Benzamide derivatives as thrombin inhibitors

Details Benzamide derivatives as thrombin inhibitors Benzamide derivatives as thrombin inhibitors

2000-10-04

2001-12-04

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...

Reexamination Certificate

active

06326386

ABSTRACT:

This invention relates to a new class of chemical compounds and to their use in medicine. In particular, the invention concerns novel amide derivatives, methods for their preparation, pharmaceutical compositions containing them and their use as thrombin inhibitors. Thrombin inhibitors have been described previously in, for example, WO94/20467.
Thrombin is a serine proteinase present in plasma and is formed by conversion from its prothrombin precursor by the action of Factor Xa. Thrombin plays a central role in the mechanism of blood coagulation by converting the soluble plasma protein; fibrinogen, into insoluble fibrin. The insoluble fibrin matrix is required for the stabilisation of the primary hemostatic plug. Many significant disease states are related to abnormal hemostasis. With respect to the coronary arterial vasculature, abnormal thrombus formation due to the rupture of an established atherosclerotic plaque is the major cause of acute myocardial infarction and unstable angina. Both treatment of an occlusive coronary thrombus by thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA) are often accompanied by an acute thrombotic reclosure of the affected vessel which requires immediate resolution. With respect to the venous vasculature, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature which can result in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism. Disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer and is characterised by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the vasculature leading to widespread organ failure.
Beyond its direct role in the formation of fibrin rich blood clots, thrombin has been reported to have profound bioregulatory effects on a number of cellular components within the vasculature and blood, (Shuman, M. A., Ann. NY Acad. Sci., 405: 349 (1986)).
The inhibition of thrombin has been implicated as a potential treatment for a number of disease states. Thrombin inhibitors may be useful in the treatment of acute vascular diseases such as coronary thrombosis, stroke, pulmonary embolism, deep vein thrombosis, restenosis, atrial fibrillation, myocardial infarction, and unstable angina. They have been described as anti-coagulant agents both in-vivo and ex-vivo, and in oedema and inflammation, whereby a low dose of thrombin inhibitor can reduce platelet and endothelial cell thrombin mediated inflammatory responses without concomitant anticoagulant effects. Thrombin has been reported to contribute to lung fibroblast proliferation, thus, thrombin inhibitors could be useful for the treatment of some pulmonary fibrotic diseases. Thrombin inhibitors have also been reported in the treatment of tumour metastasis whereby the thrombin inhibitor prevents the fibrin deposition and metastasis caused by the inappropriate activation of Factor X by cysteine proteinases produced by certain tumour cells. They have been shown to inhibit neurite retraction and thus may have potential in neurogenerative diseases such as Parkinson's and Alzheimer's disease. They have also been reported to be used in conjunction with thrombolytic agents by permitting the use of a lower dose of thrombolytic agent. Other potential uses have been described in U.S. Pat. No. 5,371,091 for the treatment of Kasabach Merritt Syndrome and hemolytic uremic syndrome, in EP565897 for the prevention of fibrin deposits in the eye during ophthalmic surgery, and in DE4126277 for the treatment of osteoporosis.
Thus, we have now found a novel class of amide derivatives which act as thrombin inhibitors shown as formula (1)
where
R
1
and R
2
independently represent a group
 or R
1
and R
2
together form a C
3-7
heterocycloalkyl or heterocycloalkenyl group which may be optionally substituted by C
1-6
alkyl, C
1-4
alkoxy, halogen, carboxylic acid or a C
1-4
carboxylic acid ester group;
R
3
represents hydrogen, C
1-3
alkyl, halogen, or C
1-2
alkoxy;
R
4
, R
5
and R
6
independently represent hydrogen, or halogen;
R
7
represents hydrogen or C
1-6
alkyl;
R
8
represents hydrogen, C
3-7
cycloalkyl, C
3-7
cycloalkenyl, C
3-7
heterocycloalkyl, C
3-7
heterocycloalkenyl, aryl, or heteroaryl, which groups are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
acyloxy, NR
9
R
10
, NHCOR
11
, NHSO
2
R
12
, COR
13
, CO
2
R
14
, CONR
15
R
16
, and SO
2
NHR
17
;
X represents a bond, a C
1-6
alkyl chain, or a C
3-6
alkenyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
acyloxy, NR
9
R
10
, NHCOR
11
, NHSO
2
R
12
, COR
13
, CO
2
R
14
, CONR
15
R
16
, and SO
2
NHR
17
;
R
9
-R
17
represent hydrogen, C
1-6
alkyl, or R
9
and R
10
or R
15
and R
16
form a C
3-7
heterocycloalkyl ring, or R
12
additionally may represent trifluoromethyl;
and pharmaceutically acceptable derivatives or solvates thereof.
Referring to the general formula (I), alkyl includes both straight and branched chain saturated hydrocarbon groups.
Referring to the general formula (I), alkenyl includes both straight and branched chain hydrocarbon groups with at least one double bond.
Referring to the general formula (I), aryl includes optionally substituted monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl.
Referring to the general formula (I), heteroaryl includes 5 or 6 membered aromatic heterocyclic rings containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, and fused bicyclic ring systems containing one or more nitrogen, sulfur, and oxygen atoms. Examples of such groups include oxadiazole, thiazole. thiadiazole, triazole, tetrazole, benzimidazole, pyridine, furan and thiophene.
Referring to the general formula (I), examples of C
3-7
cycloalkyl groups include cyclohexyl and cyclopentyl groups.
Referring to the general formula (I), a C
3-7
cycloalkenyl group includes rings containing at least one double bond incorporated in the ring.
Referring to the general formula (I), a C
3-7
heterocycloalkyl group includes rings containing containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, for example, a tetrahydropyran-4-yl group.
Referring to the general formula (I), a C
3-7
heterocycloalkenyl group includes rings containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, together with at least on double bond incorporated in the ring.
Referring to the general formula (I) where R
1
represents a group
X is suitably a bond or C
1-6
alkyl group, e.g. methyl, isopropyl or isobutyl, and R
8
suitably represents hydrogen, C
3-7
cycloalkyl, aryl, or heteroaryl. When X represents a bond, R
8
is preferably phenyl optionally substuituted by one or more halogen groups, or C
3-7
cycloalkyl, e.g. cyclobutyl, cyclopentyl or cyclohexyl. When X represents. a C
1-6
alkyl group, R
8
is preferably hydrogen, cycloalkyl, e.g. cyclohexyl, or heteroaryl, e.g. thienyl or furyl.
Referring to the general formula (l) where R
2
represents a group
X is suitably C
3-6
alkenyl, e.g. allyl, or C
1-6
alkyl, e.g. methyl, ethyl, propyl or pentyl, which optionally contains an oxygen group within the chain and is optionally substituted by a group selected from hydroxy, C
1-6
alkoxy, NHSO2R
12
, CO
2
R
14
, CONR
15
R
16
, or SO
2
NHR
17
, and R
8
is suitably hydrogen, C
3-7
heterocycloalkyl, e.g. pyrrolidine or morpholine, aryl, e.g. phenyl which is optionally substituted by CO
2
R
14
, or heteroaryl, e.g. oxadiazole optionally substituted by hydroxy, triazole, or tetrazole optionally substituted by C
1-6
alkyl.
R
3
is

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