TUBULIN INHIBITORS

• US 20110269760A1
• Filed: 07/14/2011
• Published: 11/03/2011
• Est. Priority Date: 12/03/2003
• Status: Active Grant

• Current Assignee: YM BioSciences Australia Pty Ltd (Gilead Sciences Inc.)
• Original Assignee: Cytopia Research Pty Ltd (Gilead Sciences Inc.)
• Inventors: Wilks, Andrew Frederick, Sikanyika, Harrison, Fantino, Emmanuelle, Burns, Christopher John, Harte, Michael Francis
• Granted Patent: US 8,394,806 B2
• Time in Patent Office: Days
• US Class Current: 514/235.8
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/20 Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 253/07 with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compounds of general formula (I), (II), (III) and (V) are described for use in modulating microtubule polymerisation and in the treatment of associated disease states. Use of compounds (I), (III) and (V) in the treatment of kinase-associated disease states is also described. Further described are novel compounds of formula (II), (III) and (V).

Claims

1. A method of modulating microtubule polymerisation in a subject, said method comprising administering a therapeutically effective amount of at least one compound of formula (I)

2. A method according to claim 1 wherein the compound of formula (I) is selected from the group consisting of:

3. A method according to claim 1, wherein said subject is treated for a hyperproliferation-related disorder or disease state.

4. A method according to claim 3, wherein the hyperproliferation-related disorder or disease state is selected from the group consisting of cancer, infectious diseases, vascular restenosis and inflammatory diseases.

5. A compound of formula (II)

6. A compound according to claim 5 selected from the group consisting of:

7. A compound of formula (III)

8. A compound according to claim 7, wherein

R¹ is H, C_1-6alkyl or C_1-6alkylNR⁵R⁶, where R⁵ and R⁶ are each independently H, C_1-4alkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR⁷;

Q is CH;

W is selected from C_1-4alkyl and C_2-6alkenyl;

where C_1-4alkyl or C_2-6alkenyl may be optionally substituted with C_1-4alkyl, OH, OC_1-4alkyl or NR¹⁵R¹⁶;

R¹⁵ and R¹⁶ are each independently H, C_1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR¹⁷;

A is aryl or hetaryl optionally substituted with 0-2 substituents independently chosen from halogen, C_1-4alkyl, CF₃, aryl, hetaryl, OCF₃, OC_1-4alkyl, OC_2-5alkylNR¹⁸R¹⁹, Oaryl, Ohetaryl, CO₂R¹⁸, CONR¹⁸R¹⁹, NR¹⁸R¹⁹, C_1-4alkylNR¹⁸R¹⁹, NR²⁰C_1-4alkylNR¹⁸R¹⁹, NR¹⁸COR¹⁹, NR²⁰CONR¹⁸R¹⁹ and NR¹⁸SO₂R¹⁹;

Y is selected from H, C_1-4alkyl and NR²²R²³.

9. A compound according to claim 7 wherein the compound is selected from the group consisting of:

13. A composition comprising a carrier and at least one compound according to claim 7.

14. A method to treat a hyperproliferation-related disorder or disease state in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7.

15. A method according to claim 14, wherein the hyperproliferation-related disorder or disease state is treatable by the modulation of microtubule polymerisation.

16. A method according to claim 14, wherein the hyperproliferation-related disorder or disease state is selected from the group consisting of cancer, infectious diseases, vascular restenosis or inflammatory diseases.

17. A method to treat a protein-kinase related disorder or disease state in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7.

18. A method according to claim 17, wherein the protein-kinase related disorder to disease state is selected from the group consisting of atopy, cell mediated hypersensitivity, rheumatic diseases, other autoimmune diseases and viral diseases.

19. A method to treat diseases and conditions associated with inflammation and infection in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7.

10. A compound of formula (V)

11. A compound according to claim 10 selected from the group consisting of:

12. A compound of the formula: