Arylpiperazine, methods for their preparation, pharmaceutical composition

 

The invention relates to arylpiperazines General formula Iwhere is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, R, where R is H, C1-6alkyl, CN, CF3With1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2Is N; Y IS-SO2-; Z is - N(OH)-Cho; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N. Piperazines of the formula (I) used as matrix metalloproteinases inhibitors, especially as inhibitors of MMP 13. 4 C. and 4 h.p. f-crystals.-

The text description is piperazine formula I

where ring b is a phenyl, pyridyl or pyrimidyl;

each R3 is independently selected from hydrogen, halogen, NO2, COOR, where R represents hydrogen or C1-6 alkyl, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -SO2-C1-6 alkyl, C1-6 alkoxy and up to C10, aryloxy, n=1, 2, or 3;

R represents a direct bond;

ring And represents piperazinil;

X1 and x2 are N;

Y represents-SO2-;

Z represents-N(OH)CHO;

Q represents-CH2-;

R1 represents H, C1-6 alkyl, C5-7 cycloalkyl, up to C10 aryl, up to C10 heteroaryl, up to C12 aralkyl or until the C12 heteroallyl, all optionally substituted by up to three groups independently selected from N2, CF3, halogen, C1-4 alkyl, carboxy(C1-4)alkyl, up to C6 cycloalkyl, -OR4, -SR4, C1-4 alkyl, substituted by-OR4, SR4 (and their oxidized counterparts), NR4, N-Y-R4, or C1-4 alkyl-Y -, NR4, or R1 represents a 2,3,4,5,6-pentafluorophenyl;

R4 represents hydrogen, C1-6 alkyl, up to C10 aryl, or up to C10 heteroaryl, or up to C9 aralkyl, each independently optionally substituted with halogen, N2, CN, CF3, C1-6-alkyl, -S-C1-6-alkyl, -SO-C1-6-alkyl, -SO2-C1-6-alkyl or C1-6 alkoxy;

R2 pinnae ring, the latter contains at least one heteroatom selected from N, O and S; additionally, the group Q can be associated with either R1 or R2 with the formation of 5-, 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more of O, S and N; and where any of the above alkyl groups may be linear or branched,

or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

2. Connection on p. 1, where R3 represents hydrogen, halogen, N2, CF3, C1-4 alkyl and C1-4 alkoxy, n is 1 or 2; R1 represents hydrogen, C1-6 alkyl, C5-7 cycloalkyl, up to C12 aralkyl, until the C11 heteroallyl, up to C10 aryl or C10 heteroaryl; all of which are optionally substituted by up to three halogen atoms or CF3; R2 represents hydrogen or together with R1 represents a carbocyclic or heterocyclic Spiro 5 - or 6-membered ring; R4 represents up to C10 aryl, optionally substituted with halogen, N2, CN, CF3, C1-6-alkyl, -S-C1-6-alkyl, -SO-C1-6-alkyl, -SO2-C1-6-alkyl or C1-6 alkoxy, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

3. Connection on p. 1, where R3 represents hydrogen, halogen, N2, CF3, methyl, ethyl, met silkymail, 3,4-dichlorophenyl, 2-pyridyl, 3-pyridyl, 2-pyridylethyl, 3-pyridylethyl, thiophenolate, bromothiophene, 2-pyrimidinyl, 2-pyrimidinedione, pyridylmethyl or together with R2 represents spirocyclohexane or Spiro-4-Piran; R2 represents hydrogen, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

4. The compound of formula I under item 1, where the ring, substituted R3(n), represents phenyl, 3-methylphenylene, 4-terfenadine, 3-chloraniline, 4-chloraniline or 3,4-dichloraniline ring or represents 5-chloro-2-pyridyl, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

5. The compound of formula I under item 1, where the ring is a phenyl, 3-methylphenylene, 4-terfenadine, 3-chloraniline, 4-chloraniline or 3,4-dichloraniline ring or 5-chloro-2-pyridyl and R1 is a phenyl, terbutalin, femisapien, 2-pyridylethyl, 2-pyridinediamine, 3-pyridinediamine, 4-pyridinediamine or 4-chlorophenoxyacetate, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

6. Pharmaceutical composition for inhibiting at least one metalloproteinase, which includes with farmacevtichesky acceptable carrier.

7. The method of obtaining the compounds of formula I, or its pharmaceutically acceptable salt or in vivo hydrolyzable ether complex, which includes the interaction of the compounds of formula II, or its pharmaceutically acceptable salt or in vivo hydrolyzable ether complex with the compound of the formula III

where XI1denotes X, or the predecessor of X (either by modification or by substitution), or the activated form X, suitable for interaction with YI;

YImeans Y, the predecessor of Y, or the activated form of Y suitable for interaction with XI1;

ZIindicates a protected form Z, the predecessor of Z (either by modification or by substitution ZI) or activated form Z,

with the subsequent interaction of the compounds of formula IX with an appropriate compound of the formula R1-CO-R2 with getting alkene of the formula X, which is then converted into the compound of formula XI, where Zmeans hydroxylamino predecessor of Z, and the subsequent transformation Zthe group Z in accordance with the following scheme:

where1is a corresponding ring group or Deputy for the reaction with PI;

ZIhas the above meanings;

RIis an appropriately activated group for reaction with TheI.

Priorities on items and attributes:

31.08.1998 on PP.1-8;

04.06.1999 clarification of the characteristics of PP.1-8.

 

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or pharmaceutically acceptable salt of this compound, where

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where R2together with R7form a 5-8-membered ring containing two nitrogen atom a heterocycle, R5means hydrogen, R8means alkyl, optionally substituted by alkoxygroup; or A signifies a group

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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

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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,

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R6denotes H, a or benzyl,

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n denotes 0, 1 or 2,

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