Oral administration of epothilones

• US 20030220378A1
• Filed: 04/01/2003
• Published: 11/27/2003
• Est. Priority Date: 04/04/2002
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lee, Francis Y. F.
• Granted Patent: US 6,936,628 B2
• Time in Patent Office: Days
• US Class Current: 514/365
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention relates to methods of increasing the bioavailability of orally administered epothilones. Epothilones administered by the methods of the invention are sufficiently bioavailable to have a pharmacological effect. The invention further relates to pharmaceutical compositions, pharmaceutical dosage forms, and kits for use in the methods of the invention.

Claims

1. A method of increasing the bioavailability of orally administered epothilones comprising orally administering to a human one or more epothilones of Formula I, Ia, Ib or Ic:

2. The method of claim 1 wherein the pharmaceutically acceptable acid neutralizing buffer is administered concurrently with the epothilone.

3. The method of claim 1 wherein the pharmaceutically acceptable acid neutralizing buffer is administered before the epothilone.

4. The method of claim 3 wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before the epothilone.

5. The method of claim 1 wherein the pharmaceutically acceptable acid neutralizing buffer is administered after the epothilone.

6. The method of claim 5 wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour after the epothilone.

7. The method of claim 1 wherein the pharmaceutically acceptable acid neutralizing buffer is administered before and after the epothilone.

8. The method of claim 7 wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before and not more than about 1 hour after the epothilone is administered.

9. The method of claim 1 wherein the pharmaceutically acceptable acid neutralizing buffer is administered in an amount sufficient to deliver at least about 20 milliequivalents of acid neutralization capacity.

10. The method of claim 1 wherein the pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution having a pH of between about 5 to 9.

11. The method of claim 1 wherein the epothilone is administered every 3 days to 7 days, followed by a period of 1 week to 3 weeks where there is no treatment.

12. The method of claim 11 wherein the epothilone is administered every 3 days, followed by a period of 1 week where there is no treatment.

13. The method of claim 11 wherein the epothilone is administered every 5 days, followed by a period of 1 week where there is no treatment.

14. The method of claim 11 wherein the epothilone is administered every 7 days, followed by a period of 1 week where there is no treatment.

15. The method of claim 1 wherein the pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid.

16. The method of claim 11 wherein the pH of the aqueous solution is about 7.

17. The method of claim 1 wherein the bioavailability of the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is at least about 20 percent.

18. The method of claim 1 wherein the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is orally administered as a solution in propylene glycol and ethanol, wherein the in ratio of propylene glycol:

ethanol is about 80;

20.

19. The method of claim 1 wherein the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is administered in a total amount of about 0.05 to about 200 mg/kg/day.

20. The method of claim 15 wherein the one or more epothilones of or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is administered in about 2 to 4 divided doses.

21. The method of claim 1 wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

22. The method of claim 1 comprising:

(a) orally administering an aqueous solution of a pharmaceutically acceptable acid neutralizing buffer comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid;

(b) orally administering the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof as a solution of propylene glycol; and

(c) orally administering an aqueous solution of a pharmaceutically acceptable acid neutralizing buffer comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid;

.

23. The method of claim 18 wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

24. The method of claim 22 wherein the epothilone is administered every 3 days to 7 days, followed by a period of 1 week to 3 weeks where there is no treatment.

25. The method of claim 24 wherein the epothilone is administered every 3 days, followed by a period of 1 week where there is no treatment.

26. The method of claim 24 wherein the epothilone is administered every 5 days, followed by a period of 1 week where there is no treatment.

27. The method of claim 24 wherein the epothilone is administered every 7 days, followed by a period of 1 week where there is no treatment.

29. The kit of claim 20 wherein at least one of the first component or the second component is provided as a solid oral dosage form.

30. The kit of claim 21 wherein at least one of the first component or the second component is anhydrous.

31. The kit of claim 20 wherein at least one of the first component or the second component is provided as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage form.

32. The kit of claim 23 wherein at least one of the first component or the second component is provided as a tablet.

33. The kit of claim 23 wherein at least one of the first component or the second component is anhydrous.

34. The kit of claim 23 further comprising solvents for reconstituting the first or second components.

35. The kit of claim 26 wherein the solvent for reconstituting the first component is a mixture of propylene glycol and ethanol.

43. The kit of claim 34 wherein the solvent comprises propylene glycol, ethanol, and phosphate buffer (1M, pH 8).

44. The kit of claim 35 wherein the ratio of propylene glycol:

ethanol;

phosphate buffer is about 58;

12;

30.

57. The kit of claim 20 wherein the first and second component is provided as a liquid oral dosage form.

59. The kit of claim 20 wherein the first component and the second component is provided as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage form;

the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is present as a in an amount of between about 0.05 and 200 mg; and

the pharmaceutically acceptable acid neutralizing buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity.

60. The kit of claim 20 wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione and the pharmaceutically acceptable acid neutralizing buffer comprises dibasic sodium phosphate, sodium citrate, and anhydrous citric acid.

28. A kit for use in a method of increasing the biovailability of orally administered epothilones which comprises:

(i) a first component comprising one or more epothilones of Formula I, Ia, Ib or Ic;

wherein;

P-Q is a C, C double bond or an epoxide;

G is

R is selected from the group of H, alkyl, and substituted alkyl;

R¹ is selected from the group consisting of

R¹ is

G¹ is selected from the group of H, halogen, CN, alkyl and substituted alkyl;

G² is selected from the group of H, alkyl, and substituted alkyl;

G³ is selected from the group of O, S, and NZ¹;

G⁴ is selected from the group of H, alkyl, substituted alkyl, OZ², NZ²Z³, Z²C═

O, Z⁴SO₂, and optionally substituted glycosyl;

G⁵ is selected from the group of halogen, N₃, NCS, SH, CN, NC, N(Z¹)₃⁺ and heteroaryl;

G⁶ is selected from the group of H, alkyl, substituted alkyl, CF₃, OZ⁵, SZ⁵, and NZ⁵Z^6;

G⁷ is CZ⁷ or N;

G⁸ is selected from the group of H, halogen, alkyl, substituted alkyl, OZ¹⁰, SZ¹⁰, NZ¹⁰Z¹¹;

G⁹ is selected from the group of O, S, —

NH—

NH— and

—

N═

N—

;

G¹⁰ is N or CZ¹²;

G¹¹ is selected from the group of H₂N, substituted H₂N, alkyl, substituted alkyl, aryl, and substituted aryl;

Z¹, Z⁶, Z⁹, and Z¹¹ are independently selected from the group H, alkyl, substituted alkyl, acyl, and substituted acyl;

Z² is selected from the group of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;

Z³, Z⁵, Z⁸, and Z¹⁰ are independently selected from the group H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;

Z⁴ is selected from the group of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;

Z⁷ is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ⁸, SZ⁸, and NZ⁸Z⁹; and

Z¹² is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;

with the proviso that when R¹ is

G¹, G², G³ and G⁴ cannot simultaneously have the following meanings;

G¹ and G²=H, G³=O and G⁴=H or Z²C═

O where Z²=alkyl group, and with the proviso that when R¹ is

 

G¹, G² or G⁵ cannot simultaneously have the following meanings;

G¹ and G²=H, and G⁵=F;

wherein;

P-Q is a C,C double bond or an epoxide,

R is a H atom or a methyl group,

G¹ is an H atom, an alkyl group, a substituted alkyl group or a halogen atom,

G² is an H atom, an alkyl group or a substituted alkyl group,

G³ is an O atom, an S atom or an NZ¹ group with

Z¹ being an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group, and

G⁴ is an H atom, an alkyl group, a substituted alkyl group, an OZ² group, an NZ²Z³ group, a Z²C═

O group, a Z⁴SO₂ group or an optionally substituted glycosyl group with Z² being a H atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group or a heterocyclic group,

Z³ an H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and

Z⁴ an alkyl, a substituted alkyl, an aryl, a substituted aryl or a heterocyclic group,

with the proviso that G¹, G², G³ and G⁴ cannot have simultaneously the following meanings;

G¹ and G²=H atom, G³=O atom and G⁴=H atom or Z²C═

O with Z²=alkyl group;

 

wherein G¹, G², G³, G⁴, Z¹, Z² and Z³ are as defined above;

 

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof; and

(ii) a second component comprising a pharmaceutically acceptable acid neutralizing buffer,

wherein the first component and the second component are provided as an oral dosage form or as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage.

37. The pharmaceutical composition of claim 28 wherein the pharmaceutically acceptable acid neutralizing buffer provides a liquid oral dosage form having a pH between about 5 to 9.

38. The pharmaceutical composition of claim 28 wherein the pharmaceutically acceptable acid neutralizing buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity.

39. The pharmaceutical composition of claim 28 wherein the pharmaceutically acceptable acid neutralizing buffer is a dibasic phosphate-citric acid-citrate buffer.

40. The pharmaceutical composition of claim 28 wherein the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about 0.05 and 200 mg.

41. The pharmaceutical composition of claim 28 wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11 R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]—

methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4, 17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

42. A kit comprising the pharmaceutical composition of claim 28 and a solvent for reconstituting the pharmaceutical composition to provide an oral dosage form.

46. The liquid oral dosage form of claim 37 wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

47. The liquid oral dosage form of claim 37 further comprising a pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of the one or more epothilones, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof compared to a pharmaceutical composition without the buffer.

48. The liquid oral dosage form of claim 39 wherein the pH of the liquid oral dosage form is between about 5 to 9.

49. The liquid oral dosage form of claim 39 wherein the buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity.

50. The liquid oral dosage form of claim 37 wherein the solvent is propylene glycol, ethanol, and water buffered with a phosphate buffer at pH about 8.

51. The liquid oral dosage form of claim 42 wherein the propylene glycol, ethanol, and water buffered with a phosphate buffer are present in a ratio of about 58:

12;

30.

52. The liquid oral dosage form of claim 42 wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

53. The liquid oral dosage form of claim 37 wherein the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about 0.05 and 200 mg.

54. The liquid oral dosage form of claim 39 wherein the buffer is dibasic phosphate-citric acid-citrate buffer.

58. The kit of claim 49 wherein the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about 0.05 and 200 mg and the pharmaceutically acceptable acid neutralizing buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity.

36. A pharmaceutical composition suitable for oral administration to a mammal comprising:

(i) one or more epothilones of Formula I, Ia, Ib or Ic;

wherein;

P-Q is a C, C double bond or an epoxide;

G is

R is selected from the group of H, alkyl, and substituted alkyl;

R¹ is selected from the group consisting of

R² is

G¹ is selected from the group of H, halogen, CN, alkyl and substituted alkyl;

G² is selected from the group of H, alkyl, and substituted alkyl;

G³ is selected from the group of O, S, and NZ¹;

G⁴ is selected from the group of H, alkyl, substituted alkyl, OZ², NZ²Z³, Z²C═

O, Z⁴SO₂, and optionally substituted glycosyl;

G⁵ is selected from the group of halogen, N₃, NCS, SH, CN, NC, N(Z¹)₃⁺ and heteroaryl;

G⁶ is selected from the group of H, alkyl, substituted alkyl, CF₃, OZ⁵, SZ⁵, and NZ⁵Z⁶;

G⁷ is CZ⁷ or N;

G⁸ is selected from the group of H, halogen, alkyl, substituted alkyl, OZ¹⁰, SZ¹⁰, NZ¹⁰Z¹¹;

G⁹ is selected from the group of O, S, —

NH—

NH— and

—

N═

N—

;

G¹⁰ is N or CZ¹²;

G¹¹ is selected from the group of H₂N, substituted H₂N, alkyl, substituted alkyl, aryl, and substituted aryl;

Z¹, Z⁶, Z⁹, and Z¹¹ are independently selected from the group H, alkyl, substituted alkyl, acyl, and substituted acyl;

Z² is selected from the group of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;

Z³, Z⁵, Z⁸, and Z¹⁰ are independently selected from the group H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;

Z⁴ is selected from the group of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;

Z⁷ is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ⁸, SZ⁸, and NZ⁸Z⁹; and

Z¹² is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;

with the proviso that when R¹ is

G¹, G², G³ and G⁴ cannot simultaneously have the following meanings;

G¹ and G²=H, G³=O and G⁴=H or Z²C═

O where Z²=alkyl group, and with the proviso that when R¹ is

 

G¹, G² or G⁵ cannot simultaneously have the following meanings;

G¹ and G²=H, and G⁵=F;

wherein;

P-Q is a C,C double bond or an epoxide,

R is a H atom or a methyl group,

G¹ is an H atom, an alkyl group, a substituted alkyl group or a halogen atom,

G² is an H atom, an alkyl group or a substituted alkyl group,

G³ is an O atom, an S atom or an NZ¹ group with

Z¹ being an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group, and

G⁴ is an H atom, an alkyl group, a substituted alkyl group, an OZ² group, an NZ²Z³ group, a Z²C═

O group, a Z⁴SO₂ group or an optionally substituted glycosyl group with Z² being a H atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group or a heterocyclic group,

Z³ an H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and

Z⁴ an alkyl, a substituted alkyl, an aryl, a substituted aryl or a heterocyclic group, with the proviso that G¹, G², G³ and G⁴ cannot have simultaneously the following meanings;

G¹ and G²=H atom, G³=O atom and G⁴=H atom or Z²C═

O with Z²=alkyl group;

 

wherein G¹, G², G³, G⁴, Z¹, Z² and Z³ are as defined above;

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof, in solid form; and

(ii) a solid pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of the one or more epothilones, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof when the pharmaceutical composition is reconstituted with a solvent to provide a liquid oral dosage form.

45. A liquid oral dosage form suitable for oral administration to a mammal comprising:

(i) one or more epothilones of Formula I, Ia, Ib or Ic;

wherein;

P-Q is a C, C double bond or an epoxide;

G is

R is selected from the group of H, alkyl, and substituted alkyl;

R¹ is selected from the group consisting of

R¹ is

G¹ is selected from the group of H, halogen, CN, alkyl and substituted alkyl;

G² is selected from the group of H, alkyl, and substituted alkyl;

G³ is selected from the group of O, S. and NZ¹;

G⁴ is selected from the group of H, alkyl, substituted alkyl, OZ², NZ²Z³, Z²C═

O, Z⁴SO₂, and optionally substituted glycosyl;

G⁵ is selected from the group of halogen, N₃, NCS, SH, CN, NC, N(Z¹)₃⁺ and heteroaryl;

G⁶ is selected from the group of H, alkyl, substituted alkyl, CF₃, OZ⁵, SZ⁵, and NZ⁵Z⁶;

G⁷ is CZ⁷ or N;

G⁸ is selected from the group of H, halogen, alkyl, substituted alkyl, OZ¹⁰, SZ¹⁰, NZ¹⁰Z¹¹;

G⁹ is selected from the group of O, S, —

NH—

NH— and

—

N═

N—

;

G¹⁰ is N or CZ¹²;

G¹¹ is selected from the group of H₂N, substituted H₂N, alkyl, substituted alkyl, aryl, and substituted aryl;

Z¹, Z⁶, Z⁹, and Z¹¹ are independently selected from the group H, alkyl, substituted alkyl, acyl, and substituted acyl;

Z² is selected from the group of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;

Z³, Z⁵, Z⁸, and Z¹⁰ are independently selected from the group H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;

Z⁴ is selected from the group of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;

Z⁷ is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ⁸, SZ⁸, and NZ⁸Z⁹; and

Z¹² is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;

with the proviso that when R¹ is

G¹, G², G³ and G⁴ cannot simultaneously have the following meanings;

G¹ and G²=H, G³=O and G=H or Z²C═

O where Z²=alkyl group, and with the proviso that when R¹ is

 

G¹, G² or G cannot simultaneously have the following meanings;

G¹ and G²=H, and G⁵=F;

wherein;

P-Q is a C,C double bond or an epoxide,

R is a H atom or a methyl group,

G¹ is an H atom, an alkyl group, a substituted alkyl group or a halogen atom,

G² is an H atom, an alkyl group or a substituted alkyl group,

G³ is an O atom, an S atom or an NZ¹ group with

Z¹ being an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group, and

G⁴ is an H atom, an alkyl group, a substituted alkyl group, an OZ² group, an NZ²Z³ group, a Z²C═

O group, a Z⁴SO₂ group or an optionally substituted glycosyl group with Z² being a H atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group or a heterocyclic group,

Z³ an H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and

Z⁴ an alkyl, a substituted alkyl, an aryl, a substituted aryl or a heterocyclic group, with the proviso that G¹, G², G³ and G⁴ cannot have simultaneously the following meanings;

G¹ and G²=H atom, G³=O atom and G⁴=H atom or Z²C═

O with Z²=alkyl group;

 

wherein G¹, G², G³, G⁴, Z¹, Z² and Z³ are as defined above;

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof; and

(ii) a pharmaceutically acceptable liquid carrier.

55. An article of manufacture which comprises:

(a) a sealable container suitable to carry a liquid or solid pharmaceutical;

(b) one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof; and

(c) a pharmaceutically acceptable carrier suitable to deliver the epothilone orally

56. A dispersible buffered tablet which comprises:

(i) one or more epothilones of Formula I, Ia, Ib or Ic;

wherein;

P-Q is a C, C double bond or an epoxide;

G is

R is selected from the group of H, alkyl, and substituted alkyl;

R¹ is selected from the group consisting of

R² is

G¹ is selected from the group of H, halogen, CN, alkyl and substituted alkyl;

G² is selected from the group of H, alkyl, and substituted alkyl;

G³ is selected from the group of O, S, and NZ¹;

G⁴ is selected from the group of H, alkyl, substituted alkyl, OZ², NZ²Z³, Z²C═

O, Z⁴SO₂, and optionally substituted glycosyl;

G⁵ is selected from the group of halogen, N₃, NCS, SH, CN, NC, N(Z¹)₃⁺ and heteroaryl;

G⁶ is selected from the group of H, alkyl, substituted alkyl, CF₃, OZ⁵, SZ⁵, and NZ⁵Z^6;

G⁷ is CZ⁷ or N;

G⁸ is selected from the group of H, halogen, alkyl, substituted alkyl, OZ¹⁰, G⁹ is selected from the group of O, S, —

NH—

NH— and

—

N═

N—

;

G¹⁰ is N or CZ¹²;

G¹¹ is selected from the group of H₂N, substituted H₂N, alkyl, substituted alkyl, aryl, and substituted aryl;

Z¹, Z⁶, Z⁹, and Z¹¹ are independently selected from the group H, alkyl, substituted alkyl, acyl, and substituted acyl;

Z² is selected from the group of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;

Z³, Z¹, Z⁸, and Z¹⁰ are independently selected from the group H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;

Z⁴ is selected from the group of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;

Z⁷ is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ⁸, SZ⁸, and NZ⁸Z⁹; and

Z¹² is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;

with the proviso that when R¹ is

G¹, G², G³ and G⁴ cannot simultaneously have the following meanings;

G¹ and G²=H, G³=O and G⁴=H or Z²C═

O where Z²=alkyl group, and with the proviso that when R¹ is

 

G¹, G² or G⁵ cannot simultaneously have the following meanings;

G¹ and G²=H, and G⁵=F;

wherein;

P-Q is a C,C double bond or an epoxide,

R is a H atom or a methyl group,

G¹ is an H atom, an alkyl group, a substituted alkyl group or a halogen atom,

G² is an H atom, an alkyl group or a substituted alkyl group,

G³ is an O atom, an S atom or an NZ¹ group with

Z¹ being an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group, and

G⁴ is an H atom, an alkyl group, a substituted alkyl group, an OZ² group, an NZ²Z³ group, a Z²C═

O group, a Z⁴SO₂ group or an optionally substituted glycosyl group with Z² being a H atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group or a heterocyclic group,

Z³ an H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and

Z⁴ an alkyl, a substituted alkyl, an aryl, a substituted aryl or a heterocyclic group, with the proviso that G¹, G², G³ and G⁴ cannot have simultaneously the following meanings;

G¹ and G²=H atom, G³=O atom and G⁴=H atom or Z²C═

O with Z²=alkyl group;

 

wherein G¹, G², G³, G⁴, Z¹, Z² and Z³ are as defined above;

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof; and

(ii) buffer components which are suitable to neutralize gastric fluids for a time sufficient to allow said epothilone to be absorbed.