4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate

• US 9,957,232 B2
• Filed: 09/29/2007
• Issued: 05/01/2018
• Est. Priority Date: 10/11/2006
• Status: Active Grant

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Bayer Healthcare LLC (Bayer AG)
• Inventors: Grunenberg, Alfons, Stiehl, Juergen, Tenbieg, Katharina, Keil, Birgit
• Primary Examiner(s): REESE, HEIDI L
• Application Number:
  US12/444,974
• Publication Number:
  US 20100173953A1
• Time in Patent Office: 3,867 Days
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/62 Oxygen or sulfur atoms
• CPC Class Codes: C07D 213/78 Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/81 Amides; Imides

Abstract

The present invention relates to 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate, to processes for its preparation, to pharmaceutical compositions comprising it and to its use in the control of disorders.

Claims

1. A compound of the formula (II)

2. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically suitable excipients for the treatment of solid tumors, lymphomas, sarcomas, leukemias, cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid and/or parathyroid.

3. A method for the treatment of a hyper-proliferative disorder comprising administering an effective amount of a pharmaceutical composition of claim 2 to a subject in need thereof.

4. The method of claim 3 wherein the hyper-proliferative disorder to be treated is a solid tumor, lymphoma, sarcoma, leukemia or cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid or parathyroid.

5. A pharmaceutical composition comprising the compound of the formula (II) of claim 1 and one or more inert, nontoxic, pharmaceutically suitable excipients.

6. A method for treating hyper-proliferative disorders comprising administering an effective amount of a pharmaceutical composition of claim 5 to a subject in need thereof.

7. A combination comprising the compound of the formula (II) of claim 1 and one or more other pharmaceutical agents.

8. The combination of claim 7 wherein the one or more other pharmaceutical agents are cytotoxic agents, signal transduction inhibitors, anti-cancer agents, or antiemetics.

9. The pharmaceutical composition of claim 5 comprising one or more other pharmaceutical agents.

10. The pharmaceutical composition of claim 9 wherein the one or more other pharmaceutical agents are anti-hyper-proliferative agents, cytotoxic agents, signal transduction inhibitors, anti-cancer agents and/or antiemetics.

11. A pharmaceutical composition comprising a compound of claim 1 of the formula (II) and a pharmaceutically suitable excipient for the treatment of hyper-proliferative disorders.

14. A pharmaceutical composition comprising a compound of claim 1 of the formula (II) and a pharmaceutically suitable excipient for the treatment of tumors of the digestive tract.

15. A pharmaceutical composition comprising a compound of claim 1 of the formula (II) and a pharmaceutically suitable excipient for the treatment of colorectal cancer.

16. A method for the treatment of tumors of the digestive tract comprising administering an effective amount of a pharmaceutical composition of claim 14 to a subject in need thereof.

17. A method for the treatment of colorectal cancer comprising administering an effective amount of a pharmaceutical composition of claim 15 to a subject in need thereof.

18. A method of claim 4 wherein the

cancer of the breast is invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ;

cancer of the respiratory tract is small-cell and non-small-cell lung carcinoma, bronchial adenoma or pleuropulmonary blastoma;

cancer of the brain is brain stem glioma, hypophtalmic glioma, cerebellar astrocytoma, cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor or pineal tumor;

cancer of the male reproductive organ is prostate cancer, testicular cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer or sarcoma of the uterus;

cancer of the digestive tract is anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer or salivary gland cancer;

cancer of the urinary tract is bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer or urethral cancer;

cancer of the eye is intraocular melanoma or retinoblastoma;

cancer of the liver is hepatocellular carcinoma (liver cell carcinomas with or without fibrolarnellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), or mixed hepatocellular cholangiocarcinoma;

cancer of the skin is squamous cell carcinoma, Kaposi'"'"'s sarcoma, malignant melanoma, Merkel cell skin cancer, or non-melanoma skin cancer;

cancer of the head-and-neck is laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer or oral cavity cancer;

the lymphoma is AIDS-related lymphoma, non-Hodgkin'"'"'s lymphoma, cutaneous T-cell lymphoma, Hodgkin'"'"'s disease, or lymphoma of the central nervous system;

the Sarcoma is sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, or rhabdomyosarcoma;

the Leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or hairy cell leukemia.

25. A compound of the formula (II) of claim 1 which contains H₂O in an amount of 3.6% by weight.

26. A pharmaceutical composition according to claim 2 wherein the pharmaceutically suitable excipient is water.

27. A pharmaceutical composition according to claim 26 which is a sterile injectable aqueous suspension.

28. A pharmaceutical composition according to claim 2 wherein the pharmaceutically suitable excipient is selected from vegetable oil, arachis oil, olive oil, sesame oil, coconut oil, mineral oil and liquid paraffin.

29. A pharmaceutical composition according to claim 28 which is an oily suspension.

12. A process for the preparation of the compound of the formula (II)

13. A process for the preparation of the compound of the formula (II)

19. The compound of the formula (II)

20. The compound of claim 19 which shows in the FIR spectrum a peak maximum of 353 cm⁻

1.

21. A pharmaceutical composition comprising a compound of claim 20 and one or more pharmaceutically suitable excipients for the treatment of solid tumors, lymphomas, sarcomas, leukaemia'"'"'s, cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid and/or parathyroid.

22. A method for the treatment of a hyper-proliferative disorder comprising administering an effective amount of a pharmaceutical composition of claim 21 to a subject in need thereof.

23. A method for the treatment of tumors of the digestive tract comprising administering an effective amount of a pharmaceutical composition of claim 21 to a subject in need thereof.

24. A method for the treatment of colorectal cancer comprising administering an effective amount of a pharmaceutical composition of claim 21 to a subject in need thereof.