Substituted 5-membered ring heterocycles comprising a...

Details Substituted 5-membered ring heterocycles comprising a... Substituted 5-membered ring heterocycles comprising a...

1999-07-28

2001-02-20

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S018700, C514S019300, C514S020800, C514S385000, C514S389000, C514S391000, C514S398000, C548S318500, C548S319100

Reexamination Certificate

active

06191282

ABSTRACT:

The present invention relates to substituted 5-membered ring heterocycles, their preparation and their use as medicines, in particular as inhibitors of blood platelet aggregation.
EP-A-449 079, EP-A-530 505, EP-A-566 919 and WO-A-93/18057 describe hydantoin derivatives which exhibit thrombocyte aggregation-inhibiting effects. EP-A 512 831 mentions pyrrolidone derivatives which prevent the binding of fibrinogen to blood platelets and hence aggregation of the platelets. Further investigations demonstrated that the compounds of the present invention are also strong inhibitors of blood platelet aggregation.
The present invention relates to 5-membered ring heterocycles of the general formula I,
in which
W represents R
1
-A-C(R
13
) or R
1
-A-CH═C;
Y represents a carbonyl group, a thiocarbonyl group or a methylene group;
Z represents N(R
0
), oxygen, sulphur or a methylene group;
A denotes a divalent radical from the group (C
1
-C
6
)-alkylene, (C
3
-C
7
)-cycloalkylene, phenylene, phenylene-(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkylene-phenyl or phenylene-(C
2
-C
6
)-alkenyl, or a divalent radical of a 5-membered or 6-membered saturated or unsaturated ring which can contain 1 or 2 nitrogen atoms and can be substituted once or twice by (C
1
-C
6
)-alkyl or doubly bonded oxygen or sulphur;
B denotes a divalent radical from the group (C
1
-C
6
)-alkylene, (C
2
-C
6
)-alkenylene, phenylene, phenylene-(C
1
-C
3
)-alkyl or (C
1
-C
3
)-alkylene-phenyl;
D represents C(R
2
) (R
3
), N(R
3
) or CH═C(R
3
);
E denotes tetrazolyl, (R
8
O)
2
P(O), HOS(O)
2
, R
9
NHS(O)
2
or R
10
CO;
R and R
0
denote, independently of each other, hydrogen, (C
1
-C
8
)-alkyl, (C
3
-C
8
)-cycloalkyl, optionally substituted (C
6
-C
14
)-aryl, or (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkyl which is optionally substituted in the aryl radical;
R
1
represents X—NH—C(═NH)—(CH
2
)
p
or X
1
—NH—(CH
2
)
p
, where p can represent an integer from 0 to 3;
X denotes hydrogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkylcarbonyl, (C
1
-C
6
)-alkoxycarbonyl, (C
1
-C
18
)-alkylcarbonyloxy-(C
1
-C
6
)-alkoxycarbonyl, optionally substituted (C
6
-C
14
)-arylcarbonyl, optionally substituted (C
6
-C
14
)-aryloxycarbonyl, (C
6
-C
14
)-aryl-(C
1
-C
6
)-alkoxycarbonyl which can also be substituted in the aryl radical, (R
8
O)
2
P(O), cyano, hydroxyl, (C
1
-C
6
)-alkoxy, (C
6
-C
14
)-aryl-(C
1
-C
6
)-alkoxy which can also be substituted in the aryl radical, or amino;
X
1
has one of the meanings of X or denotes R′—NH—C(═N—R″), where R′ and R″, independently of each other, have the meanings of X;
R
2
denotes hydrogen, (C
1
-C
8
)-alkyl, optionally substituted (C
6
-C
14
)-aryl, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkyl which is optionally substituted in the aryl radical, or (C
3
-C
8
)-cycloalkyl;
R
3
denotes hydrogen, (C
1
-C
8
)-alkyl, optionally substituted (C
6
-C
14
)-aryl, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkyl which is optionally substituted in the aryl radical, (C
3
-C
8
)-cycloalkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
2
-C
8
)-alkenylcarbonyl, (C
2
-C
8
)-alkynylcarbonyl, pyridyl, R
11
NH, R
4
CO, COOR
4
, CON(CH
3
)R
14
, CONHR
14
, CSNHR
14
, COOR
15
, CON(CH
3
R
15
or CONHR
15
;
R
4
denotes hydrogen or (C
1
-C
28
)-alkyl which can optionally be substituted once or more than once by identical or different radicals R
4′
;
R
4′
denotes hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C
1
-C
18
)-alkyl)-aminocarbonyl, amino-(C
2
-C
18
)-alkylaminocarbonyl, amino-(C
1
-C
3
)-alkyl-phenyl-(C
1
-C
3
)-alkylaminocarbonyl, (C
1
-C
18
)-alkylcarbonylamino-(C
1
-C
3
)-alkylphenyl-(C
1
-C
3
)-alkylaminocarbonyl, (C
1
-C
18
)-alkylcarbonylamino-(C
2
-C
18
)-alkylaminocarbonyl, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkoxycarbonyl which can also be substituted in the aryl radical, amino, mercapto, (C
1
-C
18
)-alkoxy, (C
1
-C
18
)-alkoxycarbonyl, optionally substituted (C
3
-C
8
)-cycloalkyl, halogen, nitro, tribuloromethyl or the radical R
5
;
R
5
denotes optionally substituted (C
6
-C
14
)-aryl, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkyl which is optionally substituted in the aryl radical, a monocyclic or bicyclic 5- to 12-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms from the group nitrogen, oxygen and sulphur, a radical R
6
or a radical R
6
CO—, where the aryl radical and, independently thereof, the heterocycle radical can be substituted once or more than once by identical or different radicals from the group (C
1
-C
18
)-alkyl, (C
1
-C
18
)-alkoxy, halogen, nitro, amino or trifluoromethyl;
R
6
represents R
7
R
8
N, R
7
O or R
7
S, or denotes an amino acid side chain, a natural or unnatural amino acid radical, imino acid radical, optionally N—(C
1
-C
8
)-alkylated or N—((C
6
-C
14
)-aryl-(C
1
-C
8
)-alkylated) azaamino acid radical or a dipeptide radical which can also be substituted in the aryl radical and/or in which the peptide bond can be reduced to —N—CH
2
—, and also the esters and amides thereof, where hydrogen or hydroxymethyl can optionally stand in place of free functional groups and/or where free functional groups can be protected by protective groups which are customary in peptide chemistry;
R
7
denotes hydrogen, (C
1
-C
18
)-alkyl, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkyl, (C
1
-C
18
)-alkylcarbonyl, (C
1
-C
18
)-alkoxycarbonyl, (C
6
-C
14
)-arylcarbonyl, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkylcarbonyl or (C
6
-C
14
)-aryl-(C
1
-C
18
)-alkoxycarbonyl, where the alkyl groups can optionally be substituted by an amino group and/or where the aryl radicals can be substituted once or more than once, preferably once, by identical or different radicals from the group (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkoxy, halogen, nitro, amino and trifluoromethyl, a natural or unnatural amino acid radical, imino acid radical, optionally N—(C
1
-C
8
)-alkylated or N—((C
6
-C
14
)-aryl-(C
1
-C
8
)-alkylated) azaamino acid radical or a dipeptide radical which can also be substituted in the aryl radical and/or in which the peptide bond can be reduced to —NH—CH
2
—;
R
8
denotes hydrogen, (C
1
-C
18
)-alkyl, optionally substituted (C
6
-C
14
)-aryl or (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkyl which can also be substituted in the aryl radical;
R
9
denotes hydrogen, aminocarbonyl, (C
1
-C
18
)-alkylaminocarbonyl, (C
3
-C
8
)-cycloalkylaminocarbonyl, optionally substituted (C
6
-C
14
)-arylaminocarbonyl, (C
1
-C
18
)-alkyl, optionally substituted (C
6
-C
14
)-aryl, or (C
3
-C
8
)-cycloalkyl;
R
10
denotes hydroxyl, (C
1
-C
18
)-alkoxy, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C
6
-C
14
)-aryloxy, amino or mono- or di-((C
1
-C
18
)-alkyl)-amino;
R
11
denotes hydrogen, (C
1
-C
18
)-alkyl, R
12
CO, optionally substituted (C
6
-C
14
)-aryl-S(O)
2
, (C
1
-C
18
)-alkyl-S(O)
2
, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkyl which is optionally substituted in the aryl radical, or R
9
NHS(O)
2
;
R
12
denotes hydrogen, (C
1
-C
18
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, optionally substituted (C
6
-C
14
)-aryl, (C
1
-C
18
)-alkoxy, (C
6
-C
14
)-aryl-(C
1
-C
18
)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C
6
-C
14
)-aryloxy, amino or mono- or di-((C
1
-C
18
)-alkyl)-amino;
R
13
denotes hydrogen, (C
1
-C
6
)-alkyl, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkyl which is optionally substituted in the aryl radical, or (C
3
-C
8
)-cycloalkyl;
R
14
denotes hydrogen or (C
1
-C
28
)-alkyl which can optionally be substituted once or more than once by identical or different radicals from the group hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C
1
-C
18
)-alkyl)-aminocarbonyl, amino-(C
2
-C
18
)-alkylaminocarbonyl, amino-(C
1
-C
3
)-alkylphenyl-(C
1
-C
3
)-alkylaminocarbonyl, (C
1
-C
18
)-alkylcarbonylamino-(C
1
-C
3
)-alkylphenyl-(C
1
-C
3
)-alkylaminocarbonyl, (C
1
-C
18
)-alkylcarbonyl-amino-(C
2
-C
18
)-alkylaminocarbonyl, (C
6
-C
14
)-aryl-(C
1
-C
8
)-alkoxycarbonyl which can also be substituted in the aryl

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