Novel, transient pro-drug forms of L-DOPA

• US 3,998,799 A
• Filed: 04/17/1975
• Issued: 12/21/1976
• Est. Priority Date: 11/02/1973
• Status: Expired due to Term

• Current Assignee: Interx Research Corporation
• Original Assignee: Interx Research Corporation
• Inventors: Hussain, Anwar A., Sloan, Kenneth B., Bodor, Nicolae S.
• Primary Examiner(s): Gotts, Lewis
• Assistant Examiner(s): Suyat, Reginald J.
• Application Number:
  US05/569,009
• Time in Patent Office: 614 Days
• Field of Search: 260/112.5 R, 424/177
• US Class Current: 560/251
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07D 213/55 Acids; Esters
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07K 5/06 Dipeptides
• CPC Class Codes: Y10S 930/29 Polyamino acid or polypeptide with an uninterrupted series of peptide repeating units

Abstract

There is provided, novel, transient pro-drug forms of L-DOPA (3,4-dihydroxy-L-phenylalanine), having the formula: ##STR1## wherein n represents an integer of from 2 to 50 with respect to formula (V-A), and wherein n represents an integer of from 1 to 50 with respect to formula (V-B);

R represents a hydrogen atom, an acyl group, ##STR2## --CO-pyridyl, or --CO--R₃, wherein R₃ is the residue of any N,N-C₁ -C₂ dialkylamino acid or a C₄ -C₆ cycloalkylamino acid; R₁ represents --OH, --O-lower alkyl, --O-benzyl, or a naturally occurring protein amino acid; and R₂ represents ##STR3## --CO-pyridyl, a naturally occurring protein amino acid, 3'"'"',4'"'"'-L-diacyloxy phenylalanine, or --CO-R₃.

These compounds are all useful in the treatment of Parkinson'"'"'s Disease.

Claims

1. A pro-drug compound of the formula:

##STR19## wherein R represents a hydrogen atom, an acyl group and a -CO-R₃ group, wherein R₃ represents the residue of any N,N-C₁ -C₂ dialkylamino acid or a C₄ -C₆ cycloalkylamino acid;

wherein R₁ represents a member selected from the group consisting of a hydroxyl group and a -OM group, wherein M is a member selected from the group consisting of an alkali metal and an ammonium ion; and

wherein R₂ represents a -CO-R₃ group, wherein R₃ represents the residue of any N,N-(C₁ -C₂)-dialkylamino acid or a C₄ -C₆ -cycloalkylamino acid;

##STR20## wherein R represents an acyl group;

wherein R₂ represents a hydrogen atom; and

wherein R₁ represents a -NHCH(R₄)COOR₅ group, wherein R₄ represents the residue of any naturally occurring protein amino acid, and wherein R₅ represents a member selected from the group consisting of a hydrogen atom, a C₁ -C₅ alkyl group, and a C₁ -C₅ alkylaryl group, and the HX salts thereof, wherein X is a conventional pharmaceutically acceptable acid addition salt anion;

##STR21## wherein R represents an acyl group;

wherein R₁ represents a member selected from the group consisting of a hydroxyl group, a -OCH₃ group, a -OC₂ H₅ group, a -OC₃ H₇ group, a -OC₄ H₉ group, and a -OCH₂ C₆ H₅ group; and

wherein R₂ represents an NH₂ CH(R₆)CO- group, wherein R₆ represents the residue of any naturally occurring protein amino acid, and the HX salts thereof, wherein X is defined as above;

##STR22## wherein R represents an acyl group;

wherein R₁ represents a member selected from the group consisting of a hydroxyl group, a -OCH₃ group, a -OC₂ H₅ group, a -OC₃ H₇ group, a -OC₄ H₉ group, and a -OCH₂ -C₆ H₅ group; and

wherein R₂ represents an NH₂ -CH(R₇)-CO- group, wherein R₇ represents the residue of a 3,4-diacylphenylalanine group having the formula;

##STR23## wherein R is defined as above, and the HX salts thereof, wherein X is as defined above; and

##STR24## wherein n represents an integer of from 2 to 50 with respect to formula (V-A), and wherein n represents an integer of from 1 to 50 with respect to formula (V-B).

2. The compound of claim 1:

Glycyl-3,4-diacetyloxy-L-phenylalanine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

3. The compound of claim 1:

Glycyl-3,4-diacetyloxy-L-phenylalanine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

4. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-glycine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

5. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-glycine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

6. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-glycine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

7. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-glycine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

8. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-glycine-benzyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

9. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-L-leucine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

10. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-L-leucine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

11. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-L-leucine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

12. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-L-leucine-benzyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

13. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-L-isoleucine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

14. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-L-isoleucine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

15. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-L-isoleucine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

16. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-L-isoleucine-benzyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

17. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-phenylalanine and its HX salt, wherein X represents pharmaceutically acceptable anion.

18. The compound of the claim 1:

3,4-diacetyloxy-L-phenylalanyl-phenylalanine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

19. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-phenylalanine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

20. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-phenylalanine-benzyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

21. The compound of claim 1:

Glycyl-3,4-diacetyloxy-L-phenylalanine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

22. The compound of claim 1:

Glycyl-3,4-dipivalyloxy-L-phenylalanine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

23. The compound of claim 1:

Glycyl-3,4-diacetyloxy-L-phenylalanine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

24. The compound of claim 1:

Glycyl-3,4-diacetyloxy-L-phenylalanine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

25. The compound of claim 1:

Glycyl-3,4-diacetyloxy-L-phenylalanine-benzyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

26. The compound of claim 1:

L-leucyl-3,4-diacetyloxy-L-phenylalanine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

27. The compound of claim 1:

L-leucyl-3,4-diacetyloxy-L-phenylalanine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

28. The compound of claim 1:

L-leucty-3,4-diacetyloxy-L-phenylalanine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

29. The compound of claim 1:

L-leucyl-3,4-diacetyloxy-L-phenylalanine-benzyl ester and its HX salt, wherein X represents a phramaceutically acceptable anion.

30. The compound of claim 1:

L-isoleucyl-3,4-diacetyloxy-L-phenylalanine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

31. The compound of claim 1:

L-isoleucyl-3,4-diacetyloxy-L-phenylalanine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

32. The compound of claim 1:

L-isoleucyl-3,4-diacetyloxy-L-phenylalanine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

33. The compound of claim 1:

L-isoleucyl-3,4-diacetyloxy-L-phenylalanine-benzyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

34. The compound of claim 1:

Phenylalanyl-3,4-diacetyloxy-L-phenylalanine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

35. The compound of claim 1:

Phenylalanyl-3,4-diacetyloxy-L-phenylalanine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

36. The compound of claim 1:

Phenylalanyl-3,4-diacetyloxy-L-phenylalanine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

37. The compound of claim 1:

Phenylalanyl-3,4-diacetyloxy-L-phenylalanine-benzyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

38. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-3,4-diacetyloxy-L- phenylalanine and its HX salt, wherein X represents a pharmaceutically acceptable anion.

39. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-3,4-diacetyloxy-L-phenylalanine-methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

40. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-3,4-diacetyloxy-L-phenylalanine-ethyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

41. The compound of claim 1:

3,4-diacetyloxy-L-phenylalanyl-3,4-diacetyloxy-L-phenylalanine-benzyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

42. The compound of claim 1:

##STR25## wherein n represents an integer of 7- 20.

43. The compound of claim 1:

Poly-3,4-diacetoxy-L-phenylalanine;

##STR26## wherein n represents an integer of 7 - 20.

44. The compound of claim 1:

N-[n,n-dimethylamino]-glycyl-3,4-dihydroxyl-L-phenylalanine and its M salt, wherein M represents an alkali metal.

45. The compound of claim 1:

N-[n,n-dimethylamino]-glycyl-3,4diacetyloxy-L-phenylalanine and its M salt, wherein M represents an alkali metal.

46. The compound of claim 1:

3,4-N,N-dimethylaminoglycyl-L-phenylalanine methyl ester and its HX salt, wherein X represents a pharmaceutically acceptable anion.

47. The compound of claim 1:

N-[n,n-dimethylamino]glycyl-3,4-[N,N-dimethylaminoglycyl]-L-phenylalanine and its M salt, wherein M represents an alkali metal.

48. The compound of claim 1:

N-[n,n-diethylaminoglycyl]-3,4-diacetyloxy-L-phenylalanine and its M salt, wherein M represents an alkali metal.

49. The compound of claim 1, wherein in formula (II), said C₁ -C₅ alkylaryl group is a member selected from the group consisting of a -CH₂ -C₆ H₅ group, and a -CH₂ -CH₂ -C₆ H₅ group.