Pharmaceutical compositions having appetite suppressant activity

• US 6,376,657 B1
• Filed: 10/13/1999
• Issued: 04/23/2002
• Est. Priority Date: 04/15/1997
• Status: Expired due to Term

• Current Assignee: CSIR
• Original Assignee: CSIR
• Inventors: Vleggaar, Robert, Maharaj, Vinesh, Whittal, Rory Desmond, Van Heerden, Fanie Retief, Learmonth, Robin Alec, Horak, Roelof Marthinus
• Primary Examiner(s): Gitomer, Ralph
• Assistant Examiner(s): Khare, Devesh
• Application Number:
  US09/402,962
• Time in Patent Office: 923 Days
• Field of Search: 536/5, 424/195.1, 514/278, 514/221, 514/90, 514/303, 514/326
• US Class Current: 536/5
• CPC Class Codes: A23L 33/105 Plant extracts, their artificial duplicates or their derivatives
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/78 of acrylic acid or derivatives thereof
• CPC Class Codes: A61K 36/27 Asclepiadaceae (Milkweed family), e.g. hoya
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07H 13/08 having the esterifying carboxyl radicals directly attached to carbocyclic rings
• CPC Class Codes: C07H 3/04 Disaccharides
• CPC Class Codes: C07H 3/06 Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• CPC Class Codes: C07H 5/10 to sulfur
• CPC Class Codes: C07J 15/00 Stereochemically pure steroids containing carbon, hydrogen, halogen or oxygen having a partially or totally inverted skeleton, e.g. retrosteroids, L-isomers
• CPC Class Codes: C07J 17/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton cardanolide, bufanolide C07J19/00
• CPC Class Codes: C07J 17/005 Glycosides
• CPC Class Codes: C07J 41/00 Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
• CPC Class Codes: C07J 7/002 not substituted in position 16
• CPC Class Codes: C07J 7/0025 substituted in position 16
• CPC Class Codes: C07J 7/0035 : by a hydroxy group free esterified or etherified
• CPC Class Codes: C07J 7/007 : not substituted in position 17 alfa
• CPC Class Codes: Y02P 20/582 : Recycling of unreacted starting or intermediate materials

Abstract

A pharmaceutical composition which contains an extract obtainable from a plant of the genus Trichocaulon or Hoodia containing an appetite suppressant agent having the formula (1). A process for obtaining the extract and a process for synthesizing compound (1) and its analogues and derivatives is also provided. The invention also extends to the use of such extracts and compound (1) and its analogues for the manufacture of medicaments having appetite suppressant activity. The invention further provides novel intermediates for the synthesis of compound (1).

Claims

1. An extract obtainable from a plant of the genus Trichocaulon or of the genus Hoodia which comprises an appetite suppressant agent having the formula

4. An extract as claimed in claim 1 which has been processed to a free-flowing powder.

5. A composition having appetite suppressant activity comprising the extract as claimed in claim 1.

6. A composition as claimed in claim 5 when admixed with a pharmaceutical excipient, diluent or carrier.

7. A composition as claimed in claim 5, which is prepared in unit dosage form.

8. The use of an extract as claimed in claim 1 in the manufacture of a medicament having appetite suppressant activity.

9. An extract as claimed in claim 1 for use as a medicament having appetite suppressant activity.

10. A method of combating obesity in a human or animal comprising administering to said human or animal an obesity combating amount of an extract as claimed in claim 1.

2. An extract as claimed in claim 2 wherein the plant of the genus Trichocaulon is selected from the species Trichocaulon piliferum and Trichocaulon officinale and the plant of the genus Hoodia is selected from the species Hoodia curroii, Hoodia gordonii and Hoodia lugardii.

3. An extract as claimed in claim 2 wherein substantially all the non-active impurities have been removed.

11. A compound having the structural formula:

in which R=alkyl;

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group;

R₂═

H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;

and in which the broken lines indicate the optional presence of a further bond between C4-C5 or C5-C6.

12. A compound as claimed in claim 11 wherein there is a bond between C5-C6, R=methyl, R₁=tigloyl, R₂=3-0-[-β

-D-thevetopyranosyl-(1→

4)-β

-D-cymaropyranosyl-(1→

4)-β

-D-cymaropyranosyl], the compound having the structural formula

13. A process of forming a trisaccharide and coupling the resultant trisaccharide to a steroid intermediate, which includes the steps of

i) coupling a selectively protected cymarose moiety of formula (40) and compound (45) using tin (II) chloride, AgOTf, Cp₂ZrCl₂ to produce a compound of the formula

  in which Z=TBDMS=t-butyldimethylsilyl;

ii) treating compound (57) with tetrabutylammonium fluoride and diethylaminosulphur trifluoride to produce a trisaccharide compound having the formula

and iii) coupling the trisaccharide of formula (58) with a steroid intermediate of the formula

 

using tin (II) chloride, AgOTf, Cp₂ZrCl₂ to produce compound (1) as claimed in claim 12.

14. A composition having appetite suppressant activity comprising a compound as claimed in claim 11.

15. A composition as claimed in claim 14 wherein the compound is the compound of formula (1).

16. A composition as claimed in claim 14 when admixed with a pharmaceutical excipient, diluent or carrier.

17. A composition as claimed in claim 14, which is prepared in unit dosage form.

18. The use of a compound as claimed in claim 11 in the manufacture of a medicament having appetite suppressant activity.

19. The use as claimed in claim 18 of a compound of formula (1).

20. A compound as claimed in claim 11 for use as a medicament having appetite suppressant activity.

21. A compound claim 20 which is the compound of formula (1).

22. A foodstuff or beverage comprising an effective quantity of a compound as claimed in claim 11 to have an appetite suppressant effect when ingested.

23. A foodstuff or beverage as claimed in claim 22 wherein the compound is the compound of formula (1).

24. A compound of formula (1) as claimed in claim 11 isolated from a plant of the genus Trichocaulon or from the genus Hoodia for use as a medicament having appetite suppressant activity.

25. A compound as claimed in claim 24 wherein the compound is isolated from a plant of the species Trichocaulon piliferum or Trichocaulon officinale of from Hoodia currorii, Hoodia gordonii or Hoodia lugardii.

26. A compound of claim 11, wherein R₁ is tigloyl.

27. A compound of claim 11 having the following stereochemical structure:

49. A process of coupling a monosaccharide cymarose moiety to a monosaccharide thevetose moiety and coupling the resultant disaccharide to the compound of formula (52) as claimed in claim 48 which includes the steps of

i) coupling a selectively protected cymarose moiety of formula (40) and a monosaccharide thevetose moiety of formula (50 A) using tin chloride (SnCl₂) and silver trifluoromethanesulphonate to produce a compound of the formula

 

in which Z=TBDMS=t-butyldimethylsilyl

ii) treating compound (53) with tetrabutylamtnoniumfluoride to produce a compound of the formula

iii) treating compound (54) with diethylaminosulphur trifluoride to produce a compound of the formula

iv) reacting compound (55) with compound (52) as claimed in claim 48 to produce a compound of the formula

and (v) treating compound (56) in a Raney-Nickel reaction and thereafter with a base to produce compound (1) as claimed in claim 12.

28. A compound having the structural formula

in which R=alkyl;

and

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group.

29. A compound of claim 28, wherein R₁ is tigloyl.

30. A compound of claim 28 having the following stereochemical structure:

31. A compound having the structural formula:

in which R=alkyl; and

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group.

32. A compound of claim 31, wherein R₁ is tigloyl.

33. A compound of claim 31, having the following stereochemical structure:

34. A compound having the structural formula:

in which R=alkyl; and

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group.

35. A compound of claim 34, wherein R₁ is tigloyl.

36. A compound of claim 34 having the following stereochemical structure:

37. A compound having the structural formula:

in which R=alkyl; and

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group.

38. A compound of claim 37, wherein R₁ is tigloyl.

39. A compound of claim 37 having the following stereochemical structure:

40. A compound having the structural formula:

in which R=alkyl;

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group;

R₂═

H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;

and in which the broken lines indicate the optional presence of a further bond between C4-C5 or C5-C6.

41. A compound having the structural formula:

in which R=alkyl;

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group;

R₂═

H, or one or more 6-deoxy carbohydrates, or one or more 2, 6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;

and in which the broken lines indicate the optional presence of a further bond between C4-C5 or C5-C6.

42. A compound having the structural formula:

in which R=alkyl;

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group; and

R₂═

H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;

and in which the broken lines indicate the optional presence of a further bond between C4-C5 or C5-C6.

43. A compound having the structural formula:

in which R=alkyl;

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group; and

R₂═

H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;

and in which the broken lines indicate the optional presence of a further bond between C4-C5, C5-C6 or C14-C15.

44. A compound having the structural formula:

in which R=alkyl;

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group; and

R₂═

H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;

and in which the broken lines indicate the optional presence of a further bond between C4-C5, C5-C6 or C14-C15.

45. A compound having the structural formula:

in which R=alkyl;

R₁═

H, alkyl, tigloyl, benzoyl, or any other organic ester group;

R₂═

H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;

and in which the broken lines indicate the optional presence of a further bond between C4-C5, C5-C6 or C14-C15; and

R₃═

H, alkyl, aryl, acyl, or glucoxy.

46. A compound having the structural formula:

in which R═

H, alkyl, aryl, or any steroid possessing a C14 beta hydroxy group, a C12 beta hydroxy functionality, a C17 acyl group, a C5-C6 olefin, or combinations thereof.

47. A process of coupling a monosaccharide cymarose to a steroid intermediate, which includes the steps of

i) reacting a cymarose moiety of formula (38) with a steroid intermediate of formula (15) in the presence of tin chloride in a solvent to produce a compound 3-O-[4-O-benzoyl-2-phenylthio-β

-D-cymaropyranosyl]-12,14-β

-dihydroxy-pregnan-5-ene-20-one of the formula

and (ii) treating the compound (51) with tiglic acid chloride in pyridine and thereafter with a base to produce a compound 3-O-[4-O-benzoyl-2-phenylthio-β

-D-cymaropyranosyl]-12β

-tigloyl-14β

-hydroxy-pregnan-5-ene-20-one of the formula

48. A compound of formula (52) when produced by a process as claimed in claim 47.

50. A composition having appetite suppressant activity comprising a compound of formula (1) isolated from a plant of the genus Trichocaulon or of the genus Hoodia.

51. A composition as claimed in claim 50 wherein the compound is isolated and/or purified from a plant of the species Trichocaulon piliferum or Trichocaulon officinale or from of the species Hoodia curronii, Hoodia gordonii or Hoodia lugardii.

52. A composition as claimed in claim 50 wherein the compound is isolated and/or purified from an extract derived from a plant of the species Trichocaulon piliferum, Trichocaulon officinale or from a plant of the species Hoodia currorii, Hoodia gordonii or Hoodia lugardii.

53. A composition as claimed in claim 50, when admixed with a pharmaceutical excipient, diluent or carrier.

54. A composition as claimed in claim 53 which is prepared in unit dosage form.

55. A compound having the structural formula

56. A compound having the structural formula

57. A compound having the structural formula

58. A structure of the formula 3-O-β

-D-theverosyl-(1→

4)-p-D-cymaropyranosyl-(1→

4)-β

-D-cymaropyranoside-12β

-O-tigloyl-14β

-hydroxy-pregnane-5-ene-20-one.