Carbonyl Compounds Which Can be Used as Inhibitors of Coagulation Factor Xa

Abstract

Novel compounds of the formula (I), in which D, E, G, W, X, Y, T, R1 and R2 have the meaning indicated in Patent Claim (1), are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic diseases and for the treatment of tumours.

Description

EXAMPLE 1

The preparation of N-1-(5-chloropyridin-2-yl)-N-2-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide (“A6”) is carried out analogously to the following scheme:

894 mg (4.43 mmol) of 4-nitrophenyl chloroformate are added to a solution of 570 mg (4.43 mmol) of 2-amino-5-chloropyridine and 0.73 ml (9.0 mmol) of pyridine in 50 ml of dichloromethane, and the mixture is stirred at room temperature for 1 hour. 1.49 g (4.43 mmol) of (2R,4R)-4-hydroxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride and 1.5 ml (9.0 mmol) of N-ethyldiisopropylamine are added to the resultant suspension, and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol 95:5 as eluent: N-1-(5-chloropyridin-2-yl)-N²-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide (“A6”) as colourless solid, ESI 454.

The following compounds are obtained analogously

• N-1-(5-chloropyridin-2-yl)-N-2-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 460;
• N-1-(5-chloropyridin-2-yl)-N-2-[4-(2-oxo-2H-pyrazin-1-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 455;
• N-1-(5-chloropyridin-2-yl)-N-2-[3-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 472;
• N-1-(5-chloropyridin-2-yl)-N-2-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-(R)-4,4-dimethoxypyrrolidine-1,2-dicarboxamide, ESI 498;
• N-1-(5-chloropyridin-2-yl)-N-2-[4-(3-oxomorpholin-4-yl)phenyl]-(R)-4,4-dimethoxypyrrolidine-1,2-dicarboxamide, ESI 504;
• N-1-(6-chloropyridin-3-yl)-N-2-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 454;
• N-1-(6-chloropyridin-3-yl)-N²-[4-(2-oxo-2H-pyrazin-1-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 455.

EXAMPLE 2

Preparation of N-1-(4-chlorophenyl)-4-(ethoxycarbonyloxy)-N²-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-pyrrolidine-1,2-dicarboxamide

5 g (10.9 mmol) of N-1-(4-chlorophenyl)-N-2-[4-(3-oxomorpholin-4-yl)phenyl]-4-hydroxypyrrolidine-1,2-dicarboxamide are suspended in 50 ml of THF, and 2.5 ml of triethylamine are added. 2 ml (2 eq) of ethyl chloroformate are subsequently added to the reaction mixture. After 16 hours, the mixture is subjected to aqueous work-up, and the crude product is recrystallised from ethanol, giving 5 g of colourless N-1-(4-chlorophenyl)-4-(ethoxycarbonyloxy)-N-2-[4-(3-oxomorpholin-4-yl)phenyl)-(2R,4R)-pyrrolidine-1,2-dicarboxamide (“A1”).

The following compound is obtained analogously

• N-1-(4-chlorophenyl)-4-(ethoxycarbonyloxy)-N-2-methyl-2-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-pyrrolidine-1,2-dicarboxamide.

14. Examples of the Preparation of Intermediate Compounds

14.1 All compounds of the following formula VI (where R═H or methyl; n=3, 4 or 5) can be synthesised in accordance with the following scheme

For example, synthesis of 1-(4-amino-2-methylphenyl)piperidin-2-one:

14.2 Synthesis of the phenylpiperidone unit without a methyl group

1-(4-Amino-2-methylphenyl)piperidin-2-one is prepared, for example, as indicated below

14.3 1-(4-Aminophenyl)-1H-pyrazin-2-one

14.4 1-(4-Amino-2,5-dimethylphenyl)piperidin-2-one

14.5 1-(4-Amino-3-methylphenyl)piperidin-2-one

14.6 1-(5-Aminopyridin-2-yl)piperidin-2-one

14.7 1-(4-Aminomethylphenyl)piperidin-2-one

14.8 2-(4-Aminophenyl)-2-azabicyclo[2.2.2]octan-3-one

14.9 1-(3-Amino-6-ethylphenyl)pyrrolidin-2-one

14.10 2-(4-Amino-2-trifluoromethylphenyl)-2-azabicyclo[2.2.2]octan-3-one

14.11 1-(4-Amino-3-chlorophenyl)pyrrolidin-2-one

14.12 1-(4-Amino-2-trifluoromethylphenyl)piperidin-2-one

14.13 3(4-Amino-2-methylphenyl)-1,3-oxazinan-2-one

14.14 4-(4-Aminophenyl)morpholin-3-one

14.15 1-(4-Aminophenyl)pyridin-2-one

14.16 1-(4-Amino-2-methylphenyl)piperidin-2-one

14.17 1-(4-Aminophenyl)-1H-pyridin-4-one

14.18 1-(4-Aminophenyl)-4-tert-butyloxycarbonylpiperazin-2-one

14.19 1-(3-Aminophenyl)piperidin-2-one

14.20 1-(4-Aminophenyl)-2-caprolactam

14.21 1-(4-Amino-3-fluorophenyl)piperidin-2-one

14.22 1-(4-Amino-2-fluorophenyl)piperidin-2-one

14.23 1-(4-Amino-2-fluorophenyl)-2-caprolactam

14.24 4-(4-Amino-2-fluorophenyl)-1,4-oxazepan-5-one

14,25 4-(4-Amino-3-phenoxyphenyl)morpholin-3-one

14.26 2-[3-(4-Chlorophenyl)ureido]cyclopentanecarboxylic acid

14.27 1-(4-Chlorophenylcarbamoyl)piperidine-3-carboxylic acid

14.28 4-(4-Aminophenyl)-1,4-oxazepan-3-one

The TEMPO oxidation is carried out in accordance with the following literature:

• L, DeLuca et al., J. Org. Chem. 68, 4999-5001 (2003).

Pharmacological Data

Affinity to Receptors

TABLE 1
Compound
No.  FXa-IC50 [M]
“A1” 2.0 × 10−9

The following examples relate to pharmaceutical compositions.

EXAMPLE A

Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

EXAMPLE B

Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.

EXAMPLE C

Solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄. 12H₂O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.

EXAMPLE D

Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

EXAMPLE E

Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to give tablets in a conventional manner in such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F

Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

EXAMPLE G

Capsules

2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

EXAMPLE H

Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims

1. Compounds of the formula I

2. Compounds according to claim 1 in which D denotes a mono- or bicyclic, aromatic carbocyclic or heterocyclic ring having 0 to 4 N, O and/or S atoms which is unsubstituted or mono- or disubstituted by Hal,

3. Compounds according to claim 1 in which D denotes phenyl, pyridyl, thienyl, furyl or imidazolyl, each of which is mono- or disubstituted by Hal,

4. Compounds according to claim 1 in which R1 and R2 each, independently of one another, denote H, ═O, COOR3, OH, OA, NH2, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, N3, ethynyl, vinyl, allyloxy, NHCOA, NHSO2A, OCH2COOA, OCH2COOH, —OCOOR3, —OCON(R3)2 or OSO2N(R3)2, where one of the radicals R1 or R2 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2

5. Compounds according to claim 1 in which G denotes (CH2)n, (CH2)nNH—, —CH═CH— or —CH═CH—CH═CH—,

6. Compounds according to claim 1 in which X denotes —[C(R4)2]nCONR3[C(R4)2]n—,

7. Compounds according to claim 1 in which X denotes —CONH— or —CON(CH2COOA)-,

8. Compounds according to claim 1 in which Y denotes cycloalkylene, Het-diyl or Ar-diyl,

9. Compounds according to claim 1 in which Y denotes pyridinediyl, piperidinediyl, cyclohexylene, or phenylene which is unsubstituted or mono- or disubstituted by A, OA, Cl, F, COOCH3, COOH, phenoxy or aminocarbonyl,

10. Compounds according to claim 1 in which T denotes a monocyclic, saturated or unsaturated heterocyclic ring having 1 or 2 N and/or O atoms which is mono- or disubstituted by ═O, ═S or ═NH and may be mono- or disubstituted by Hal, A and/or OA,

11. Compounds according to claim 1 in which T denotes piperidin-1-yl, pyrrolidin-1-yl, pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, pyridazin-2-yl, pyrazin-1-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octan-2-yl, imidazolidinyl, thiazolyl or 1,4-oxazepanyl, each of which is mono- or disubstituted by ═O or ═NH and where the radicals may also be mono- or disubstituted by Hal, A and/or OA,

12. Compounds according to claim 1 in which Ar denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, A, OA, SO2A, COOR2, SO2NH2, CN, COCA, COOH or phenoxy,

13. Compounds according to claim 1 in which D denotes a mono- or bicyclic, aromatic carbocyclic or heterocyclic ring having 0 to 4 N, O and/or S atoms which is unsubstituted or mono- or disubstituted by Hal,R1 and R2 each, independently of one another, denote H, ═O, COOR3, OH, OA, NH2, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, N3, ethynyl, vinyl, allyloxy, NHCOA, NHSO2A, OCH2COOA, OCH2COOH, —OCOOR3, —OCON(R3)2 or OSO2N(R3)2, where one of the radicals R1 or R2 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2 R3 denotes H, A, phenyl, benzyl or [C(R4)2]nCOOA,R4 denotes H or A,W denotes N, CR3 or an sp2-hybridised C atom,E together with W denotes a 3- to 7-membered saturated carbocyclic or heterocyclic ring having 0 to 3 N, 0 to 2 O and/or 0 to 2 S atoms, which may contain a double bond,G denotes (CH2)n, (CH2)nNH—, —CH═CH— or —CH═CH—CH═CH—,X denotes —[C(R4)2]nCONR3[C(R4)2]n—,Y denotes cycloalkylene, Het-diyl or Ar-diyl,Ar denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, A, OA, SO2A, COOR2, SO2NH2, CN, COCA, COOC or phenoxy,T denotes a monocyclic, saturated or unsaturated heterocyclic ring having 1 or 2 N and/or O atoms which is mono- or disubstituted by ═O, ═S or ═NH and may be mono- or disubstituted by Hal, A and/or OA,A denotes unbranched or branched alkyl having 1-10 C atoms and in which 1-7H atoms may be replaced by F,Hal denotes F, Cl, Br or I,n denotes 0, 1 or 2,

14. Compounds according to claim 1 in which D denotes phenyl, pyridyl, thienyl, furyl or imidazolyl, each of which is mono- or disubstituted by Hal,R1 and R2 each, independently of one another, denote H, ═O, COOR3, OH, OA, NH2, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, N3, ethynyl, vinyl, allyloxy, NHCOA, NHSO2A, OCH2COOA, OCH2COOH, —OCOOR3, —OCON(R3)2 or OSO2N(R3)2, where one of the radicals R1 or R2 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2 R3 denotes H, A or CH2COOA,R4 denotes H or A,W denotes N, CR3 or an sp2-hybridised C atom,E together with W denotes a 3- to 7-membered saturated carbocyclic or heterocyclic ring having 0 to 3 N, 0 to 2 O and/or 0 to 2 S atoms, which may contain a double bond,G denotes (CH2)n, (CH2)nNH—, —CH═CH— or —CH═CH—CH═CH—,X denotes —CONH— or —CON(CH2COOA)-,Y denotes pyridinediyl, piperidinediyl, cyclohexylene, or phenylene which is unsubstituted or mono- or disubstituted by A, OA, Cl, F, COOCH3, COOH, phenoxy or aminocarbonyl,T denotes piperidin-1-yl, pyrrolidin-1-yl, pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, pyridazin-2-yl, pyrazin-1-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octan-2-yl, imidazolidilyl, thiazolyl or 1,4-oxazepanyl, each of which is mono- or disubstituted by ═O or ═NH and where the radicals may also be mono- or disubstituted by Hal, A and/or OA, P1 A denotes unbranched or branched alkyl having 1-10 C atoms and in which 1-7H atoms may be replaced by F,Hal denotes F, Cl, Br or I,n denotes 0, 1 or 2,

15. Compounds according to claim 1 in which D denotes phenyl, pyridyl or thienyl, each of which is mono- or disubstituted by Hal,R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H, ═O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 C atoms,R3 denotes H or A,R4 denotes H or A,

16. Compounds according to on claim 1 in which D denotes phenyl, pyridyl or thienyl, each of which is mono- or disubstituted by Hal,R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H, ═O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 C atoms,R3 denotes H or A,R4 denotes H or A,

17. Compounds according to claim 1 in which X denotes —[C(R4)2]nCONR3[C(R4)2]n— or —[C(R4)2]nCO[C(R4)2]n—,

18. Compounds according to claim 1 in which X denotes CONH or COCH2,

19. Compounds according to claim 1 in which D denotes phenyl, pyridyl or thienyl, each of which is mono- or disubstituted by Hal,R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H, ═O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 C atoms,R3 denotes H or A,R4 denotes H or A,

20. Compounds according to claim 1 in which D denotes phenyl, pyridyl or thienyl, each of which is mono- or disubstituted by Hal,R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H, ═O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 C atoms,R3 denotes H, OH or A,R4 denotes H or A,

21. Compounds according to claim 1 in which D denotes phenyl, pyridyl or thienyl, each of which is mono- or disubstituted by Hal,R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H, A or OH,R3 denotes H or A,R4 denotes H or A,

22. Compounds according to claim 1 in which D denotes phenyl, pyridyl, thienyl, furyl or imidazolyl, each of which is mono- or disubstituted by Hal,R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H, ═O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 C atoms,R3 denotes H or A,R4 denotes H or A,

23. Compounds according to claim 1 in which R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H or A,

24. Compounds according to one claim 1 in which D denotes phenyl which is mono- or disubstituted by Hal,R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H or A,R3 denotes H or A,

25. Compounds according to claim 1 in which D denotes phenyl which is mono- or disubstituted by Hal,R1 denotes —OCOOR3, —OCON(R3)2 or OSO2N(R3)2,R2 denotes H or A,R3 denotes H or A,

26. Compounds according to claim 1 selected from the group

27. Process for the production of compounds of formula I according to claim 1 and pharmaceutically usable derivatives, solvates, salts and stereoisomers, characterised in that daβ man a) for the preparation of compounds of the formula I in whichW denotes N andG denotes NH,

28. Compounds of the formula I according to claim 1 as inhibitors of coagulation factor Xa.

29. Compounds of the formula I according to claim 1 as inhibitors of coagulation factor VIIa.

30. Medicaments comprising at least one compound of the formula I according to claim 1 and/or pharmaceutically usable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants

31. Medicaments comprising at least one compound of the formula I according to claim 1 and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.

32. Use of compounds according to claim 1 and/or physiologically acceptable salts, salts and solvates thereof for the preparation of a medicament for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, migraine, tumours, tumour diseases and/or tumour metastases.

33. Use of compounds according to claim 1 and/or physiologically acceptable salts, salts and solvates thereof for the preparation of a medicament for the prevention and treatment of thromboembolic diseases and/or thromboses as a consequence of a surgical intervention, genetically caused diseases having increased thrombosis suitability, diseases of the arterial and venous vascular system, cardiac insufficiency, atrial fibrillation, thrombophilia, tinnitus and/or sepsis.

34. Use according to claim 33, where the surgical interventions are selected from the group thorax operations, operations in the abdominal region, orthopaedic interventions, hip and knee joint replacement, CABG (coronary artery bypass grafting), artificial heart-valve replacement, operations with use of a heart-lung machine, vascular surgery, organ transplants and use of central vein catheters.

35. Set (kit) consisting of separate packs of (a) an effective amount of a compound of the formula I according to claim 1 and/or pharmaceutically usable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios,and(b) an effective amount of a further medicament active ingredient.

36. Use of compounds of the formula I according to claim 1 and/or pharmaceutically usable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, migraine, tumours, tumour diseases and/or tumour metastases,