Substituted aryl and heteroaryl derivatives, their...

Details Substituted aryl and heteroaryl derivatives, their... Substituted aryl and heteroaryl derivatives, their...

2001-10-18

2002-11-12

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S423000, C514S637000, C514S564000, C546S309000, C548S530000, C564S161000, C564S244000, C562S439000, C562S440000

Reexamination Certificate

active

06479524

ABSTRACT:

The present invention relates to new substituted aryl and heteroaryl derivatives of general formula
Ar—A—(HCR
1
)—X—Y,  (I)
the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts with inorganic or organic acids or bases which have valuable properties.
The compounds of the above general formula I wherein Y does not contain a cyano group, have valuable pharmacological properties, particularly an antithrombotic activity, and
the compounds of the above general formula I wherein Y contains a cyano group, are valuable intermediate products for preparing the compounds of general formula I wherein R
5
denotes an optionally substituted amino-C
1-3
-alkyl, amidino, guanidino or guanidino-C
1-3
-alkyl group.
The present invention thus relates to the new compounds of the above general formula I and the preparation thereof, the pharmaceutical compositions containing the pharmacologically active compounds and their use.
In the above general formula
A denotes an ethynylene group, a vinylene or ethylene group optionally substituted by a C
1-3
-alkyl or carboxy-C
1-3
-alkyl group or by a chlorine, bromine or iodine atom,
R
1
denotes a hydrogen atom, a C
1-3
-alkyl or carboxy-C
1-3
-alkyl group,
Ar denotes a phenyl group substituted by the groups R
2
to R
4
, wherein
R
2
denotes
a C
1-6
-alkyl- or C
3-7
-cycloalkyl-C
1-3
-alkyl group, which may be substituted in the C
1-6
- and C
1-3
-alkyl moieties by a carboxy, phenyl, amino, C
1-3
-alkylamino, carboxy-C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, N-(carboxy-C
1-3
-alkyl)-C
1-3
-alkylamino, C
3-7
-cycloalkylamino, phenylamino, N—(C
1-3
-alkyl)-phenylamino, N—(C
1-4
-alkanoyl)-phenylamino, heteroarylamino, N—(C
1-3
-alkyl)-heteroarylamino, N-(carboxy-C
1-3
-alkyl)-phenylamino or N-(carboxy-C
1-3
-alkyl)-heteroarylamino group,
a carboxy-C
1-5
-alkyl group which is substituted in the alkyl moiety by a C
1-3
-alkylamino, N,N-di-(C
1-3
-alkyl)-amino, pyrrolidino, piperidino or hexamethyleneimino group,
a carboxy-C
1-5
-alkyl group wherein the hydrogen atoms of a methylene group are replaced by a n-C
2-5
-alkylene bridge,
a phenyl, phenyloxy or phenylsulphonyl group, which may be substituted in each case in the phenyl moiety by a fluorine, chlorine, bromine or iodine atom, by a C
1-3
-alkyl, carboxy-C
1-3
-alkyl or C
1-3
-alkoxy group,
a C
1-5
-alkylamino, carboxy-C
1-3
-alkylamino, di-(C
1-5
-alkyl)-amino, N-(carboxy-C
1-3
-alkyl)-C
1-5
-alkylamino, C
3-7
-cycloalkylamino, N-(carboxy-C
1-3
-alkyl)-C
3-7
-cycloalkylamino, phenylamino, N—(C
1-3
-alkyl)-phenylamino, N-(carboxy-C
1-3
-alkyl)-phenylamino, heteroarylamino, N—(C
1-3
-alkyl)-heteroarylamino or N-(carboxy-C
1-3
-alkyl)-heteroarylamino group,
a C
1-5
-alkylcarbonylamino, C
3-7
-cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C
1-5
-alkylsulphonylamino, arylsulphonylamino, heteroarylsulphonylamino, N—(C
1-3
-alkyl)-C
1-5
-alkylcarbonylamino, N—(C
1-3
-alkyl)-C
3-7
-cycloalkylcarbonylamino, N—(C
1-3
-alkyl)-arylcarbonylamino, N—(C
1-3
-alkyl)-heteroarylcarbonylamino, N—(C
1-3
-alkyl)-C
1-5
-alkylsulphonylamino, N—(C
1-3
-alkyl)-arylsulphonylamino or N—(C
1-3
-alkyl)-heteroarylsulphonylamino group, whilst
the above-mentioned N—(C
1-3
-alkyl) moieties may additionally be substituted by a carboxy, carboxy-C
1-3
-alkylaminocarbonyl or N—(C
1-3
-alkyl)-carboxy-C
1-3
-alkylaminocarbonyl group or, with the exception of the &agr;-carbon atom in relation to the nitrogen atom, by a hydroxy, carboxy-C
1-3
-alkoxy, amino, carboxy-C
1-3
-alkylamino or N—(C
1-3
-alkyl)-carboxy-C
1-3
-alkylamino group,
a 5- to 7-membered cycloalkyleneimino group,
an amino, C
1-5
-alkylamino, C
3-7
-cycloalkylamino, arylamino, aryl-C
1-3
-alkylamino, heteroarylamino or heteroaryl-C
1-3
-alkyl-amino group, which are substituted in each case at the amino nitrogen atom by a C
1-3
-alkylcarbonyl, carboxy-C
1-3
-alkylcarbonyl, carboxy-C
1-3
-alkylaminocarbonyl, 2-oxo-pyrrolidinylcarbonyl or piperazinocarbonyl group, whilst additionally
(i) the above-mentioned amino group, which is monosubstituted by a C
1-3
-alkylcarbonyl, carboxy-C
1-3
-alkylcarbonyl or carboxy-C
1-3
-alkylaminocarbonyl group, is substituted by a 5- to 7-membered cycloalkyleneimino group or by a N,N-di-(C
1-5
-alkyl)-amino group, and
(ii) the alkyl moiety of the above-mentioned C
1-3
-alkylcarbonyl group is substituted by a carboxy, amino, hydroxy, carboxy-C
1-3
-alkoxy, carboxy-C
1-3
-alkylaminocarbonyl, carboxy-C
1-3
-alkylamino, N—(C
1-3
-alkyl)-carboxy-C
1-3
-alkylamino or amino-C
1-3
-alkylcarbonylamino group or by a carboxy or hydroxy group and by an amino or trifluoroacetylamino group,
a carbimino group which is substituted at the nitrogen atom by a carboxy-C
1-3
-alkoxy, amino, C
1-3
-alkylamino, carboxy-C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino or N-(carboxy-C
1-3
-alkyl)-C
1-3
-alkylamino group and at the carbon atom by a C
1-5
-alkyl group, by a phenyl group optionally substituted by a C
1-3
-alkyl or C
1-3
-alkoxy group or by a heteroaryl group optionally substituted by a C
1-3
-alkyl group,
a heteroaryl or heteroaryl-C
1-3
-alkyl group, which may in each case additionally be substituted in the heteroaryl moiety by a phenyl or heteroaryl group or by a phenyl or heteroaryl group and by a carboxy-C
1-3
-alkyl or C
1-3
-alkoxycarbonyl-C
1-3
-alkyl group,
a 5-oxo-4,5-dihydro-pyrazolyl or 6-oxo-4,5-dihydro-pyridazinyl group optionally substituted by 1 to 3 C
1-3
-alkyl groups wherein an alkyl substituent may at the same time be substituted by a carboxy or C
1-3
-alkoxycarbonyl group, or
a carbonyl group which is substituted
by a hydrogen atom, by a hydroxy, C
1-5
-alkoxy or C
3-7
-cycloalkoxy group,
by a C
1-5
-alkyl or C
3-7
-cycloalkyl group optionally substituted by a carboxy group,
by a C
1-3
-alkyl group substituted by a piperazino group,
by a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, by a C
1-3
-alkyl, carboxy-C
1-3
-alkyl, C
1-3
-alkoxy or carboxy group,
by an amino, C
1-5
-alkylamino, carboxy-C
1-3
-alkylamino, C
3-7
-cycloalkylamino, phenylamino or heteroarylamino group, each of which may additionally be substituted at the amino nitrogen atom by a C
1-5
-alkyl, C
3-7
-Cycloalkyl, phenyl-C
1-3
-alkyl, carboxy-C
1-3
-alkyl, 2-[di-(C
1-3
-alkyl)-amino]-ethyl, 3-[di-(C
1-3
-alkyl)-amino]-propyl, di-(C
1-3
-alkyl)-amino, 2-(N-carboxy-C
1-3
-alkyl-C
1-3
-alkylamino)-ethyl, 3-(N-carboxy-C
1-3
-alkyl-C
1-3
-alkylamino)-propyl or N-carboxy-C
1-3
-alkyl-C
1-3
-alkylamino, phenyl, pyridyl, pyrrolidinyl or piperidinyl group,
by a pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group optionally substituted by one or two C
1-3
-alkyl groups onto which a phenyl ring may be fused via two adjacent carbon atoms,
by a C
3-6
-cycloalkyleneimino, C
5-8
-bicycloalkyleneimino, morpholino, piperazino, dihydropyrazolo, tetrahydropyrazolo, tetrahydroisoxazolo, tetrahydropyrazinyl or tetrahydropyridazinyl group optionally substituted by a C
1-3
-alkyl or carboxy-C
1-3
-alkyl group or
by a C
3-6
-cycloalkyleneimino group optionally substituted by a C
1-3
-alkyl, carboxy-C
1-3
-alkyl, hydroxy, hydroxy-C
1-3
-alkyl, amino, carboxy, carboxy-C
1-3
-alkoxy-C
1-3
-alkyl, carboxy-C
1-3
-alkylamino-C
1-3
-alkyl or carboxy-C
1-3
-alkylaminocarbonyl-C
1-3
-alkyl group,
by a C
5-8
-bicycloalkyleneimino, morpholino, piperazino, dihydropyrazolo, tetrahydropyrazolo, tetrahydroisoxazolo, tetrahydropyrazinyl or tetrahydropyridazinyl group optionally substituted by a C
1-3
-alkyl or carboxy-C
1-3
-alkyl group,
R
3
denotes
a hydrogen, fluorine, chlorine, bromine or iodine atom, a formyl or trifluoromethyl group,
a C
1-3
-alkoxy, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, C
1-4
-alkanoylamino or N—(C
1-4
-alkanoyl)-C
1-3
-alkylamino group,
a C
1-3
-alkyl group optionally substituted by a hydroxy, C
1-3
-alkoxy, carboxy, carboxy-C
1-3
-alkoxy, carboxy-C
1-3
-alkylamino, N—(C
1-3
-alkyl)-carboxy-C
1-3
-alkylamino or carboxy-C
1-3
-alkylaminocarbonyl group,
a C
2-

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