Antagonists of the corticotropin-releasing factor

 

The invention relates to new compounds of General formulas I, II, IIIor their pharmaceutically acceptable salts, in which the dotted lines indicate optional double bonds; A is-CR7or N; - - NR1R2, -CR1R2R11, -C(= CR2R12R1, -NHchr1R2, -HR1R2, -Schr1R2, -chr2OR12, -chr2SR12, -C(S)R2or-C(O)R2N-ethyl-2,2,2-triptorelin; G is oxygen, sulfur, NH, NH3hydrogen, methoxy, ethoxy, triptoreline, methyl, ethyl, dimethoxy, NH2, NHCH3N(CH3)2or trifluoromethyl; Y Is N; Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands; R1- C1-C6alkyl which may be optionally substituted by one or two substituents R8independently from each other selected from the group comprising hydroxy, fluorine, chlorine, bromine, iodine, CF3C1-C4alkoxy, -O-CO-(C1-C4alkyl), where (C1-C4) alkyl part vishey - 1-C12alkyl, aryl or -(C1-C4alkylene)aryl, where aryl is phenyl, naphthyl; R3is methyl, ethyl, fluorine, chlorine, bromine, iodine, cyano, methoxy, OCF3, methylthio, methylsulphonyl, CH2HE or CH2OCH3; R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, COOH, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -NHCOCH3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano, nitro; R5is phenyl, naphthyl, pyridyl, pyrimidyl, where each of the above groups R5substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6the alkyl or C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6alkyl)O (5may be optionally substituted with one hydroxy-group; R6is hydrogen or C1-C6alkyl; R7is hydrogen, methyl; R11is hydrogen, hydroxy, fluorine or methoxy; R12is hydrogen or C1-C4alkyl, and R16and R17independently of one another represent hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy, except that both R16and R17cannot both be methoxy or ethoxy; or R16and R17together form oxo (=O) group; provided that if G is an atom of oxygen, sulfur, NH or NCH3he is joined by a double bond to a five-membered ring of the formula III, and further provided that R6is absent when the nitrogen atom to which it is linked, is attached by a double bond to an adjacent carbon atom in the ring. The compounds are antagonists of the corticotropin-releasing factor, which allows their use in pharmaceutical compositions. Describes how to obtain these compounds. 9 C. and 17 C.p. f-crystals.

Description text in facsimile form (see graphic part)and

Claims

1. Compounds I, II or III

A - -CR7or N;

In is-NR1R2, -CR1R2R11, -C(=CR2R12R1, -NHchr1R2, -Ochr1R2, -Schr1R2, -chr2OR12, -chr2SR12, -C(S)R2or-C(O)R2N-ethyl-2,2,2-triptorelin;

G is oxygen, sulfur, NH, NH3hydrogen, methoxy, ethoxy, triptoreline, methyl, ethyl, dimethoxy, NH2, N3N(CH3)2or trifluoromethyl;

Y - N;

Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands;

R1- C1-C6alkyl which may be optionally substituted by one or two substituents R8independently from each other selected from the group comprising hydroxy, fluorine, chlorine, bromine, iodine, CF3C1-C4alkoxy, -O-CO-(C1-C4alkyl), where (C1-C4) alkyl part of the above mentioned groups of R1can optionally having one carbon-carbon double or triple bond;

R2- C1-C12alkyl, aryl or -(C1-C4alkylene)aryl, where the aryl alsultany, CH2OH or CH2Och3;

R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2Och3, -CH2Och2CH3, -CH2CH2Och3, -CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, COOH, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -N3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano, nitro;

R5is phenyl, naphthyl, pyridyl, pyrimidyl, where each of the above groups R5substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6-alkyl or C1-C6-alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6alkyl)O(C1-C6) alkyl, and where C1-C4alkyl and C1-C4the alkyl part of the above mentioned groups of R5may be optionally substituted with one hydroxy-group;XI, fluorine or methoxy;

R12is hydrogen or C1-C4alkyl;

R16and R17independently of one another represent hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy, except that both R16and R17cannot both be methoxy or ethoxy, or R16and R17together form oxo (=O) group;

provided that, if G is an atom of oxygen, sulfur, NH or NCH3he is joined by a double bond to a five-membered ring of the formula III, and further provided that R6is absent when the nitrogen atom to which it is linked, is attached by a double bond to an adjacent carbon atom in the ring.

2. Connection on p. 1, where In is-NR1R2, -NHchr1R2, -Schr1R2or-Ochr1R2; R1- C1-C6alkyl which may be optionally substituted by one Deputy, selected from hydroxyl, fluorine, CF3or C1-C2CNS group, and R2- benzyl or C1-C6alkyl.

3. Connection on p. 1, where R1- C1-C6alkyl which may be substituted by fluorine, CF3, hydroxy or1-C2alkoxyl and may have one carbon-carbon double or triple bond.

6. Connection on p. 1, where R4- methyl, -CH2HE, cyano, triptoreline, methoxy, chlorine, trifluoromethyl, -SOON3, -CH2Och3-CH2CL, -CH2F, ethyl, amino or nitro.

7. Connection on p. 1, where R5is phenyl substituted with two or three substituents.

8. Connection on p. 1, where R6is hydrogen, methyl or ethyl.

9. Connection on p. 1, where R5- pyridyl, substituted with two or three substituents.

10. Connection on p. 7, where these substituents chosen independently from one another from the group comprising fluorine, chlorine,1-C4alkoxy, trifluoromethyl, C1-C6alkyl which may be optionally substituted with one hydroxyl group.

11. Connection on p. 9, where these substituents chosen independently from one another from the group comprising fluorine, chlorine,1-C4alkoxy, trifluoromethyl, C1-C6alkyl which may be optionally substituted with one hydroxyl group.

12. Connection on p. 1, which is 2-(4-bromo-2,6-dimethylphenoxy)-4-(1-ethylpropoxy)-3,6-dimethylpyridine;

2-(4-ethyl-2,6-dimethylphenoxy)-4-(1-ethylpropoxy)-3,6-dimethylpyridine;

3-ethyl-4-(1-ethylpropoxy)-6-methyl-2-(2,4,6-trimethylphenol)pyridine;

2-(2,6-dimethyl-4-propylenoxide)-4-(1-ethoxy-2,6-dimethylphenoxy)-4-(1-ethylpropoxy)-3,6-dimethylpyridine;

2-(4-chloro-2,6-dimethylphenoxy)-4-(1-ethylpropoxy)-3,6-dimethylpyridine;

4-(1-methoxymethylethoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine;

[3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]diethylamine;

[3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]ethylpropylamine;

butyl-[3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]ethylamine;

butyl-[2-(4-chloro-2,6-dimethylphenoxy)-3,6-dimethylpyridin-4-yl]ethylamine;

methyl ester of 4-(1-ethylpropylamine)-6-methyl-2-(2,4,6-trimethylphenol)nicotinic acid;

4-(1-ethylpropylamine)-6-methyl-2-(2,4,6-trimethylphenol)pyridine-3-yl]methanol;

[2-(4-chloro-2,6-dimethylphenoxy)-3,6-dimethylpyridin-4-yl]ethyl-Propylamine;

1-(ethylpropyl)-[6-methyl-3-nitro-2-(2,4,6-trimethylphenol)pyridine-4-yl]amine;

N4-(1-ethylpropyl)-6-methyl-3-nitro-N2-(2,4,6-trimetilfenil)pyridine-2,4-diamine;

N4-(1-ethylpropyl)-6-methyl-2-(2,4,6-trimethylphenol)pyridine-3,4-diamine;

3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]-ethyl-(2,2,2-triptorelin)amine;

N4-(1-ethylpropyl)-6-methyl-N2-(2,4,6-trimetilfenil)pyridine-2,3,4-triamine;

[3-chloromethyl-6-methyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]-(1-ethylpropyl)amine;

[3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]-1-(1-ethylpropyl)amine;

(1-ethylpropyl)-[2-methyl-5-nitro-6-(2,4,6-trimethylpyridine-3-yloxy)PR-2,6-dimethylphenoxy)-3,6-dimethylpyridin-4-yl]diethylamine;

4-(1-ethylpropoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine;

N-butyl-[2,5-dimethyl-7-(2,4,6-trimetilfenil)-6,7-dihydro-5H-pyrrolo-[2,3-d]pyrimidine-4-yl]ethylamine;

4-(butylamino)-2,5-dimethyl-7-(2,4,6-trimetilfenil)-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-he;

(1-ethylpropyl)-[5-methyl-3-(2,4,6-trimetilfenil)-3H-imidazo[4,5-b]pyridin-7-yl]amine;

[2,5-dimethyl-3-(2,4,6-trimetilfenil)-3H-imidazo[4,5-b]Piri-DIN-7-yl]-(1-ethylpropyl)amine;

N4-(1-ethylpropyl)-6,N3-dimethyl-2-(2,4,6-trimethylphenol)pyridine-3,4-diamine;

N4-(1-ethylpropyl)-6,N3,N3-trimethyl-2-[2,4,6-trimethylphenol)pyridine-3,4-diamine;

6-(1-ethylpropoxy)-2-methyl-N4-(2,4,6-trimetilfenil)pyrimidine-4,5-diamine;

[4-(1-ethylpropoxy)-3,6-dimethylpyridin-2-yl]-(2,4,6-trimethyl-phenyl)amine;

6-(ethylpropylamine)-2,7-dimethyl-9-(2,4,6-trimetilfenil)-7,9-dihydropyran-8-he;

or pharmaceutically acceptable salt of one of the foregoing compounds.

13. Pharmaceutical composition having antagonistic activity against the corticotropin-releasing factor, characterized in that it includes a connection on p. 1 effective for this quantity and pharmaceutically acceptable carrier.

14. The way antagonistic effects on corticotropin-releasing factor, wherein the connection is used under item (1) - Rev. src="https://img.russianpatents.com/img_data/71/719006.gif">

in which R7is hydrogen, methyl;

D - chloro, hydroxy or cyano;

R19is methyl or ethyl;

R5is phenyl or pyridyl, substituted with two or three substituents, which independently of each other selected from1-C4of alkyl, chlorine and bromine, except that only one such Deputy may be bromine;

R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2Och3, -CH2Och2CH3, -CH2CH2Och3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -NHCOCH3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, -COO(C1-C4alkyl), -CO(C1-C4alkyl), C1-C3alkoxy, C1-C3thioalkyl, fluorine, chlorine, cyano and nitro;

A - N, CH or CLO3;

Z is O, NH, N(CH3)3, S, or CH2provided that, if a is CH or CLO3then Z must be O or S.

the l, chlorine or cyano.

17. The connection formulas

in which R19is methyl or ethyl;

R1is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2Och3, -CH3Och2CH3, -CH2With2Och3, -CH2CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, COOH, cyano, or-COO(C1-C4)alkyl, where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano;

A - N SN or CLO3;

In is-NR1R2, -CR1R2R11, -C(=CR2R12R1, -NHchr1R2, -Ochr1R2, -chr2OR12,

provided that, if a represents CH or CLO3then In" means-NR1R2-The other1R2-Ochr1R2or cyano and R4is the electron group, such as NO2, -COO(C1-C4alkyl), -C(=O)CH3, -COOH or cyano.

18. Connection on p. 17, where In represents-NR1

or its pharmaceutically acceptable salt,

in which A is-CR7or N;

In is-NR1R2, -NHchr1R2, -Ochr1R2or-Schr1R2;

Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another can be hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands;

R1- C1-C6alkyl which may be optionally substituted by one or two substituents R8independently from each other selected from the group comprising hydroxy, fluorine, chlorine, bromine, iodine, CF3and C1-C4alkoxy;

R3- C1-C12alkyl, aryl or -(C1-C4alkylene)aryl, where aryl is phenyl, naphthyl;

R3is methyl or ethyl;

R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2Och3, -CH2Och2CH3, -CH2CH2Och3, -CH2CF3, CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, cyano, or-COO(C3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano and nitro;

R5is phenyl or pyridyl, substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6the alkyl and C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6alkyl)O(C1-C6)alkyl, -NHCH3, -N(CH3)2, -COOH, -COO(C1-C4alkyl), -CO(C1-C4alkyl), where C1-C4alkyl and C1-C6the alkyl part of the above mentioned groups of R5may be optionally substituted with one hydroxy-group;

R7is hydrogen or methyl;

or pharmaceutically acceptable salts of such compounds, including interaction in the presence of a base compound of formula IV

in which R19is methyl or ethyl;

D - chlor;

A, Z, R4and R5have the above values,

with compounds of the formula

NR,

which has the above meanings;

and then the optional conversion of the compounds of formula I, obtained organisations formula I

or its pharmaceutically acceptable salt,

in which

A - -CR7or N;

In is-NR1R2, -CR1R2R11, -C(=CR2R12R1, -NHchr1R2, -Ochr1R2, -Schr1R2, -chr2OR12, -chr2SR12, -C(S)R2or-C(O)R2;

Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands;

R1- C1-C6alkyl which may be optionally substituted by one or two substituents R8independently from each other selected from the group comprising hydroxy, fluorine, chlorine, bromine, iodine, CF3C1-C4alkoxy, where C1-C6alkyl and C1-C4alkyl part is C1-C4CNS group can optionally having one carbon-carbon double or triple bond;

R2- C1-C12alkyl, aryl or -(C1-C4alkylene)aryl, where aryl is phenyl, naphthyl;

R3is methyl, ethyl;

R4is hydrogen, C1-C4alkyl,sub>3
, -CH2CH2Och3, CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2-N3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -N3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano and nitro;

R5is phenyl or pyridyl, substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6the alkyl and C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6alkyl)O(C1-C6)alkyl, and where C1-C4alkyl and C1-C6the alkyl part of the above mentioned groups of R5may be optionally substituted with one hydroxy-group;

R7is hydrogen or methyl;

provided that, if a represents CH or CLO3, R4is the electron group, such as NO2, -COO(C1-C4alkyl), -C(=O)CH3, -COOH or CN;

or its pharmaceutically pickup is>/img>

in which R19is methyl or ethyl;

A - N, CH or CLO3moreover, if a is N, and R4have the values specified above for V and R4and if a represents CH or CLO3then In" means-NR1R2, -Ochr1R2and R4is the electron group, such as NO2, -COO(C1-C4alkyl), -C(=O)CH3, -COOH or CN;

with the compound of the formula

R5ZH,

in which R5and Z have the above values,

and then the optional conversion of the compounds of formula I, obtained in the result of implementation of such reactions, its pharmaceutically acceptable salt.

21. The method according to p. 20, where R4is the nitro-group in the compound of formula I and the compound of formula XII.

22. The method of obtaining the compounds of formula IV

in which R19is methyl or ethyl;

D - chlor;

A - -CR7or N;

Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands;

R4is hydrogen, C1Och2CH3, -CH2CH2Och3, -CH2CF3, CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2-N3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -N3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano and nitro;

R5is phenyl or pyridyl, substituted with one to three substituents selected independently of one another from fluorine, chlorine, C1-C6the alkyl and C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6alkyl)O(C1-C6)alkyl, -N3, -N(CH3)2, -COOH, -COO(C1-C4alkyl), -CO(C1-C4alkyl), where C1-C4alkyl and C1-C6the alkyl part of the above mentioned groups of R5may be optionally substituted with one hydroxy-group;

including interaction with phosphorus trichloride compounds of the formula X

in which R19

in which R19is methyl or ethyl;

Z is O, S, or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands;

R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2Och3, -CH2Och2CH3, -CH2CH2Och3, -CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -N3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano and nitro;

R5is phenyl or pyridyl, substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6the alkyl and C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, Amin whom sub> alkyl), -CO1-C4alkyl), where C1-C4alkyl and C1-C6the alkyl part of the above mentioned groups of R5may be optionally substituted with one hydroxy-group,

including interaction in the presence of a base compound of formula XI

in which R4, R7and R19have the above values,

with the compound of the formula R5OH, or R5SH,

where R5has the above values.

24. Connection on p. 1, which is N-[3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]-N-ethyl-2,2,2-triptorelin.

25. The composition according to p. 13, characterized in that as a connection on p. 1 it includes N-[3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]-N-ethyl-2,2,2-triptorelin.

26. The method according to p. 14, characterized in that as a connection on p. 1 using N-[3,6-dimethyl-2-(2,4,6-trimethylphenol)pyridine-4-yl]-N-ethyl-2,2,2-triptorelin.

 

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The invention relates to new biologically active compounds, methods of treating diseases with their use and pharmaceutical compositions based on these compounds

The invention relates to the technical field of herbicides and plant growth regulators, in particular of herbicides for selective control of weeds in cultivated plants

The invention relates to new pyridinesulfonamide General formula I or their acceptable for agriculture salts, have a weed-killing activity, as well as to a method for their production and compositions for combating the growth of unwanted vegetation

The invention relates to the derivatives of triazolopyrimidine General formula (I), method of production thereof and to pharmaceutical compositions based on

The invention relates to a series of substituted 5-arylpyrimidines, to methods for their preparation, to pharmaceutical remedies containing these compounds and to their use in therapy, in particular in the treatment of a range of diseases and disorders of the Central nervous system (CNS)
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