CYCLOPAMINE ANALOGUES AND METHODS OF USE THEREOF

• US 20080269272A1
• Filed: 07/10/2008
• Published: 10/30/2008
• Est. Priority Date: 08/27/2004
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Discovery, Inc. (Infinity Pharmaceuticals, Inc.)
• Inventors: Foley, Michael A., Porter, James R., Castro, Alfredo C., Adams, Julian, Tremblay, Martin R., Nevalainen, Marta, Janardanan Nair, Somarajan Nair
• Granted Patent: US 7,875,628 B2
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 491/04 Ortho-condensed systems

Abstract

The present invention provides compositions and methods for modulating smoothened-dependent pathway activation. The present invention provides analogs of cyclopamine that can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, Ptc loss-of-function or smoothened gain-of-function mutations. The compounds of the present invention are particularly useful in treating cancers.

Claims

1. A method to treat cancer in a subject, which method comprises administering to a subject in need thereof an effective amount of a compound of Formula 1:

2. The method of claim 1, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are hydrogen.

3. The method of claim 1, wherein R¹ is hydroxyl, sugar, —

OP(L)(OR²⁰)₂, —

X—

C(L)-R²¹, or —

X—

C(L)-X—

R²¹;

or R¹ and R² taken together, along with the carbon to which they are bonded, form —

C(O)—

.

4. The method of claim 1, wherein R⁴ and R⁵ taken together form a double bond.

5. The method of claim 4, wherein R¹ and R² taken together, along with the carbon to which they are bonded, form —

C(O)—

.

6. The method of claim 1, wherein R¹ is hydroxyl and R² is H.

7. The method of claim 6, wherein R⁵ and R⁶ taken together form a double bond;

or R⁵ and R⁶ taken together form a group represented by 1b;

8. The method of claim 1, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

9. The method of claim 1, wherein R⁵ and R⁶ taken together form a double bond and R¹⁰ and R¹¹ taken together form a double bond.

10. The method of claim 5, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

11. The method of claim 6, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

12. The method of claim 1, wherein R⁸ and R⁹ are hydrogen;

or R⁸ and R⁹ taken together, along with the carbon to which they are bonded, is —

C(O)—

.

13. The method of claim 1, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

14. The method of claim 2, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

15. The method of claim 5, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

16. The method of claim 6, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

17. The method of claim 1 wherein compound of formula 1 has the formula:

18. The method of claim 1 wherein the compound of formula 1 is selected from the group consisting of:

19. The method of claim 1, wherein the compound of formula 1 has the formula:

20. The method of claim 1, wherein the cancer is located in the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, paragangliomas, pancreas, stomach, skin, esophagus, liver and biliary tree, bone, intestine, colon, rectum, ovaries, prostate, lung, breast, lymphatic system, blood, bone marrow central nervous system, or brain.

21. The method of claim 20, wherein the cancer is basal cell carcinoma, pancreatic cancer, prostate cancer, sarcoma, lymphomas, leukemia, gastric cancer, esophageal cancer, biliary cancer, colon cancer, multiple myeloma, small cell lung cancer, glioma, breast cancer, hepatocellular or medulloblastoma.

22. The method of claim 20, wherein the compound is used in combination with radiation therapy or another anti-cancer chemotherapeutic agent.

23. The method of claim 20, wherein the compound is administered locally to a tumor.

24. The method of claim 20, wherein the compound is administered systemically.

25. The method of claim 20, wherein the mode of administration of said compound is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intra-arterial, intrathecal, subcutaneous, buccal, or nasal.

26. The method of claim 20, wherein the mode of administration is oral, intravenous, or topical.

27. A method for antagonizing the hedgehog pathway in a cell, comprising contacting a cell expressing smoothened with an effective amount of the compound of formula 1 as defined in claim 1, or a pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein said contacting is in vitro.

29. The method of claim 27, wherein said contacting is in vivo.

30. The method of claim 27, wherein said cell expressing smoothened is within the body of an organism.

31. A method of treating psoriasis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula 1 as defined in claim 1, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the mode of administration of said compound is topical.