or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, possibly substituted OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, (iii) compounds (VII) or their salts in which Z, Z' and G independently indicate O or S; R indicates saturated linear or branched C1-C10-alkyl; at least, one out of R2 and R3 indicates saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, NO2, OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl. The compounds in question reveal improved action upon stimulation of keratin fibers growth, particularly, human keratin fibers, that prevents their falling down and increases their density.

EFFECT: higher efficiency.

31 cl, 13 ex, 6 tbl

FIELD: biology, medicine.

SUBSTANCE: invention proposes using the tissue factor (TF) inhibitor in preparing a medicinal agent for treatment or prophylaxis of insulin-secreting cells transplant rejection, for treatment or prophylaxis of immediate blood-mediated inflammatory response (IBMIR) and corresponding methods for treatment. Nicotinamide, enalapril, and arginine that are TF inhibitors reduced synthesis and secretion of TF, and TF is a trigger mechanism for IBMIR, and anti-TF and iFVIIa block IBMIR initiated by human Langerhans islets. Inhibition of this response before carrying out the clinic transplantation of Largenhans islets can provide decreasing loss of transplanted tissue in the absence of harmful effect on the patient hemostasis.

EFFECT: valuable medicinal properties of inhibitor.

13 cl, 8 dwg, 1 tbl

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