Heterocyclic compound, process for its production and pharmaceutical composition based on it

 

The present invention relates to a heterocyclic compound of the formula I, where R' represents a C1-C6alkyl, halogen, optionally substituted heterocyclic group or optionally substituted C6-C10aryl, R2represents carboxyl or gidroksiaminopirimidinov group, Ar represents phenyl or thienyl, And represents C1-C6alkylene, X is oxa-group or a single bond, Y represents TIA group, sulfinil or sulfonyl, Z is methylene, m and n are each an integer from 0 to 1, m+n=1 or 2, or its salt. The compounds may be used as inhibitors of matrix metalloproteinases or the production of tumor necrosis factor -. Also described pharmaceutical composition based compounds and method for their preparation. 3 S. and 6 C.p. f-crystals, 1 PL.

Description text in facsimile form (see graphic part)n

Claims

1. Heterocyclic compound of the formula

where R1represents C1-C6alkyl, halogen, optionally substituted gets xinnuo or gidroksiaminopirimidinov group;

AG represents phenyl or thienyl;

A represents C1-C6alkylen;

X represents oxygraph or single bond;

Y represents tigroup, sulfinil or sulfonyl;

Z is methylene;

m and n = 0 or 1;

m + n = 1 or 2

or its salt, in which heterocyclic group, R1selected from the group which consists of

(1) unsaturated 5 - or 6-membered heterophilically group containing 1 nitrogen atom, (2) a saturated 5 - or 6-membered heterophilically group containing 1 or 2 nitrogen atom, (3) unsaturated 5 - or 6-membered heterophilically group containing 1 sulfur atom, (4) unsaturated bicyclic 9-or 10-membered heterocyclic group containing 1 nitrogen atom, (5) unsaturated 5 - or 6-membered heterophilically group containing 1 to 2 oxygen atoms, (6) saturated 5 - or 6-membered heterophilically group containing 1 to 2 oxygen atoms, (7) unsaturated 5 - or 6-membered heterophilically group containing 1 oxygen atom and 1 or 2 nitrogen atom, (8) unsaturated bicyclic 9 - or 10-membered heterocyclic group containing 1 to 2 oxygen atoms, (9) unsaturated bicyclic 9 - or 10-membered heterocyclic group, the content is 1 nitrogen atom, and each of the above heterocyclic and C6-C10aryl groups optionally substituted by the group, including the following (A1) -(A35):

(A1) halogen;

(A2) C1-C6alkyl;

(A3) C1-C6alkoxy;

(A4) halogen (C1-C6)alkyl;

(A5) halogen (C1-C6)alkoxy;

(A6) C2-C6alkenyl;

(A7) acyl;

(A8) (C1-C6)alkylthio, (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl;

(A9), (C6-C10)aryl;

(A10) halogen (C6-C10) aryl;

(A11) hydroxyl;

(A12) hydroxy(C1-C6)alkyl, protected hydroxy (C1-C6)alkyl;

(A13) amino;

(A14) carboxyl;

(A15) protected carboxyl;

(A16) nitro(C2-C6)alkenyl;

(A17) (C1-C6)alkylenedioxy;

(A18) acylamino;

(A19) nitro;

(A20) (C6-C10) aryl(C1-C6)alkoxy;

(A21) carbarnoyl (C2-C6)alkenyl, optionally N-substituted by the group consisting of C1-C6of alkyl, (C6-C10) aryl, (C1-C6)alkoxy (C6-C10) aryl and halogen (C6-C10) aryl;

(A22) (C1-C6)alkylaminocarbonyl;

(A23) (C1-C6)alkoxycarbonyl;

(A26) (C1-C6)alkanoyloxy, optionally substituted heterocyclic group of the above groups (1) through (10);

(A27) (C3-C6)cycloalkylcarbonyl;

(A28) C1-C6alkoxy, substituted by the group, including carboxyl protected carboxyl, C1-C6alkanoyl,3-C6cycloalkylcarbonyl and C1-C6allylcarbamate;

(A29) (C1-C6)allylcarbamate (C1-C6)alkyl;

(A30) (C1-C6)alkoxycarbonyl (C1-C6)alkyl;

(A31) amino (C1-C6)alkyl;

(A32) (C1-C6)allylcarbamate (C1-C6)alkyl;

(A33) a heterocycle-carbylamine, heterocyclic group selected from the above groups (1) through (10), and optionally substituted N-protecting group;

(A34) the above heterocyclic groups (1) through (10), optionally substituted C1-C6the alkyl, and

(A35) oxo.

2. Connection on p. 1, in which a group of the formula

is one of the following:

R1represents C1-C6alkyl; halo the config phenyl or optionally substituted naphthyl;

AG represents phenyl or thienyl;

m and n = 0 or 1;

m + n = 1 or 2;

where the above heterocyclic group is as follows: (1) pyrrolyl, pyrrolidyl, pyridyl, pyridyl N-oxide;

(2) pyrrolidinyl, piperidinyl, piperidino;

(3) thienyl;

(4) indolyl, isoindolyl, indolizinyl, hinely; ethanolic, tetrahydroisoquinoline, indazole;

(5) furyl;

(6) oxolane;

(7) oxazolyl, isoxazolyl;

(8) benzofuranyl, benzodithiophene, benzodioxolyl;

(9) benzothieno, dihydrobenzofuranyl, and data heterocyclic group optionally substituted by a group, including groups (B1) to (B8):

(B1) C1-C6alkanoyl;

(B2) C1-C6alkyl;

(B3) C1-C6alkoxy;

(B4) C1-C6alkoxycarbonyl;

(B5) carbarnoyl or C1-C6alkoxycarbonyl;

(B6) C1-C6alkoxycarbonyl;

(B7) halogen and

(B8) oxo and

the above aryl optionally substituted by a group that includes the following (A1) to (A34):

(A1) halogen;

(A2) C1-C6alkyl;

(A3) C1-C6alkoxy;

(A4) halogen (C1-C6)alkyl;

(A5) halogen (C1-C6)alkoxy;

(A6)2-C6alkenyl;

(A7) acyl; (A8) (C1-Cb>)aryl;

(A10) halogen (C6-C10) aryl;

(A11) hydroxyl;

(A12) hydroxy(C1-C6)alkyl or protected hydroxy (C1-C6)alkyl;

(A13) amino;

(A14) carboxyl;

(A15) protected carboxyl;

(A16) nitro (C2-C6)alkenyl;

(A17) (C1-C6)alkylenedioxy;

(A18) acylamino;

(A19) nitro;

(A20) (C6-C10) aryl (C1-C6)alkoxy;

(A21) carbarnoyl (C2-C6)alkenyl, optionally N-substituted by a group comprising lower alkyl;

(C6-C10) aryl, (C1-C6)alkoxy (C6-C10) aryl and

halogen (C6-C10) aryl;

(A22) (C1-C6)alkylaminocarbonyl;

(A23) (C1-C6)alkanoyloxy;

(A24) (C1-C6)alkoxy (C1-C6)alkanoyloxy;

(A25) (C1-C6)alkoxycarbonyl;

(A26) (C2-C6)alkanoyloxy, optionally substituted by the above heterocyclic group (1);

(A27) (C3-C6) cycloalkylcarbonyl;

(A28) C1-C6alkoxy, substituted by the group, including carboxyl protected carboxyl;

C1-C6alkanoyl,3-C6cycloalkylcarbonyl and

C1-C6Alki is alkoxycarbonyl (C1-C6)alkyl;

(A31) amino (C1-C6)alkyl;

(A32) (C1-C6)allylcarbamate (C1-C6)alkyl;

(A33) a heterocycle-carbylamine, heterocyclic group selected from the above groups (2), (4) and (5), and optionally substituted N-protecting group,

(A34) heterocyclic group (7) of the above optionally substituted C1-C6the alkyl.

3. Connection on p. 2 having the formula

where R1represents C1-C6alkyl, benzothiazyl, phenyl, halogenfree, naphthyl or (halogen)(phenyl)phenyl;

m and n = 0 or 1;

m + n = 1.

4. Connection on p. 2, having the following formula:

where R2is carboxyl or hydroxyaminobuteroyl;

m and n = 0 or 1;

m + n = 1;

R1represents halogen; heterocyclic group includes pyridyl, thienyl, furyl, benzofuranyl or sensational, and heterocyclic group optionally substituted group containing C1-C6alkanoyl, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl and (C1-C6)allylcarbamate; naphthyl or phenyl, optionally substituted by a group

(C4) halogen (C1-C6)alkyl;

(C5) halogen(C1-C6)alkoxy;

(C6) C1-C6alkenyl;

(C7) (C1-C6)allylcarbamate, carbarnoyl, phenyl (C1-C6)allylcarbamate, C1-C6alkanoyl;

(C8) (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl;

(C9) phenyl, naphthyl;

(C10) halogenfree;

(C11) hydroxyl;

(C12) mono - or dihydroxy(C1-C6)alkyl, phenoxycarbonylamino(C1-C6)alkyl;

(C13) amino;

(C14) carboxyl;

(C15) (C1-C6)alkylenedioxy;

(C16) (C1-C6)alkanolamine; phenyl (C1-C6)alkanolamine, halogenfrei (C1-C6)alkanolamine, (C1-C6)alkoxy(C1-C6)-alkanolamine, phenoxy (C1-C6)alkanolamine, (C1-C6)alkoxyphenyl (C1-C6)alkanolamine, (C1-C6)alkylphenoxy (C1-C6)alkanolamine, halogenfree (C1-C6)alkanolamine, carboxy (C1-C6)alkanolamine, (C1-C6)alkoxycarbonyl (C1-C6)alkanolamine, (C1-C6)allylcarbamate (C1-C6)alkanolamine, halogen (C1-C6)alkanoyl is aroylamino, phenyl (C1-C6)alkoxy (C1-C6)alkanolamine, piperidinyloxy (C1-C6)alkanolamine, N-(C1-C6)alkoxycarbonylmethyl-(C1-C6)alkanolamine, pyridyloxy (C1-C6)alkanolamine, hydroxy (C1-C6)alkanolamine, (C1-C6)alkanoyloxy (C1-C6)alkanolamine;

(C1-C6)allylcarbamate(C1-C6)alkanolamine;

N,N-di(C1-C6alkyl) carbanilate;

(C1-C6)alcoholimpaired-carbonyloxy (C1-C6)alkanolamine, phenyl (C1-C6)allylcarbamate (C1-C6) -alkanolamine;

(C1-C6)alkoxycarbonyl (C1-C6)alkanolamine;

amino (C1-C6)alkanolamine, fluorenylmethoxycarbonyl (C1-C6)alkanolamine;

(C1-C6)alkylamino (C1-C6)alkanolamine, [N,N-di(C1-C6alkyl) amino] (C1-C6)alkanolamine;

[N-C1-C6alkyl-N-(C1-C6alkoxycarbonyl) amino] (C1-C6)alkanolamine, [N - C1-C6alkyl-N-(fluorenylmethoxycarbonyl) amino] (C1-C6)alkanolamine, [N-C1-C6alkyl-N-(MB>-C6alkyl)carbarnoyl)amino](C1-C6)alkanolamine, benzoylamine(C1-C6)alkanolamine;

(C1-C6)alkanolamine (C1-C6)alkanolamine; (C1-C6)alkanesulfonyl (C1-C6)alkanolamine;

(C1-C6)alkoxy (C1-C6)alkanolamine (C1-C6)alkanolamine;

cyclo (C3-C6)alkoxycarbonyl (C1-C6)alkanolamine;

pyridylmethylamine (C1-C6)alkanolamine, morpholinosydnonimine (C1-C6)alkanolamine, phenyl(C1-C6)alkoxycarbonyl(C1-C6)alkanolamine;

(C1-C6)alkoxysilylated (C1-C6)alkanolamine; hydroxy(C1-C6)alkylamino (C1-C6)alkanolamine, morpholino (C1-C6)alkanolamine, oxoacridine (C1-C6)alkanolamine; oxopyrrolidin (C1-C6)alkanolamine; trimethylhydantoin (C1-C6)alkanolamine; and (C2-C6)alkynylamino (C1-C6)alkanolamine; (C1-C6)alkoxy (C1-C6)alkylamino (C1-C6)alkanolamine; phenyl(C1-C6)alkylamino (C1-C6

phenyl(C1-C6)alkoxycarbonyl; (C1-C6)alkoxy (C1-C6)alkoxycarbonyl; halogen(C1-C6)alkoxycarbonyl; amino (C1-C6)alkoxycarbonyl; phthalimido (C1-C6)alkoxycarbonyl; carbamoylation; (mono - or di-(C1-C6alkyl)carbamoylating; afterburning; halogenopyrimidines; (C1-C6)alkoxyalkanols; (C1-C6)alkenylamine; cyclo (C3-C6)alkyl (C1-C6)alkylcarboxylic; phenyl (C1-C6)alkylcarboxylic; halogen(C1-C6)alkylcarboxylic; (C1-C6)alkoxy (C1-C6)alkylcarboxylic; hydroxy (C1-C6)alkylcarboxylic; (C1-C6alkyl) (diphenyl) silyloxy(C1-C6)Alki carbamoylating; carboxy(C1-C6)alkylcarboxylic; (C1-C6)alkoxycarbonyl (C1-C6)alkylcarboxylic; (C1-C6)allylcarbamate (C1-C6)alkylcarboxylic or pyridylcarbonyl; (C1-C6)alkylsulfonyl; and (C2-C6)alkanolamine; and (C3-C6) cycloalkylcarbonyl; and (C2-C6ub>1-C6)alkoxy;

(C18) C2-C6alkenyl, mono - or di (C1-C6alkyl) carbarnoyl (C2-C6)alkenyl; 2-(methylcarbamoyl)ethynyl; 2-(ethylcarbamate)ethynyl; 2-(propellerblades)ethynyl; 2-(isopropylcarbamate)ethynyl; 2-(dimethylcarbamoyl)ethynyl, phenylcarbamoyl(C2-C6)alkenyl, (C2-C6)alkoxycarbonyl (C2-C6)alkenyl, halogenerator (C2-C6)alkenyl,

(C19) (C1-C6)alkylaminocarbonyl;

(C20) (C1-C6)alkanoyloxy;

(C21) (C1-C6)alkoxy(C1-C6)alkanoyloxy;

(C22) (C1-C6)alkoxycarbonyl;

(C23) pyridyl(C1-C6)alkanoyloxy;

(C24) (C3-C6) cycloalkylcarbonyl;

(C25) carboxy(C1-C6)alkoxy;

(C1-C6)alkoxycarbonyl (C1-C6)alkoxy, (C1-C6)alkanoyl (C1-C6)alkoxy, (C3-C6) cycloalkylcarbonyl (C1-C6)alkoxy; a (C1-C6)allylcarbamate (C1-C6)alkoxy;

(C) (C1-C6)allylcarbamate (C1-C6)alkyl;

(On 27) (C1-C6alkoxycarbonyl(C1-C6)alkyl);

(S) amino (C1-C6)alkyl;1-C6)alkoxycarbonyl - tetrahydroisoquinolinium, pyrrolidinylcarbonyl;

(A31) oxazolyl, (C1-C6)alkyloxyaryl.

5. Connection on p. 4, in which a group of the formula:

is one of the following:

R2is carboxyl or hydroxyaminobuteroyl;

m = 0;

n = 1;

a group of the formula

represents a group of formula (a) - (e):

where R11represents halogen, naphthyl, phenyl, mono - or dehalogenans, mono - or di(C1-C6)alkylphenyl, (C1-C6)alkoxyphenyl, trihalogen(C1-C6)alkylphenyl, trihalogen(C1-C6)alkoxyphenyl, (C2-C6)alkenylphenol, (C1-C6)allylcarbamate, carbamoylmethyl, phenyl(C1-C6)allylcarbamate, (C1-C6)alkanolamines, (C1-C6)alkyldiphenyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl, phenylphenyl, (halogen)(phenyl)phenyl, halogenfrei, hydroxyphenyl, mono - or dihydroxy(C1-C6alkylenedioxy, (C1-C6)alkanesulfonyl, (C1-C6)alkanolamines, (C3-C6)cycloalkylcarbonyl, phenyl(C1-C6)alkoxyphenyl, mono - or di(C1-C6alkyl)carbarnoyl(C2-C6)alkenylphenol, phenylcarbamoyl(C2-C6)alkenylphenol, (C1-C6)alkoxycarbonyl(C2-C6)alkenylphenol, halogenerator (C2-C6)alkenylphenol, (C1-C6)alkylcarboxylic, (C1-C6)alkanoyloxy, (C1-C6)alkoxy(C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonylmethyl, pyridyl(C1-C6)alkanoyloxy, cyclo(C3-C6)alkylcarboxylic, carboxy(C1-C6)alkoxyphenyl, (C1-C6)alkoxycarbonyl (C1-C6)alkoxyphenyl, (C1-C6)alkanoyl(C1-C6)alkoxyphenyl, (C3-C6) cycloalkylcarbonyl (C1-C6)alkoxyphenyl, (C1-C6)allylcarbamate(C1-C6)alkoxyphenyl, (C1-C6)allylcarbamate(C1-C6)alkylphenyl, (C1-C6)alkoxycarbonyl(C1-C6)alkylphenyl, amino, (AMINOPHENYL, 1,2,3,4-tetrahydroisoquinolinium, N-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolinium, pyrrolidinylcarbonyl, oxazolidinyl, (lower)allyloxycarbonyl;

where R12is1-C6alkyl, optionally substituted by a group comprising phenyl, halogenfree, (C1-C6)alkoxyphenyl,1-C6alkoxy, phenoxy,

(C1-C6)alkoxyphenyl, halogenfree, (C1-C6)alkylphenoxy, carboxyl, (C1-C6)alkoxycarbonyl, (C1-C6)allylcarbamate, halogen, (C2-C6)alkenylamine, (C1-C6)alkoxy-(C1-C6)alkoxy, phenyl (C1-C6)alkoxy, piperidinyloxy, N-(C1-C6)alkoxycarbonylmethyl, pyridyloxy, hydroxyl, (C1-C6)alkanoyloxy, mono - or di (C1-C6)allylcarbamate, piperidinylcarbonyl, phenyl (C1-C6)allylcarbamate, (C1-C6)alkoxycarbonyl, amino, fluorenylmethoxycarbonyl, mono - or di (C1-C6)alkylamino, N-(C1-C6alkyl) -N-(C1-C6alkoxycarbonyl) amino, N-(C1-C6alkyl) amino, N-(mono - or di (C1-C6alkyl)carbarnoyl) amino, benzoylamine, (C1-C6)alkanolamine, (C1-C6)alkanesulfonyl, (C1-C6)alkoxy(C1-C6)alkanolamine, cyclo(C3-C6)allyloxycarbonyl, pyridylcarbonyl, morpholinosydnonimine, phenyl(C1-C6)alkoxycarbonyl, (C1-C6)alkoxylalkyl, hydroxy (C1-C6)alkylamino, morpholino, oxoacridine, oxopyrrolidin, trimethylhydantoin, pyridyl, (C2-C6)alkynylamino, (C1-C6)alkoxy (C1-C6)alkylamino, phenyl (C1-C6)alkylamino, pyridyl (C1-C6)alkylamino, and cyclo (C3-C6)alkyl;

(C)

where M represents oxygen or sulfur;

R13represents C1-C6alkyl, phenyl (C1-C6)alkyl, (C1-C6)alkoxy (C1-C6)alkyl, halogen (C1-C6)alkyl, amino (C1-C6)alkyl, phthalimido (C1-C6)alkoxycarbonyl, (C2-C6)alkenyl, phenyl;

(d)

where R15represents hydrogen or C1-C6alkyl;

is, (C2-C6)alkenyl, (C3-C6) cycloalkyl (C1-C6)alkyl, phenyl (C1-C6)alkyl, halogen (C1-C6)alkyl, (C1-C6)alkoxy (C1-C6)alkyl, hydroxy (C1-C6)alkyl, (C1-C6alkyl) (diphenyl) silyloxy (C1-C6)alkyl, carboxy (C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, (C1-C6)allylcarbamate(C1-C6)alkyl or pyridyl;

(e)

where R16is sensational, benzofuranyl, thienyl, furyl, (C1-C6)alkylpyridine, pyridyl, (C1-C6)alkoxyphenyl, (C1-C6)alkoxycarbonylmethyl, (C1-C6)alkanolamines, (C1-C6)alkyltetrahydrofuranes;

6. Connection on p. 5, in which a group of the formula

is the same group as (a), (C), (d) and (e) p. 5 and

the group with the following formula (b):

(b)

where R12represents C1-C6alkyl, phenyl (C1-C6)alkyl, halogenfrei (C1-C6)alkyl, (C1-C6)alkoxyphenyl (C1-C6)alkyl, (C1-C6)al>)alkyl, halogenfree (C1-C6)alkyl, (C1-C6)alkylphenoxy (C1-C6)alkyl, carboxy (C1-C6)alkyl, (C1-C6)alkoxycarbonyl (C1-C6)alkyl, (C1-C6)allylcarbamate (C1-C6)alkyl, halogen (C1-C6)alkyl, (C2-C6)alkenylamine (C1-C6)alkyl, (C1-C6)alkoxy (C1-C6)alkoxy (C1-C6)alkyl, phenyl (C1-C6)alkoxy (C1-C6)alkyl, piperidinyloxy (C1-C6)alkyl, (N-tert-butoxycarbonylmethylene (C1-C6)alkyl, pyridyloxy (C1-C6)alkyl, hydroxy (C1-C6)alkyl, (C1-C6)alkanoyloxy(C1-C6)alkyl, mono - or di (C1-C6)allylcarbamate (C1-C6)alkyl, piperidinecarboxylate (C1-C6)alkyl, phenyl (C1-C6)allylcarbamate (C1-C6)alkyl, (C1-C6)alkoxycarbonyl (C1-C6)alkyl, amino (C1-C6)alkyl, fluorenylmethoxycarbonyl- (C1-C6)alkyl, mono - or and(C1-C6)alkylamino (C1-C6)alkyl, N-C1-C6alkyl-N-(C1-C6alkoxycarbonyl) amino- (C1-C6alkyl-N-(mono - or di(C1-C6)allylcarbamate) amino (C1-C6)alkyl, N-(mono - or di(C1-C6alkyl)carbarnoyl)amino-( C1-C6)alkyl, benzoylamine (C1-C6)alkyl, (C1-C6)alkanolamine (C1-C6lower)alkyl, (C1-C6)alkanesulfonyl (C1-C6)alkyl, (C1-C6)alkoxy (C1-C6)alkanolamine (C1-C6)alkyl, cyclo (C3-C6)alkoxycarbonyl (C1-C6)alkyl, pyridylcarbonyl (C1-C6)alkyl, morpholinosydnonimine (C1-C6)alkyl, phenyl (C1-C6)alkoxycarbonyl (C1-C6)alkyl, (C1-C6)alkoxysilylated (C1-C6)alkyl, hydroxy (C1-C6)alkylamino (C1-C6)alkyl, morpholino (C1-C6)alkyl, oxoacridine (C1-C6)alkyl, oxopyrrolidin (C1-C6)alkyl, trimethylhydantoin (C1-C6)alkyl, pyridyl (C1-C6)alkyl, (C2-C6)alkynylamino (C1-C6)alkyl, (C1-C6)alkoxy (C1-C6)alkylamino (C1-C6)alkyl, phenyl (C1-C6)alkylamino (C1-C6)alkyl, Piri/sub>-C6)alkylamino, (C1-C6alkoxycarbonyl) (phenyl) (C1-C6)alkyl, amino (C1-C6)alkoxy (C1-C6)alkyl, (C1-C6alkoxycarbonyl) (C1-C6alkoxy)-( C1-C6)alkyl, (amino) (carboxy) (C1-C6)alkyl, (C1-C6alkoxycarbonyl) (carboxy) (C1-C6)alkyl, (amino) (C1-C6alkoxycarbonyl) (C1-C6)alkyl, (C1-C6alkoxycarbonyl) (C1-C6alkoxycarbonyl) (C1-C6)alkyl, (amino) (phenyl(C1-C6)alkoxy) (C1-C6)alkyl, (C1-C6alkoxycarbonyl)-(phenyl(C1-C6)alkoxy) (C1-C6)alkyl, (amino) (pyridyl) (C1-C6)alkyl, (C1-C6alkoxycarbonyl) (pyridyl) (C1-C6)alkyl, (amino) (hydroxy) (C1-C6)alkyl, (C1-C6alkoxycarbonyl) (hydroxy) (C1-C6)alkyl, (amino)(amino) (C1-C6)alkyl, (C1-C6alkoxycarbonyl) (amino) (C1-C6)alkyl, (amino) (C1-C6alkoxycarbonyl) (C1-C6)alkyl, (C1-C6alkoxycarbonyl) (C1-C6alkoxycarbonyl) (C1-C6With6cycloalkyl)-( C1-C6)alkyl.

7. Connection on p. 5, in which a group of the formula

is a group of the following formulas (a) to (e):

where R11is bromo, 2-naphthyl, phenyl, 3(or 4)-chlorophenyl, 2(or 3, or 4)-forfinal, 3,4-dichlorophenyl, 3,5-differenl, 3 (or 4)-were, 4-ethylphenyl, 4-isopropylphenyl, 4-(tert-butyl)phenyl, 3,4-dimetilfenil, 4-methoxyphenyl, 4-ethoxyphenyl, 4-triptoreline, 4-trifloromethyl, 4-ethenylene, 4-methylcarbamoylmethyl, 4-ethylcarbamate, 4-carbamoylmethyl, 4-benzylcarbamoyl, 4-acetylphenyl, 4-methylthiophenyl, 4-ethylthiophene, 4-methylsulfinylphenyl, 4-methylsulfinylphenyl, phenylphenyl, 4-phenyl-3-forfinal, 4-(4-forfinal)phenyl, 3(or 4)-hydroxyphenyl, 3(or 4)-hydroxymethylene, 4-(1,2-dihydroxyethyl)phenyl, 4-(phenoxycarbonylamino)phenyl, 3(or 4)-AMINOPHENYL, 4-carboxyphenyl, 3,4-methylenedioxyphenyl, 4-(methanesulfonamido)phenyl, 3-(2-butenylamine)phenyl, 3-(cyclopropanecarbonyl)phenyl, 3-(cyclobutanecarbonyl)phenyl, 3-(cyclopentanecarbonyl)phenyl, 4-benzyloxyphenyl, 4-(2-methylcarbamoyl)ethynyl)phenyl, 4-(2-(ethylcarbamate)ethynyl)phenyl, 4-(2-(propellerblades)ethynyl)phenyl, 4-(2-(isopropylcarbamate)ethynyl)phenyl, 4-(2-(4-tortenelmebol)ethynyl)phenyl, 4-(methylaminorex)phenyl, 4-(ethylenedicarboxylic)phenyl, 4-propanolamine, 4-(methoxyethoxy)phenyl, 4-(ethoxycarbonyl)phenyl, 4-(3-(3-pyridyl)acryloyloxy)phenyl, 4-(cyclopropylmethoxy)phenyl, 4-(carboxymethoxy)phenyl, 4-(ethoxycarbonylmethoxy)phenyl, 4-(tert-butoxycarbonylmethyl)phenyl, 4-(propenyloxy)phenyl, 4-(cyclopropylmethoxy)phenyl, 3(or 4)-(methylcarbamoylmethyl)phenyl, 4-(ethylcarboxylate)phenyl, 4-(profilereminder.exe)phenyl, 3(or 4)-(methylcarbamoylmethyl)phenyl, 4-(methoxycarbonylamino)phenyl, 4-(tert-butoxycarbonylamino)phenyl, 4-aminomethylphenol, 4-(methylcarbamoylmethyl)phenyl, 3-(2(or 3)-fuelleborni)phenyl, 3-(1,2,3,4-tetrahydroisoquinolinium)phenyl, 3-(N-(tert-butoxycarbonyl)-1,2,3,4 - tetrahydroisoquinolinium)phenyl, 3-(pyrrolidinylcarbonyl)phenyl, 4-(1,3-oxazolyl)phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl,

where R12represents methyl, ethyl, propyl, isopropyl, butyl, ' isobutyl, tert-butyl, neopentyl, phenylmethyl, 4-chloroformate, 4-methoxyphenethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, isopropoxyphenyl, 1-methoxyethyl, 2-way shall oximeter, 2-carboxyethyl, 2-methoxycarbonylethyl, 2-tert-butoxycarbonylmethyl, 2-methylcarbamoylmethyl, 2-chloroethyl, chloromethyl, allyloxymethyl, (2 ethoxyethoxy)methyl, benzoyloxymethyl, 4-piperidinyloxy, (N-tert-butoxycarbonyl-4-piperidinyl)oxymethyl, 3(or 4)-pyridylacetate, hydroxymethyl, 2-hydroxyethyl, acetoxymethyl, 1-acetoxyethyl, methylcarbamoylmethyl, 1-(N-methyl-N-ethylcarbamate)methyl, (piperidinecarboxylate)methyl, (benzylcarbamoyl)methyl, (tert-butoxycarbonylamino)methyl, aminomethyl, 1-amino-ethyl, 1-(tert-butoxycarbonylamino)ethyl, 2-amino-ethyl, methoxycarbonylmethyl, 2-(methoxycarbonylamino)ethyl, ethoxycarbonylmethyl, propoxycarbonyl, 1-(fluorenylmethoxycarbonyl)methyl, 2-(tert-butoxycarbonylamino)ethyl, 2-(fluorenylmethoxycarbonyl)ethyl, 1-linosopril, 1-aminopropyl, 1-(tert-butoxycarbonylamino)propyl, 1-(tert-butoxycarbonylamino)isopropyl, 1,5-diaminopentane, 1,5-bis(tert-butoxycarbonylamino)pencil, methylaminomethyl, ethylaminomethyl, 2-(N-methyl-N-ethylamino) methyl, (dimethylamino)methyl, (pentylamine)methyl, tert-butylaminoethyl, (3-methylamino)ethyl, 3-(1-(N-methyl-N-methoxycarbonylamino)methyl, 1-(N-methyl-N-tert-butoxycarbonylamino)methyl, 1-(N-ethyl-N-tert-butoxycarbonyl ethyl-N-(dimethylcarbamoyl)amino)methyl, 1-(dimethylcarbamoyl)methyl, 1-(N-(ethylcarbamate)amino)methyl, 2-(N-(ethylcarbamate)amino)ethyl, benzoylmethyl, 2-benzoylbenzoate, acetamidomethyl, isobutylamine, pivaloyloxymethyl, 1-(methanesulfonamido)methyl, 2-(methanesulfonamido)ethyl, methoxyaminomethyl, cyclopentanecarbonitrile, pyridylcarbonyl, morpholinosydnonimine, benzyloxycarbonylamino, 1-(4-methoxyphenylacetylene)methyl, 1-(2-hydroxyethylamino)methyl, morpholinomethyl, 1-(2-oxo-1,3-oxazolidin-1-yl)methyl, 1-(2-oxopyrrolidin-1-yl)methyl, 1-(3,4,4-trimethylhydantoin-1-yl)methyl, allelomimetic, 1-(2-ethoxyethylene)methyl, benzylamine, 1-(3-pyridylmethylamine)methyl, 2-phenyl-1-amino-ethyl, 1-amino-1-phenylmethyl, l-tert-butoxycarbonylamino-1-phenylmethyl, 1-amino-2-phenylethyl, 1-tert-butoxycarbonylamino-2-phenylethyl, 1-amino-2-methoxyethyl, 1-tert-butoxycarbonylamino-2-methoxyethyl, 1-amino-3-carboxypropyl, 1-tert-butoxycarbonylamino-3-carboxypropyl, 1-amino-3-(tert-butoxycarbonyl)propyl, 1-tert-butoxycarbonylamino-3-tert-butoxycarbonylmethyl etc., 1-amino-2-benzyloxyethyl, 1-tert-butoxycarbonylamino-2-benzyloxybenzoate, 1-amino-2-(3-pyridyl)ethyl, 1-tert-butoxycarbonylamino-2-(3-pyridyl)ethyl, 1-amine the Ino-2-hydroxyethyl, 1,5-diaminopentane, 1-tert-butoxycarbonylamino-5-aminopentyl, 1,5-bis(tert-butoxycarbonylamino)pentyl, 1-amino-5-(tert-butoxycarbonylamino)pentyl, 1-amino-2-cyclohexylethyl, 1-tert-butoxycarbonylamino-2-cyclohexylethyl,

where M = O;

R13represents methyl, ethyl, propyl, isopropyl, benzyl, 2-methoxyethyl, 2-chloroethyl, 2-amino-ethyl, 2-phthalimidomethyl, allyl, phenyl;

or M = S;

R13represents methyl, ethyl,

(d)

where R15represents hydrogen;

R14represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 1-naphthyl, 3(or 4)-chlorophenyl, 3-methoxyphenyl, allyl, cyclohexylmethyl, benzyl, 2-chloroethyl, methoxymethyl, 2-methoxyethyl, 2-hydroxyethyl, 2-((tert-butyl)(diphenyl)silyloxy)ethyl, carboxymethyl, ethoxycarbonylmethyl, methylcarbamoylmethyl or 3-pyridyl;

R14represents ethyl;

R15represents methyl,

(e)

where R16is 2-benzothiazyl, 2-benzofuranyl,

2(or 3)-thienyl, 2-furyl, 3-pyridyl,

1-methyl-4-pyridyl, 6-methyl-3-pyridyl,

6-methoxy-3-pyridyl,

5-methoxycarbonylamino-3-pyridyl,

5-acetyl-2-thienyl, 2-metelka R1, Ah, A, X, Y, Z, m and n are defined in paragraph 1,

or its salts, which comprises conducting the reaction removal hydroxyamino group in the compound of the formula

where R1, Ar, A, X, Y, Z, m and n are defined in paragraph 1;

R3ais hydroxyamino group,

or its salts.

9. The pharmaceutical composition active inhibitor of matrix metalloproteinases (MMP) or tumor necrosis factor-(TNF-), which includes a connection on p. 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.

Priority items:

07.01.1999 on PP.1, 8 and 9;

19.07.1999 on PP.1, 2, 8 and 9.

 

Same patents:

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-OR SIG6N(R7)-, where R6- alkyl, R5choose from the group of alkyl, aryl, including heteroaryl, -COR7, -SO2R7and-COR10where R7Is H, alkyl or aryl, including heteroaryl, R2Is F, Cl, Br, J, alkyl, aryl, including heteroaryl, formyl, acyl, C(O)NR7R10or C(O)or SIG7, m = 0, 1, or 2, R3selected from the group comprising R7OR7N(R7)(R10) and CH(R7)C(O)R8, R8is R7OR7and NR7R10, R9is hydrogen, alkyl, aryl, including heteroaryl, -C(O)R10, -SO2R10, -C(S)OTHER10, -C(NH)NH(R10), -C(O)OTHER10, R10- H, alkyl, or aryl, including heteroaryl, and in each case, it is not necessarily different from R7X represents an ion halogen provided that 1) when two alkyl groups are the same carbon or nitrogen, they are not necessarily linked together with the formation of a cyclic structure, and (2) nitrogen heteroaryl ring R1

The invention relates to 2-(iminomethyl)aminoaniline derivative of General formula I, And where the aromatic residue of the formula Ia, R1and R2independently H, halogen, HE, linear or branched C1-C6alkyl, linear or branched C1-C6alkoxyl, R3-H, linear or branched C1-C6alkyl, or-COR4where R4-C1-C6alkyl or the residue IC, linear or branched C1-C6the five-membered alkyl or a heterocycle containing 1-4 heteroatoms selected from O, S, N, and in particular: thiophene, furan, pyrrole or thiazole, carbon atoms which is unsubstituted or substituted by one or more groups selected from linear or branched C1-C6of alkyl, C1-C6alkoxyl or halogen; X is-CO-N(R3)-X'-, -NH-CO-X'-, -CH=,-CO -, or a bond, and X' represents -(CH2)n- where n = 0-6; Y means Y'-, -Y'-NH-CO-, -CO-Y', Y'-CO-, -N(R3)-Y'-, -Y,-N(R3)-, Y'-CH2-N(R3)-CO-, -Y'-O-, -Y'-O-Y' - or a bond, and Y' is -(CH2)n- where n = 0-6; Неt-pyrrole, pyrrolidine, furan, thiophene, imidazole, imidazoline, oxazole, isoxazol, oxazoline, isoxazole, thiazole, thiazoline, thiazolidine, thiazolidine, azetidine, piperidine, imidazolidine, they

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< / BR>
in which X denotes O or S;

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Ar denotes one of the following groups or WITH:

< / BR>
T represents hydrogen or (C1-C6)alkyl;

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< / BR>
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