Benzamide derivatives as thrombin inhibitors

Details Benzamide derivatives as thrombin inhibitors Benzamide derivatives as thrombin inhibitors

2001-03-30

2002-08-27

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...

C546S309000

Reexamination Certificate

active

06441008

ABSTRACT:

BACKGROUND OF THE INVENTION
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 International Patent Application No. WO97/22589.
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 pre-disposition 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 haemolytic 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 (I)
where
R
1
represents C
1-4
alkyl or C
3-8
cycloalkyl;
R
2
represents C
1-4
alkyl or C
3-4
alkenyl;
R
3
represents hydrogen, C
1-3
alkyl or halogen;
R
4
represents C
1-6
alkyl;
and pharmaceutically acceptable derivatives or solvates thereof.
Referring to the general formula (I), alkyl includes both straight and branched chain saturated hydrocarbon groups, e.g. methyl, ethyl and isopropyl; cycloalkyl includes saturated cyclic hydrocarbon groups, e.g. cyclopentyl and cyclohexyl; alkenyl includes both straight and branched chain hydrocarbon groups containing one double bond, e.g. propenyl, 2-methylpropenyl and butenyl.
It will be appreciated that a compound of formula (I) contains a chiral centre at the position denoted by *. Thus, each compound within formula (I) may exist in two distinct optical isomeric forms. The scope of the present invention extends to cover individual enantiomers of compounds of formula (I) and mixtures of enantiomers of compounds of formula (I) in any proportion, including racemic mixtures. Generally it is preferred to use a compound of formula (I) in the form of a purified single enantiomer, most preferably the (S) isomer.
Referring to general formula (I), R
1
suitably represents propyl, isopropyl, butyl, cyclopentyl or cyclohexyl. R
1
is preferably isopropyl.
R
2
is suitably methyl, ethyl, propyl or isopropyl. R
2
is preferably ethyl.
R
3
is suitably methyl or chloro. R
3
is preferably methyl.
R
4
is suitably methyl or ethyl. R
4
is preferably methyl.
Suitable compounds of general formula (I) for use according to the invention include:
N-Ethyl-N-isopropyl-3-methyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
N,N-Diisopropyl-3-methyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
N-Isopropyl-3,N-dimethyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
3,N-Dimethyl-N-propyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
3-Methyl-N,N-dipropyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
N-Ethyl-3-methyl-N-propyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
N-Butyl-3-methyl-N-propyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
N-Cyclohexyl-N-isopropyl-3-methyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
N-Isopropyl-3-methyl-N-propyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
3-Chloro-N-isopropyl-N-propyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide;
3-Chloro-N,N-diisopropyl-5-[2-(pyridin-4-ylamino)-butoxy]-benzamide;
and pharmaceutically acceptable derivatives or solvates thereof.
Particular compounds of general formula (I) for use according to the invention include:
N-Ethyl-N-isopropyl-3-methyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide; and pharmaceutically acceptable derivatives or solvates thereof.
By “a pharmaceutically acceptable derivative” is meant any pharmaceutically acceptable salt, or a metabolically labile derivative, for example a derivative of an amine group, of a compound of formula (I) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof. It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds of formula (I). Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice, which is incorporated herein by reference.
Preferred pharmaceutically acceptable derivatives of the compounds of formula (I) are pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-su

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