CYCLOPAMINE ANALOGS

• US 20090216022A1
• Filed: 08/27/2008
• Published: 08/27/2009
• Est. Priority Date: 12/28/2006
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Behnke, Mark L., Grogan, Michael J., Castro, Alfredo C., Lescarbeau, Andre, Peluso, Stephane, Janardanannair, Somarajannair, Austad, Brian, Tremblay, Martin, Charette, Andre B.
• Granted Patent: US 8,669,365 B2
• Time in Patent Office: Days
• 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:

wherein

Y is CR⁷R⁸;

R¹ is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group;

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

or R¹ and R² taken together form ═

O, ═

S, ═

N(OR⁹), ═

N(R⁹), ═

C(R⁹)₂, or ═

N(N(R⁹)₂);

each of R³, R⁴, and R⁵ is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;

or R³ and R⁴ or R⁴ and R⁵ taken together form a bond;

R⁶ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —

OR⁹, —

C(O)R⁹, —

CO₂R⁹, —

SO₂R⁹, —

C(O)N(R⁹)(R⁹), —

[C(R⁹)₂]_qR⁹, —

[(W)—

N(R⁹)C(O)]_qR⁹, —

[(W)—

C(O)]_qR⁹, —

[(W)—

C(O)O]_qR⁹, —

[(W)—

OC(O)]_qR⁹, —

[(W)—

SO₂]_qR⁹, —

[(W)—

N(R⁹)SO₂]_qR⁹, —

[(W)—

C(O)N(R⁹)]_qR⁹, —

[(W)—

O]_qR⁹, —

[(W)—

N(R⁹)]_qR⁹, —

[(W)—

S]_qR⁹, or a nitrogen protecting group;

each W independently for each occurrence is a diradical;

each q is independently 1, 2, 3, 4, 5, or 6;

each of R⁷ and R⁸ is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and

each R⁹ is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;

said process comprising the steps of;

contacting a compound of formula 136a with a haloalkylzinc phosphate cyclopropanating agent;

wherein R¹, R², R³, R⁴, R⁵, R⁶ are as defined above;

to form said 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, where said haloalkylzinc phosphate cyclopropanating agent is formed by combining a phosphoric acid of formula 141a, a dialkylzinc, and a dihaloalkylane of formula 141b:

wherein

each of X and X′

is independently chloride, bromide, or iodide;

each of R⁷ and R⁸ is independently H, alkyl, halide, amido, or ester; and

each of R¹⁰ and R¹¹ is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl;

or R¹⁰ and R¹¹ taken together have the formula 141c, 141d, or 141e;

wherein

m independently for each occurrence is 0, 1, 2, 3, or 4;

n independently for each occurrence is 0, 1, or 2; and

each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is, independently, alkyl, aryl, aralkyl, or halide.

6. The process of claim 5, wherein R¹⁰ and R¹¹ are each 2,6-dimethylphenyl.

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

wherein

Y is CR⁷R⁸;

R¹ is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group;

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

or R¹ and R² taken together form ═

O, ═

S, ═

N(OR⁹), ═

N(R⁹), ═

C(R⁹)₂, or ═

N(N(R⁹)₂);

each of R³, R⁴, and R⁵ is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;

or R³ and R⁴ or R⁴ and R⁵ taken together form a bond;

R⁶ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —

OR⁹, —

C(O)R⁹, —

CO₂R⁹, —

SO₂R⁹, —

C(O)N(R⁹)(R⁹), —

[C(R⁹)₂]_qR⁹, —

[(W)—

N(R⁹)C(O)]_qR⁹, —

[(W)—

C(O)]_qR⁹, —

[(W)—

C(O)O]_qR⁹, —

[(W)—

OC(O)]_qR⁹, —

[(W)—

SO₂]_qR⁹, —

[(W)—

N(R⁹)SO₂]_qR⁹, —

[(W)—

C(O)N(R⁹)]_qR⁹, —

[(W)—

O]_qR⁹, —

[(W)—

N(R⁹)]_qR⁹, —

[(W)—

S]_qR⁹, or a nitrogen protecting group;

each W independently for each occurrence is a diradical alkylene having 1-6 carbon atoms;

each q is independently 1, 2, 3, 4, 5, or 6;

each of R⁷ and R⁸ is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and

each R⁹ is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;

said process comprising the steps of;

contacting a compound of formula 137a with a haloalkylzinc phosphate cyclopropanating agent;

wherein

R¹, R², R³, R⁴, R⁵, R⁶ are as defined above;

to form a compound with formula 137b;

wherein

R¹, R², R³, R⁴, R⁵, R⁶ and Y are as defined above; and

contacting said compound of formula 137b with an acid to give said compound of formula 137.

8. A process for preparing a compound of formula 142:

comprising the steps of;

contacting a compound of formula 142a with a cyclopropanating agent to form a compound formula 142b;

and combining said compound of formula 142b with an acid to give said compound of formula 142;

wherein

Y is CR⁷R⁸;

R¹ is a protected hydroxyl group;

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

each of R³, R⁴, and R⁵ is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;

or R³ and R⁴, or R⁴ and R⁵ taken together form a bond;

R⁶ is a nitrogen protecting group;

each of R⁷ and R⁸ is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and

each R⁹ is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl.

9. The process of claim 8, wherein R⁷ and R⁸ are both H.

10. The process of claim 8, wherein said protected hydroxyl group is an ester or a carbonate.

11. The process of claim 8, wherein said nitrogen protecting group is a carbamate.

12. The process of claim 8, wherein said nitrogen protecting group is an amide.

13. The process of claim 8, wherein R² and R³ are H and R⁴ and R⁵ taken together form a bond.

14. The process of claim 8, wherein said cyclopropanating agent is generated from a dihaloalkane and a metal species.

15. The process of claim 14, wherein said metal species is dialkyl zinc or a zinc copper couple.

16. The process of claim 8, wherein said cyclopropanating agent is generated from a dihaloalkane species and a dialkyl zinc species, and a phosphoric acid species or a salt thereof.

17. The process of claim 8, wherein said phosphoric acid species has a structure of formula 151:

or a salt thereof;

wherein

each of R¹⁰ and R¹¹ is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl;

or R¹⁰ and R¹¹ taken together have the formula 151a, 151b, or 151c;

wherein

m independently for each occurrence is 0, 1, 2, 3, or 4;

n independently for each occurrence is 0, 1, or 2; and

each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is, independently, alkyl, aryl, aralkyl, or halide.

18. The process of claim 8, wherein said acid is acetic acid, trifluoromethanesulfonic acid, phosphoric acid, methanesulfonic acid or HCl.

19. The process of claim 8, wherein said acid is BF₃, zinc chloride, zinc methanesulfonate, or a zinc salt.

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

comprising the steps of;

contacting a compound of formula 156a with a cyclopropanating agent to form a compound formula 156b;

and combining said compound of formula 156b with an acid to give said compound of formula 156;

wherein

R¹ is an oxygen protecting group selected from the group consisting of formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, pivaloate, benzoates, alkyl carbonate, alkenyl carbonate, aryl carbonates, aralkyl carbonate, 2,2,2-trichloroethyl carbonate, alkoxymethyl ether, aralkoxymethyl ether, alkylthiomethyl ether, aralkylthio ether, arylthio ether, trialkylsilyl ether, alkylarylsilyl ether, benzyl ether, arylmethyl ether, allyl ether; and

R² is a nitrogen protecting group selected from the group consisted of formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phenyl acetyl, benzoyl, alkyl carbamates, aralkyl carbamates, aryl carbamates, allyl, aralkyl, triarylmethyl, alkoxymethyl, aralkoxymethyl, N-2-cyanoethyl, diarylphosphinamides, dialkylphosphinamidates, diarylphosphinamidates, and trialkylsilyl.

21. The process of claim 20, where said cyclopropanating agent is formed by combining a phosphoric acid of formula 158a, a dialkylzinc, and a dihaloalkylane of formula 157b:

wherein

each of X and X′

is, independently, chloride, bromide, or iodide;

each of R⁷ and R⁸ is, independently, H, alkyl, halide, amido, or ester; and

each of R¹⁰ and R¹¹ is, independently, alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl;

or R¹⁰ and R¹¹ taken together have the formula 158c, 158d, or 158e;

wherein

m independently for each occurrence is 0, 1, 2, 3, or 4;

n independently for each occurrence is 0, 1, or 2; and

each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is, independently, alkyl, aryl, aralkyl, or halide.

22. The process of claim 21, wherein said oxygen protecting group is alkyl carbonate, aralkyl carbonate, benzoate, pivaloate, or formate.

23. The process of claim 21, wherein said nitrogen protecting group is benzoyl, trichloroacetyl, trifluoroacetyl, formyl, alkyl carbamates, aralkyl carbamates, or aryl carbamates.

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

25. The process of claim 21, wherein said nitrogen protecting group is benzylcarbamate.