Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with cyclic amino group as crf antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidine and pyrrolopyridine of general formula (I), substituted with a cyclic amino group (II), or their pharmaceutically acceptable salts having CRF antagonist properties. In general formula the cyclic amino group has formula , in which the cyclic amino group is a 6-member saturated cyclic amine, the said cyclic amine is substituted with a group of formula -(CH2)mX; in which X is -CO2H, -CONH2,-P(=O)(OH)2 or -S(=O)2OH; Y is N or CH; m is an integer selected from 1, 2 and 3; R4 is hydrogen; R5 is hydrogen; R6 is C1-5alkyl; R7 and R8 are identical or different and independently represent hydrogen, C1-5alkyl, Ar is phenyl which is unsubstituted or substituted with one or more substitutes which are identical or different and are selected from a group consisting of halogen, C1-5alkyl, C1-5alkoxy, C1-5alkylthio, trifluoromethyl and trifluoromethoxy.

EFFECT: compounds can be used for therapeutic or preventive treatment of diseases where CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension etc.

12 cl, 6 dwg, 1 tbl, 10 ex

 

The technical FIELD

The invention relates to a therapeutic agent against diseases in respect of which believe that they involve a factor in the release of corticotropin (CRF), such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug addiction or dependence on drugs, cerebral infarction, cerebral ischemia, cerebral edema, the outer head wounds, inflammation associated with immune disease, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain and other

DESCRIPTION of the PRIOR art,

CRF is a hormone, comprising 41 amino acid (Science, 213, 1394-1397, 1981; J. Neurosci., 7, 88-100, 1987), and suggest that CRF plays a Central role in biological reactions to stress (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995). In relation to the CRF has the following two paths: the path that CRF acts on peripheral immune system or the sympathetic nervous system via the hypothalamus-hypotize-adrenal system, and the path that CRF acts as a neurotransmitter in the Central nervous system (Corticotropin Releasing Factor; Basic and Clinical Studies of a Neuropeptide, pp. 29-52, 1990). Intraventricular introduction CRF rats with UD is by the pituitary gland and normal rats causes such anxiety symptom in both types of rats (Pharmacol. Rev., 43, 425-473, 1991; Brain Res. Rev., 15, 71-100, 1990). Namely, it is assumed involvement of CRF in the hypothalamus-hypotize-adrenal system, and the path that CRF acts as a neurotransmitter in the Central nervous system.

Overview Owens and nemerov (Owens and Nemeroff) in 1991 considered diseases involving CRF (Pharmacol. Rev., 43, 425-474, 1991). Namely, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, horey Huntington, eating disorder, hypertension, gastrointestinal diseases, drug addiction, inflammation associated with immune diseases and other Recently reported that CRF is involved in epilepsy, cerebral infarction, cerebral ischemia, cerebral oedema and external wounds of the head (Brain Res. 545, 339-342, 1991; Ann.Neurol. 31, 48-498, 1992; Dev. Brain Res. 91, 245-251, 1996, Brain Res. 744, 166-170, 1997). In line with this, the antagonist against CRF receptors are useful as therapeutic agents against diseases described above.

Well-known opioid analgesics for their ability to reduce the perception of pain without loss of consciousness. At least three major types of opioid receptors (δ, µ, κ) is involved in the modulation of a wide variety of opioid effects. In the study of opioid selective agonist δ-opioid receptor have shown promising therapeutic potential as analge the logical devices without harmful side effects related to morphine and other opioid drugs that are selective in relation to the µ-opioid receptor. There are several evidences showing that stimulation of the δ-opioid receptor could ease the pain process (J. Pharmacol. Exp. Ther. 307, 1079-1089, 2003).

WO02/002549, WO00/053604 and WO04/058767 reveal derivatives pyrrolopyridine and pyrrolopyrimidine as antagonists of CRF receptors. However, none of the sources are not disclosed compounds provided by the present invention.

The PROBLEM addressed by the INVENTION

The aim of the present invention is to provide an antagonist against CRF receptors and/or δ agonist for receptors which is effective as a therapeutic or preventive agent against diseases for which it is believed that they involve CRF such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug addiction or dependence on drugs, cerebral infarction, cerebral ischemia, cerebral edema, the outer head wounds, inflammation associated with immune disease, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain and other

TOOLS FOR PROBLEM SOLVING

The authors present invention seriously investigated derivatives pyrrolopyrimidine and pyrrolopyridine, substituted cyclic amino group, which have high affinity against CRF receptors and/or δ receptors with which it was accomplished the present invention.

The present invention is derived pyrrolopyrimidine and pyrrolopyridine, substituted cyclic amino group, explained below.

Derived pyrrolopyrimidine or pyrrolopyridine, substituted cyclic amino group represented by the following formula [I]:

(in which the cyclic amino group represented by the following formula [II]:

in which the cyclic amino group is 3-8-membered saturated cyclic amine or a 3-8-membered saturated cyclic amine, coupled With1-5alkilinity or1-4alkylen-O-C1-4alkilinity bridge between any different two carbon atoms of the cyclic amine specified cyclic amine represented by -(CR1R2)m-(CHR3)n-X, R4and R5independently the same or different carbon atoms of the cyclic amine;

X represents-CO2R9, -CON(R10R11, -P(O=)(R12R13or-S(=O)kR14;

Y represents N Il is CR 15;

R1represents hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;

R2represents hydrogen or C1-5alkyl;

R3represents hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;

m represents an integer selected from 0, 1, 2, 3, 4 and 5;

n represents 0 or 1;

provided that when X represents-CO2R9or-CON(R10R11and n is 0, then m represents an integer selected from 1, 2, 3, 4 and 5;

R4represents hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;

R5represents hydrogen or C1-5alkyl;

R6represents hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl,3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkane or-N(R16R17;

R7and R8are the same or different and independently represent hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl,3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkane, -N(R18R19, -CO2R20, cyano, nitro, C1-5alkylthio, trifluoromethyl or triptoreline; or R7and R8taken together to form-CH2CH 2-CH2-CH2- or-CH=CH-CH=CH-;

R9represents hydrogen, C1-20alkyl, aryl, C3-8cycloalkyl or-CHR1aOC(=O)-AND1-R1bwhere specified With1-20alkyl optionally contains one to four double bonds and/or one to four triple bond, and/or specified With1-20alkyl optionally substituted by one of the substituents selected from the group consisting of hydroxy, halogen, cyano, C1-10alkoxy, C1-5alkoxycarbonyl,3-8cycloalkyl, -C(=O)N(R2aR2b, -N(R3aR3band aryl, the said aryl optionally substituted by one or more substituents, which are the same or different and selected from the group consisting of halogen, C1-5the alkyl and C1-5alkoxy;

R1arepresents hydrogen or C1-5alkyl;

And1represents oxygen or a single bond;

R1bis1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R2aand R2bare the same or different and are independently hydrogen or C1-3alkyl;

R3aand R3bare the same or different and are independently hydrogen or C1-3alkyl; or R3aand R3btaken together to form -(CH2)s-And2-(CH2)t-;

And2is methyl is h, oxygen, sulfur, NR4aor single bond;

R4arepresents hydrogen, C1-5alkyl or benzyl;

s and t are identical or different and represent independently an integer selected from 1, 2 or 3;

R10represents hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R11represents hydrogen, C1-5alkyl, C3-8cycloalkyl,3-8cycloalkyl-C1-5alkyl or-CHR5a-(CH2)u-C(=O)R5bor R10and R11taken together to form -(CH2)v-And3-(CH2)w-;

R5arepresents hydrogen, C1-5alkyl, aryl or heteroaryl where specified With1-5alkyl optionally substituted by one of the substituents selected from the group consisting of aryl, heteroaryl, hydroxy, hydroxycarbonyl, 4-hydroxyphenyl,1-5alkoxy, amino, guanidino, mercapto, C1-5alkylthio or aminocarbonyl, or R10and R5ataken together to form -(CH2)p-;

p represents 3 or 4;

u represents 0 or 1;

R5brepresents hydroxy, C1-5alkoxy, benzyloxy, or-N(R6aR6b;

R6aand R6bare the same or different and are independently hydrogen or C1-3alkyl;

v and w are the same or different and are illegal is isimo integer selected from 1, 2 or 3;

And3represents methylene, oxygen, sulfur or NR7a;

R7arepresents hydrogen, C1-5alkyl or benzyl;

R12and R13are the same or different and independently represent-OR21or-N(R22R23;

R14is-OR21or-N(R22R23;

k represents 1 or 2;

R15represents hydrogen, C1-5alkyl, halogen, cyano or-CO2R24;

R16and R17are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R18and R19are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R20represents hydrogen or C1-5alkyl;

R21represents hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R22and R23are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R24represents hydrogen or C1-5alkyl;

Ar represents aryl or heteroaryl, which are unsubstituted or substituted one or more for what estately, which are the same or different, selected from the group consisting of halogen, C1-5of alkyl, C3-8cycloalkyl,2-5alkenyl,2-5the quinil,1-5alkoxy, C1-5alkylthio,1-5alkylsulfonyl,1-5alkylsulfonyl, cyano, nitro, hydroxy, -CO2R25, -C(=O)R26, -CON(R27R28, -OC(=O)R29, -NR30CO2R31, -S(O)rN(R32R33, trifloromethyl, triptoreline, deformedarse, formatosi, methylendioxy, Ethylenedioxy and-N(R34R35;

R25represents hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R26represents hydrogen or C1-5alkyl;

R27and R28are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R29represents hydrogen or C1-5alkyl;

R30represents hydrogen or C1-5alkyl;

R31represents hydrogen or C1-5alkyl;

R32and R33are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

r represents 1 or 2;

R34and R35are the same or different and represent the keys independently hydrogen, With1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl, individual isomers, racemic or non-racemic mixtures of their isomers or N-oxide, or pharmaceutically acceptable salts and hydrates.

Terms used in this description have the following meanings.

The term “3-8-membered saturated cyclic amine” means aziridine, azetidine, pyrrolidine, piperidine, ASEAN or asokan.

The term “C1-5alkylene” means alkylene straight or branched chain containing 1 to 5 carbon atoms, such as methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene or similar.

The term “3-8-membered saturated cyclic amine, coupled With1-5alkilinity or1-4alkylen-O-C1-4alkilinity bridge between any different two carbon atoms of the cyclic amine” includes, for example, 8-azabicyclo[3.2.1]Oct-8-yl, 9-azabicyclo[3.3.1]non-9-yl, 7-azabicyclo[2.2.1]hept-7-yl, 3-oxa-7-azabicyclo[3.3.1]non-7-yl and 3-oxa-9-azabicyclo[3.3.1]non-9-yl.

The term “C1-20alkyl” denotes an alkyl group with straight or branched chain containing 1-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, tridecyl, 3,7,11,15-tetramethylhexadecane or similar.

The term “C1-20Alki is, which optionally contains one to four double bonds and/or one to four triple bond” includes, for example, allyl, 3,7-dimethyl-OCTA-2,6-dienyl, but-3-inyl, dodec-11-inyl or similar.

The term “C1-10alkoxy” denotes alkoxygroup straight or branched chain containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentylamine, decyloxy, 3,7-dimethyl-octyloxy or similar.

The term “C1-5alkoxy-C1-5alkyl” refers to substituted C1-5alkyl group having the above With1-5alkoxygroup as a substituent, such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl or similar.

The term “hydroxy-C1-5alkyl” refers to substituted C1-5alkyl group having a hydroxy-group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxyphenyl or similar.

The term “cyano-C1-5alkyl” refers to substituted C1-5alkyl group having a cyano, such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 4-cyanomethyl, 5-cyanophenyl or similar.

The term “C3-8cycloalkyl” denotes a cyclic alkyl group of 3-8 carbon atoms, such as cyclopropyl, the CEC shall Outil, cyclopentyl, cyclohexyl, cycloheptyl or similar.

The term “C3-8cycloalkyl-C1-5alkyl” refers to substituted C1-5alkyl group having the above With3-8cycloalkyl group as a substituent, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl or similar.

The term “C3-8cycloalkane” denotes cyclic alkoxygroup with 3-8 carbon atoms, such as cyclopropane, CYCLOBUTANE, cyclopentyloxy or similar.

The term “halogen” means fluorine atom, chlorine, bromine or iodine.

The term “aryl” denotes a monocyclic or bicyclic group with 6-12 carbon atoms in the cycle, having at least one aromatic ring, such as phenyl, naphthyl, or similar.

The term “C1-5alkoxycarbonyl” denotes a carbonyl group having the aforementioned1-5alkoxygroup, such as methoxycarbonyl, etoxycarbonyl, t-butoxycarbonyl or similar.

The term “heteroaryl” denotes a monocyclic or bicyclic group with 5-12 atoms in the cycle, having at least one aromatic ring having 1-4 ring atoms, which may be the same or different and are selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, imidazolyl, hinely, indolyl, benzofuranyl, hee shall oxalyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,5]oxadiazolyl or similar.

The term “C2-5alkenyl” means alkenylphenol group with a straight or branched chain containing 2-5 carbon atoms, such as vinyl, Isopropenyl, allyl or similar.

The term “C2-5quinil” means alkylamino group with a straight or branched chain containing 2-5 carbon atoms, such as ethinyl, prop-1-inyl, prop-2-inyl or similar.

The term “C1-5alkylthio” means allylthiourea straight or branched chain containing 1-5 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio or similar.

The term “C1-5alkylsulfonyl” means alkylsulfonyl group with a straight or branched chain containing 1 to 5 carbon atoms, such as methanesulfonyl, econsulting or similar.

The term “C1-5alkylsulfonyl” denotes alkylsulfonyl group with a straight or branched chain containing 1-5 carbon atoms, such as methanesulfonyl, econsultancy or similar.

The term “aryl or heteroaryl, which are unsubstituted or substituted by one or more substituents, which are identical or different, selected from the group consisting of halogen, C1-5of alkyl, C3-8cycloalkyl,2-5alkenyl,2-5the quinil, 1-5alkoxy, C1-5alkylthio,1-5alkylsulfonyl,1-5alkylsulfonyl, cyano, nitro, hydroxy, -CO2R25, -C(=O)R26, -CON(R27R28, -OC(=O)R29, -NR30CO2R31, -S(O)rN(R32R33, trifloromethyl, triptoreline, deformedarse, formatosi, methylendioxy, Ethylenedioxy and-N(R34R35includes, for example, 2,4-dimetilfenil, 2,6-dimetilfenil, 2,4-dibromophenyl, 2-bromo-4-isopropylphenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-4-triptoreline, 4-methoxy-2-were, 2-chloro-4-trifloromethyl, 4-isopropyl-2-methylthiophenyl, 2,4,6-trimetilfenil, 4-bromo-2,6-dimetilfenil, 4-bromo-2,6-diethylphenyl, 4-chloro-2,6-dimetilfenil, 2,4,6-tribromophenyl, 2,4,5-tribromophenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, 4-bromo-2,6-dichlorophenyl, 6-chloro-2,4-dibromophenyl, 2,4-dibromo-6-forfinal, 2,4-dibromo-6-were, 2,4-dibromo-6-methoxyphenyl, 2,4-dibromo-6-methylthiophenyl, 2,6-dibromo-4-isopropylphenyl, 2,6-dibromo-4-triptoreline, 2-bromo-4-triptoreline, 4-bromo-2-chlorophenyl, 2-bromo-4-chlorophenyl, 4-bromo-2-were, 4-chloro-2-were, 2,4-acid, 2,6-dimethyl-4-methoxyphenyl, 4-chloro-2,6-dibromophenyl, 4-bromo-2,6-differenl, 2,6-dichloro-4-triptoreline, 2,6-dichloro-4-trifloromethyl, 2,6-dibromo-4-trifloromethyl, 2-chloro-4,6-dimetilfenil, 2-bromo-4,6-acid, 2-bromo-4-isopropyl-6-methoxyphenyl, 2,4-dimethoxy-6-methylphen the l, 6-dimethylamino-4-methylpyridin-3-yl, 2-chloro-6-triptorelin-3-yl, 2-chloro-6-cryptomaterial-3-yl, 2-chloro-6-methoxypyridine-3-yl, 6-methoxy-2-triptorelin-3-yl, 2-chloro-6-diformylpiridine-3-yl, 6-methoxy-2-methylpyridin-3-yl, 2,6-dimethoxypyridine-3-yl, 4,6-dimethyl-2-cryptomaterial-5-yl, 2-dimethylamino-6-methylpyridin-3-yl, 6-dimethylamino-2-methylpyridin-3-yl, 2,3-dihydrobenzo[1,4]dioxin-5-yl and benzo[1,3]dioxol-4-yl, 5,7-dimethylbenzo[1,2,5]thiadiazole-4-yl, 5,7-dimethylbenzo[1,2,5]oxadiazol-4-yl, 2-isopropoxy-6-triptorelin-3-yl, 2-metakix-6-methylpyridin-3-yl, 2,6-dimethylpyridin-3-yl, 2-bromo-6-methoxypyridine-3-yl, 2-chloro-6-dimethylaminopyridine-3-yl, 2,6-dichloropyridine-3-yl, 2,4-dimethyl-6-dimethylaminopyridine-3-yl, 2,4,6-trimethylpyridine-3-yl, 2,4,6-trimethylpyridine-5-yl, 4,6-dimethyl-2-dimethylaminopyridine-5-yl, 5-iodine-3-methylpyridin-2-yl, 3-methyl-5-methylaminomethyl-2-yl, 3-dimethylamino-5-methylpyridin-2-yl, 5-methyl-3-methylaminomethyl-2-yl, 3-chloro-5-methylpyridin-2-yl, 3-amino-5-methylpyridin-2-yl, 5-methyl-3-nitropyridine-2-yl, 5-diethylamino-3-methylpyridin-2-yl, 5-fluoro-3-methylpyridin-2-yl, 5-chloro-3-methylpyridin-2-yl, 5-dimethylamino-3-methylpyridin-2-yl, 5-amino-3-methylpyridin-2-yl, 3-methyl-5-nitropyridine-2-yl, 3-bromo-5-methylpyridin-2-yl, 4-chloro-2,5-acid, 4,5-dimethyl-2-methoxyphenyl, 5-fluoro-2,4-dimetilfenil, 2,4-dimethoxy-5-were, 2-chloro-4-methoxy-5-were, 2-chloro-5-f the PR-4-were, 2-bromo-4,5-acid, 2-bromo-5-fluoro-4-methoxyphenyl, 2-chloro-4,5-acid, 2,5-dichloro-4-methoxyphenyl, 2,4-dichloro-5-forfinal, 2-chloro-5-fluoro-4-methoxyphenyl, 2,4,5-trichlorophenyl, 2-chloro-5-fluoro-4-were, 5-fluoro-4-methoxy-2-were, 4,5-dimethoxy-2-were, 5-chloro-4-methoxy-2-were, 2,4,5-trimetilfenil, 6-methoxy-4-methylpyridin-3-yl, 4-methoxy-6-methylpyridin-3-yl, 4,6-dimethylpyridin-3-yl, 2-chloro-4-isopropylphenyl, 2-chloro-4-were, 4-amino-2-chlorophenyl, 2-chloro-4-dimethylcarbamoyl, 2-chloro-4-methylcarbamoylmethyl, 4-carbarnoyl-2-chlorophenyl, 2-chloro-4-methylsulfinylphenyl, 4-carboxy-2-chlorophenyl, 2-chloro-4-itfeel, 2-bromo-4-methylthiophenyl, 2-bromo-4-methylsulfinylphenyl, 2-bromo-4-dimethylaminophenyl, 2-bromo-4-methylsulfinylphenyl, 2-bromo-4-cyclopentylphenol, 2-bromo-4-tert-butylphenyl, 2-bromo-4-propylphenyl, 2-bromo-4-were, 2-bromo-4-trifloromethyl, 2-bromo-4-methoxyphenyl, 2-bromo-4-ethoxyphenyl, 4-isopropyl-2-methylsulfinylphenyl, 4-cyclopentyl-2-methylthiophenyl, 4-butyl-2-methylthiophenyl, 4-methoxy-2-methylthiophenyl, 2-methylthio-4-propylphenyl, 2-dimethylamino-4-isopropylphenyl, 2-iodine-4-isopropylphenyl, 2-fluoro-4-were, 2,4-differenl, 2-chloro-4-methoxyphenyl, 2-chloro-4-hydroxyphenyl, 4-cyano-2-methoxyphenyl, 4-bromo-2-methoxyphenyl, 2-methoxy-4-were, 4-chloro-2-methoxyphenyl, 2-hydroxy-4-were, 4-fluoro-2-methoxyphenyl, 2-hydroxy-4-were, 4-cyano-2-methoxyphenyl, 2-chloro-4-IU is eltigani, 2-methoxy-4-triptoreline, 4-isopropyl-2-methoxyphenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-ethoxycarbonylphenyl, 2-chloro-4-methylaminophenol, 4-cyano-2-triptoreline, 4-cyano-2-were, 2-methyl-4-trifloromethyl, 2-cyano-4-triptoreline, 4-carboxamido-2-triptoreline, 4-methoxy-2-triptoreline, 4-fluoro-2-were, 4-hydroxy-2-were, 4-methoxy-2-ethoxycarbonylphenyl, 2-ethyl-4-methoxyphenyl, 2-formyl-4-methoxyphenyl, 4-chloro-2-triptoreline, 4-dimethylamino-2-triptoreline, 4-deformedarse-2-were, 2-cyano-4-methoxyphenyl, 4-hydroxy-2-triptoreline, 4-isopropyl-2-triptoreline, 4-diethylamino-2-were, 4-fluoro-2-triptoreline, 4-propoxy-2-triptoreline, 4-dimethylamino-2-methylthiophenyl, 4-isopropyl-2-isopropylphenyl, 2-ethylthio-4-isopropylphenyl, 4-methylamino-2-methylthiophenyl, 2-methylthio-4-propionitrile, 4-acetyl-2-methylthiophenyl, 4-cyano-2-methylthiophenyl, 4-methoxy-2-methylthiophenyl, 4-ethyl-2-methylthiophenyl, 4-bromo-2-methylthiophenyl, 4-isopropyl-2-methylsulfinylphenyl, 2,4-dimethylthiophenol, 4,6-dimethyl-2-isopropylphenyl, 4,6-dimethyl-2-isopropylphenyl, 2-acetyl-4,6-dimetilfenil, 2,6-dimethyl-4-triptoreline, 2,6-dimethyl-4-isopropylphenyl, 4-acetyl-2,6-dimetilfenil, 2,4,6-triethylene, 4,6-dimethyl-2-methylthiophenyl, 4,6-dimethyl-2-itfeel, 2-formatosi-4,6-dimetilfenil, 4,6-dimethyl-2-isopropoxyphenyl, 4,6-dimethyl-2-e is oxetanyl, 2,6-dichloro-4-ethoxyphenyl, 2-bromo-4,6-acid, 2-bromo-6-hydroxy-4-methoxyphenyl, 2,6-dibromo-4-ethoxyphenyl, 4-bromo-2-methoxy-6-were, 2,6-dibromo-4-methoxyphenyl, 4,6-dibromo-2-trifloromethyl, 2,4-dibromo-6-triptoreline, 4-bromo-2-chloro-6-were, 4-chloro-2,6-acid, 2,4-dichloro-6-methoxyphenyl, 4,6-dichloro-2-methylthiophenyl, 4,6-dichloro-2-triptoreline, 2,6-dimethoxy-4-ethylphenyl, 4,6-dimethyl-2-methoxyphenyl, 2,6-dimethoxy-4-were, 2-chloro-6-methoxy-4-were, 4,6-dimethyl-2-ethoxyphenyl, 6-hydroxy-2,4-dimetilfenil, 4-cyano-2-methoxy-6-were, 6-fluoro-2-methoxy-4-were, 4-acetyl-2-methoxy-6-were, 2-chloro-4,6-acid, 2,6-dimethoxy-4-ethoxyphenyl, 2,4,6-trimethoxyphenyl, 4,6-dibromo-2-trifloromethyl, 2-bromo-4-dimethylamino-6-methoxyphenyl, 4-bromo-2-methoxy-6-were, 4,6-dimethoxy-2-propoxyphenyl, 4,6-dichloro-2-propoxyphenyl, 2-bromo-6-hydroxy-4-methoxyphenyl, 2,4,6-tryptophanyl, 2-bromo-6-fluoro-4-were, 4 deformedarse-2,6-dimetilfenil, 2,6-dimethyl-4-ethoxyphenol, 2,6-dimethyl-4-isopropoxyphenyl, 2,6-dimethyl-4-methylthiophenyl, 2,6-dimethyl-4-methylsulfinylphenyl, 2,6-dimethyl-4-methylsulfinylphenyl, 2,3-dichlorophenyl, 4-methoxy-2,3-dimetilfenil, 2-chloro-3-fluoro-4-methoxyphenyl, 2,3,4-trichlorophenyl, 4-methoxy-2,5-dimetilfenil, 4-cyano-2,6-dimetilfenil and 4-fluoro-2,6-dimetilfenil.

“Pharmaceutically acceptable salt” in the present invention include, for example, the R, salt with inorganic acid, such as sulfuric, hydrochloric, Hydrobromic acid, phosphoric acid, nitric acid or similar; salts with organic acid such as acetic, oxalic, lactic, tartaric, fumaric, maleic, citric acid, benzolsulfonat, methanesulfonate, p-toluensulfonate acid, camphorsulfonate, econsultancy, glucoheptonate, gluconic, glutamic, glycolic, malic, malonic, almond, galactosemia, naphthalene-2-sulfonic acid or similar; salts with one or more metal ions such as lithium ions, sodium, potassium, calcium, magnesium, zinc, aluminum or similar; salt with niinami, such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine, or similar.

Compounds of the present invention includes all isomers such as diastereomers, enantiomers, geometric isomers and tautomeric forms. In the compound represented by the formula [I], if a cyclic amino group has one or more chiral carbon atoms and/or if there is axelina chirality between Ar and pyrrolopyrimidine (or pyrrolopyridine) ring, there can be multiple stereoisomers (diastereomers or enantiomers). The compound of the present invention includes all of the individual isomer is in and racemic and non-racemic mixtures of isomers.

Preferred examples of the compounds of the present invention are as follows.

Namely, preferred are compounds represented by the following formula [I]:

(in which the cyclic amino group represented by the following formula [II]:

in which the cyclic amino group is 3-8-membered saturated cyclic amine or a 3-8-membered saturated cyclic amine, coupled With1-5alkilinity or1-4alkylen-O-C1-4alkilinity bridge between any different two carbon atoms of the cyclic amine specified cyclic amine substituted by a group RA -(CR1R2)m-(CHR3)n-X, R4and R5independently the same or different carbon atoms of the cyclic amine;

X represents-CO2R9, -CON(R10R11, -P(O=)(R12R13or-S(=O)kR14;

Y is N or CR15;

R1represents hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;

R2represents hydrogen or C1-5alkyl;

R3represents hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;

m represents an integer selected from 0, 1, 2,3, 4 and 5;

n represents 0 or 1;

provided that when X represents-CO2R9or-CON(R10R11and n is 0, then m represents an integer selected from 1, 2, 3, 4 and 5;

R4represents hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;

R5represents hydrogen or C1-5alkyl;

R6represents hydrogen, C1-5alkyl, C3-8cycloalkyl,3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkane or-N(R16R17;

R7and R8are the same or different and independently represent hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl,3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkane, -N(R18R19, -CO2R20, cyano, nitro, C1-5alkylthio, trifluoromethyl or triptoreline; or R7and R8taken together to form-CH2-CH2-CH2-CH2or-CH=CH-CH=CH;

R9represents hydrogen, C1-10alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R10and R11are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R12and R13the two which are the same or different and independently represent-OR 21or-N(R22R23;

R14is-OR21or-N(R22R23;

k represents 1 or 2;

R15represents hydrogen, C1-5alkyl, halogen, cyano or-CO2R24;

R16and R17are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R18and R19are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R20represents hydrogen or C1-5alkyl;

R21represents hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R22and R23are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R24represents hydrogen or C1-5alkyl;

Ar represents aryl or heteroaryl, which are unsubstituted or substituted by one or more substituents, which are identical or different, selected from the group consisting of halogen, C1-5of alkyl, C3-8cycloalkyl,2-5alkenyl,2-5the quinil,1-5alkoxy, C1-5alkylthio,1-5alcalali the Nile, With1-5alkylsulfonyl, cyano, nitro, hydroxy, -CO2R25, -C(=O)R26, -CON(R27R28, -OC(=O)R29, -NR30CO2R31, -S(O)rN(R32R33, trifloromethyl, triptoreline, deformedarse, formatosi, methylendioxy, Ethylenedioxy and-N(R34R35;

R25represents hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R26represents hydrogen or C1-5alkyl;

R27and R28are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

R29represents hydrogen or C1-5alkyl;

R30represents hydrogen or C1-5alkyl;

R31represents hydrogen or C1-5alkyl;

R32and R33are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl;

r represents 1 or 2;

R34and R35are the same or different and independently represent hydrogen, C1-5alkyl, C3-8cycloalkyl or3-8cycloalkyl-C1-5alkyl, individual isomers, racemic or non-racemic mixtures of their isomers or N-oxide, or pharmaceutically acceptable with the Lee and hydrates.

More preferable are compounds represented by the formula [I]in which Y is N.

More preferable are compounds represented by the formula [I]in which Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4and R5represent hydrogen.

More preferable are compounds represented by the formula [I]in which Y is N; the cyclic amino group is a 4-7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4and R5represent hydrogen; R6is1-5alkyl; R7and R8are the same or different and are independently hydrogen or C1-5alkyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of halogen, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline and-N(R34R35(where R34and R35are the same or different and are independently hydrogen or C1-3alkyl).

More preferable are compounds represented by the formula [I]in which X represents-CO2H, -CONH2, -P(O=)(OH)2or-S(=O)2 HE; Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4and R5represent hydrogen; R6is1-3alkyl; R7and R8are the same or different and are independently hydrogen or C1-3alkyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline and dimethylamino. More preferable are compounds represented by the formula [I]in which X represents-CO2H; Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4and R5represent hydrogen; R6is methyl; R7and R8are the same or different and are independently hydrogen or methyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio and trifluoromethyl is.

Other preferred compounds are compounds represented by the formula [I]in which Y represents CR15. More preferable are compounds represented by the formula [I]in which Y represents CR15; m represents an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4and R5represent hydrogen; R15represents a hydrogen or halogen. More preferable are compounds represented by the formula [I]in which Y is CH; the cyclic amino group is a 4-7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4and R5represent hydrogen; R6is1-5alkyl; R7and R8are the same or different and are independently hydrogen or C1-5alkyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of halogen, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline and-N(R34R35(where R34and R35are the same or different and are independently hydrogen or C1-3alkyl). More preferable are compounds represented by the formula [I], to the second X represents-CO 2H, -CONH2, -P(O=)(OH)2or-S(=O)2HE; Y represents CH; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4and R5represent hydrogen; R6is1-3alkyl; R7and R8are the same or different and are independently hydrogen or C1-3alkyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline and dimethylamino. More preferable are compounds represented by the formula [I]in which X represents-CO2H; Y is CH; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4and R5represent hydrogen; R6is methyl; R7and R8are the same or different and are independently hydrogen or methyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C alkoxy, C1-3alkylthio and trifloromethyl.

Preferred cyclic amino group is a 6-membered saturated amine. Preferred X is-CO2H, -CONH2, -P(O=)(OH)2or-S(=O)2HE. More preferred X is-CO2H.

Preferred Y is N or CH.

Preferred R1represents hydrogen.

Preferred R2represents hydrogen.

Preferred R3represents hydrogen.

Preferred R4represents hydrogen.

Preferred R5represents hydrogen.

Preferred R6is1-3alkyl. More preferred R6represents methyl.

Preferred R7is1-3alkyl. More preferred R7represents methyl.

Preferred R8represents hydrogen or C1-3alkyl. More preferred R8represents hydrogen or methyl.

Preferred Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline and dimethylamino. Preferred Ar is phenyl, which is substituted by two or t is EMA substituents, which are the same or different, selected from the group consisting of chlorine, bromine and C1-3the alkyl.

Particularly preferred compounds of the present invention are:

{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}acetic acid

{1-[7-(4-bromo-2,6-dimetilfenil)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(4-bromo-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(4-chloro-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(4-chloro-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(2,6-dibromo-4-isopropylphenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(2,6-dibromo-4-isopropylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[3,6-dimethyl-1-(2,4,6-tribromophenyl)-1H-pyrrolo[2,-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(4-bromo-2,6-dichlorophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[3,6-dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(2,6-dibromo-4-chlorophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(2-bromo-4-isopropylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(4-isopropyl-2-methylsulfinylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

{1-[1-(2,4-dibromophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid

3-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(4-bromo-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidin-yl}-propionic acid

3-{1-[1-(4-chloro-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(4-chloro-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(2,6-dibromo-4-isopropylphenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(2,6-dibromo-4-isopropylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(4-bromo-2,6-dichlorophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[3,6-dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(2,6-dibromo-4-chlorophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(4-methoxy-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(2-bromo-4-isopropylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(4-isopropyl-2-methylsulfinylphenyl)-3,6-imethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

3-{1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid

4-{1-[1-(4-bromo-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-butyric acid

4-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-butyric acid

{8-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-8-azabicyclo[3.2.1]Oct-3-yl}-acetic acid

{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-3-yl}-acetic acid

2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-ndimethylacetamide

3-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionamide

{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-ylmethyl}-phosphonic acid

{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-methanesulfonamide acid

2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine--yl}-econsultancy acid

Amide 2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-econsultancy acid

{1-[7-(4-isopropyl-2-methylsulfinylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-acetic acid

4-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-butyric acid

2-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-3,3-dimethylpiperidin-4-yl}-ndimethylacetamide

2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetoxymethyl ether of 2,2-dimethyl-propionic acid

and ethyl ester of (S)-2-(2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetylamino)-3-phenylpropionic acid

Compounds represented by formula [I]can be obtained, for example, using the process shown in the following reaction schemes 1 to 4 [in the following reaction scheme, R1, R2, R3, R4, R5, R6, R7, R8, m, n, Y and Ar have the meanings defined above; L1L2and L3are the same or different and are represented is Aut independently chlorine, bromine, iodine, methanesulfonate, benzosulfimide, p-toluensulfonate or triftormetilfullerenov; Xarepresents-CN, CO2(C1-5alkyl), -CON(R10R11or-S(O)2N(R22R23; Xbis OR9or N(R10R11; Rarepresents C1-5alkyl; d represents an integer selected from 1, 2, 3, 4, 5 and 6; e and f are the same or different are independently integers selected from 1, 2 and 3].

Reaction scheme 1

Stage 1:

Connection (3), the compound of the present invention, can be obtained by reaction of the compound (1) with compound (2) in an inert solvent or without solvent in the presence or absence of a base. The base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and similar; inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and similar; a metal alcoholate such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and similar; amides of metals such as sodium amide, diisopropylamide lithium and similar; and Grignard reagents such as methylmagnesium and similar. The inert solvent includes, for example, SP is the mouths of such as methanol, ethanol, isopropyl alcohol, ethylene glycol and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene, xylene and similar; esters such as ethyl acetate, ethyl formate and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.

Stage 2:

When Xandrepresents a cyano, cyano can become carboxypropyl,1-5alkoxycarbonyl group or karbamoilnuyu group using acid or base in an inert solvent or without solvent. Here, the acid includes, for example, organic acids such as formic acid, acetic acid, triperoxonane acid, benzolsulfonat acid, methanesulfonate acid, p-toluensulfonate acid, benzoic acid, triftormetilfullerenov acid and similar; inorganic acids such as sulfuric acid, hydrochloric acid, Hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or similar. The base includes, for example, inorganic bases such as carbon is tons of sodium, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and similar; a metal alcoholate such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, tert-butanol, and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene, xylene and similar; esters such as ethyl acetate, ethyl formate and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.

Reaction scheme 2

Stage 3:

The hydroxy-group in the compound (5), which can be obtained by a method similar to that described in stage 1, can turn into a L2using the halogenation agent or sulphurouses agent in the presence or absence of a base in an inert solvent or without solvent. In this description of the halogenation reagent includes, for example, oxochloride phosphorus, exobrain phosphorus, pentachloride the FOSFA the RA, trichloride phosphorus, pentabromide phosphorus, tribromide phosphorus, thionyl chloride, thienylboronic, oxalicacid, oxalipatin, PPh3-CCl4, PPh3-CBr4and similar. Sulfonyloxy reagent includes, for example, p-toluensulfonate, methanesulfonate, p-toluensulfonyl anhydride, methanesulfonyl anhydride, triftormetilfullerenov anhydride, N-phenylbis(triftormetilfullerenov) and similar. The base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-diethylaniline and similar; inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and similar; a metal alcoholate such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and similar; amides of metals such as sodium amide, diisopropylamide lithium and similar; and Grignard reagents such as methylmagnesium and similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene, xylene and similar; esters such as ethyl acetate, atilt the MIAT and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.

When L2not an atom of iodine, L2can be transformed into an atom of iodine to implement the next stage using sodium iodide or potassium iodide in an inert solvent.

Stage 4:

L2in the Compound (6) can turn into a cyano by reaction of the compound (6) with a cyanide in the presence or absence of the phase transfer catalyst or crown-ether in an inert solvent. In this description cyanides include, for example, potassium cyanide, sodium cyanide and similar. The phase transfer catalyst includes, for example, tetrabutylammonium, tetrabutylammonium, tetrabutylammonium, tetrabutylammonium bisulfate, tetraethylammonium, Tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltriethylammonium, benzyltriethylammonium and similar. Crown-ether includes, for example, 15-crown-5, 18-crown-6 and similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, is trangleball and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene, xylene and similar; esters such as ethyl acetate, ethyl formate and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.

Stage 5:

Cyano in the compound (7) can be transformed into carboxypropyl or karbamoilnuyu group method similar to that described in stage 2.

Reaction scheme 3

Step 6:

The compound (6) can be transformed to Compound (9) with the reaction of the Compound (6) with trialkylphosphites. In this description, trialkylphosphites includes, for example, trimethylphosphite, triethylphosphite, triisopropylphosphine and similar.

Step 7:

The group of the phosphate ester in the Compound (9) can be either hydrolyzed using acid or base in an inert solvent. Here, the acid includes, for example, organic acids such as formic acid, acetic acid, triperoxonane acid, benzolsulfonat acid, methanesulfonate acid, p-toluensulfonate acid, benzoic acid, triftormetilfullerenov acid is one and the same; inorganic acids such as sulfuric acid, hydrochloric acid, Hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or similar. The base includes, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride and similar; a metal alcoholate such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene, xylene and similar; esters such as ethyl acetate, ethyl formate and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.

Step 8:

The compound (11) can be obtained by reaction of the compound (6) with sulfite in the presence or absence of the phase transfer catalyst or crown-ether in an inert solvent. In this description, the sulfite includes, for example, sodium sulfite, potassium sulfite and similar. Catalysis is Thor phase transfer includes, for example, tetrabutylammonium, tetrabutylammonium, tetrabutylammonium, tetrabutylammonium bisulfate, tetraethylammonium, Tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltriethylammonium, benzyltriethylammonium and similar. Crown-ether includes, for example, 15-crown-5, 18-crown-6 and similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene, xylene and similar; esters such as ethyl acetate, ethyl formate and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.

Reaction scheme 4

Step 9:

When Xbis not a hydroxy-group, the compound (13), the compound of the present invention can be synthesized from Compound (12) using the methods usual for amidation of carboxyl group, receipt of ester by ka is boxilai group or alkylation of carboxylate in the presence or absence of a base in an inert solvent. Conventional methods for amidation of carboxyl group or receipt of ester at the carboxyl group are: for example, the reaction of the mixed acid anhydride obtained by the interaction of the Compound (12) with a complex ether of halogenarenes acid (for example, etelcharge.com or isobutylparaben) or acid chloride of acid (for example, benzoyl chloride or revalorisation); the reaction in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCl), carbonyldiimidazole (CDI), diphenylphosphoryl (DPPA), diethylthiophosphate or similar, and optional additives, such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide, 4-dimethylaminopyridine or equivalent; or reaction with galogenangidridy obtained by the interaction of the compound (12) with a halogenation reagent such as thionyl chloride, oxalicacid or similar; the usual method for alkylation of carboxytherapy is the reaction with the alkylating reagent, such as alkylhalogenide or alkylsulfonate in the presence or absence of additives to accelerate the reaction, such as NaI or KI. When R9contains alkoxycarbonyl group, alkoxycarbonyl group can become carboxypropyl using the method described in Protective Group in Organic Synthesi (T.W. Greene, P. G. M. Wuts; 3rded., 1999, John Wiley & sons, Inc.). The base includes amines such as triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and similar; inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium hydride and similar; a metal alcoholate such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and similar. The acid includes, for example, organic acids such as formic acid, acetic acid, triperoxonane acid, benzolsulfonat acid, methanesulfonate acid, p-toluensulfonate acid, benzoic acid, triftormetilfullerenov acid and similar; inorganic acids such as sulfuric acid, hydrochloric acid, Hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; DIMET sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.

Reaction scheme 5

Step 10:

Connection (15), the compound of the present invention can be obtained by the reaction of compound (6) with compound (14) in the presence or absence of a base in an inert solvent. The base includes amines such as triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and similar; inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride and similar; a metal alcoholate such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.

Reaction scheme 6

Stage 11:

The compound (1) can be obtained by the reaction of the compound (16) with Compound (17) in the presence or absence of a base in an inert solvent or without solvent. The base includes amines such as triethylamine, N,N-diisopropylethylamine, or pyridine and similar; inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and similar; a metal alcoholate such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and similar; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.

The compound of the present invention can be converted into a salt in an inert solvent with an inorganic acid, such as sulfuric acid, hydrochloric acid, Hydrobromic acid, phosphoric acid, nitric acid or similar, with an organic acid, such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzols Lifanova acid, methansulfonate acid, p-toluensulfonate acid, benzoic acid, camphorsulfonic acid, econsultancy acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactosemia acid, naphthalen-2-sulfonic acid or similar, with an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, or equivalent, or with an organic base, such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine 2-aminoethanol, benzathine, or similar. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and similar; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and similar; hydrocarbons such as benzene, toluene and similar; esters such as ethyl acetate, ethyl formate and similar; ketones such as acetone, methyl ethyl ketone and similar; amides such as N,N-dimethylformamide, N-organic, N,N-dimethylacetamide and similar; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these is inert solvents.

The compound of the present invention is useful as a therapeutic or preventive agent against diseases for which it is believed that they involve CRF. For this purpose, the compound of the present invention is administered in dosage forms as tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections and similar, using conventional technologies for the addition of conventional fillers, binding agents, disintegrators, pH-regulating agents, solvents, etc.

The compound of the present invention may be administered for the treatment of an adult patient in a dose of 0.1-500 mg per day in one portion or several portions orally or parenterally. The dose may be appropriately increased or decreased depending on the type of disease and age, body weight and symptoms of the patient.

The EMBODIMENT of the INVENTION

The present invention is explained in detail with reference to the following examples and examples, tested, but not limited to.

Example 1

Synthesis of {1-[1-(4-methoxy-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetic acid (compound 1-013)

(1) In nitrogen atmosphere, to a mixture of 1-(4-methoxy-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-ol (1.5 g), triethylamine (1.0 g) in CHClsub> 3(9 ml) was added triftormetilfullerenov anhydride (1.0 ml) with cooling in an ice bath, and the mixture was stirred for 30 minutes. The reaction extinguished with water and the mixture was extracted with CHCl3. The organic phase is washed with saturated aqueous NaHCO3, dried over MgSO4and filtered. The filtrate was concentrated under reduced pressure, obtaining the crude 1-(4-methoxy-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-ilen ether triftormetilfullerenov acid (2,19 g). This substance is used in the next stage without further purification.

(2) a Mixture of crude 1-(4-methoxy-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-ilen ether triftormetilfullerenov acid (1.1 g), N,N-diisopropylethylamine (0.65 g) and piperidine-4-yl-acetonitrile (1.6 g) was heated at 150°C in a sealed tube for 7 hours. After cooling to room temperature, the mixture is poured into ethyl acetate and water, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over MgSO4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent:hexane:ethyl acetate=3/1)to give {1-[1-(4-methoxy-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetonitrile (0,58 g) in the form bled the yellow crystals.

(3) a Mixture of {1-[1-(4-methoxy-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetonitrile (0.40 g) and conc. HCl (4 ml) was heated at the boil under reflux for 5 hours. After cooling to room temperature, conc. HCl was removed under reduced pressure. To the residue was added a saturated aqueous solution of NaHCO3and CHCl3and the mixture was separated. The aqueous phase was extracted with CHCl3. The organic phase is washed with 5% aqueous solution of KHSO4, dried over MgSO4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: CHCl3:methanol=40/1) and the resulting solid was rinsed with methanol, receiving the connection specified in the header (0.21 g).

Example 2

Synthesis of 3-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-propionamide (connection 1-040)

(1) Suspension of 7-(4-bromo-2,6-dimetilfenil)-4-chloro-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g), 3-(piperidine-4-yl)propionitrile (1.4 g) and N,N-diisopropylethylamine (1.4 g) in EtOH (4 ml) was heated at 100°C in a sealed tube for 11 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified using colonics the th chromatography (silica gel: Wako gel C200, eluent:hexane:ethyl acetate: CHCl3=8/2/1)to give 3-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-propionitrile (2.0 g) as white crystals.

(2) 3-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-propionitrile (0.40 g) was added H2SO4(4 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured on ice and then podslushivaet addition of 4M aqueous NaOH solution. The mixture was extracted with ethyl acetate and the organic phase was dried over Na2SO4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakogel C200, eluent: CHCl3:methanol=60/1), receiving the oil. The oily product was led from diethyl ether, obtaining the target compound (0.33 g) as white crystals.

Example 3

Synthesis of the hydrochloride (2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-ethyl)-phosphonic acid (compound 1-046)

(1) To a solution of 2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-ethanol (0,93 g), which was obtained by the method similar to that described in example 1 in CHCl3(10 ml), was added to methanesulfonanilide (0,47 g) and pyridine (0.64 g) and the mixture was stirred at room temperature for 3 hours. In the reaction mixture was added water and the mixture was extracted with CHCl3. The organic phase is washed with water and brine, dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure, obtaining a brown oil. The oily product was led from diisopropyl ether, receiving 2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-ethyl ester methanesulfonic acid (1.0 g).

(2) a Mixture of 2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-ethyl ester methanesulfonic acid (0,70 g) and NaI (0,59 g) in acetone (14 ml) was heated at the boil under reflux for 3 hours. After cooling to room temperature was added water and the mixture was extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=10/1)to give 1-(4-bromo-2,6-dimetilfenil)-4-[4-(2-Iodate)-piperidine-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.65 g) as white crystals.

(3) In a nitrogen atmosphere, a mixture of 1-(4-bromo-2,6-dimetilfenil)-4-[4-(2-Iodate)-piperidine-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.25 to whom) and triethylphosphite (10 ml) was heated at 160°C for 4.5 hours. After the reaction was completed, excess triethyl phosphate was removed under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=1/1)to give a colorless oil. The oily product was led from diisopropyl ether(10 ml)to give diethyl ether 2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-ethyl)-phosphonic acid (0.16 g) as white crystals.

(4) a Mixture of diethyl ether 2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-ethyl)-phosphonic acid (67 mg) and 6M HCl (4 ml) was heated at the boil under reflux for 10 hours. Then add 12 M HCl (2 ml) and the reaction mixture was heated at the boil under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, giving the target compound in the form of an amorphous substance (13 mg).

Example 4

Synthesis of 2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-econsultancy acid (compound 1-048)

A mixture of 1-(4-bromo-2,6-dimetilfenil)-4-[4-(2-Iodate)-piperidine-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.25 g), Na2SO3(0.28 g), tetrabutylammonium (16 mg), ethanol (5 ml), tetrahydrofuran (5 ml) and water is (3 ml) was heated at the boil under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: ethyl acetate:methanol=5/1)to give the target compound (56 mg) as a yellow amorphous substance.

Example 5

Synthesis of the hydrochloride of ethyl ether {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid (compound 1-050)

To a solution of {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetic acid (100 mg) in CHCl3(4 ml) in an ice cooling bath, was added ethanol (20 mg), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (61 mg) and dimethylaminopyridine (26 mg)and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ethyl acetate and water and separated. The organic phase is washed with saline, dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=4/1)to give ethyl ester of {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid (99 mg). Ethyl ester {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid astrals in ethanol (2 ml) and the solution while cooling in an ice bath, was added a solution (60 ml), 4M HCl in ethyl acetate. After stirring at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was led from diisopropyl ether (1 ml). The crystals were filtered, obtaining the target compound (95 mg).

Example 6

Synthesis of 1-cyclohexyloxycarbonyloxy ether {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetic acid (compound 1-071)

Suspension of the hydrochloride {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetic acid (300 mg), 1-chlorotestosterone (293 mg), potassium carbonate (196 mg) and NaI (213 mg) in DMF (3 ml) was heated at 60°C for 3 hours. After cooling to room temperature, added water and the mixture was extracted with ethyl acetate. The organic phase is washed with brine and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakogel C200, eluent: hexane:ethyl acetate=4/1)to give the target compound (225 mg) as a colourless oil.

Example 7

Synthesis of (S)-2-(2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetylamino)-3-phenylpropionic acid (compound 1-074)

(1) To a solution of hydrochloride {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetic acid (300 mg), the hydrochloride of L-phenylalaninamide ester (204 mg), 1-hydroxybenzotriazole (108 mg) and triethylamine (90 mg) in DMF (3 ml) in a cooling bath of ice, was added the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (170 mg)and the mixture was stirred at room temperature for 4 hours. In the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous NaHCO3and brine, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=1/1)to give ethyl ester of (S)-2-(2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetylamino)-3-phenylpropionic acid (222 mg) as a colourless oil.

(2) a Mixture of ethyl ester of (S)-2-(2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetylamino)-3-phenylpropionic acid (140 mg), 4M NaOH (1 ml) and EtOH (2 ml) was stirred at room temperature for 24 hours. In the reaction mixture was added a 1M solution of KHSO4(10ml)and the mixture was extracted with ethyl acetate. The organic phase is washed with saline and conc who was narrowly under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: CHCl3:MeOH=9/1)to give the target compound (35 mg) as an amorphous substance.

Example 8

Synthesis of ethyl ester of 4-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-2-cyano-butterboy acid (compound 1-063)

In nitrogen atmosphere, to a solution of ethyl ester tsianuksusnogo acid (93 mg) in THF (3 ml) was added sodium hydride (33 mg) and the mixture was stirred for 30 minutes. Then added 2-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-ethyl ester methanesulfonic acid (300 mg), and the mixture was heated at the boil under reflux for 3 hours. Was added ethyl ether tsianuksusnogo acid (93 mg)and the reaction mixture was heated at the boil under reflux for 1 hour. And then was added NaI (7 mg), and the mixture was heated at the boil under reflux for 2 hours. After cooling to room temperature, the reaction mixture was added a 5% aqueous solution of KHSO4and the mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4and was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane:e is ylacetic=4/1), receiving the target compound (57 mg) as a colourless oil.

Example 9

Synthesis of {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetic acid

(1) a Mixture of 1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-ylamine (10.0 g), 3-cyanomethyl-5-methanesulfonylaminoethyl ether methanesulfonate acid (11.3 g) and N,N-diisopropylethylamine (of 8.25 g) in N-organic (10 ml) was heated at 135°C for 4 hours. To the reaction mixture were added 3-cyanomethyl-5-methansulfonate-pentalogy ether methanesulfonate acid (2,60 g), and the mixture was heated at 135°C for 4.5 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ethyl acetate, hexane and water (10/1/3) and shared. The aqueous phase was extracted with a mixture of ethyl acetate and hexane (10/1). The combined organic phase was washed with saline, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate:CHCl3=4/1/0,5), receiving solid. The solid is crystallized from diisopropyl ether, obtaining {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetonitrile (8,61 g) as a solid.

(2) a Mixture of {1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetonitrile (10.0 g) and concentrated HCl (100 ml) was heated at the boil under reflux for 10 hours. After evaporation of concentrated HCl under reduced pressure, to the residue was added an aqueous solution of NaHCO3and CHCl3and the mixture was distributed. The organic phase is washed with water, 1M aqueous solution of KHSO4and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=1/1)to give a solid. The solid was led from EtOH and washed with water, obtaining the target compound (6.0 g) in the form of crystals.

Reference example 1

Synthesis of 3-cyanomethyl-5-methanesulfonylaminoethyl ether methanesulfonate acid

(1) To a solution of dimethyl 3-oxoglutarate acid (523 g) in toluene (750 ml) was added zanoxolo acid (511 g), NH4OAc (46,3 g) and acetic acid (90,1 g) and was heated at the boil under reflux, with de-hydration using traps Dean-stark for 8 hours. After cooling to room temperature, the reaction mixture was washed with water, saturated aqueous NaHCO3and a salt solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure, obtaining the crude dimethyl 3-cyanometallates acid (403 g) in the form of oil.

1H NMR (200 MHz, CDCl3) δ ppm 3,39 (d, J=0,88 Hz, 2H), 3,62 (s, 2H), and 3.72 (s, 3H), 3,74 (s, 3H), 5,51 (s, 1H).

(2) To a solution of the crude dimethyl 3-cyanometallates acid (403 g) in methanol (500 ml) was added 5% Pd-C and the mixture was stirred at room temperature for 4 days. Pd-C was removed by filtration and the filtrate was concentrated under reduced pressure, obtaining the (untreated) dimethyl ether 3-cyanometallates acid (212 g). The residue was purified by distillation, obtaining the crude dimethyl 3-cyanometallates acid (tripedia 130-150°C, 133 PA) as a yellow oil.

1H NMR (200 MHz, CDCl3) δ ppm 2,46-2,61 (m, 5H), 2,62-2,78 (m, 4H), 3,71 (C, 6N).

(3) In an atmosphere of nitrogen, dimethyl ether 3-cyanometallates acid (212 g) was added to a suspension of LiAlH4(50.0 g) in THF (1.8 l) at -20°C. After stirring for 30 minutes, the reaction mixture was slowly added water (200 ml). The insoluble substance was removed by filtration and the filtrate was concentrated under reduced pressure, obtaining 5-hydroxy-3-(2-hydroxyethyl)-pentenenitrile (131 g).

1H NMR (200 MHz, CDCl 3) δ ppm 1,38 is 1.91 (m, 4H) 1,98-of 2.36 (m, 1H) 2,50 (d, J=5,71 Hz, 2H) 3,51-3,90 (m, 4H).

(4) In a nitrogen atmosphere, a solution of 5-hydroxy-3-(2-hydroxyethyl)-pentenenitrile (100 g) and Et3N (170 g) in THF (500 ml) was cooled to -15°C. and to it was slowly added MsCl (168 g)and the mixture was stirred at room temperature for 1.5 hours. Once added to the reaction mixture water (1.2 l), and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and dried, obtaining the target compound (145 g) as pale brown crystals.

1H NMR (200 MHz, CDCl3) δ ppm 1,65-of 2.09 (m, 5H), 2,68 (d, J=5,75 Hz, 2H), 3,20 (C, 6N), the 4.29 (t, J=6,45 Hz, 4H).

*1: Connection no. = number of connections, Approx.No. = the number of the example, the solvent for crystallization: EtOAc = ethyl acetate; MeOH = methanol, EtOH = ethanol, IPE = diisopropyl ether, Et2O = diethyl ether, THF = tetrahydrofuran (THF)

Analytical data of non-crystalline compounds are presented below.

1-045:

MS (ES, negative): 504 (M-1)-, 506 (M+1)+; NMR (300 MHz, DMSO-d6) δ 1,33 was 1.69 (4H, m), 1,75 and 2.13 (3H, m), 1,88 (6N, (C), 2,42 (3H, d, J=1.1 Hz), 2,47 (3H, m), 2,80-of 3.25 (2H, m), 3,63-of 3.97 (2H, m), 6,77 (1H, users), 7,19 (1H, users), 7,507,62 (2H, m).

1-046:

MS (ES, negative): 518 (M-1)-, 520 (M+1)+; NMR (300 MHz, DMSO-d6) δ 1.18 to 1,98 (N, m)1,88 (6N, (C), 2,42 (3H, d, J=0.9 Hz), 2,80-of 3.27 (2H, m), 3,65-of 3.94 (2H, m), 6,60-6,85 (1H, m), 7,08-7,22 (1H, m), 7,19 (1H, users), 7,50 to 7.62 (2H, m).

1-047:

MS (ES, negative): 504 (M+1)-, 506 (M+1)+; NMR (300 MHz, DMSO-d6) δ 1.30 and of 2.53 (2H, m), 1,74-of 2.15 (3H, m), 1,84 (6N, (C), 2,32 (3H, s), 2,43 (3H, d, J=1.1 Hz), 2,47 (2H, d, J=6.4 Hz), 2,62-2,78 (2H, m), 3,36-to 3.52 (2H, m), 6,47 (1H, s), 6,94-6,98 (1H, m), 7,44 (2H, s).

1-048:

MS (ES, negative): 518 (M-1)-, 520 (M+1)+; NMR (300 MHz, DMSO-d6) δ 1,20-1,87 (7H, m), 1,84 (6N, (C), 2,40-2,60 (2H, m), 2,43 (3H, d, J=0.9 Hz), 2.49 USD (3H, s), 2,60-of 2.75 (2H, m), 3,41-3,55 (2H, m), 6,46 (1H, s), 6,94-6,97 (1H, m), 7,44 (2H, s).

1-063:

MS (ES, positive): 566 (M+1)+, 568 (M+3)+; NMR (300 MHz, CDCl3) δ 1,28-1,70 (6N, m)of 1.35(3H, t, J=7,1 Hz), 1,72-2,12 (3H, m), 1,84 (6N, (C), of 1.94 (3H, s), is 2.37 (3H, s), 2.49 USD (3H, s), 2,82-of 3.00 (2H, m), 3.46 in-3,55 (1H, m), 3,90-4.09 to (2H, m), 4,30 (2H, square, J=7,1 Hz), 7,33 (2H, s).

1-067

MS (ES, positive): 566 (M+1)+, 568 (M+3)+; NMR (300 MHz, CDCl3) δ of 0.90 and 1.35 (4H, m)of 1.45 and 1.80 (10H, m), 1,82-of 2.05 (2H, m), 1,92 (6N, (C), a 2.36 (2H, d, J=7,00 Hz), 2,44 (3H, s), 2.49 USD (3H, s), 2,70-to 2.85 (2H, m), 3,52-3,61 (2H, m), 3,92 (2H, d, J=6,37 Hz), to 6.43 (1H, s), 6,59-only 6.64 (1H, m), 7,29 (2H, s).

1-068

MS (ES, positive): 594 (M+1)+, 596 (M+3)+; NMR (300 MHz, CDCl3) δ 1,50-of 1.65 (4H, m), 1,80-2,00 (1H, m), 1,92 (6N, C)to 2.41 (2H, d, J=7,00 Hz), 2,44 (3H, s), a 2.45-2.49 USD (3H, m), 2,70-and 2.83 (2H, m), 3,50-3,62 (2H, m), 5,11 (2H, s), 6.42 per (1H, s), 6,59-only 6.64 (1H, m), 7,25-7,40 (6N, m).

1-069

MS (ES, positive): 555 (M+1)+, 557 (M+3)+; NMR (300 M is C, CDCl3) δ 1,48 is 1.70 (4H, m), 1,78-of 1.95 (3H, m), 1,92 (6N, in), 2.25 (6N, (C), a 2.36 (2H, d, J=7,00 Hz), 2,44 (3H, s), 2,46-of 2.50 (3H, m), 2,70-2,82 (2H, m), 3,52-3,62 (2H, m), 6.42 per (1H, s), 6,59-6,63 (1H, m), 7,29 (2H, C).

1-070

MS (ES, positive): 606 (M+1)+, 608 (M+3)+; NMR (200 MHz, CDCl3) δ 1,42-of 1.78 (4H, m)to 1.60 (3H, s), 1.69 in (3H, s)of 1.73 (3H, s), 1,80 is 1.96 (1H, m), 1,92 (6N, (C), 2,01-to 2.18 (4H, m), a 2.36 (2H, d, J=6,80 Hz), 2,44 (3H, s), 2,46 is 2.51 (3H, m), 2,68-to 2.85 (2H, m), 3,49-3,63 (2H, m), 4,63 (2H, d, J=7,00 Hz), 5,03-of 5.15 (2H, m), and 5.30-5,42 (2H, m), 6.42 per (1H, s), 6,58-6,63 (1H, m), 7,29 (2H, s).

1-071

MS (ES, positive): 640 (M+1)+, 642 (M+3)+; NMR (300 MHz, CDCl3) δ 1,20-1,62 (10H, m), and 1.54 (3H, d, J=5,40 Hz), 1.70 to to 1.82 (2H, m), 1,82-2,04 (3H, m), 1,92 (6N, (C), 2,37-to 2.42 (2H, m), is 2.44 (3H, s), 2,46-of 2.50 (3H, m), 2,70-2,82 (2H, m), 3,49-3,61 (2H, m), 4,58-4,70 (1H, m), 6.42 per (1H, s), 6,59-6,63 (1H, m), to 6.80 (1H, square, J=5,40 Hz), 7,29 (2H, s).

1-072

MS (ES, positive): 584 (M+1)+, 586 (M+3)+; NMR (300 MHz, CDCl3) δ 1,23 (N, C), 1,50-of 1.65 (4H, m), 1,82 is 1.91 (1H, m), 1,92 (6N, (C), 2,43 (2H, d, J=6,99 Hz), a 2.45 (3H, s), 2,46-of 2.50 (3H, m), 2.71 to 2,82 (2H, m), 3,50-3,61 (2H, m), 5,79 (2H, s), 6.42 per (1H, s), 6,59-6,63 (1H, m), 7,29 (2H, s).

1-073

MS (ES, positive): 645 (M+1)+, 647 (M+3)+; NMR (300 MHz, CDCl3) δ of 1.27 (3H, t, J=7,15 Hz), 1,40-to 1.61 (3H, m), 1.70 to at 1.91 (2H, m), 1,92 (6N, (C), 2,17-of 2.23 (2H, m), of 2.45 (3H, s), 2,46-2,49 (3H, m), 2,69-of 2.81 (2H, m), 3,14 is 3.23 (2H, m), 3,48-3,59 (2H, m), 4,20 (2H, square, J=7,15 Hz), 4,91-to 4.98 (1H, m), of 5.89-to 5.93 (1H, m), 6.42 per (1H, s), 6,59-6,63 (1H, m), 7,10-to 7.18 (2H, m), 7,22-7,37 (5H, m).

1-075

MS (ES, positive): 598 (M+1)+, 600 (M+3)+; NMR (300 MHz, CDCl3) δ 1.18 to 1,43 (N, m), 1,50-1,72 (7H, m), 1,83 e 2.06 (2H, m), 1,92 (6N, C)to 2.35 (2H, d, J=6.9 Hz), of 2.45 (3H, s), 2,47-of 2.50 (3H, m), 2.71 to 2,84 (2H, m), 3,50 at 3.69 (4H, m), 4,10 (2H, d, J=6,68 Hz), 6.42 per (1H, s), 6,60-6,63 (1H, m), 7,29 (2H, s).

1-076

MS (ES, positive): 611 (M+1)+, 613 (M+3)+; NMR (300 MHz, CDCl3) δ 0,95-1,05 (6N, m)of 1.29 (3H, t, J=7,15 Hz), 1,48-1,77 (6N, m), 1,83-to 2.18 (2H, m), 1,92 (6N, in), 2.25 (2H, d, J=6,99 Hz), 2,44 (3H, s), 2,47-of 2.50 (3H, m), 2,70-and 2.83 (2H, m), 3,49-3,62 (2H, m), 4,20 (2H, square, J=7,15 Hz), 4,60-4,72 (1H, m), of 5.85 (1H, d, J=8,24 Hz), 6.42 per (1H, s), 6,59-6,62 (1H, m), 7,29 (2H, s).

1-077

MS (ES, positive): 556 (M+1)+, 558 (M+3)+; NMR (300 MHz, CDCl3) δ of 1.30 (3H, t, J=7,15 Hz), 1,50-1,70 (3H, m), 1.85 to to 2.15 (2H, m), 1,92 (6N, (C), 2,40-of 2.50 (2H, m), is 2.44 (3H, s), 2,47-of 2.50 (3H, m), 2,72-2,84 (2H, m), 3,52-3,62 (2H, m), 4,24 (2H, square, J=7,15 Hz), with 4.64 (2H, s), to 6.43 (1H, s), 6,59-6,63 (1H, m), 7,29 (2H, s).

1-078

MS (ES, positive): 643 (M+1)+, 645 (M+3)+, 647 (M + 5)+, 649 (M+7)+; NMR (300 MHz, CDCl3) δ 1,45-2,05 (N, m), 2,43 is 2.46 (3H, m), 2,52 (3H, s), to 2.57 (2H, t, J=7,07 Hz), 2,82-3,03 (2H, m), 3,47 of 3.56 (1H, m), 4,10-of 4.25 (2H, m), 6,59-6,63 (1H, m), 7,82 (2H, s).

1-082

MS (ES, positive): 465 (M+1)+; NMR (300 MHz, CDCl3) δ 1,20-1,80 (10H, m), of 1.85 (3H, s)2,02 (3H, s), 2,2-2,43 (5H, m), of 2.51 (3H, m), 2,92-3,03 (2H, m), 3,13 (6N, (C), 3,91-Android 4.04 (2H, m), 6,44-6,48 (1H, m), of 7.96 (1H, s).

*2: 1 HCl salt

*3: After standing connection, purified using column chromatography, was obtained crystals.

The test example 1 [test binding of CRF receptor]

As a drug receptor was used membrane of the amygdala of the monkey.

As125I-labeled ligand was used125 I-CRF.

The binding reaction using125I-labeled ligand was performed using the following method, described in The Journal of Neuroscience, 7, 88 (1987).

Getting receptor membranes:

The amygdala of the monkey homogenized in 50 mm Tris-HCl buffer (pH 7.0)containing 10 mm MgCl2, 2 mm EDTA (ethylenediaminetetraacetic acid) and centrifuged at 48000 × g for 20 min and the precipitate was washed once with Tris-HCl buffer. The washed precipitate suspended in 50 mm Tris-HCl buffer (pH 7.0)containing 10 mm MgCl2, 2 mm EDTA, 0.1% of bovine serum albumin and 100 kallikrein units/ml Aprotinin, to obtain a preparation of the membrane.

Test the binding of CRF receptor:

The preparation of the membrane (0.3 mg protein/ml),125I-CRF (0.2 nm) and the test drug was subjected to reaction at 25°C for 2 hours. Upon completion of the reaction, the reaction mixture was filtered, Prokaeva under vacuum through a glass filter (GF/C), treated with 0.3% polyethylenimine, and the glass filter was washed three times with phosphate buffered saline containing 0.01% of Triton-X-100. After washing was measured radioactivity of the filter paper in a gamma counter.

The amount of bound125I-CRF, when the reaction was carried out in the presence of 1 μm CRF, took the degree of nonspecific binding125I-CRF, and the difference between the total degree swazilan the I 125I-CRF and the degree of nonspecific binding125I-CRF was accepted for the degree of specific binding125I-CRF. The curve of inhibition were obtained using the reaction of a certain concentration (0.2 nm)125I-CRF with different concentrations of each of the test drugs in the above-described conditions. Along the curve of inhibition was determined by the concentration of the test drug, in which binding125I-CRF inhibited by 50% (IC50).

In the result, it was found that the compounds 1-001, 1-002, nearby 1-003, 1-004, 1-005, 1-006, 1-007, 1-008, 1-009, 1-010, 1-011, 1-012, 1-014, 1-015, 1-016, 1-017, 1-018, 1-019, 1-020, 1-021, 1-022, 1-023, 1-024, 1-025, 1-026, 1-027, 1-028, 1-029, 1-030, 1-031, 1-032, 1-033, 1-034, 1-035, 1-039, 1-042, 1-045, 1-047, 1-048, 1-049, 1-053, 1-056, 1-061, 1-072, 1-073 can be examples of typical connection with figure IC50100 nm or less.

The test example 2 [test binding of δ receptor]

As a drug receptor used membranes of rat brain.

3H-DPDPE ([D-Pen2,D-Pen5]-encephalin) was used as a3N-labeled ligand.

The binding reaction using3N-labeled ligand was performed using the following method.

Getting receptor membranes:

Rat brain homogenized in 50 mm Tris-HCl buffer (pH 7.4)containing 10 mm MgCl2and 1 mm EDTA, and centrifuged at 48000×g for 20 min and the precipitate was washed once with Tris-HCl, Botero is. The washed precipitate suspended in 50 mm Tris-HCl buffer (pH 7.4)containing 10 mm MgCl2and 1 mm EDTA to obtain a preparation of the membrane.

Test the binding of the Delta opioid receptor:

The preparation of membranes (1 mg protein/ml),3H-DPDPE (1.5 nm) and the test drug was subjected to reaction at 25°C for 70 minutes. Upon completion of the reaction, the reaction mixture was filtered, Prokaeva under vacuum through a glass filter (GF/C), treated with 0.3% polyethylenimine, and the glass filter was washed three times with Tris-HCl buffer (pH 7.4)containing 10 mm MgCl2and 1 mm EDTA. After washing, the filters were added to scintillation cocktail and measured the radioactivity of the filter in a liquid scintillation counter.

The amount of bound3H-DPDPE, when the reaction was carried out in the presence of 10 μm of naltrindole, took the degree of nonspecific binding3H-DPDPE, and the difference between the total degree of binding3H-DPDPE and the degree of nonspecific binding3H-DPDPE was accepted for the degree of specific binding3H-DPDPE. The curve of inhibition were obtained using the reaction of a certain concentration (1.5 nm)3H-DPDPE with various concentrations of each of the test drugs in the above-described conditions. Along the curve of inhibition was determined by the concentration of the test drug, in which binding3H-DPDPE inhibits the I by 50% (IC 50).

In the result, it was found that the compounds 1-001, 1-002, nearby 1-003, 1-004, 1-005, 1-006, 1-011, 1-012, 1-016, 1-018, 1-019, 1-020, 1-021, 1-022, 1-025, 1-026, 1-027, 1-032, 1-045, 1-047 and 1-048 can be examples of typical compounds, with index IC50500 nm or less.

The EFFECT of the INVENTION

According to the present invention are provided compounds having high affinity against CRF receptors and/or δ receptors. These compounds have excellent pharmacokinetic properties, including metabolic stability, bioavailability and concentrations in the brain. These compounds are effective against diseases in respect of which it is believed that they involve CRF such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug addiction or dependence on drugs, cerebral infarction, cerebral ischemia, cerebral edema, the outer head wounds, inflammation associated with immune disease, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain and other

1. Derived pyrrolopyrimidine or pyrrolopyridine, substituted cyclic amino group represented by the following formula (I):

in the cyclic aminor the PAP represented by the following formula (II):

in which the cyclic amino group is a 6-membered saturated cyclic amine specified cyclic amine substituted amino group represented by -(CH2)mX;
X represents-CO2H, -CONH2, -P(=O)(OH)2or-S(=O)2OH;
Y represents N or CH;
m represents an integer selected from 1, 2 and 3;
R4represents hydrogen;
R5represents hydrogen;
R6is1-5alkyl;
R7and R8are the same or different and independently represent hydrogen, C1-5alkyl;
Ar represents phenyl, which is unsubstituted or substituted by one or more substituents, which are identical or different, selected from the group consisting of halogen,
With1-5of alkyl, C1-5alkoxy, C1-5alkylthio, trifloromethyl, triptoreline;
or their pharmaceutically acceptable salts.

2. Derived pyrrolopyrimidine, substituted cyclic amino group according to claim 1, represented by formula (I)in which Y is N; X, a cyclic amino group, m, R4, R5, R6, R7, R8and Ar have the meanings defined in claim 1; or their pharmaceutically acceptable salts.

3. Derived pyrrolopyrimidine, substituted cyclic amino group according to claim 1, represented by formula (I)in which X, qi is symbolic of the amino group, m, R4, R5, R6, R7, R8have the meanings given in claim 1; Y is N; Ar represents phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of halogen, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline, or their pharmaceutically acceptable salts.

4. Derived pyrrolopyrimidine, substituted cyclic amino group according to claim 1, represented by formula (I)in which X, a cyclic amino group, m, R4, R5have the meanings given in claim 1; R6represents C1-3alkyl; R7and R8are the same or different and are independently hydrogen or C1-3alkyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline, or their pharmaceutically acceptable salts.

5. Derived pyrrolopyrimidine, substituted cyclic amino group according to claim 1, represented by formula (I)in which X represents-CO2H; Y is N; the cyclic amino group, m R4and R5have the meanings given in claim 1; R6is methyl;
R7R 8are the same or different and are independently hydrogen or methyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio and trifloromethyl; or their pharmaceutically acceptable salts.

6. Derived pyrrolopyridine, substituted cyclic amino group according to claim 1, represented by formula (I)in which Y represents CH; X, a cyclic amino group, m, R4, R5, R6, R7, R8and Ar have the meanings defined in claim 1; or their pharmaceutically acceptable salts.

7. Derived pyrrolopyridine, substituted cyclic amino group according to claim 1, represented by formula (I)in which X, a cyclic amino group, m, R4, R5, R6, R7, R8have the meanings given in claim 1; Y is CH; Ar represents phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of halogen, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline, or their pharmaceutically acceptable salts.

8. Derived pyrrolopyridine, substituted cyclic amino group according to claim 1, represented by formula (I)in which X, cyclizes the second amino group, R4, R5have the meanings given in claim 1; R6represents C1-3alkyl; R7and R8are the same or different and are independently hydrogen or C1-3alkyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio, trifloromethyl, triptoreline, or their pharmaceutically acceptable salts.

9. Derived pyrrolopyridine, substituted cyclic amino group according to claim 1, represented by formula (I)in which X represents-CO2H; Y is CH; a cyclic amino group, m, R4, R5have the meanings given in claim 1; R6is methyl; R7and R8are the same or different and are independently hydrogen or methyl; Ar is phenyl, which is substituted by two or three substituents, which are identical or different, selected from the group consisting of chlorine, bromine, C1-3of alkyl, C1-3alkoxy, C1-3alkylthio and trifloromethyl; or their pharmaceutically acceptable salts.

10. Compounds represented by formula (I)according to claim 1, which is selected from the group consisting of the following:
{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-and the]-piperidine-4-yl}acetic acid,
{1-[7-(4-bromo-2,6-dimetilfenil)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(4-bromo-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(4-bromo~2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(4-chloro-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(4-chloro-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(2,6-dibromo-4-isopropylphenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(2,6-dibromo-4-isopropylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[3,6-dimethyl-1-(2,4,6-tribromophenyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(4-bromo-2,6-dichlorophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[3,6-dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(2,6-dibromo-4-chlorophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(2-bromo-4-isopropylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(4-isopropyl-2-methylsulfinylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
{1-[1-(2,4-dibromophenyl)-3,6-imethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}acetic acid,
3-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-b]pyrimidine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(4-bromo-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(4-chloro-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(4-chloro-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(2,6-dibromo-4-isopropylphenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(2,6-dibromo-4-isopropylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(4-bromo-2,6-dichlorophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[3,6-dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(2,6-dibromo-4-chlorophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(4-methoxy-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(2-bromo-4-isopropylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(4-isopropyl-2-methylsulfinylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
3-{1-[1-(2,4-dibromophenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionic acid,
4-{1-[1-(4-bromo-2,6-dimetilfenil)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-butyric acid,
4-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-butyric acid,
{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-3-yl}-acetic acid,
2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-acetamide", she
3-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-propionamide,
{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-ylmethyl}-phosphonic acid,
{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-methanesulfonamide acid,
2-{1-[1-(4-bromo-2,6-dimetilfenil)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-piperidine-4-yl}-econsultancy acid,
{1-[7-(4-isopropyl-2-methylsulfinylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-acetic acid,
4-{1-[7-(4-bromo-2,6-dimetilfenil)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-piperidine-4-yl}-butyric acid.

11. Antagonist of CRF receptors, including derived pyrrolopyrimidine or Pyrrhus is lepirudin, substituted cyclic amino group, its pharmaceutically acceptable salt according to any one of claims 1 to 10 as an active ingredient.

12. The application of the derived pyrrolopyrimidine or pyrrolopyridine, substituted cyclic amino group, its pharmaceutically acceptable salt according to any one of claims 1 to 10 for the production of an antagonist of CRF receptors.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a novel method of producing pyrrolo[2,3-d]pyrimidine derivatives of general formula V, which have protein kinase inhibiting properties, including a method of producing novel intermediate compounds. The method of producing compounds of formula V , where X1 is an activating group selected from chlorine, bromine, iodine, R1 is (C1-C6)alkyl; a is an integer from 0 to 4; R2 is hydrogen or (C1-C6)alkyl, involves linking an activated pyrrolopyrimidine compound of formula IIa , where L1 is a leaving group and X is an activating group selected from chlorine, bromine, iodide; with an amine of formula IIIa or its salt, where R1 is (C1-C6)alkyl; a is an integer from 0 to 4; R2 is hydrogen or (C1-C6)alkyl and P is a nitrogen protecting group labile to hydrogenolysis, such as benzyl; in the presence of a base to obtain a compound of formula IVa and subsequent removal from the obtained compound of formula IVa of the activating group X1 and the nitrogen protecting group P through hydrogenolysis in the presence of hydrogen or a hydrogen source and a catalyst in any order.

EFFECT: method increases output of the desired product.

26 cl, 8 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of modulating expression of a target gene induced by β-catenin using an agent which increases linkage of p300 with β-catenin and reduces linkage of CBP with β-catenin, involving bringing a composition containing β-catenin, CBP and p300, where β-catenin is more likely linked to CBP than p300, into contact with an agent in an amount which is effective for changing the probability of linking β-catenin to CBP compared to p300, where the said agent is a compound with a structure selected from formula (I), or its stereoisomers: where A represents -(C=O)-, B represents -(CHR4)-, D represents -(C=O)-, E represents -(ZR6)-, G represents -(XR7)n-> W represents (C=O)NH-, X represents nitrogen or CH, Z represents CH, n = 0 or 1. Values of substitutes R1 and R2 are indicated in the formula of invention. The invention also relates to a composition for modulating expression of a target gene induced by β-catenin.

EFFECT: novel compounds have useful biological properties.

9 cl, 7 tbl, 30 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) and their pharmaceutically acceptable salts which have PDE9A inhibition properties. In formula (I) R1 represents alkyl with 1-8 carbon atoms or cycloalkyl with 5-6 carbon atoms which, if necessary, can have up to three substitutes independently selected from: alkyl with 1-6 carbon atoms, hydroxy, halogen and trifluoromethyl, where the alkyl with 1-6 carbon atoms, if necessary, can be substituted with 1-3 substitutes independently selected from halogen and trifluoromethyl, R2 represents phenyl or aromatic mono- or bicyclic heteroaryl with 5-10 atoms in the ring and up to 5 heteroatoms selected from: sulphur, oxygen and/or nitrogen, where phenyl is substituted with 1-3 substitutes, and the heteroaryl, if necessary, can be substituted with 1-3 substitutes in each case independently selected from: alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, hydroxyl and halogen.

EFFECT: compounds can be used for preparing medicinal agents for enhancing perception, ability to concentrate, learning capability and memory enhancement.

9 cl, 1 dwg, 2 tbl, 78 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine-condensed derivatives of formula , where n is selected from 0, 1, 2, 3 and 4, Z1 is selected from N, C(O) and CR3, where R3 represents hydrogen, Z2 is selected from N and CR4, where R4 is selected from hydrogen and halogen, where the bond between Z1 and Z2 is selected from a single bond and a double bond, R1 is selected from C1-C4alkyl and C1-C4alkoxy, R2 is selected from NR5C(O)R6, C(O)NR5R6 and NR5R6, where R5 represents hydrogen, and R6 is selected from hydrogen, C1-C4alkyl and phenyl, where phenyl as R6 is optionally substituted with 1-2 radicals independently selected from a group comprising halogen(C1-C4)alkyl, heteroaryl(C0-C4)alkyl and heterocycloalkyl(C0-C4)alkyl, where any heteroaryl or heterocycloalkyl substitute R6 can be optionally substituted with a substitute independently selected from C1-C4alkyl and heterocycloalkyl, where the said heteroaryl and heterocyclyl represent a saturated or unsaturated 5-6-member ring containing 1 or 2 N atoms as a heteroatom, and to their pharmaceutically acceptable salts, hydrates, solvates and isomers. The invention also relates to a pharmaceutical composition base on a formula I compound and to use of formula I compound for preparing a medicinal agent which can be used for treating diseases or disorders associated with anomalous or disrupted kinase activity, primarily diseases or disorders related to anomalous activation of kinase Ab1, Bcr-Ab1, BMX, BTK, CHK2, c-RAF, CSK, c-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

EFFECT: novel compounds have useful biological properties.

7 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

where Xa represents 2 to 4 condensed cycloalkyl, aryl, heterocyclic rings containing 1 to 2 heteroatoms, chosen of N and O, and heteroaryl rings containing 1 to 4 heteroatoms, chosen of N, O or S where said rings can be additionally substituted. (Radical values R1-R4, R1, Y and n are specified in the patent claim), specific representatives of said compounds and a pharmaceutical composition containing them.

EFFECT: new compounds are effective in stimulation of endogenous development or release of growth hormone and can be used in treating obesity, osteoporosis and for increasing muscle bulk and muscle strength.

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of pyrazolo[1,5-a]pyrimidine with general formula 1 (values of radicals are given in the formula of invention), a pharmaceutical composition containing said derivatives and use of the novel compounds for preparing a medicinal agent for treating one or more diseases associated with cyclin-dependant kinalse CDK2.

EFFECT: novel compounds have useful biological properties.

36 cl, 87 tbl, 607 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: present invention relates to antagonists of serotonin 5-HT5 receptors with general formula 1 and their pharmaceutically acceptable salts and/or hydrates, particularly to substituted 3-sulphonyl-[1,2,3]triazolo[1,5-a]quinazolines and 3-sulphonyl-thieno[2,3-e][1,2,3]triazolo [1,5-a]pyrimidines, as active compounds for pharmaceutical compositions and medicinal agents, and methods of producing said compounds. In general formula 1 , Ar is a phenyl which is unsubstituted or substituted with halogen or at least one lower alkyl; R1 is a hydrogen atom or optionally substituted amine group, or optionally substituted 5-6 member azaheterocyclyl, bonded by a nitrogen atom to a carbon atom of a triazolopyrimidine ring with 1-2 heteroatoms selected from nitrogen, oxygen or sulphur, and optionally annulated with a benzene ring; where the substitutes are selected from hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C8cycloalkyl, alkoxy group, acyl, saturated or unsaturated optionally annulated 5-7 member heterocyclyl, where heteroatoms are selected from nitrogen, oxygen or sulphur, optionally substituted phenyl; R2 and R3 together with carbon atoms to which they are bonded form an optionally substituted benzene or thiophene ring, where substitutes are selected from C1-C5alkyl or halogen atom.

EFFECT: invention also relates to pharmaceutical compositions and medicinal agents, a method of treating or preventing development of CNS diseases mediated by action of serotonin 5-HT5 receptors, for example Alzheimer's disease.

20 cl, 6 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention provides novel pyrrolo[2,3-c]pyridine derivatives of formula (I), where radicals R1, R2, R3, R4 and R5 are as indicated in paragraph 1 of the formula of invention, or their pharmaceutically acceptable salts, as well as methods of producing the said compounds and a pharmaceutical composition having proton pump inhibiting effect.

EFFECT: novel compounds which exhibit excellent proton pump inhibiting effect and can have reversible proton pump inhibiting effect are obtained and described.

6 cl, 927 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the trihydrate of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of formula (I) .

EFFECT: novel compound is obtained, which is thermodynamically stable and has antibacterial activity.

1 cl, 3 tbl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

where Xa represents 2 to 4 condensed cycloalkyl, aryl, heterocyclic rings containing 1 to 2 heteroatoms, chosen of N and O, and heteroaryl rings containing 1 to 4 heteroatoms, chosen of N, O or S where said rings can be additionally substituted. (Radical values R1-R4, R1, Y and n are specified in the patent claim), specific representatives of said compounds and a pharmaceutical composition containing them.

EFFECT: new compounds are effective in stimulation of endogenous development or release of growth hormone and can be used in treating obesity, osteoporosis and for increasing muscle bulk and muscle strength.

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel deazapurines of formula (I): and pharmaceutically acceptable salts thereof, where n = 0; R1 is H, -NH2, -NHCH3, -NH-Ac, -OH, F, -OCH3, -CN, -NH(C=O)OC2H5; R2 is H, -NRARB, -ORA, C1-20alkyl, C1-20halogenalkyl, C6-10aryl, where RA and RB each independently represents H, C1-20alkyl, where C6-10aryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of C1-20alkyl, C1-20alkoxy and C1-20thioalkyl; each R3 independently represents H, halogen, CN, C1-20alkyl, C1-20alkoxy, C1-20thioalkyl, a -G-RC group, where G is absent or represents CH2-, -(CH2)2-, -CH=CH-CH2-, -CH-CH-, -OC-, -O- or (C=O) and where RC is H, -NRF-RG , -ORF, -SRF, -S(=O)RF, -S(=O)2RF, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, tert-butyl dimethyl silyloxy, heterocycle, C6-10aryl, C5-14heteroaryl with one N atom as a heteroatom, where RF and RG each independently represents H, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-10aryl, 6-member heterocycle with one O atom as a heteroatom, where RF and RG together form a 3-, 4-, 5-, 6-, 7- or 8-member cycloalkyl, cycloalkenyl, where the said heterocycle relates to a non-aromatic 5-, 6-, 7-member ring or bi- or tri-cyclic group containing condensed 6-member rings with 1-2 heteroatoms independently selected from O, S, N; where each of the said alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of O, halogen, OH, -CN, C1-20halogenalkyl, -CH2CF3, C1-20alkyl, C1-20alkoxy, C3-6cycloalkyl, C6-10aryl, 5- or 6-member heterocycle with one or two N atoms as heteroatoms, NHRh, NRhRi, N-ORh, ORh, C(=O)Rh, S(=O)Rh, S(=O)2Rh, =CR4R5, =NR4, where Rh and Rj present C1-20alkyl, C6-10aryl, and each of R4, R5 independently represents H, OH, ORx or C1-6alkyl, where Rx is C1-6alkyl, where the said aryl can be independently further unsubstituted or substituted with one or more substitutes selected from a group consisting of halogen, C1-20alkyl or C1-20alkoxy.

EFFECT: compounds can inhibit cytokine induced expression of adhesion molecules with endothelial cells, which enables their use in pharmaceutical compositions.

54 cl

Organic compounds // 2379309

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (I) in free or salt form, where Q is a bond, R1 and R2 independently represent H or C1-C8alkyl, or R3 is C1-C8alkyl, R4 and R5 independently represent halogen, C1-C8alkyl, C1-C8haloalkyl, C3-C15carbocyclic group, nitro group, cyano-group, C1-C8alkylsulphonyl group, R6 is H or C1-C8alkyl; W is a group of formula (Wa1) or (Wa2), where A independently represents C or N, or W represents a group of formula (Wb); where Y independently represents C or N; and Z represents N, O or S, or W represents a group of formula (Wc), where Y independently represents C or N; and Z represents O or S; X represents -SO2-, -CH2-, -CH(C1-C8alkyl)- or a bond; m and n each independently represents an integer from 0 to 3; and p is 1, to a pharmaceutical composition with CRTh2 antagonist activity, as well as to use thereof as a medicinal agent and production method thereof.

EFFECT: new compounds which can be used in medicine are obtained and described.

10 cl, 153 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel antagonists of serotonin 5-HT6 receptors - substituted 2-amino-3-sulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of general formula 1 and substituted 2-amino-3-sulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of general formula 2 or their pharmaceutically acceptable salts and/or hydrates, method of producing said compounds and pharmaceutical compositions, medicinal agents and treatment method. In compounds of formula 1 and general formula 2 , Ar is phenyl which is possibly substituted with halogen atoms, or a 6-member nitrogen-containing heteroaryl; R1 is a hydrogen atom, C1-C3alkyl which is possibly substituted with phenyl, C1-C5alkoxycarbonyl; R2 is a hydrogen atom, halogen or C1-C3alkyl; R13 and R23 are optionally identical substitutes selected from a hydrogen atom, optionally substituted C1-C3alkyl or R13 and R23 together with the nitrogen atom with which they are bonded form a nitrogen-containing 6-member saturated heteroaryl optionally substituted with C1-C5alkoxycarbonyl, where the said heteroaryl has 1-2 heteroatoms selected from nitrogen.

EFFECT: compounds can be used to prevent and treat diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors for enhancing mental capacity.

14 cl, 3 tbl, 19 dwg, 16 ex

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