Methods of use of cyclopamine analogs

• US 9,145,422 B2
• Filed: 10/15/2013
• Issued: 09/29/2015
• Est. Priority Date: 12/28/2006
• Status: Active Grant

• Current Assignee: Johns Hopkins University, Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Castro, Alfredo C., Grogan, Michael J., McGovern, Karen J., Tremblay, Martin R.
• Primary Examiner(s): Kosar, Andrew D
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US14/054,350
• Publication Number:
  US 20140107142A1
• Time in Patent Office: 714 Days
• Field of Search: 514/455, 514/47, 514/169, 514/222, 514/226.2, 514/261, 514/262.2, 514/278
• US Class Current: 1/1
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/664 Amides of phosphorus acids
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• 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 307/94 : spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07J 69/00 : Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom

Abstract

The invention provides methods for treating various conditions using derivatives of cyclopamine having the following formula:

Claims

1. A method for treating a hyperproliferative disorder, the method comprising administering to a subject an effective amount of a compound having the formula:

2. The method of claim 1, wherein when R², R³, and R⁴ are H;

R¹ is not hydroxyl or a sugar; and

when R⁴ is hydroxyl, then R¹ is not a sugar or hydroxyl; and

when R⁴ is hydroxyl, then R¹ and R² together are not C═

O.

3. The method of claim 1, wherein R¹ is sulfonamido.

4. The method of claim 1, wherein the condition is selected from the group consisting of skin cancers, cancers of the central nervous system, cancers of the gastrointestinal tract, cancers of the pulmonary system, genitourinary cancers, breast cancer, hepatocellular cancer, brain cancers, and cancers of the hematopoietic system.

17. The method of claim 1, wherein the compound is selected from the group consisting of:

22. The method of claim 1, wherein the compound is

23. The method of claim 22, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

24. The method of claim 4, wherein the compound is

25. The method of claim 24, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

30. The method of any one of claim 22, 24, 26 or 28, wherein the compound is administered topically.

5. A method of treating a condition mediated by the hedgehog pathway, the method comprising administering to a subject an effective amount of a compound having the formula:

6. The method of claim 5, wherein when R², R³, and R⁴ are H;

R¹ is not hydroxyl or a sugar; and

when R⁴ is hydroxyl, then R¹ is not a sugar or hydroxyl; and

when R⁴ is hydroxyl, then R¹ and R² together are not C═

O.

7. The method of claim 5 wherein R¹ is sulfonamido.

8. The method of claim 5 wherein the condition is small cell lung cancer.

9. The method of claim 5, wherein the condition is pancreatic cancer.

10. The method of claim 5, wherein the condition is medulloblastoma.

11. The method of claim 5, wherein the condition is selected from the group consisting of multiple myeloma, leukemia, myelodysplastic syndrome, non-Hodgkin'"'"'s lymphoma, and Hodgkin'"'"'s disease.

12. The method of claim 5, wherein the compound is administered orally.

13. The method of claim 5, wherein the compound is administered intravenously.

14. The method of claim 5, wherein the compound is administered topically.

18. The method of claim 5, wherein the compound is selected from the group consisting of:

26. The method of claim 5, wherein the compound is

27. The method of claim 26, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

15. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of a compound having the formula:

16. The method of claim 15, wherein when R², R³, and R⁴ are H;

R¹ is not hydroxyl or a sugar; and

when R⁴ is hydroxyl, then R¹ is not a sugar or hydroxyl; and

when R⁴ is hydroxyl, then and R¹ and R² together are not C═

O.

19. The method of claim 15, wherein the compound is selected from the group consisting of:

28. The method of claim 15, wherein the compound is

29. The method of claim 28, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

20. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of a compound having following structure:

21. The method of claim 20, wherein R¹ is sulfonamido.