Derivatives of 2-aminopyridine, pharmaceutical compositions on their basis and intermediate substances

 

The invention relates to new derivatives of 2-aminopyridine of General formula (I)

where And denotes the radical

in which R1, R2and R3mean hydrogen, halogen, HE, alkyl or alkoxy and the other,

or radical

in which R8means hydrogen, x is the radical -(CH2)m-Q, m is an integer from 0 to 6, Y represents alkyl, alkenylphenol or alkenylphenol chain or other, R10is hydrogen or alkyl, or their salts. The compounds of formula (I) possess an inhibitory activity against NO-synthase and can find application in medicine. 3 c. and 8 C.p. f-crystals.

Description text in facsimile form (see graphic part).

Claims

1. Derivatives of 2-aminopyridine of General formula (I)

where And denotes

radical

in which R1, R2and R3independently from each other represent a hydrogen atom, halogen, a group HE, a normal or branched alkyl radicals, Allakaket or alkoxy,together form a cycle of methylendioxy; and R5and R6independently represent a hydrogen atom, normal or branched C1-C6is an alkyl radical or aromatic cycle, which may be substituted by one or more groups selected from a halogen atom, a group HE and a normal or branched alkyl radical with 1-6 carbon atoms;

or radical

in which R8denotes a hydrogen atom;

X represents the radical -(CH2)m-Q-, - (CH2)m-CH=CH-Q-, - (CH2)m-C (=W)-Q-, -(CH2)m-NR11-C(=W)-Q-, -(CH2)m-NR11-C(=W)-NR12-Q-, -(CH2)m-CH=CH-C(=W)-Q, where Q denotes a bond or piperazine, W represents an oxygen atom; m is an integer from 0 to 6;

Y denotes alkyl, alkenylphenol or alkenylphenol chain, each of which may be linear or branched and may contain up to 10 carbon atoms and being substituted by a radical NR13R14,or Y represents the radical - (CH2)n-NR13-(CH2)p-, where n and p are integers from 0 to 6;

R10denotes a hydrogen atom or an alkyl radical with 1-6 carbon atoms;

R11, R12, R13and R14independently represent the PAP-X-Y - is not a simple relationship, normal or branched alkilinity radical or one of the radicals-O-, -S-, -NH - or-NH-CO-NH-alkylene; and provided that when a is a phenyl radical, a group-X-Y - not can be-NH-CO-NH-, and when And indicates 3,4,5-trialmaster, the group-X-Y - is-CO-NH-CH2group,

or salts of the compounds of General formula (I).

2. Connection on p. 1, characterized in that a denotes the radical

in which R1, R2and R3independently represent a hydrogen atom, a group HE, a normal or branched alkyl radicals or alkoxy having from 1 to 6 carbon atoms, or a radical-NR5R6or R1and R2or R2and R3together form a cycle of methylendioxy;

R5and R6independently represent a hydrogen atom or normal or branched C1-C6is an alkyl radical, preferably a hydrogen atom or the radical methyl or ethyl;

radical 3,5-di-tert-butyl-4-hydroxyphenyl or 4-(dimethyl-amino)phenyl;

or the radical

in which R8denotes a hydrogen atom;

X denotes a radical-NH-CO - or-CO-Q-, where Q denotes a radical piperazine;

Y represents the radical -(CH2)1-C6is an alkyl radical, and n and p are integers from 0 to 6, or Y denotes alkyl, alkenylphenol or alkenylphenol chain, each of which is linear or branched and may contain up to 10 carbon atoms;

R10denotes a hydrogen atom or a methyl radical.

3. Connection under item 1 or 2, characterized in that it represents one of the following compounds:

the amide hydrochloride of 6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-guide-roxiprin]-4-methyl-2-pyridinemethanol acid;

the amide hydrochloride of 6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-guide-roxiprin]-4-methyl-2-pyridinemethanol acid;

the amide hydrochloride of 6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinemethanol acid;

hydrochloride of 1-[4-(2-amino-5-pyridinyl)-3-butenyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]piperazine;

hydrochloride of 1-[4-(2-amino-5-pyridinyl)butyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]piperazine;

hydrochloride of 1-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]piperazine;

hydrochloride of 1-[4-(2-amino-6-pyridinyl)-3-butenyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]Pipera original)butyl]-2,6-dihydroxybenzamide;

the hydrochloride of N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihyd-oxybenzone;

hydrochloride 5-amino-N-[(6-amino-4-methyl-2-pyridinyl)-butyl]-2-hydroxybenzamide;

the hydrochloride of N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-methylbenzamide ;

N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-(1-methylethyl)benzamide;

the hydrochloride of N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2-hydroxy-4,6-dimethoxybenzamide;

the hydrochloride of N-[(6-amino-4-methyl-2-pyridinyl)butyl]-3,5-bis(1,1-dimethylethyl)-4-hydroxybenzamide;

the amide hydrochloride of 6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridinemethanol acid;

the amide hydrochloride of 6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridineboronic acid;

the hydrochloride of 6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridinylamino;

the amide hydrochloride-amino-N-[4-(dimethylamino)phenyl]-5-(6-amino-2-pyridinyl)-4-pentenovoi acid;

the amide hydrochloride,6-diamino-N-[4-(dimethylamino)phenyl]-2-pyridinylamino acid;

the amide hydrochloride of 6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridineboronic acid;

the amide hydrochloride of 6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinemethanol acid;

the IDA 6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinemethanol acid;

hydrochloride {[4-(6-amino-4-methyl-2-pyridinyl)butyl]-amino}-N-[(4-dimethylamino)phenyl]ndimethylacetamide;

the hydrochloride of 6-amino-N-[3-(4-hydroxy-Z-methoxyphenyl)-2-propenyl]-4-methyl-2-pyridine-butane amine;

the hydrochloride of 6-amino-N-[4-chloro-2-(phenylamino)phenyl]-4-methyl-2-pyridinesulfonamide;

the hydrochloride of N-[6-amino-4-methyl-2-pyridinyl)butyl]-1,3-benzodioxol-5-ndimethylacetamide;

fumarate of N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-N-(1,3-benzodioxol-5-ylmethyl)amine;

fumarate of N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-N-[(E)-3-phenyl-2-propenyl)amine;

the amide fumarate (E)-N-[4-(6-amino-4-methyl-2-pyridinyl)-butyl]-3-(1,3-benzodioxol-5-yl)-2-propanolol acid;

2-({[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}methyl)-4-methoxyphenol;

N-[2-(benzyloxy)-4,5-dimethoxybenzyl]-4-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-2-pyridinyl]-1-butanamine;

6-(4-{[2-(benzyloxy)-4,5-dimethoxybenzyl]amino}butyl)-4-methyl-2-pyridylamine;

2-({[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}methyl)-4,5-dimethoxyphenol;

fumarate amide N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-6-hydroxy-2,5,7,8-tetramethyl-2-romancenovel acid.

4. Connection on p. 3, characterized in that it represents one of the following compounds:

the amide hydrochloride of 6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-PI is the notes;

hydrochloride of 1-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]piperazine;

the hydrochloride of N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2-hydroxy-5-methoxybenzamide;

the hydrochloride of N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihyd-oxybenzone;

the hydrochloride of N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-methylbenzamide;

N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-(1-methylethyl)benzamide;

the amide hydrochloride of 6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridineboronic acid;

hydrochloride amide N-[(6-amino-4-methyl-2-pyridinyl)-butyl]-1,3-benzodioxol-5-carboxylic acid;

the amide hydrochloride of 6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinemethanol acid;

hydrochloride {[4-(6-amino-4-methyl-2-pyridinyl)butyl]-amino}-N-[(4-dimethylamino)phenyl]ndimethylacetamide;

the hydrochloride of 6-amino-N-[3-(4-hydroxy-Z-methoxyphenyl)-2-propenyl]-4-methyl-2-pyridine-butanamine.

5. Connection on p. 4, characterized in that it represents one of the following compounds:

the amide hydrochloride of 6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridinemethanol acid;

N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-(1-methylethyl)benzamide;

hydrochloride is riginal)butyl]-amino}-N-[(4-dimethylamino)phenyl]ndimethylacetamide;

the hydrochloride of 6-amino-N-[3-(4-hydroxy-3-methoxyphenyl)-2-propenyl]-4-methyl-2-pyridinylamino;

2-({[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}methyl)-4,5-dimethoxyphenol.

6. Compounds of General formula (II) and (III)

in which a denotes

radical

in which R1, R2and R3independently represent a hydrogen atom, halogen, a group HE or SH, normal or branched alkyl radicals, Alcoxy or alkoxy having from 1 to 6 carbon atoms, a radical-NR5R6or R1and R2or R2and R3together form a cycle of methylendioxy; and R5and R6independently represent a hydrogen atom, normal or branched C1- C6is an alkyl radical or aromatic cycle, which may be substituted by one or more groups selected from a halogen atom, a group HE and a normal or branched alkyl radical with 1-6 carbon atoms;

or radical

in which R6denotes a hydrogen atom;

X represents the radical -(CH2)m-Q-, -(CH2)m-CH=CH-Q-, - (CH2)m-C(=W) -Q-, -(CH2)m

Y denotes alkyl, alkenylphenol or alkenylphenol chain, each of which may be linear or branched and may contain up to 10 carbon atoms and being substituted by a radical NR13R14or Y represents the radical - (CH2)n-NR13-(CH2)p-, where n and p are integers from 0 to 6;

R10denotes a hydrogen atom or an alkyl radical with 1-6 carbon atoms;

R11, R12, R13and R14independently represent a hydrogen atom or normal or branched C1- C6is an alkyl radical;

Y' represents a normal or branched alkyl chain with 1 to 8 carbon atoms;

provided that the group-X-Y - is not a simple relationship, a normal or branched alkilinity radical or one of the radicals-O-, -S-, -NH - or-NH-CO-NH-alkylene;

and provided that when a is a phenyl radical, a group-X-Y - not can be-NH-CO-NH-;

and, in addition, subject (only for compounds of General formula (III)) that when a is a phenyl radical, a phenyl radical, substituted by one or more halogen atoms, or nafcillin radical, X can be-NH-CO - or is almost acceptable salt as a medicine, possessing inhibitory activity against NO-synthase and against lipid peroxidation.

8. Pharmaceutical composition having inhibitory activity against NO-synthase and against lipid peroxidation, containing as active principle at least one connection on the PP.1-5 or a pharmaceutically acceptable salt of this compound.

9. The compound of General formula (I) according to one of paragraphs.1-5 or a pharmaceutically acceptable salt of this compound, used for the production of pharmaceuticals for inhibition of NO-synthase.

10. The compound of General formula (I) according to one of paragraphs.1-5 or a pharmaceutically acceptable salt of this compound, used for the production of pharmaceuticals for inhibition of lipid peroxidation.

11. The compound of General formula (I) according to one of paragraphs.1-5 or a pharmaceutically acceptable salt of this compound, used for the production of medicines that has both the ability to inhibit NO-synthase and inhibit lipid peroxidation.

 

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where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

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The invention relates to new derivatives chromane General formula I,

,

where R is hydrogen, halide or NR1R1group; R1means hydrogen or alkyl group with 1-10 carbon atoms; R2means R1or NR1R1; R3means hydrogen or CO2R1; Ar1means a phenyl group or a 5-or 6-membered heterocyclic ring containing as the heteroatom atom N; m = 1, 2, or 3; n = 1, when this symbol is the group -(CO)nand n is 0, 1 or 2, when this symbol is the group (X); X is alkyl group with 1-4 carbon atoms; R4means hydroxyl or CNS group with 1-10 carbon atoms; and their pharmaceutically acceptable salts, having agonistic activity against beta-3-adrenergic receptor

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< / BR>
where R and R are independently selected from the group consisting of hydroxyl and a moiety that can be converted in vivo in hydroxyl, such as acyloxy, -OR4, -OC(O)R7or-OC(O)OR4(where R4represents alkyl, alkenyl, quinil or aryl; and R7represents amino, alkylamino, aminoalkyl and alkylsulfonyl); and R3represents-CH2- or-CH2CH2-; or its pharmaceutically acceptable salt, where the specified compound or salt is optically active because they contain more than 50% (by weight relative to all stereoisomers) 2S stereoisomers

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

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< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

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< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

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< / BR>
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The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

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