Phosphonates, process for preparing the same and medicaments

Details Phosphonates, process for preparing the same and medicaments Phosphonates, process for preparing the same and medicaments

1999-07-15

2000-03-14

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

514 89, 514 91, 514277, 514315, 514336, 540542, 546 22, 546184, 546192, 548400, 548413, C07F 959, C07F 9572, C07F 9553, A61K 31675

Patent

active

060373342

DESCRIPTION:

BRIEF SUMMARY
The invention concerns new phosphonates of the general formula I ##STR2## in which R.sup.1, R.sup.2 are the same or different and denote a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkinyl group or an aralkyl group or R.sup.1 and R.sup.2 together denote an alkylene residue which, together with the bound oxygen atoms and the phosphorus atom carrying the oxygen atoms, forms a saturated 5-membered to 8-membered ring; cycloalkyl residue or an optionally substituted aryl residue; The invention also concerns the optically active forms, racemates and mixtures of diastereomers of these compounds.
The invention also concerns processes for the production of the above-mentioned compounds, pharmaceutical preparations that contain such compounds as well as the use of these compounds in the production of pharmaceutical preparations.
The phosphonates of the general formula I, their solvates and their salts intervene in the process of blood coagulation by the reversible inhibition of factor Xa and thus they prevent formation of hyaline thrombi. They can therefore be used to combat and prevent diseases such as thrombosis, apoplexy, coronary infarction, inflammations and arteriosclerosis.
Factor Xa is a serine protease of the coagulation system which catalyses the proteolytic conversion of prothrombin into thrombin. Thrombin as the last enzyme of the coagulation cascade on the one hand cleaves fibrinogen to form fibrin which becomes an insoluble gel after cross-linking by factor XIIIa and forms the matrix for a thrombus; on the other hand thrombin activates platelet aggregation by proteolysis of its receptor on the blood platelets and in this way also contributes to thrombus formation. When a blood vessel is damaged these processes are necessary in order to stop bleeding. No measurable thrombin concentrations are present in blood plasma under normal conditions. An increase in the thrombin concentration can lead to the formation of thrombi and hence to thromboembolic diseases which occur very frequently above all in industrial countries. The formation of thrombin can be prevented by inhibiting factor Xa.
It has recently been reported that amidinoarylpropanoic acid derivatives such as (+)-(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]3-3-(7-amidin o-2-naphthyl]propanoic acid-hydrochloride-pentahydrate (DX-9065a; formula IIa) inhibit factor Xa (J. Med. Chem. 1994, 37, 1200-1207; Thrombosis and Haemostasis 1994, 71, 314-319; EP-0-540-051-A-1). Further known factor Xa inhibitors are 1,2-bis-(5-amidino-2-benzofuranyl)-ethane (DABE, formula IIb; Thrombosis Research 1980, 19, 339-349) and also phenyl-amino-methyl-naphthamidines of the general formula IIc (WO96/16940). ##STR3##
The new phosphonates according to the invention of the general formula I as well as hydrates, solvates and physiologically tolerated salts thereof are potent and selective factor Xa inhibitors.
In the general formula I the substituents R.sup.1 and R.sup.2 can be the same or different.
If R.sup.1, R.sup.2 in the general formula I denote an alkyl group, this can be straight-chained or branched and contain 1 to 6 carbon atoms. A methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl group are preferred.
If R.sup.1, R.sup.2 in the general formula I denote a cycloalkyl group, this can be substituted or unsubstituted and contain 3 to 8 carbon atoms. A cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl group are preferred.
If R.sup.1, R.sup.2 in the general formula I denote a hydroxyalkyl group, this can be straight-chained or branched and contain 1 to 6 carbon atoms. A hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl group are preferred.
If R.sup.1, R.sup.2 in the general formula I denote an alkenyl group, this can be straight-chained or branched and contain 2 to 6 carbon atoms. A vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 1-pentenyl and 1-hexenyl group are preferred.
If R.sup.1, R.sup.2 in the general formula I denote

REFERENCES:
Chemical Abstracts, vol. 123,No. 21, Nov. 20, 1995, Ikeuchi et al., "Preparation of aromatic amidine derivatives as inhibitors of human blood coagulation factor for treatment and prevention . . . ".
Nagahara et al., "Dibasic (Amidinoaryl) propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors", J. Med. Chem. 94; vol. 37 (8) pp. 1200-1207, Daiichi Pharmaceutical Company Ltd.

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