RU99106161A

RU99106161A - DERIVATIVES OF PHENOXYACIC ACID AND PHENOXYMETHILETHRAZOLE, possessing anti-tumor activity

Info

Publication number: RU99106161A
Application number: RU99106161/14A
Authority: RU
Inventors: Роберто Ди ДОМЕНИКО; Зилке ХАНСЕН; Бригитте КАЛУЦА; Эрнесто Мента; Ральф Шумахер
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 1998-03-30
Filing date: 1999-03-29
Publication date: 2001-01-10

Claims

1. The use of compounds of formula (I)

where the group -OC (R1) (R2) - (CH ₂ ) _p -A may be in the ortho, meta or para position,
A is selected from the group comprising —COOH, —COO- (C ₁ -C ₄ ) alkyl, —CN or a group of the formula

in which R 'denotes hydrogen or (C ₁ -C ₄ ) alkyl, or the group A- (CH ₂ ) _p C (R1) (R2) is selected from phenyl, benzyl or (indolyl) methyl, which may be substituted with R4- in groups
p is 0, 1 or 2,
R1 and R2 independently of each other are selected from the group comprising hydrogen or (C ₁ -C ₈ ) alkyl, or they, together with the carbon atom to which they are attached, form a (C ₃ -C ₇ ) cycloalkyl group,
R4 represents from 0 to 2 substituents independently selected from the group including chlorine, bromine, iodine, fluorine, linear or branched (C ₁ -C ₈ ) alkyl, hydroxy-, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) acyl, or group

in formula (I) denotes a naphthyl group, which in turn is substituted by R4 groups,
n denotes an integer from 1 to 4,
m is 0 or 1,
B is selected from the group consisting of linear or branched (C ₁ -C ₁₀ ) alkyl, —CO — C (R 3) = CH — R, —CH = C (R 3) —CO — Ar, —CO — CH (R 3) - CH ₂ -R or -CO-CH (R3) -CH ₂ NR5R6, when m is 0, or -CH = C (R3) -CO-Ar, when m is 1,
R is selected from the group comprising hydrogen, —Ar or —COAr,
R3 is selected from the group consisting of hydrogen or (C ₁ -C ₈ ) alkyl,
R5 and R6 independently of each other denote (C ₁ -C ₄ ) alkyl group or together with the nitrogen atom to which they are attached form a piperidino, piperazino, (C ₁ -C ₈ ) alkylpiperazino, morpholino or thiomorpholino group,
Ar means a phenyl group which may be unsubstituted or may be substituted by 1-3 radicals, independently of one another selected from the group including chlorine, bromine, iodine, fluorine, linear or branched (C ₁ -C ₈ ) alkyl, hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) acyl,
their stereoisomers or their salts with pharmaceutically acceptable acids or bases in the manufacture of a medicinal product having antagonistic activity against MDM2.

2. The use according to claim 1 for the treatment of tumors.

3. The use according to claim 2, wherein the tumor to be treated is sarcoma.

4. The compounds of formula (I)

in which R 'denotes hydrogen or (C ₁ -C ₄ ) alkyl,
or the group A- (CH ₂ ) _p C (R1) (R2) is selected from phenyl, benzyl or (indolyl) methyl, which may be substituted by R4 groups,
p is 0, 1 or 2,
R1 and R2 independently of each other are selected from the group comprising hydrogen or (C ₁ -C ₈ ) alkyl, or they, together with the carbon atom to which they are attached, form a (C ₃ -C ₇ ) cycloalkyl group,
R4 represents from 0 to 2 substituents independently selected from the group including chlorine, bromine, iodine, fluorine, linear or branched (C ₁ -C ₈ ) alkyl, hydroxy-, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) acyl, or group

in formula (I) denotes a naphthyl group, which in turn is substituted by R4 groups,
n denotes an integer from 1 to 4,
m is 0 or 1,
B is selected from the group consisting of linear or branched (C ₁ -C ₁₀ ) alkyl, —CO — C (R 3) = CH — R, —CH = C (R 3) —CO — Ar, —CO — CH (R 3) - CH ₂ -R or -CO-CH (R3) -CH ₂ NR5R6, when m is 0, or -CH = C (R3) -CO-Ar, when m is 1,
R is selected from the group comprising hydrogen, -Ar or -COAr,
R3 is selected from the group consisting of hydrogen or (C ₁ -C ₈ ) alkyl,
R5 and R6 independently of each other denote (C ₁ -C ₄ ) alkyl group or they, together with the nitrogen atom to which they are attached, form a piperidino, piperazino, (C ₁ -C ₈ ) alkylpiperazino, morpholino or thiomorpholino group ,
Ar denotes a phenyl group which may be unsubstituted or may be substituted by 1-3 radicals, independently of one another selected from the group including chlorine, bromine, iodine, fluorine, linear or branched (C ₁ -C ₈ ) alkyl, hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) acyl,
their stereoisomers or their salts with pharmaceutically acceptable acids or bases, provided that when m is 0, then A is selected from the group consisting of -COO- (C ₁ -C ₄ ) alkyl, -CN or a group of the formula

in which R 'is hydrogen or (C ₁ -C ₄ ) alkyl, and when m is 0 and A represents -COO- (C ₁ -C ₄ ) alkyl group, then B can denote only a group of the formula -CO-CH (R3 ) -CH ₂ NR5R6.

5. Compounds according to claim 4, in which m is 0, R represents hydrogen and A represents a tetrazole group.

6. Compounds according to claim 4, in which A is phenyl, substituted by 1-2 chlorine atoms.

7. Compounds according to any one of paragraphs. 4-6, in which R4 represents 1-2 chlorine atoms.

8. Compounds according to any one of paragraphs. 4-7, in which the group -OC (R1) (R2) - (CH ₂ ) _p -A is in para position.

9. Compounds of one of the following formulas:

10. Pharmaceutical compositions containing at least one compound according to any one of claims 4 to 9 in a mixture with pharmaceutically acceptable excipients.