Methods and Compositions for the Enzymatic Synthesis of Gangliosides

• US 20070275908A1
• Filed: 03/04/2004
• Published: 11/29/2007
• Est. Priority Date: 03/06/2003
• Status: Active Grant

• Current Assignee: La Jolla Pharmaceutical Company (Innoviva, Inc.)
• Original Assignee: Neose Technologies, Inc.
• Inventors: Wang, Zhi-Guang, Johnson, Karl, Defrees, Shawn
• Granted Patent: US 7,888,331 B2
• Time in Patent Office: Days
• US Class Current: 514/25
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07H 15/00 : Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
• CPC Class Codes: C07H 15/10 : containing unsaturated carbon-to-carbon bonds
• CPC Class Codes: C07H 15/18 : Acyclic radicals, substituted by carbocyclic rings
• CPC Class Codes: C07H 15/26 : Acyclic or carbocyclic radicals, substituted by hetero rings

Abstract

Novel synthetic glycosphingolipids and pharmaceutical compositions containing such synthetic glycosphingolipids are described. Methods of making the novel synthetic glycosphingolipid compounds and compositions as well as their use in the field of neuroprotection and cancer treatment is also described.

Claims

1. A compound having the formula:

2. The compound according to claim 1, with the proviso that when X is NHR⁴, in which R⁴ is a member selected from H and —

C(═

O)R⁵, in which R⁵ is substituted or unsubstituted alkyl;

Y is OH; and

Z is O, R⁵ is other than a member selected from substituted or unsubstituted alkyl.

3. The compound according to claim 1, wherein R¹ has the formula:

4. The compound according to claim 3, wherein R¹³ is a member selected from substituted or unsubstituted heteroaryl wherein said heteroaryl comprises at least one endocyclic nitrogen atom.

5. The compound according to claim 4, wherein R¹³ is substituted or unsubstituted pyridyl.

6. The compound according to claim 3, wherein R¹³ is —

C(O)NR^13aR^13b, wherein

R^13a and R^13b are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.

7. The compound according to claim 3, wherein R¹¹ is NR^11aR^11b in which

R^11a and R^11b are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

8. The compound according to claim 1, wherein R¹ has the formula:

9. The compound according to claim 8, wherein R¹³ is a member selected from substituted or unsubstituted heteroaryl wherein said heteroaryl comprises at least one endocyclic nitrogen atom.

10. The compound according to claim 9, wherein R¹³ is substituted or unsubstituted pyridyl.

11. The compound according to claim 8, wherein R¹³ is —

C(O)NR^13aR^13b, wherein

R^13a and R^13b are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.

12. The compound according to claim 8, wherein R¹¹ is NR^11aR^11b in which

R^11a and R^11b are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

13. A compound according to claim 1, wherein R¹ has the formula:

14. The compound according to claim 3, wherein R⁵ is CH₃.

15. The compound according to claim 1, wherein the saccharide has a formula that is selected from the group consisting of:

16. The compound according to claim 1, wherein the saccharide is deacetylated.

17. The compound according to claim 1, having a formula which is a member selected from FIG. 16.

18. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

19. A method for the prevention or treatment of a disorder of the nervous system in an animal or human comprising the step of administering to an animal or human in need thereof a therapeutically effective amount of the compound of claim 1.

20. The method of claim 19, wherein said disorder of the nervous system is selected from the group consisting of Parkinson'"'"'s disease, ischemia, stroke, Alzheimer'"'"'s disease, depression, anxiety, encephalitis, meningitis, amyotrophic lateral sclerosis, trauma, spinal cord injury, nerve injury, neuropathy and nerve regeneration.

21. A method for the treatment of a glioma in a human comprising the step of administering to the human in need thereof a therapeutically effective amount of the compound claim 1.

22. A method of synthesizing a synthetic glycosphingolipid compound of claim 1, comprising:

(a) contacting an acceptor molecule comprising a sphingoid moiety and a glucose (Glc) with a galactosyltransferase enzyme and a galactose (Gal) donor molecule to form;

(b) contacting the

 

with a trans-sialidase enzyme and a sialic acid (Sia) donor molecule to form;

(c) contacting the

 

with a N-acetyl galactose (GalNAc)-transferase enzyme and a GalNAc donor molecule to form;

 

(d) contacting the

 

with a galactosyltransferase enzyme and a galactose (Gal) donor molecule to form

(e) contacting the

 

with a fatty acid moiety under conditions appropriate to form said synthetic glycosphingolipid.