Substituted isoindoles and their use
View Patent ↗The invention relates to coagulation of the blood. Disclosed are novel compounds of formula (I), a method for the production of these compounds, pharmaceutical compositions containing them, and methods of using them for the prevention and/or treatment of various diseases.
1. A compound of the formula (I)
in which
R 1 and R 2 together represent O and
R 3 and R 4 together represent O,
or
R 1 represents hydrogen, hydroxy or (C 1 -C 4 )-alkoxy,
R 2 represents hydrogen and
R 3 and R 4 together represent O,
or
R 1 and R 2 together represent O,
R 3 represents hydrogen, hydroxy or (C 1 -C 4 )-alkoxy and
R 4 represents hydrogen,
R 5 represents halogen, trifluoromethyl or methyl,
A represents (C 1 -C 4 )-alkanediyl which may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,
a represents 0 or 1,
B represents a group
in which
R 6 represents hydrogen or (C 1 -C 4 )-alkyl,
b represents 0 or 1,
D represents piperazine,
which may be mono- or disubstituted, independently of one another, by hydroxy, carbamoyl, (C 1 -C 4 )-alkanoyl, (C 3 -C 7 )-cycloalkanoyl, (C 3 -C 7 )-cycloalkyl, 5- to 10-membered heterocyclyl, (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 6 )-alkyl,
which for its part may be substituted by hydroxy, cyano, (C 1 -C 4 )-alkoxy, mono- or di-(C 1 -C 6 )-alkylamino, mono- or di-(C 1 -C 6 )-alkylaminocarbonyl, 5- to 10-membered heterocyclyl, 5- or 6-membered heterocyclylcarbonyl or 5- to 10-membered heteroaryl, (C 6 -C 10 )-aryl,
which for its part may be substituted by halogen, trifluoromethyl, nitro, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
5- to 10-membered heteroaryl,
which for its part may be substituted by cyano, amino or (C 1 -C 4 )-alkyl, or 5- to 10-membered heteroarylcarbonyl,
or a salt thereof.
2. The compound as claimed in claim 1 ,
in which
the thiophenecarboxylic acid substituent is attached to the phenyl ring in the ortho-position to the point of attachment of the fused heterocycle,
R 1 and R 2 together represent O and
R 3 and R 4 together represent O,
or
R 1 represents hydrogen, hydroxy, methoxy or ethoxy,
R 2 represents hydrogen and
R 3 and R 4 together represent O,
or
R 1 and R 2 together represent O,
R 3 represents hydrogen, hydroxy, methoxy or ethoxy and
R 4 represents hydrogen,
R 5 represents halogen or trifluoromethyl,
A represents (C 1 -C 4 )-alkanediyl, which may be substituted by hydroxy,
a represents 0 or 1,
B represents a group
in which
R 6 represents hydrogen,
b represents 0 or 1,
D represents piperazine,
which may be mono- or disubstituted, independently of one another, by hydroxy, carbamoyl, acetyl, cyclopropanoyl, (C 3 -C 6 )-cycloalkyl, 5- to 10-membered heterocyclyl, (C 1 -C 3 )-alkyl,
which for its part may be substituted by hydroxy, methoxy, mono- or dimethylamino, mono- or di-(C 1 -C 3 )-alkylaminocarbonyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heterocyclylcarbonyl or 5- or 6-membered heteroaryl, phenyl,
which for its part may be substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy, or 5- or 6-membered heteroaryl,
which for its part may be substituted by cyano, amino or methyl,
or a salt, hydrate, hydrate of the salt, or solvate thereof.
3. The compound as claimed in claim 1 ,
in which
the thiophenecarboxylic acid substituent is attached to the phenyl ring in the ortho-position to the point of attachment of the fused heterocycle,
R 1 and R 2 together represent O and
R 3 R 4 together represent O,
or
R 1 represents hydrogen, hydroxy or methoxy
R 2 represents hydrogen and
R 3 and R 4 together represent O,
or
R 1 and R 2 together represent O,
R 3 represents hydrogen, hydroxy or methoxy and
R 4 represents hydrogen,
R 5 represents chlorine or bromine,
A represents methanediyl, ethanediyl or propane-1,3-diyl, which radicals may be substituted by hydroxy,
a represents 0 or 1,
B represents a group
b represents 0 or 1,
D represents piperazine,
which may be mono- or disubstituted, independently of one another, by methyl, ethyl, n-propyl or isopropyl,
which for their part may be substituted by hydroxy or pyridyl, or pyridyl,
which for its part may be substituted by amino or methyl,
or a salt thereof.
4. A process for preparing compounds of the formula (1) as defined in claim 1 , characterized in that
either
(A1) a compound of the formula (VII)
in which A and R 5 are as defined in claim 1 ,
is converted, by reaction with an amine or alcohol,
into a compound of the formula (I)
or
(A2) a compound of the formula (IX)
in which A, B and D are as defined in claim 1 ,
is converted with a compound of the formula (III)
in which R 5 is as defined in claim 1 and X represents a leaving group,
into a compound of the formula (I)
or
(B 1) a compound of the formula (XI)
in which R 5 is as defined in claim 1 ,
is converted with a compound of the formula (XII)
HO-A a -B b -D (XII),
in which A, a, B, b and D are as defined in claim 1 ,
into a compound of the formula (I)
or
(B2) a compound of the formula (XIII)
in which A, a, B, b and D are as defined in claim 1 ,
is converted with a compound of the formula (III)
into a compound of the formula (I)
or
(C) a compound of the formula (XVI)
in which A, a, B, b and D are as defined in claim 1 ,
is converted with a compound of the formula (III) into a compound of the formula (I).
5. A pharmaceutical composition, comprising at least one compound of the formula (I) as defined in claim 1 and at least one pharmaceutically suitable excipient.
6. A method for the treatment of thromboembolic disorders, comprising administering an effective amount of a compound of claim 1 .
7. A method for the treatment of disseminated intravascular coagulation (DIC) comprising administering an effective amount of a compound of claim 1 .
8. A method for delaying the onset of coagulation of blood in vitro, characterized in that a compound of the formula (I) as defined in claim 1 is added.
9. The method of claim 6 , wherein the thromboembolic disorder is selected from the group consisting of myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms and deep venous thromboses.
10. The method of claim 9 wherein said angina pectoris is unstable angina.
11. The method of claim 8 , wherein said blood is banked blood or a biological sample containing factor Xa.