US 5,627,173 AGranted

Phosphonoacetic acid derivatives and their use for treating degenerative joint disorders

AssigneeHoechst Aktiengesellschaft

InventorsRolf Graeve, Werner Thorwart, Ruth Raiss, Klaus U. Weithmann, Stefan M ullner

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Abstract

Phosphonoacetic acid derivatives and their use for treating degenerative joint disorders Compounds of the formula I ##STR1## are suitable for producing pharmaceuticals for the treatment and prophylaxis of degenerative joint disorders, of rheumatic disorders accompanied by cartilage breakdown, such as rheumatoid arthritis, joint trauma and chondrolysis as a consequence of prolonged immobilization of the joint, of inflammations, septic shock, disorders with impaired leukocyte adhesion, disorders caused by an elevated concentration of tumor necrosis factor alpha, such as cachexia or Crohn's disease.

Claims32

Dependent claims

A compound selected from at least one of a compound of the formula (I) ##STR145## a physiologically tolerated salt thereof, and a stereoisomer thereof, where at least two of the radicals R.sup.1, R.sup.2 and R.sup.3 are present and are, independently of one another, selected from:

1) OH,
2) (C.sub.1 -C.sub.12)-alkoxy,
3) --O--(C.sub.1 -C.sub.12 )-alkyl-COOH,
4) --O--(C.sub.1 -C.sub.12)-alkyl-C(O)--O--(C.sub.1 -C.sub.12)-alkyl,
5) (C.sub.3 -C.sub.12)-cycloalkoxy,
6) (C.sub.3 -C.sub.6)-alkenyloxy,
7) (C.sub.5 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.3)-alkoxy,
8) heteroaryl-(C.sub.1 -C.sub.3)-alkoxy, where the hetero atoms are selected from N, S and O,
9) heterocycloalkyl-(C.sub.1 -C.sub.3)-alkoxy where the heteroatoms are selected from N, S and O, the heterocyclo alkyl radical is unsubstituted or substituted once to three times by (C.sub.1 -C.sub.3)-alkyl, and the heterocycloalkyl group has five or six members,
10) phenyl-(C.sub.1 -C.sub.3)-alkoxy,
11) benzyloxy substituted once to three times by halomethyl or (C.sub.1 -C.sub.3)-alkoxy,
12) phenoxy substituted once to three times by (C.sub.1 -C.sub.3)-alkoxy,
13) two of the radicals R.sup.1, R.sup.2 or R.sup.3 which are substituents on two directly adjacent carbon atoms of the aromatic ring together form a methylenedioxy or ethylenedioxy radical on the aromatic ring,
14) a radical of the formula II, III or IV ##STR146## where R.sup.8 is (C.sub.1 -C.sub.4)-alkyl, or hydrogen, 15) a group of the formula V ##STR147## R.sup.1, is defined as for R.sup.1 from 1) to 12), and (C-A-C), R.sup.5, R' and R.sup.7 are as defined below, or
16) R.sup.1 and R.sup.7 are a covalent bond and thus form a compound of the formula Ia ##STR148## where R.sup.2 and R.sup.3 are as defined above and R.sup.5 and R.sup.6 are as defined below, or
17) R.sup.1 and R.sup.5 are a covalent bond and thus form a compound of the formula 1b ##STR149## where R.sup.2 and R.sup.3 are as defined above and R.sup.6 and R.sup.7 are as defined below, and
R.sup.5 is
1) CN,
2) CH.sub.2 NHR.sup.9 where R.sup.9 is hydrogen atom or --(C.sub.1 -C.sub.3)-alkyl, or
3) a radical of the formula VI ##STR150## where R.sup.10 is
1) hydrogen,
2) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted once to four times by --COOH, --C(O)--O--(C.sub.1 -C.sub.3)-alkyl or ##STR151## where R is hydrogen, (C.sub.1 -C.sub.3)-alkyl or forms, together with the nitrogen atom to which it is bonded, a morpholine ring, or
3)trialkylsilyl,
R.sup.6 and R.sup.7 are, independently of one another,
1) hydrogen or
2) (C.sub.1 -C.sub.6)-alkyl, (C-A-C ) is
1) (CH.dbd.CH--CH.dbd.C),
2) (CH.sub.2 --CH.sub.2 --CH.sub.2 --CH),
3) (CH.sub.2 --CH.sub.2 --CH),
4) (--CH.sub.2 --C) or
5) (--CH.dbd.C)
with the proviso that when the radical R.sup.5 is a CN group, not more than one of the radicals R.sup.1, R.sup.2 or R.sup.3 is a hydroxyl radical, or when the radical R.sup.10 is a hydrogen atom, none of othe radicals R.sup.1, R.sup.2 or R.sup.3 is a hydroxyl radical, or when the radical R.sup.10 is methyl, ethyl or t-butyl, the radicals R.sup.1, R.sup.2 or R.sup.3 are not methoxy, and the compounds ##STR152## are excepted.

29 more elements

A Pharmaceutical composition containing an effective amount of at least one compound of the formula (I) ##STR174## a physiologically tolerated salt thereof, or a stereoisomer thereof, where at least two of the radicals R.sup.1, R.sup.2 and R.sup.3 are present and are, independently of one another, selected from

1) OH,
2) (C.sub.1 -CH.sub.12)-alkoxy,
3) --O--(C.sub.1 -CH.sub.12)-alkyl-COOH,
4) --O--(C.sub.1 -C.sub.12)-alkyl-C(O)--O--(C.sub.1 -C.sub.12)-alkyl,
5) (C.sub.3 -CH.sub.12)-cycloalkoxy,
6) (C.sub.3 -C.sub.6)-alkenyloxy,
7) (C.sub.5 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.3)-alkoxy,
8) heteroaryl-(C.sub.1 -C.sub.3)-alkoxy, where the heteroatoms are selected from N, S and O,
9) heterocycloalkyl-(C.sub.1 -C.sub.3)-alkoxy where the heteroatoms are selected from N, S and O, the heterocycloalkyl radical is unsubstituted or substituted once to three times by (C.sub.1 -C.sub.3)-alkyl, and the heterocycloalkyl group has five or six members,
10) phenyl-(C.sub.1 -C.sub.3)-alkoxy,
11) benzyloxy substituted once to three times by halomethyl or (C.sub.1 -C.sub.3)-alkoxy,
12) phenoxy substituted once to three times by (C.sub.1 -C.sub.3)-alkoxy,
13) two of the radicals R.sup.1, R.sup.2 or R.sup.3 which are substituents on two directly adjacent carbon atoms of the aromatic ring together form a methylenedioxy or ethylenedioxy radical on the aromatic ring,
14) a radical of the formula II, III or IV ##STR175## where R.sup.8 is (C.sub.1 -C.sub.4)-alkyl or hydrogen, 15) a group of the formula V ##STR176## where R' is defined as for R.sup.1 from 1) to 12), and (C-A-C), , R.sup.5, R.sup.6 and R.sup.7 are as defined below, or
16) R.sup.1 and R.sup.7 form a compound of the formula Ia ##STR177## where R.sup.2 and R.sup.3 are as defined above and R.sup.5 and R.sup.6 are as defined below, and
17) R.sup.1 and R.sup.5 form a compound of the formula 1b ##STR178## where R.sup.2 and R.sup.3 are as defined above and R.sup.6 and R.sup.7 are as defined below, and
R.sup.5 is selected from
1) CN,
2) CH.sub.2 NHR.sup.9, where R.sup.9 is hydrogen or --C(O)--(C.sub.1 -C.sub.3)-alkyl, and
3) a radical of the formula VI ##STR179## where R.sup.10 is selected from
1) hydrogen,
2) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted once to four times by a group selected from --COOH, --C(O)--O--(C.sub.1 -C.sub.3)-alkyl and ##STR180## where R is hydrogen, (C.sub.1 -C.sub.3)-alkyl or forms, together with the nitrogen atom to which it is bonded, a morpholine ring, and
3) trialkylsilyl,
R.sup.6 and R.sup.7 are, independently of one another,
1) hydrogen or
2) (C.sub.1 -C.sub.6)-alkyl, and
(C-A-C) is selected from
1) (CH.dbd.CH--CH.dbd.CH--CH),
2) (CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH),
3) (CH.sub.2 --CH.sub.2 --CH.sub.2 --CH),
4) (CH.sub.2 --CH.sub.2 --CH),
5) (--CH.sub.2 --CH) and
6) (--CH.dbd.C).

30 more elements

Dependencies are inferred from the claim text.

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Abstract

1) OH,
2) (C.sub.1 -C.sub.12)-alkoxy,
3) --O--(C.sub.1 -C.sub.12 )-alkyl-COOH,
4) --O--(C.sub.1 -C.sub.12)-alkyl-C(O)--O--(C.sub.1 -C.sub.12)-alkyl,
5) (C.sub.3 -C.sub.12)-cycloalkoxy,
6) (C.sub.3 -C.sub.6)-alkenyloxy,
7) (C.sub.5 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.3)-alkoxy,
8) heteroaryl-(C.sub.1 -C.sub.3)-alkoxy, where the hetero atoms are selected from N, S and O,
9) heterocycloalkyl-(C.sub.1 -C.sub.3)-alkoxy where the heteroatoms are selected from N, S and O, the heterocyclo alkyl radical is unsubstituted or substituted once to three times by (C.sub.1 -C.sub.3)-alkyl, and the heterocycloalkyl group has five or six members,
10) phenyl-(C.sub.1 -C.sub.3)-alkoxy,
11) benzyloxy substituted once to three times by halomethyl or (C.sub.1 -C.sub.3)-alkoxy,
12) phenoxy substituted once to three times by (C.sub.1 -C.sub.3)-alkoxy,
13) two of the radicals R.sup.1, R.sup.2 or R.sup.3 which are substituents on two directly adjacent carbon atoms of the aromatic ring together form a methylenedioxy or ethylenedioxy radical on the aromatic ring,
14) a radical of the formula II, III or IV ##STR146## where R.sup.8 is (C.sub.1 -C.sub.4)-alkyl, or hydrogen, 15) a group of the formula V ##STR147## R.sup.1, is defined as for R.sup.1 from 1) to 12), and (C-A-C), R.sup.5, R' and R.sup.7 are as defined below, or
16) R.sup.1 and R.sup.7 are a covalent bond and thus form a compound of the formula Ia ##STR148## where R.sup.2 and R.sup.3 are as defined above and R.sup.5 and R.sup.6 are as defined below, or
17) R.sup.1 and R.sup.5 are a covalent bond and thus form a compound of the formula 1b ##STR149## where R.sup.2 and R.sup.3 are as defined above and R.sup.6 and R.sup.7 are as defined below, and
R.sup.5 is
1) CN,
2) CH.sub.2 NHR.sup.9 where R.sup.9 is hydrogen atom or --(C.sub.1 -C.sub.3)-alkyl, or
3) a radical of the formula VI ##STR150## where R.sup.10 is
1) hydrogen,
2) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted once to four times by --COOH, --C(O)--O--(C.sub.1 -C.sub.3)-alkyl or ##STR151## where R is hydrogen, (C.sub.1 -C.sub.3)-alkyl or forms, together with the nitrogen atom to which it is bonded, a morpholine ring, or
3)trialkylsilyl,
R.sup.6 and R.sup.7 are, independently of one another,
1) hydrogen or
2) (C.sub.1 -C.sub.6)-alkyl, (C-A-C ) is
1) (CH.dbd.CH--CH.dbd.C),
2) (CH.sub.2 --CH.sub.2 --CH.sub.2 --CH),
3) (CH.sub.2 --CH.sub.2 --CH),
4) (--CH.sub.2 --C) or
5) (--CH.dbd.C)
with the proviso that when the radical R.sup.5 is a CN group, not more than one of the radicals R.sup.1, R.sup.2 or R.sup.3 is a hydroxyl radical, or when the radical R.sup.10 is a hydrogen atom, none of othe radicals R.sup.1, R.sup.2 or R.sup.3 is a hydroxyl radical, or when the radical R.sup.10 is methyl, ethyl or t-butyl, the radicals R.sup.1, R.sup.2 or R.sup.3 are not methoxy, and the compounds ##STR152## are excepted.

29 more elements