Urea derivatives with antiproteolytic activity

Details Urea derivatives with antiproteolytic activity Urea derivatives with antiproteolytic activity

2002-06-26

2004-03-16

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S238200, C514S352000, C514S359000, C514S447000, C514S452000, C514S471000, C544S236000, C544S238000, C546S115000, C546S269100, C546S332000, C564S191000

Reexamination Certificate

active

06706715

ABSTRACT:

This application is entitled to the benefit of earlier filed application EP 01115353.3, filed Jun. 26, 2001.
The present invention relates to compounds of the formula I,
in which R
1
, R
2
, R
4
, R
5
, D
1
, D
2
, X
1
, X
2
, X
3
, A and B have the meanings indicated below.
The compounds of the formula I are valuable pharmacologically active compounds. They act as serine protease inhibitors and especially exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of thromboembolic diseases and other diseases where serine protease activity is responsible for the disease. The preferred targets are the blood clotting enzymes, especially factor VIIa. Compounds of said invention can in general be applied in conditions in which an undesired activity of factor VIIa is present or for the cure or prevention of the disease of which an inhibition of factor VIIa is intended.
The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
Normal haemeostasis is the result of a complex balance between the processes of clot initiation, formation and clot dissolution. The complex interactions between blood cells, specific plasma proteins and the vascular surface, maintain the fluidity of blood unless injury and blood loss occurs. Many significant disease states are related to abnormal haemostasis. For example, local thrombus formation due to rupture of atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Treatment of an occlusive coronary thrombus by either thrombolytic therapy or percutaneous angioplasty may be accompanied by acute thrombolytic reclosure of the affected vessel. There continues to be a need for safe and effective therapeutic anticoagulants to limit or prevent thrombus formation.
The widely used blood-clotting inhibitors like heparin and related sulfated polysaccharides like LMWH and heparin sulfate exert their anti-clotting effects by promoting the binding of a natural regulator of the clotting process, anti-thrombin III, to thrombin and to factor Xa. The inhibitory activity of heparin primarily is directed toward thrombin, which is inactivated approximately 100 times faster than factor Xa. Hirudin and hirulog are two additional thrombin-specific anticoagulants presently in clinical trials. However, these anticoagulants which inhibit thrombin also are associated with bleeding complications. Preclinical studies in baboons and dogs have shown that targeting enzymes involved at earlier stages of the coagulation cascade, such as factor Xa or factor VIIa, prevents clot formation without producing the bleeding side effects observed with direct thrombin inhibitors (L. A. Harker et al., Thromb. Hemostas. 74 (1995) 464).
Specific inhibition of the factor VIIa/tissue factor catalytic complex using monoclonal antibodies (WO-A-92/06711) or a protein such as chloromethyl ketone inactivated factor VIIa (WO-A-96/12800 and WO-A-97/47651) is an extremely effective means of controlling thrombus formation caused by acute arterial injury or the thrombotic complications related to bacterial septicemia. There is also experimental evidence suggesting that inhibition of factor VIIa/tissue factor activity inhibits restenosis following balloon angioplasty (L. A. Harker et al., Haemostasis 26 (1996) S1:76). Bleeding studies have been conducted in baboons and indicate that inhibition of the factor VIIa/tissue factor complex has the widest safety window with respect to therapeutic effectiveness and bleeding risk of any anticoagulant approach tested including thrombin, platelet and factor Xa inhibition (L. A. Harker et al., Thromb. Hemostas. 74 (1995) 464).
A specific inhibitor of factor VIIa that has a favorable property profile would have substantial practical value in the practice of medicine. In particular, a factor VIIa inhibitor would be effective under circumstances where the present drugs of choice, like heparin and related sulfated polysaccharides, are ineffective or only marginally effective. Certain inhibitors of factor VIIa have already been described. EP-A-987274, for example, discloses compounds containing a tripeptide unit which inhibit factor VIIa. However, the property profile of these compounds is still not ideal, and there is a need for further low molecular weight factor VIIa-specific blood clotting inhibitors that are effective and do not cause unwanted side effects
The present invention satisfies this need by providing novel factor VIIa activity urea derivatives of the formula I.
Thus, a subject of the present invention are compounds of the formula I,
wherein D
1
and D
2
independently from one another are
1. hydrogen atom,
2. —C(O)—(C
1
-C
6
)-alkyl,
3. —C(O)-aryl,
4. —C(O)—(C
1
-C
6
)-alkyl-aryl,
5. —C(O)—O—(C
1
-C
6
)-alkyl,
6. —C(O)—O—(C
1
-C
6
)-alkyl-aryl,
7. —C(O)—O—(C
1
-C
6
)-aryl or
8. —NH
2
, or
D
1
is hydrogen atom, when D
2
is
1. —OH,
2. —O—C(O)—(C
1
-C
6
)-alkyl,
3. —O—C(O)-aryl,
4. —O—C(O)—(C
1
-C
6
)-alkyl-aryl or
5. —NH
2
, or
D
2
is hydrogen atom, when D
1
is
1. —OH,
2. —O—C(O)—(C
1
-C
6
)-alkyl,
3. —O—C(O)-aryl,
4. —O—C(O)—(C
1
-C
6
)-alkyl-aryl or
5. —NH
2
, or
D
1
and D
2
together with the nitrogen atom to which they are attached form a cycle of the formula VIII
 or D
1
and R
4
or D
2
and R
4
together form a cycle of the formulae VIIIa to VIIId,
wherein X
1
and X
2
independently from one another are selected from the group consisting of a carbon atom substituted by R
4
, wherein R
4
is as defined below, and a nitrogen atom,
wherein R
4
and R
5
independently from one another are
1. hydrogen atom,
2. —(C
1
-C
6
)-alkyl,
3. —OH,
4. —O—(C
1
-C
6
)-alkyl,
5. halogen,
6. —NH
2
or
7. —NO
2
,
wherein X
3
is oxygen atom, sulfur atom or NH,
wherein A is
1. —X
4
—, wherein —X
4
— is
1.1 a covalent bond,
1.2 —CH
2
—,
1.3 —CH(OH)—,
1.4 —CH(NH
2
)—,
1.5 —CH(COOH)—,
1.6 —CH(CONH
2
)—,
1.7 —CH(CH
2
—OH)—,
1.8 —CH(—CH
2
—NH
2
)—,
1.9 —CH(—CH
2
—COOH)— or
1.10 —CH(—CH
2
—CONH
2
)—,
2. —N(R
3
)—X
4
—, wherein —X
4
— is as defined above and wherein R
3
is
a) hydrogen atom,
b) —OH or
c) —NH
2
, or
3. —O—X
4
—, wherein —X
4
— is as defined above,
R
1
and R
2
together with each carbon atoms to which they are attached form
1. -aryl, wherein aryl is unsubstituted or mono- or disubstituted independently of one another by R
6
,
2. heteroaryl, wherein heteroaryl is unsubstituted or mono- or disubstituted independently of one another by R
6
,
3. a 3- to 8-membered cyclic group, wherein said cyclic group is saturated or partially saturated and unsubstituted or mono- or disubstituted independently of one another by R
6
or ═O, or
4. a 3- to 8-membered cyclic group, containing up to 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, wherein said cyclic group is saturated or partially saturated and unsubstituted or mono- or disubstituted independently of one another by R
6
or ═O, wherein R
6
is
1. halogen,
2. —(CH
2
)
n
—OH, wherein n is the inter zero, 1 or 2,
3. —(CH
2
)
n
—O—R
10
, wherein R
10
is —(C
1
-C
6
)-alkyl or —(C
1
-C
6
)-alkyl-aryl, and n is the integer zero, 1 or 2,
4. —(CH
2
)
n
—COOR
11
, wherein R
11
is hydrogen atom, —(C
1
-C
6
)-alkyl or —(C
1
-C
6
)-alkyl-aryl, and n is the integer zero, 1 or 2,
5. —(CH
2
)
n
—C(O)N(H)R
12
, wherein R
12
is hydrogen atom or —(C
1
-C
6
)-alkyl, and n is the integer zero, 1 or 2,
6. —NO
2
,
7. —N(H)R
12a
, wherein R
12a
is hydrogen atom, formyl, acetyl, sulfonylmethyl, amidosulfonyl or —(C
1
-C
6
)-alkyl,
8. —CF
3
,
9. —SO
2
—R
13
, wherein R
13
is methyl, ethyl or —NH
2
,
10. —CN,
11. —(C
1
-C
6
)-alkyl,
12. —(C
1
-C
6
)-alkyl-aryl,
13. -heteroaryl,
14. —(C
1
-C
6
)-alkyl-heteroaryl or
15. -heterocycloalkyl,
B is 1. —N(R
7
)—(CH—(R
8
))
p
-aryl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by
1.1. —(C
1
-C
6
)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another

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