(S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, and related compounds as GABA aminotransferase inactivators for the treatment of epilepsy, addiction and hepatocellular carcinoma

Patent metadata

Field	Value
Publication number	US-9670141-B2
Application number	US-201615289480-A
Country	US
Kind code	B2
Filing date	Oct 10, 2016
Priority date	Oct 9, 2015
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

Cyclopentene carboxylic acid-related compounds as GABA-AT inhibitors for treatment of various addictions, disorders and disease states.

First claim

We claim:

1. A compound of a formula

wherein each of R 1 and R 2 is independently selected from H, F, Cl, Br and I, providing at least one of R 1 and R 2 is not H, or a salt thereof.

2. The compound of claim 1 wherein said amino substituent has an (S) stereochemical configuration.

3. The compound of claim 2 wherein at least one of R 1 and R 2 is F.

4. The compound of claim 1 wherein said compound is a salt comprising a substituent selected from an ammonio substituent, a carboxylate substituent and a combination thereof.

5. The compound of claim 4 , wherein the salt is an ammonium salt and said ammonium salt has a counter ion that is the conjugate base of a protic acid.

6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically-acceptable carrier component.

7. A compound of a formula

wherein each of R 1 and R 2 is independently selected from H and F, provided at least one of R 1 and R 2 is F, or a salt thereof.

8. The compound of claim 7 wherein each of R 1 and R 2 is F.

9. The compound of claim 7 wherein said compound is a salt comprising a substituent selected from an ammonio substituent, a carboxylate substituent and a combination thereof.

10. The compound of claim 9 wherein the salt is an ammonium salt and said ammonium salt has a counter ion that is the conjugate base of a protic acid.

11. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically-acceptable carrier component.

12. A method of modulating GABA-AT activity, said method comprising:
providing a compound of a formula

wherein each of R 1 and R 2 is independently selected from H, F, Cl, Br and I, providing at least one of R 1 and R 2 is not H, or a salt thereof; and
contacting said compound with a medium comprising a γ-aminobutyric acid aminotransferase, said compound in an amount sufficient to modulate γ-aminobutyric acid aminotransferase activity.

13. The method of claim 12 wherein at least one of R 1 and R 2 is F.

14. The method of claim 12 wherein said compound is a salt comprising a substituent selected from an ammonio substituent, a carboxylate substituent and a combination thereof.

15. The method of claim 14 wherein the salt is an ammonium salt and said ammonium salt has a counter ion that is the conjugate base of a protic acid.

16. The method of claim 12 wherein said contact is in vivo.

17. A method of modulating dopamine levels responsive to ingestion of an addictive substance, said method comprising:
providing a compound of claim 7 ; and
contacting said compound with a cellular medium comprising a γ-aminobutyric acid aminotransferase, said compound in an amount sufficient to modulate dopamine levels responsive to ingestion of an addictive substance, thereby increasing γ-aminobutyric acid levels in said medium.

18. The method of claim 17 wherein each of R 1 and R 2 is F.

19. The method of claim 17 wherein said compound is a salt comprising a substituent selected from an ammonio substituent, a carboxylate substituent and a combination thereof.

20. The method of claim 19 wherein the salt is an ammonium salt and said ammonium salt has a counter ion that is the conjugate base of a protic acid.

21. The method of claim 17 wherein said contact is with a mammalian subject comprising said cellular medium.

22. The method of claim 21 providing treatment of excessive dopamine release in a mammalian subject in need thereof.

23. A method for treatment of substance addiction, said method comprising administering to a mammalian subject in need thereof a compound of claim 7 , said compound in an amount sufficient to increase γ-aminobutyric acid levels and modulate dopamine levels in the hippocampus of said subject, thereby reducing glucose metabolism in said hippocampus.

24. The method of claim 23 wherein each of R 1 and R 2 is F.

25. The method of claim 23 wherein said compound is a salt comprising a substituent selected from an ammonio substituent, a carboxylate substituent and a combination thereof.

26. The method of claim 25 wherein the salt is an ammonium salt and said ammonium salt has a counter ion that is the conjugate base of a protic acid.

27. The method of claim 23 providing treatment of said subject for at least one of cocaine, heroin, alcohol, barbiturates, amphetamines, cannabis, methadone, opioids, stimulants and nicotine addiction.

28. A method of modulating ornithine aminotransferase activity, said method comprising:
providing a compound of a formula

wherein each of R 1 and R 2 is independently selected from H, F, Cl and Br, providing at least one of R 1 and R 2 is not H, or a salt thereof; and
contacting said compound with a medium comprising an ornithine aminotransferase, said compound in an amount sufficient to modulate ornithine aminotransferase activity.

29. The method of claim 28 wherein at least one of R 1 and R 2 is F.

30. The method of claim 28 wherein said compound is a salt comprising a substituent selected from an ammonio substituent, a carboxylate substituent and a combination thereof.

31. The method of claim 30 wherein the salt is an ammonium salt and said ammonium salt has a counter ion that is the conjugate base of a protic acid.

32. The method of claim 28 wherein said contact is in vivo.

33. A method of reducing activity of an ornithine aminotransferase expressed by a human hepatocellular carcinoma, said method comprising:
providing a compound of a formula

wherein R 1 and R 2 are selected from H and F, and at least one of R 1 and R 2 is F; or a salt thereof; and
contacting a cellular medium comprising a hepatocellular carcinoma expressing an ornithine aminotransferase with an amount of said compound effective to reduce ornithine aminotransferase activity, thereby reducing glutamate production in said cellular medium.

34. The method of claim 33 wherein each of R1 and R2 is F.

35. The method of claim 34 wherein said compound is provided in a pharmaceutical composition.

36. The method of claim 34 wherein such contact is in vivo.

37. The method of claim 36 wherein said contact is with a human subject in need thereof.

38. A method for treatment of psychological and neurological disorders, said method comprising administering to a mammalian subject in need thereof a compound of claim 7 , said compound in an amount sufficient to increase γ-aminobutyric acid levels in said subject.

39. The method of claim 38 wherein said neurological disorder is selected from epilepsy, partial seizures, complex partial seizures, secondary generalized seizures, tonic-clonic seizures, succinic semi

Assignees

• Univ Northwestern

Inventors

• Silverman Richard B
• Takaya Kenji
• Le Hoang V
• Juncosa Jose I

Classifications

• A61P25/06

  Antimigraine agents · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/36

  Opioid-abuse · CPC title