Compounds that inhibit factor Xa activity

• US 6,794,507 B2
• Filed: 02/19/2003
• Issued: 09/21/2004
• Est. Priority Date: 08/23/2000
• Status: Expired due to Fees

• Current Assignee: Morphochem AG (Deinove SA)
• Original Assignee: Morphochem AG (Deinove SA)
• Inventors: Cappi, Michael W., Schabbert, Silke, Eckl, Robert, Fuchs, Thilo
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US10/362,149
• Publication Number:
  US 20030153510A1
• Time in Patent Office: 580 Days
• Field of Search: 544/386, 514/255, 514/307, 514/330, 546/146, 546/226
• US Class Current: 544/386
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 211/32 by oxygen atoms
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 217/06 with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 295/24 Oxygen atoms
• CPC Class Codes: C07D 309/12 only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate or a pharmaceutically acceptable formulation thereof. Those compounds can be used for inhibiting factor Xa and for the prevention and/or treatment of thromboembolic conditions.

Claims

1. A compound of formula (I):

wherein

X is Cl, Br or R¹—

N═

CH(—

NH₂)—

wherein

R¹ is H, —

OH, —

C(═

O)OR², aralkyl, an alkyloxy or a heteroalkyl group i

R² is alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl;

Ar is arylene, heteroarylene, heteroarylalkylene or aralkylene, X being bonded directly to the aromatic ring system;

R³ is H, alkyl, heteroalkyl or aralkyl;

the groups R⁴ independently of one another are alkyl groups that may be substituted by one or more —

OH or —

NH₂ radicals, or are heteroalkyl groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups or aralkyl groups, it being possible for those groups to be substituted by one or more unsubstituted groups selected from alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl and aralkyl, or are hydroxyl groups or glycosyloxy groups;

n is an integer from 0 to 5;

R⁵ is H, alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl;

R⁶ and R⁷ independently of each other are H, alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, such as, for example, aryl-heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, it being possible for those groups to be substituted by one or more groups selected from alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, aralkyl, —

OH and —

NH₂, or together form part of a heterocycloalkyl ring system, or of a heteroaryl ring system, it being possible for those systems to be substituted by one or more groups selected from alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, aralkyl, —

OH and —

NH₂; and

R⁸ is H, alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl or, together with R⁵, forms part of a heterocycloalkyl ring system;

or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof.

2. A compound according to claim 1 wherein X═

R¹—

N═

C(—

NH₂)—

.

3. A compound according to claim 1 wherein R¹═

H, OH or C₁-C₄-alkoxy.

4. A compound according to claim 1 wherein Ar is a substituted or unsubstituted meta-phenylene.

5. A compound according to claim 1 wherein Ar is substituted in the para-position to X by an OH, NH₂, C₁-C₄-alkoxy, C₁-C₄-alkylamino or C₂-C₆-dialkylamino group or by a halogen atom.

6. A compound according to claim 1 wherein R³═

H.

7. A compound according to claim 1 wherein the radicals R⁴ independently of one another are an OH, —

OCH₂COOH, —

COOH, C₁-C₄-alkoxy or glycosyloxy group or a halogen atom.

8. A compound according to claim 1 wherein n =0, 1 or 2.

9. A compound according to claim 1 wherein R⁵ is H, C₁-C₆-alkyl, C₁-C₆-heteroalkyl or the side chain of a natural amino acid.

10. A compound according to claim 1 wherein R⁶ and R⁷ together form part of an aryl-piperazinyl ring.

11. A compound according to claim 1 wherein R⁸═

H or C₁-C₆-alkyl.

12. A pharmaceutical composition comprising a compound of claim 1 and optionally excipients and/or adjuvants.

13. A method for treating a subsject suffering from a condition mediated by factor Xa activity, comprising administering to the subject an effective amount of a compound of claim 1.

14. The method of claim 13 wherein the subject is suffering from a thromoembolic condition, arterial resenosis, septicgemia, cancer or acute inflammation.

15. A method for treating a subject undergoing vascular surgery, comprising administering to the subject an effective amount of a compound of claim 1.

16. The method of claim 15 wherein the subject is susceptible to a thromboembolic condition.

17. A method of inhibiting factor Xa activity in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of claim 1.

18. A compound of claim 1 wherein R⁴ is substituted by alkoxy, acyl or acyloxy.

19. A compound of claim 1 wherein R⁶ or R⁷ is alkoxy, acyl or acyloxy, or together R⁶ and R⁷ form an arylheterocycloc alkyl ring system.