Methods for treatment of conditions associated with lactosylceramide

• US 5,972,928 A
• Filed: 12/24/1997
• Issued: 10/26/1999
• Est. Priority Date: 05/21/1997
• Status: Expired due to Term

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Chatterjee, Subroto
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): SACKEY, EBENEZER O
• Application Number:
  US08/998,262
• Time in Patent Office: 671 Days
• Field of Search: 514/625, 514/627, 514/237.8, 514/331, 514/428, 514/238.2, 514/212
• US Class Current: 514/217.12
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention includes methods for treatment and prophylaxis of diseases, post-surgical disorders and bacterial infections associated with lactosylceramide. The methods generally provide for administration for a mammal, particularly a human, of a therapeutically effective amount of a compound that inhibits UDPGal:GlcCerβ1->4 galactosylceramide (GalT-2). In vitro and in vivo assays for detecting compounds with therapeutic capacity to modulate GalT-2 are also provided.

Claims

1. A method for treating a disease, post-surgical disorder, or bacterial infection modulated by lactosylceramide in a mammal suffering from or susceptible to the disease, post-surgical disorder, or bacterial infection, the method comprising administering to the mammal a therapeutically effective amount of a compound represented by the following Formula I:

##STR3## wherein R and R¹ are independently selected from the group consisting of hydrogen and straight-chained or branched C₁ -C₆ alkyl with or without a substituent, and further wherein R and R¹ may be joined to form a 5, 6 or 7-membered ring;

R² is branched or straight-chained C₆ -C₃₀ alkyl with or without one to three double bonds; and

R³ is selected from the group consisting of straight-chained or branched C₆ -C₃₀ alkyl with or without one to three double bonds and aryl or substituted aryl where the substituent is halo, C₁ -C₄ alkoxy, methlenedioxy, C₁ -C₄ mercapto, amino or substituted amino in which the amino substituent may be C₁ -C₄ alkyl.

2. The method of claim 1 wherein the disease or post-surgical disorder is accompanied by unwanted cell proliferation.

3. The method of claim 1 or 2 wherein the disease is atherosclerosis or polycystic kidney disease.

4. The method of claim 1 wherein the disease is an inflammatory disease involving a proinflammatory cytokine.

5. The method of claim 4 wherein the proinflammatory cytokine is TNF-α

or IL-6.

6. The method of claim 1 wherein the mammal is suffering from or susceptible to neovascularization.

7. The method of claim 1 wherein the mammal is suffering from or susceptible to post-surgical keloid formation.

8. The method of claim 1 wherein the mammal is suffering from or susceptible to undesired restenosis.

9. The method of claim 1 wherein the mammal is suffering from or susceptible to undesired restenosis associated with angioplasty.

10. The method of claim 9 wherein the angioplasty is balloon angioplasty.

11. The method of claim 1 wherein the mammal is suffering from or susceptible to a lipid storage disease.

12. The method of claim 11 wherein the lipid storage disease is Gaucher'"'"'s disease.

21. The method of any one of claims 1-20 wherein the compound inhibits cell proliferation by at least 25% in a standard in vitro cell proliferation assay.

22. The method of any one of claims 1-20 wherein the compound inhibits cell adhesion by at least 25% in a standard in vitro cell adhesion assay.

24. The method of any one of claims 1-20 wherein the compound is represented by the following Formula I:

##STR4## wherein R and R¹ are independently selected from the group consisting of hydrogen and straight-chained or branched C₁ -C₆ alkyl with or without a substituent, and further wherein R and R¹ may be joined to form a 5, 6 or 7-membered ring;

R² is selected from the group consisting of branched or straight-chained C₆ -C₃₀ alkyl with or without one to three double bonds; and

R³ is selected from the group consisting of straight-chained or branched C₆ -C₂₀ alkyl with or without one to three double bonds and aryl or substituted aryl where the substituent is halo, C₁ -C₄ alkoxy, methylenedioxy, C₁ -C₄ mercapto, amino or substituted amino in which the amino substituent may be C₁ -C₄ alkyl.

25. The method of claim 24 wherein R and R¹ are joined to form a 5, 6 or 7-membered ring.

26. The method of claim 25 wherein R and R¹ are joined to form a pyrrolidino, morpholino, thiomorpholino, piperidino or azacycloheptyl ring.

27. The method of any one of claims 1-20 wherein the compound is selected from the group consisting of:

1-phenyl-2-decanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-piperdino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol;

1-morpholino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene; and

1-pyrrolidino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene.

28. The method of any one of claims 1-20 wherein the compound is (1R, 2R)-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) or trans-(2R, 3R)-1-pyrrolidino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene.

33. The method of claim 1 wherein R and R¹ are joined to form a 5, 6 or 7-membered ring.

34. The method of claim 1 wherein R and R¹ are joined to form a pyrrolidino, morpholino, thiomorpholino, piperidino or azacycloheptyl ring.

13. A method for reducing restenosis following angioplasty in a mammal, comprising performing an angioplasty surgical procedure and administering a GalT-2 inhibitor compound to the mammal in an amount sufficient to reduce the restenosis.

14. The method of claim 13 wherein the angioplasty procedure is a balloon angioplasty.

15. The method of claim 13 wherein a GalT-2 inhibitor compound is administered to the mammal prior to performing the angioplasty procedure.

16. The method of claim 13 wherein a GalT-2 inhibitor compound is administered to the mammal by a stent.

17. The method of claim 13 wherein a GalT-2 inhibitor compound is administered to the mammal orally, intramuscularly or intraperitoneally.

23. The method of any one of claims 13-20 wherein the compound exhibits an IC₅₀ of about 100 μ

m or less in a standard in vitro GalT-2 inhibition assay.

18. A method for treating a mammal suffering from or susceptible to a atherosclerosis, neovascularization, polycystic kidney disease or post-surgical keloid, comprising to the mammal a therapeutically effective amount of a GalT-2 inhibitor compound.

19. A method for treating a mammal suffering from or susceptible to a lipid storage disease, comprising to the mammal a therapeutically effective amount of a GalT-2 inhibitor compound.

20. The method of claim 19 wherein the lipid storage disease is Gaucher'"'"'s disease.

29. A method for treating a mammal suffering from or susceptible to undesired cell proliferation, atherosclerosis, post-surgical disorder, bacterial infection, neovascularization, polycystic kidney disease, post-surgical disorder, lipid storage disease or an inflammatory disease involving a proinflammatory cytokine, comprising administering to the mammal a therapeutically effective amount of a compound of the following Formula I:

##STR5## wherein R and R¹ are independently selected from the group consisting of hydrogen and straight-chained or branched C₁ -C₆ alkyl with or without a substituent, and further wherein R and R¹ may be joined to form a 5, 6 or 7-membered ring;

R² is selected from the group consisting of branched or straight-chained C₆ -C₃₀ alkyl with or without one to three double bonds; and

R³ is selected from the group consisting of straight-chained or branched C₆ -C₂₀ alkyl with or without one to three double bonds and aryl or substituted aryl where the substituent is halo, C₁ -C₄ alkoxy, methylenedioxy, C₁ -C₄ mercapto, amino or substituted amino in which the amino substituent may be C₁ -C₄ alkyl.

30. The method of claim 29 wherein R and R¹ are joined to form a 5, 6 or 7-membered ring.

31. The method of claim 30 wherein R and R¹ are joined to form a pyrrolidino, morpholino, thiomorpholino, piperidino or azacycloheptyl ring.

32. The method of claim 29 wherein the compound is selected from the group consisting of:

1-phenyl-2-decanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-piperidino-1-propanol;

1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol;

1-morpholino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene;

1-pyrrolidino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene;

(1R,2R)-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP); and

trans-(2R,3R)-1-pyrrolidino-2-hexadecanoylamino-3-hydroxyoctadec-4,5-ene.