Enzymatic transamination of cyclopamine analogs

• US 8,703,448 B2
• Filed: 07/01/2011
• Issued: 04/22/2014
• Est. Priority Date: 08/05/2009
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Austad, Brian C., Bahadoor, Adilah, Belani, Jitendra D., Janardanannair, Somarajannair, Johannes, Charles W., Keaney, Gregg F., White, Priscilla L., Wallerstein, Sheldon L.
• Primary Examiner(s): HANLEY, SUSAN MARIE
• Application Number:
  US13/175,053
• Publication Number:
  US 20120083607A1
• Time in Patent Office: 1,026 Days
• Field of Search: 435/119, 435/193, 546/15
• US Class Current: 435/119
• 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: C12P 17/18 containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin e.g. Rifamycin C12P17/189

Abstract

The invention relates to the preparation of amino-cyclopamines by the enzymatic transamination of a corresponding keto-cyclopamines in the presence of a cofactor and an amino donor.

Claims

1. A process for preparing a compound of formula (II):

2. The process according to claim 1, wherein the co-factor is pyridoxal phosphate (PLP).

3. The process according to claim 1, wherein the co-factor is a co-enzyme.

4. The process according to claim 3, wherein the co-enzyme is selected from L-alanine dehydrogenase (LADH), lactate dehydrogenase (LDH), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD), formate dehydrogenase (FDH), and glucose dehydrogenase (GDH).

5. The process according to claim 1, wherein the process further comprises adding a pyruvate reductase mix to the solution.

6. The process according to claim 1, wherein the enzyme preferentially generates a compound of formula (II) or a salt thereof wherein the newly-formed amino group has (R) stereochemistry or (S) stereochemistry.

7. The process according to claim 1, wherein the enzyme preferentially generates an enantiomerically pure compound of formula (II) or salt thereof.

8. The process according to claim 1, wherein the enzyme is an omega amine transaminase, a broad-range transaminase, a glutamate-pyruvate transaminase or a glutamate-oxaloacetic transaminase.

9. The process according to claim 8, wherein the enzyme is an omega amine transaminase.

10. The process according to claim 9, wherein the omega amine transaminase is selected from the group consisting of ATA-101, ATA-102, ATA-103, ATA-104, ATA-105, ATA-106, ATA-107, ATA-108, ATA-109, ATA-110, ATA-113, ATA-114, ATA-115, ATA-116, ATA-117, ATA-124, an omega amine transaminase from Chromobacterium violaceum, an omega amine transaminase from Alcaligenes denitrificans, an omega amine transaminase from Arthrobactercitreus, an omega amine transaminase from Klebsiella pneumoniae, an omega amine transaminase from Bacillus thuringiensis, an omega amine transaminase from Bacillus cereus, and an omega amine transaminase from Vibrio fluvialis.

11. The process according to claim 1, wherein the amino donor molecule is an amine or salt thereof.

12. The process according to claim 1, wherein the amino donor molecule is an amino acid, a polypeptide and/or a salt thereof.

13. The process according to claim 1, wherein the amino donor molecule is selected from pyridoxamine, methylbenzylamine, 2-aminobutane, propyl amine, isopropyl amine, 1,1,1-trifluoropropan-2-amine, 1,1,1,3,3,3-hexafluoropropan-2-amine, benzyl amine, 2-amino-1-butanol, 1-amino-1-phenylethane, 1-amino-1-(2-methoxy-5-fluorophenyl)ethane, 1-amino-1-phenylpropane, 1-amino-1-(4-hydroxyphenyl)propane, 1-amino-1-(4-bromophenyl)propane, 1-amino-1-(4-nitrophenyl)propane, 1-phenyl-2-aminopropane, 1-(3-trifluoromethylphenyl)-2-aminopropane, 2-aminopropanol, 1-amino-1-phenylbutane, 1-phenyl-2-aminobutane, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminobutane, 1-phenyl-3-aminobutane, 1-(4-hydroxyphenyl)-3-aminobutane, 1-amino-1-(2-naphthyl)ethane, cis-2-methylcyclopentanamine, trans-2-methylcyclopentanamine, cis-3-methylcyclopentanamine, trans-3-methylcyclopentanamine, cis-2-ethylcyclopentanamine, trans-2-ethylcyclopentanamine, cis-3-ethylcyclopentanamine, trans-3-ethylcyclopentanamine, cis-2-methylcyclohexanamine, trans-2-methylcyclohexanamine, cis-3-methylcyclohexanamine, trans-3-methylcyclohexanamine, cis-2-ethylcyclohexanamine, trans-2-ethylcyclohexanamine, cis-3-ethylcyclohexanamine, trans-3-ethylcyclohexanamine, 1-aminotetralin, 2-aminotetralin, 2-amino-5-methoxytetralin, 1-aminoindane, 2-aminoindane, 2-amino-1-propanol, cis-1-amino-2-indanol, trans-1-amino-2-indanol, 1-amino-6-hydroxyindanamine, taurine, and salts thereof.

14. The process according to claim 1, wherein the amino donor molecule is selected from glycine, alanine, aspartic acid, phenylalanine, 2-aminopentanedioic acid, 3-aminobutyrate, γ

-aminobutyrate, β

-alanine, asparagine, cysteine, glutamic acid, glutamine, proline, selenocysteine, serine, tyrosine, arginine, histidine, ornithine, isoleucine, leucine, lysine, methionine, threonine, tryptophan, valine, and polypeptides thereof and/or salts thereof.

15. The process according to claim 1, wherein the amino donor molecule is a chiral amino donor molecule.

16. The process according to claim 1, wherein the solution is a buffered solution.

17. The process according to claim 1, wherein the pH of the solution is between about 5 and about 9.

18. The process according to claim 1, wherein R¹ is H, aralkyl or —

CO₂R¹⁶.

19. The process according to claim 1, wherein R² and R³ taken together form a double bond or form a group:

20. The process according to claim 1, wherein R² and R³ taken together form a double bond.

21. The process according to claim 1, wherein X is a bond.

22. The process according to claim 1, wherein X is the group —

C(R¹⁹)₂—

.

23. The process according to claim 1, wherein R⁴ is H.

24. The process according to claim 1, wherein each of R⁵ and R⁶ is independently H, or R⁵ and R⁶ taken together with the carbon to which they are bonded form C═

O.

25. The process according to claim 1, wherein R⁷ and R⁸ are each H.

26. The process according to claim 1, wherein R⁹ and R¹⁰ are each H.

27. The process according to claim 1, wherein R¹¹ is a H.

28. The process according to claim 1, wherein R¹² and R¹³ are each H.

29. The process according to claim 1, wherein R⁹ is H and R¹⁰ and R¹¹ taken together form a double bond.

30. The process according to claim 1, wherein R¹³ is H, and R¹¹ and R¹² taken together form a double bond.

31. The process according to claim 1, wherein each of R⁹, R¹⁰, R¹¹, R¹² and R¹³ is H.

32. The process according to claim 1, wherein R¹⁴ and R¹⁵ are each H.

33. The process according to claim 1, wherein the compound of formula (I) or a salt thereof and a compound of formula (II) or a salt thereof are selected from the compounds provided in Tables 1, 2, 3, 4 or 5.

34. The process according to claim 1, wherein the compound of formula (I) is a compound of formula (I-a):

35. The process according to claim 1, further comprising contacting a compound of formula (II) or a salt thereof with a sulfonylating agent to provide a compound of formula (III):

36. The process according to claim 35, wherein the sulfonylating agent is selected from benzenesulfonyl chloride, benzenesulfonyl anhydride, p-toluenesulfonyl chloride, p-toluenesulfonyl anhydride, methanesulfonyl chloride, and methanesulfonyl anhydride.

37. The process according to claim 36, wherein the sulfonylating agent is methanesulfonyl chloride or methanesulfonyl anhydride, and R²³ is —

CH₃.