Antitumor effect potentiators

• US 20030165576A1
• Filed: 02/05/2003
• Published: 09/04/2003
• Est. Priority Date: 06/23/2000
• Status: Active Grant

• Current Assignee: Mitsubishi Tanabe Pharma Corporation (Mitsubishi Chemical Group Corp.)
• Original Assignee: Mitsubishi Tanabe Pharma Corporation (Mitsubishi Chemical Group Corp.)
• Inventors: Tanaka, Hiroshi, Fujii, Akihiro, Oshita, Kouichi, Kawaguchi, Takafumi, Otsuki, Makio
• Granted Patent: US 6,930,115 B2
• Time in Patent Office: Days
• US Class Current: 424/649
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4406 only substituted in position 3, e.g. zimeldine nicotinic acid A61K31/455
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/243 : Platinum; Compounds thereof
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

When used concurrently with an antitumor agent, a compound having a Rho kinase inhibitory activity, such as (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide, reinforces an antitumor effect of the antitumor agent and is useful as an antitumor effect potentiator.

Particularly, a compound having a Rho kinase inhibitory activity used with an antitumor agent in combination can reduce the dose of the antitumor agent, which in turn affords provision of a sufficient effect and/or reduction of side effects.

Claims

1. An antitumor effect potentiator comprising a compound having a Rho kinase inhibitory activity as an active ingredient, which reinforces an antitumor effect of an antitumor agent.

2. The antitumor effect potentiator of claim 1, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I)

3. The antitumor effect potentiator of claim 1, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I′

)

4. The antitumor effect potentiator of claim 1, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.

5. The antitumor effect potentiator of claim 4, wherein the compound having a Rho kinase inhibitory activity is (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.

6. The antitumor effect potentiator of claim 1 or 2, wherein the antitumor agent is selected from cisplatin, etoposide and paclitaxel.

7. The antitumor effect potentiator of claim 6, wherein the antitumor agent is cisplatin.

8. A pharmaceutical composition for potentiation of antitumor effect, which comprises a compound having a Rho kinase inhibitory activity and a pharmaceutically acceptable carrier, which reinforces an antitumor effect of an antitumor agent.

9. The pharmaceutical composition for potentiation of antitumor effect of claim 8, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.

10. The pharmaceutical composition for potentiation of antitumor effect of claim 8, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I′

), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.

11. The pharmaceutical composition for potentiation of antitumor effect of claim 8, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.

12. The pharmaceutical composition for potentiation of antitumor effect of claim 11, wherein the compound having a Rho kinase inhibitory activity is (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.

13. The pharmaceutical composition for potentiation of antitumor effect of claim 8 or 9, wherein the antitumor agent is selected from cisplatin, etoposide and paclitaxel.

14. The pharmaceutical composition for potentiation of antitumor effect of claim 13, wherein the antitumor agent is cisplatin.

36. A commercial package comprising the pharmaceutical composition for potentiation of antitumor effect of any of claims 8 to 14 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for reinforcing an antitumor effect of an antitumor agent.

15. A pharmaceutical composition for the treatment of tumor, which comprises a compound having a Rho kinase inhibitory activity, an antitumor agent and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition for treatment of tumor of claim 15, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.

17. The pharmaceutical composition for treatment of tumor of claim 15, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I′

), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.

18. The pharmaceutical composition for treatment of tumor of claim 15, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)-cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.

19. The pharmaceutical composition for treatment of tumor of claim 18, wherein the compound having a Rho kinase inhibitory activity is (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.

20. The pharmaceutical composition for treatment of tumor of claim 15 or 16, wherein the antitumor agent is selected from cisplatin, etoposide and paclitaxel.

21. The pharmaceutical composition for treatment of tumor of claim 20, wherein the antitumor agent is cisplatin.

37. A commercial package comprising the pharmaceutical composition for treatment of tumor of any of claims 15 to 21 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for treatment of tumor.

22. A method of treating a tumor, which comprises administering a pharmaceutically effective amount of a compound having a Rho kinase inhibitory activity and a pharmaceutically effective amount of an antitumor agent to a patient.

23. The method of claim 22, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.

24. The method of claim 22, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I′

), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.

25. The method of claim 22, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.

26. The method of claim 22, wherein the compound having a Rho kinase inhibitory activity is (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.

27. The method of claim 22 or 23, wherein the antitumor agent is selected from cisplatin, etoposide and paclitaxel.

28. The method of claim 27, wherein the antitumor agent is cisplatin.

29. Use of a compound having a Rho kinase inhibitory activity for the production of an antitumor effect potentiator.

30. The use of claim 29, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.

31. The use of claim 29, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I′

), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.

32. The use of claim 29, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.

33. The use of claim 32, wherein the compound having a Rho kinase inhibitory activity is (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.

34. The use of claim 29 or 30, wherein the antitumor agent is selected from cisplatin, etoposide and paclitaxel.

35. The use of claim 34, wherein the antitumor agent is cisplatin.