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

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< / BR>
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