Substituted oxindol derivatives and medicaments containing the same
View Patent ↗The present invention relates to novel oxindole derivatives of the general formula (I), wherein the substituents A, B, R 1 , R 2 and R 3 are as defined in Claim 1 , and medicaments containing the same for the prophylaxis and/or treatment of vasopressin-dependent or oxytocin-dependent diseases.
1. A compound of the general formula (I),
wherein
A is C 6-10 -aryl, which can be substituted with a maximum of four residues R 4 that are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, (CH 2 ) 0-2 —CN, CF 3 , OCF 3 , CONH 2 , CONH(C 1 -C 4 alkyl), CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), NHCHO, NHCONH 2 , N(C 0 -C 4 alkylene)CONH 2 , N(C 0 -C 4 alkylene)CONH(C 1 -C 4 alkyl), NHCOCH 3 , NO 2 , (CH 2 ) 0-2 —OH, O—C 1 -C 6 alkyl, (CH 2 ) 0-2 —O—C 1 -C 4 alkyl, O—C 0 -C 4 alkylene-phenyl, phenyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl,
B is an aromatic or partially aromatic monocyclic or bicyclic C 6-10 , that can be substituted with the residues R 6 , R 7 , R 8 and/or R 9 , wherein R 6 , R 7 , R 8 and R 9 are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, (CH 2 ) 0-2 —CN, CF 3 , OCF 3 , CONH 2 , CONH(C 1 -C 4 alkyl), CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), NHCHO, N(C 0-4 alkylene)CONH(C 1 -C 4 NHCOCH 3 , NO 2 , OH, O—C 1 -C 4 alkyl, (CH 2 ) 0-2 —O—(CH 2 ) 0 -3-CH 3 , O-alkylene-phenyl, phenyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl,
R 1 is hydrogen, C 1 -C 6 alkyl, OH, O—(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), CN, CONH 2 , OCF 3 , CF 3 , Br, F, Cl, J, NO 2 , NHCHO, NHCO(C 1 -C 4 alkyl) or NHCONH 2 ,
R 2 is hydrogen, C 1 -C 4 alkyl, O—(C 1 -C 4 alkyl), Cl or F,
R 3 is a residue (W)—(X) —(Y)—Z, wherein
W is C 1 -C 4 alkylene, (C 0 -C 4 alkylene)-O—(C 0 -C 4 alkylene) or (C 0 -C 4 alkylene)-NR 15 —(C 0 -C 4 alkylene), wherein R 15 is hydrogen or C 1 -C 4 alkyl,
X is CO, SO 2 , (C═NH) or (C═N—CN): and
Y is a residue selected from the group consisting of
wherein Y can additionally be substituted with R 10 and/or R 11 , wherein
R 10 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, O—C 1 -C 4 alkyl, O—C 1 -C 4 alkylene-phenyl, NH 2 , NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl),
R 11 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, O—C 1 -C 4 alkyl, O—C 0 -C 4 alkylene-phenyl, NH 2 , NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), and
Z is a residue selected from the group consisting of
wherein Z can additionally be substituted with R 12 and/or R 13 , wherein
R 12 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, O—C 1 -C 4 alkyl, O—C 0 -C 4 alkylene-phenyl, NH 2 , NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl),
R 13 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, O(C 1 -C 4 alkyl), O—C 0 -C 4 alkylene-phenyl, NH 2 , NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl),
R 14 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 0 -C 4 alkylene-phenyl, and
their tautomeric, enantiomeric and/or diastereomeric forms, as well as the physiologically compatible saltsthereof.
2. The compound of claim 1 , wherein A is a phenyl ring that can be substituted with a maximum of four residues R 4 and B is a phenyl ring that can be substituted with the residues R 6 , R 7 , R 8 and/or R 9 , wherein the residues R 4 , R 6 , R 7 , R 8 and R 9 shall have the meanings cited in claim 1 , and their tautomeric, enantiomeric and/or diastereomeric forms, as well as the physiologically compatible saltsthereof.
3. The compound of claim 1 , wherein
A is a phenyl ring that can be substituted with a maximum of two residues R 4 that are selected independently of one another from the group consisting of hydrogen, chlorine, O—C 1 -C 4 alkyl, (CH 2 ) 0-2 —O—(CH 2 ) 0-2 —CH, ad C 1 -C 6 alkyl,
B is a phenyl ring that can be substituted with the residues R 6 , R 7 , R 8 and/or R 9 , wherein R 6 , R 7 , R 8 and R 9 are selected independently of one another from the group consisting of hydrogen, fluorine, chlorine, O—C 1 -C 4 alkyl, (CH 2 ) 0-2 —O—(CH 2 ) 0-2 —CH 3 and C 1 -C 6 alkyl,
R 1 is hydrogen, CN, F, Cl, C 1-4 alkyl, OH or O—(C 1-4 alkyl),
R 2 is hydrogen,
R 3 is a residue (W)—(X)—(Y)—Z, wherein
W is O, CH 2 NH, NHCH 2 , OCH 1 , CH 2 O or NH,
X is CO,
Y is a residue selected from the group consisting of
Z is a residue selected from the group consisting of
wherein Z can additionally be substituted with R 12 and/or R 13 , wherein
R 12 is hydrogen or C 1 -C 4 alkyl,
R 13 is hydrogen or C 1 -C 4 alkyl and wherein
R 14 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl,
and their tautomeric, enantiomeric and/or diastereomeric forms, as well as the physiologically compatible saltsthereof.
4. The compound of claim 1 , wherein
A is a phenyl ring that can be substituted with a maximum of two residues R 4 that are selected independently of one another from the group consisting of hydrogen, chlorine, O—C 1 -C 4 alkyl, (CH 2 ) 0-2 —O—(CH 2 ) 0-2 —CH 3 and C 1 -C 6 alkyl,
B is a phenyl ring that can be substituted with the residues R 6 and/or R 7 wherein R 6 and R 7 are selected independently of one another from the group consisting of hydrogen, fluorine, chlorine, O—C 1 -C 4 alkyl and C 1 -C 6 alkyl,
R 1 is hydrogen, F, Cl, CH 3 , CN, CH 2 CH 3 , OCH 3 or OCH 2 CH 3 ,
R 2 is hydrogen,
R 3 is a residue (W)—(X)—(Y)—Z, wherein
W is O, CH 2 , or NH,
X is CO,
Y is a residue selected from the group
Z is a residue selected from the group
wherein Z can be substituted with R 12 and/or R 13 , wherein
R 12 is hydrogen or C 1 -C 4 alkyl,
R 13 is hydrogen or C 1 -C 4 alkyl and
R 14 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl,
and their tautomeric, enantiomeric and/or diastereomeric forms, as well as the physiologically compatible saltsthereof.
5. The compound of claim 1 , wherein
A is a phenyl ring that can be substituted with a maximum of two residues R 4 that are selected independently of one another from the group consisting of hydrogen, chlorine, O—C 1 -C 4 alkyl, (CH 2 ) 0-2 —O—(CH 2 ) 0-2 —CH 3 , and C 1 -C 6 alkyl,
B is a phenyl ring that can be substituted with the residues R 6 and/or R 7 , wherein R 6 and R 7 are selected independently of one another from the group consisting of hydrogen, fluorine, chlorine, O—C 1 -C 4 alkyl, and C 1 -C 6 alkyl,
R 1 is Cl, CH 3 , CN, CH 2 CH 3 or OCH 3 ,
R 2 is hydrogen,
R 3 is a residue (W)—(X) —(Y)—Z, wherein
W is CH 2 , —O or NH,
X is CO,
Y is a residue
Z is a residue
wherein
R 14 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl,
and their tautomeric, enantiomeric and/or diastereomeric forms, as well as the physiologically compatible saltsthereof.
6. The compound of claim 1 , wherein
A is a phenyl ring that can be substituted with a maximum of two residues R 4 that are selected independently of one another from the group consisting of hydrogen, chlorine, O—C 1 -C 4 alkyl and C 1 -C 4 alkyl,
B is a phenyl ring that is substituted with the residues R 6 and/or R 7 , wherein R 6 and R 7 are selected independently of one another from the group consisting of hydrogen, fluorine, chlorine, O—C 1 -C 4 alkyl, and C 1 -C 6 alkyl,
R 1 is hydrogen, Cl, CH 3 , CN, CH 2 CH 3 , OCH, or OCH 2 CH 3 ,
R 2 is hydrogen,
R 3 is a residue (W)—(X) —(Y)—Z, wherein
W is CH 2 , O or NH,
X is CO,
Y is a residue
and
Z is a residue
wherein R 14 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 1 -C 4 alkynyl,
and their tautomeric, enantiomeric and/or diastereomeric forms, as well as the physiologically compatible saltsthereof.
7. A method for treating a disease selected from the group consisting of hypertension, pulmonary hypertension, cardiac insufficiency, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), and ischemia of the heart, the method comprising administering the compound of claim 1 to a subject in need thereof.