Antagonists nociceptin, amide derivative, an analgetic, the method of initiating the antagonistic action to nociceptin, the method of treatment of pain, pharmaceutical compositions

 

Describes antagonist nociceptin containing amide derivative and its pharmaceutically acceptable salts of formula (1), where R1and R2the same or different and each is a hydrogen atom, lower alkyl, optionally substituted hydroxy, amino, lower alkylamino or di(lower)alkylamino, R3, R4is a hydrogen atom, ring a is chinaillon, 5,6,7,8-tetrahydropyridinium, 2,3-dihydro-1H-cyclopent[b] chinaillon, ring C is a phenyl, teinila, fullam, pirrallo, pyrrolidinium or oxazolyl; X is a group of the formulawhere E is a single bond or-O -; ring G is phenyl, naphthyl, benzofuranyl, 2,3-dihydrobenzofuranyl, cyclohexyl or 5,6,7,8-tetrahydro-2-naphthyl, R5has different values, t = 0 or 1-5, m = 0 or 1-8, n = 0 or 1-4. Describes the amide derivative of formula (1') and (1"), as well as analgetic on the basis of the compounds of formula (1') and (1"), the method of initiating the antagonistic action to nociceptin, including the introduction of the compounds of formula (1), a method of treating pain, comprising introducing the compound of formula (1') or (1") and pharmaceutical compositions containing the compounds of formula (1), (1') or (1"). The technical result is cativ acute pain. 9 C. and 5 C.p. f-crystals, 48 PL.

Description text in facsimile form (see drawings) T Then

Claims

1. Antagonist nociceptin containing amide derivative of the formula [1]where R1and R2the same or different and each is a hydrogen atom, lower alkyl, optionally substituted hydroxy, amino, lower alkylamino or di(lower)-alkylamino; R3and R4each of them is a hydrogen atom; ring a is



ring C is a phenyl, teinila, fullam, pirrallo, pyrrolidinium or oxazolyl;
X is a group of the formula

where E represents a single bond or-O-;
the ring G is phenyl, naphthyl, lansoprasole, 2,3-dihydrobenzofuranyl, cyclohexyl or 5,5,7,3-tetrahydro-2-naphthyl;
R5is a halogen atom, hydroxy, lower alkyl, optionally substituted with any halogen, hydroxy, lower alkanoyloxy the PWM alkoxy; amino, lower alkylamino, di(lower)alkylamino, nitro, cyano, lower alkanoyl, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, lower alkylsulfonyl or phenyl;
t = 0 or an integer from 1 to 5, which represent the number of substituents on the ring G, where if t is an integer from 2 to 5, each R5may be the same or different;
m = 0 or an integer from 1 to 8;
n = 0 or an integer from 1 to 4
or its pharmaceutically acceptable salt as an active ingredient.

2. Antagonist nociceptin under item 1, characterized in that it contains amide derivative of formula 1, in which ring a is chinaillon or its pharmaceutically acceptable salt as an active ingredient.

3. Antagonist nociceptin under item 1, characterized in that it contains amide derivative, in which ring C is a phenyl, or its pharmaceutically acceptable salt as an active ingredient.

4. Derived amide of the formula [1']

where R2a hydrogen atom or lower alkyl, optionally substituted by hydroxy;
ring E, ring G, R5, 1, m and n are such as defined in paragraph 1,
or its pharmaceutically acceptable salt.

5. Derived amide under item 4, where Col is svodnoe amide under item 5, in which the amino group replaces in position 4 of the quinoline structure, R2is stands, substituting in position 2 quinoline structure, E is-O -, and ring In the phenyl is Deputy formula

where the ring G, R5, t, m and n are such as defined in paragraph 1,
in position 2, or its pharmaceutically acceptable salt.

7. Derived amide under item 6, or its pharmaceutically acceptable salt, which is selected from a group including:
N-(4-amino-2-methyl-6-chinolin)-2-[(4-ethylenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(2,4-dichlorphenoxy)-methyl]benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-(phenoxymethyl)benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-methoxyphenoxy)-methyl)benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3,5-dimethylphenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3,4-dimethoxyphenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-nitrophenoxy)-methyl]benzamide,
N-(4-amino-2-methyl-6-chinolin)-2-[(2,3-dimethoxyphenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3-methylphenoxy)-methyl]benzamide,
N(4-amino-2-methyl-6-chinolin)-2-[(3,5-dimethoxyphenoxy)-methyl)benzamide hydro is l)-2-[(4-acetylphenol)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-hydroxyphenoxy)methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-methoxyethoxyethoxy) methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3-methoxyphenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-cianfrocca)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-methylphenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-triptoreline)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3-nitrophenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(2-nitrophenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-acetoxyphenyl)methyl] - benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(2-methoxyphenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-aminophenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3-chlorophenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-pertenece)methyl)-benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3,4-dichlorophenoxy)methyl]-benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(2-chlorophenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-dimethy the d hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-(4-biphenyloxy)-benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-isopropylphenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-nitrophenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-bromophenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-propylenoxide)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3-pertenece)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(3-triptoreline) methyl]benzamide hydrochloride
Methyl ester 4-[2-(N-(4-amino-2-methyl-6-chinolin)-carbarnoyl)benzyloxy] benzoic acid hydrochloride,
N-(4-amino-2-methyl-6-chinolin)-2-[(4-iodinase)methyl]-benzamide,
N-(4-amino-2-methyl-6-chinolin)-2-(3-pyridyloxy)-benzamide hydrochloride
4-[2-{ (4-amino-2-methyl-6-chinolin)carbarnoyl} benzyloxy]-benzoate hydrochloride,
N-(4-amino-2-methyl-6-chinolin)-2-[(3-cianfrocca)methyl]-benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin} -2-[(4-methylphenoxy)methyl] -benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(2-chloro-4-ethylenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(4-chloro-3-methylphenoxy)-methyl] benzamide hydrochloride
N-(4-amino-2-methyl-6-chinolin)-2-[(2-chloro N-(4-amino-2-methyl-6-chinolin)-2-[(4-chloro-3-methylphenoxy)-methyl]benzamide,
4[2-{ (4-amino-2-methyl-6-chinolin)carbarnoyl}benzyloxy]-benzilate hydrochloride
N-(4-amino-2-methyl-b-chinolin)-2-[(4-hydroxymethylene)-methyl]benzamide hydrochloride, and
N-(4-amino-2-methyl-6-chinolin)-2-[(4-ethylenoxy)methyl] -benzamide hydrochloride monohydrate.

8. Derived amide of the formula [1"]

where ring A, R5and t such that as defined in paragraph 1;
R2is a hydrogen atom or lower alkyl, optionally substituted hydroxy,
or its pharmaceutically acceptable salt.

9. Antagonist nociceptin containing the amide derivative according to any one of paragraphs. 4-8, or its pharmaceutically acceptable salt as an active ingredient.

10. Analgetic containing the amide derivative according to any one of paragraphs.4-8 or its pharmaceutically acceptable salt as an active ingredient.

11. The method of initiating the antagonistic action to nociceptin, including the introduction of the amide derivative according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt.

12. A method of treating pain, comprising the introduction of an amide derivative according to any one of paragraphs.4-8, or its pharmaceutically acceptable salt.

13. Pharmaceutical composition having antagonistic action to nociceptin that content is the media.

14. Pharmaceutical composition for use as analgetika, which contains amide derivative according to any one of paragraphs.4-8 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

 

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The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

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Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

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< / BR>
where a represents an optionally unsaturated 5 - or 6-membered ring which may contain heteroatom selected from N and S, and which may be substituted by oxo or (1-6C) alkyl; R1, R2and R3independently of one another represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom; X is an atom of O or S and n = 1 or 2, or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin

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< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13made the>alkyl; p is 0 to 3, and R3may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt

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< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
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