Cyclopamine analogs

• US 8,669,365 B2
• Filed: 08/27/2008
• Issued: 03/11/2014
• Est. Priority Date: 12/28/2006
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Austad, Brian, Behnke, Mark L., Castro, Alfredo C., Grogan, Michael J., Janardanannair, Somarajannair, Lescarbeau, Andre, Peluso, Stephane, Tremblay, Martin, Charette, Andr B.
• Primary Examiner(s): Kosar, Andrew D
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US12/199,722
• Publication Number:
  US 20090216022A1
• Time in Patent Office: 2,022 Days
• Field of Search: 546/15, 546/17, 546/115, 549/331
• US Class Current: 546/15
• 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 novel derivatives of cyclopamine having the following formula:

Claims

1. A process for preparing a compound of formula 136:

2. The process of claim 1, wherein R⁷ and R⁸ are both H.

3. The process of claim 1, wherein R¹ is a protected hydroxyl.

4. The process of claim 1, wherein R⁶ is a nitrogen protecting group.

5. The process of claim 1,

wherein each of R¹⁰ and R¹¹ is independently aryl.

6. The process of claim 1, wherein R¹⁰ and R¹¹ are each 2,6-dimethylphenyl.

7. A process for preparing a compound of formula 137:

8. The process according to claim 7,

wherein

R¹ is a protected hydroxyl group;

R² is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; and

R⁶ is a nitrogen protecting group.

9. The process of claim 7, wherein R⁷ and R⁸ are both H.

10. The process of claim 7, wherein said protected hydroxyl group is an ester or a carbonate.

11. The process of claim 7, wherein said nitrogen protecting group is a carbamate.

12. The process of claim 7, wherein said nitrogen protecting group is an amide.

13. The process of claim 7, wherein R² and R³ are H and R⁴ and R⁵ taken together form a bond.

14. The process of claim 7,

wherein each of R¹⁰ and R¹¹ is independently aryl.

15. The process of claim 7, wherein said acid is acetic acid, trifluoromethanesulfonic acid, phosphoric acid, methanesulfonic acid or HCl.

16. The process of claim 7, wherein said acid is BF₃, zinc chloride, zinc methanesulfonate, or a zinc salt.

23. The process of claim 7, wherein R¹⁰ and R¹¹ are each 2,6-dimethylphenyl.

17. A process for preparing a compound of formula 156:

18. The process of claim 17,

wherein each of R¹⁰ and R¹¹ is, independently, aryl.

19. The process of claim 17, wherein said oxygen protecting group is alkyl carbonate, aralkyl carbonate, benzoate, pivaloate, or formate.

20. The process of claim 17, wherein said nitrogen protecting group is benzoyl, trichloroacetyl, trifluoroacetyl, formyl, alkyl carbamates, aralkyl carbamates, or aryl carbamates.

21. The process of claim 17, wherein said oxygen protecting group is benzylcarbonate.

22. The process of claim 17, wherein said nitrogen protecting group is benzylcarbamate.

24. The process of claim 17, wherein R¹⁰ and R¹¹ are each 2,6-dimethylphenyl.

25. A process for preparing a compound of formula 136: