Cyclopamine analogs

Patent metadata

Field	Value
Publication number	US-9951083-B2
Application number	US-201615289887-A
Country	US
Kind code	B2
Filing date	Oct 10, 2016
Priority date	Dec 28, 2006
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The invention provides derivatives of cyclopamine having the following formula:

First claim

It is claimed:

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

wherein
Y is CR 7 R 8 ;
R 1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group; R 2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 1 and R 2 taken together form ═O, ═S, ═N(OR 9 ), ═N(R 9 ), ═C(R 9 ) 2 , or ═N(N(R 9 ) 2 );
each of R 3 , R 4 , and R 5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 3 and R 4 or R 4 and R 5 taken together form a bond;
R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 9 , —C(O)R 9 , —CO 2 R 9 , —SO 2 R 9 , —C(O)N(R 9 )(R 9 ), —[C(R 9 ) 2 ] q R 9 , —[(W)—N(R 9 )C(O)] q R 9 , —[(W)—C(O)]R 9 , —[(W)—C(O)O] q R 9 , —[(W)—OC(O)] q R 9 , —[(W)—SO 2 ] q R 9 , —[(W)—N(R 9 )SO 2 ] q R 9 , —[(W)—C(O)N(R 9 )] q R 9 , —[(W)—O] q R 9 , —[(W)—N(R 9 )] q R 9 , —[(W)—S] q R 9 , 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 R 7 and R 8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and
each R 9 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 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined above;
to form said compound of formula 136;
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 R 7 and R 8 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R 10 and R 11 taken together have the formula 141c or 141d;

wherein
m independently for each occurrence is 0, 1, 2, 3, or 4; and
each of R 12 , R 13 , and R 14 , is, independently, alkyl, aryl, aralkyl, or halide.

2. The process of claim 1 , wherein R 7 and R 8 are both H.

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

4. The process of claim 1 , wherein R 6 is a nitrogen protecting group.

5. The process of claim 1 wherein R 10 and R 11 are each 2,6-dimethylphenyl.

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

wherein
Y is CR 7 R 8 ;
R 1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group; R 2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 1 and R 2 taken together form ═O, ═S, ═N(OR 9 ), ═N(R 9 ), ═C(R 9 ) 2 , or ═N(N(R 9 ) 2 );
each of R 3 , R 4 , and R 5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 3 and R 4 or R 4 and R 5 taken together form a bond;
R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 9 , —C(O)R 9 , —CO 2 R 9 , —SO 2 R 9 , —C(O)N(R 9 )(R 9 ), —[C(R 9 ) 2 ] q R 9 , —[(W)—N(R 9 )C(O)] q R 9 , —[(W)—C(O)] q R 9 , —[(W)—C(O)O] q R 9 , —[(W)—OC(O)] q R 9 , —[(W)—SO 2 ] q R 9 , —[(W)—N(R 9 )SO 2 ] q R 9 , —[(W)—C(O)N(R 9 )] q R 9 , —[(W)—O] q R 9 , —[(W)—N(R 9 )] q R 9 , —[(W)—S] q R 9 , 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 R 7 and R 8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester;
each R 9 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
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined above;
to form a compound with formula 137b

wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined above; and
contacting said compound of formula 137b with an acid to give said compound of formula 137;
where said haloalkylzinc phosphate cyclopropanating agent is formed by combining a phosphoric acid formula 141a, a dialkylzinc, and a dihaloalkylane of formula 141b:

wherein
each of X and X′ is independently chloride, bromide, or iodide;
each of R 7 and R 8 is independently H, alkyl, halide, amido, or ester;
each of R 10 and R 11 is independently alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R 10 and R 11 taken together have the formula 141c or 141d;

wherein
m independently for each occurrence is 0, 1, 2, 3, or 4; and
each of R 12 , R 13 , and R 14 , is, independently, alkyl, aryl, arakyl, or halide.

7. The process of claim 6 ,
wherein
R 1 is a protected hydroxyl group;
R 2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; and
R 6 is a nitrogen protecting group.

8. The process of claim 6 wherein R 7 and R 8 are both H.

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

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

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

12. The process of claim 6 , wherein R 2 and R 3 are H and R 4 and R 5 taken together form a bond.

13. The process of claim 6 , wherein said acid is acetic acid, trifluoromethanesulfonic acid, phosphoric acid, methanesulfonic acid or HCl.

14. The process of claim 6 , wherein said acid is BF 3 , zinc chloride, zinc methanesulfonate, or a zinc salt.

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

comprising the steps of:
contacting a compound of formula 156a with a haloalkylzinc phosphate cyclopropanating agent to form a compound formula 156b;

and combining said c

Assignees

• Infinity Pharmaceuticals Inc

Inventors

• Austad Brian
• Behnke Mark L
• Castro Alfredo C
• Grogan Michael J
• Janardanannair Somarajannair
• Lescarbeau Andre
• Peluso Stephane
• Charette Andre B
• Tremblay Martin R

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D491/04

  Ortho-condensed systems · CPC title