Benzamidine derivatives and their use as anti-coagulants

Details Benzamidine derivatives and their use as anti-coagulants Benzamidine derivatives and their use as anti-coagulants

2001-08-08

2002-10-15

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S180000, C544S219000

Reexamination Certificate

active

06465459

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to benzamidine derivatives and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, thereby being useful as anti-coagulants. It also relates to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods of their use.
BACKGROUND OF THE INVENTION
Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin which polymerizes to form insoluble fibrin.
In the coagulation cascade, the prothrombinase complex is the convergent point of the intrinsic (surface activated) and extrinsic (vessel injury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology (1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serine protease inhibitor with three Kunitz-like domains which competes with factor Va for free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of the factor VIIa and tissue factor complex.
Factor Xa can be activated by two distinct complexes, by tissue factor-VIIa complex on the “Xa burst” pathway and by the factor IXa-VIIIA complex (TENase) of the “sustained Xa” pathway in the coagulation cascade. After vessel injury, the “Xa burst” pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the “sustained Xa” pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the “Xa burst” pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.
The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inactivator of factors Va and VIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteolycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique “tethered ligand” thrombin receptor (
Cell
(1991), Vol.64, p. 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.
Published data with the proteins antistasin and tick anti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors are efficacious anti-coagulants (
Thrombosis and Haemostasis
(1992), Vol. 67, pp. 371-376; and
Science
(1990), Vol. 248, pp. 593-596).
The active site of factor Xa can be blocked by either a mechanism-based or a tight binding inhibitor (a tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor link (
Thrombosis Res
(1992), Vol. 67, pp. 221-231; and
Trends Pharmacol. Sci.
(1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of tight-binding inhibitors (
Thrombosis Res.
(1980), Vol. 19, pp.339-349). Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives have also been shown to be tight-binding inhibitors of thrombin (
Biochem.
(1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (
Thrombosis Res.
(1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones (
Thrombosis Res.
(1980), Vol. 17, pp. 545-548). However, these compounds demonstrate poor selectivity for factor Xa.
Related Disclosures
European Published Patent Application 0 540 051 (Nagahara et al.) describes aromatic amidine derivatives which are stated to be capable of showing a strong anticoagulant effect through reversible inhibition of factor Xa.
The synthesis of &agr;,&agr;′-bis(amidinobenzylidene)cycloalkanones and &agr;,&agr;′-bis(amidino-benzyl)cycloalkanones is described in
Pharmazie
(1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.
SUMMARY OF THE INVENTION
This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa and are therefore useful as pharmacological agents for the treatment of disease-states characterized by thrombotic activity.
Accordingly, in one aspect, this invention provides compounds selected from the group consisting of the following formulae:
wherein
A is —C(R
11
)═ or —N═;
Z
1
and Z
2
are independently —O—, —N(R
8
)—, —S—, or —OCH
2
—;
R
1
and R
3
are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, —N(R
8
)R
9
, —C(O)OR
8
, —C(O)N(R
8
)R
9
, —C(O)N(R
8
)CH
2
C(O)N(R
8
)R
9
, —N(R
8
)C(O)N(R
8
)R
9
, —N(R
8
)C(O)R
8
, —N(R
8
)S(O)
2
R
12
, or —N(R
8
)C(O)N(R
8
)CH
2
C(O)N(R
8
)R
9
;
R
2
is hydrogen; halo; alkyl; haloalkoxy; —OR
8
; —C(O)OR
8
; —C(O)N(R
8
)R
9
;
—N(R
8
)R
9
; —C(O)N(R
8
)(CH
2
)
m
C(O)OR
8
(where m is 0 to 3); —N(R
8
)(CH
2
)
n
C(O)OR
8
(where n is 1 to 3); —N((CH
2
)
n
N(R
8
)R
9
)(CH
2
)
n
C(O)OR
8
(where each n is 1 to 3); —O(CH
2
)
n
C(O)N(R
8
)R
9
(where n is 1 to 3); —O(CH
2
)
p
C(O)OR
8
(where p is 1 to 6); —N(R
8
)(CH
2
)
n
C(O)N(R
8
)(CH
2
)
n
C(O)OR
8
(where each n is independently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;
or R
2
is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of —OR
8
, —C(O)N(R
8
)R
9
, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
or R
2
is piperazin-1-yl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, —C(O)N(R
8
)R
9
, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R
2
is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, —C(O)N(R
8
)R
9
, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R
2
is piperidin-1-yl (optionally substituted by one or more substituents selected from the group consisting of carboxy, —C(O)N(R
8
)R
9
, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R
2
is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, c

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