IP Library › Granted Patent US 7,220,875

Granted Patent B2

US 7,220,875 · App. 10/766,990 · Granted May 22, 2007

Amino acid derived prodrugs of propofol, compositions and uses thereof

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Quick Facts

Patent No.: US 7,220,875
App. No.: 10/766,990
Granted: May 22, 2007
Kind: B2

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Abstract

The present invention provides propofol prodrugs, methods of making propofol prodrugs, pharmaceutical compositions of propofol prodrugs and methods of using propofol prodrugs and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as migraine headache pain and post-chemotherapy or post-operative surgery nausea and vomiting.

Claims (105)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate or n-oxide thereof, wherein:

X is selected from the group consisting of a bond, CH 2 , NR 11 , O and S;

m is 1 or 2;

n is 0 or 1;

R 1 is selected from the group consisting of hydrogen, [R 5 NH(CHR 4 ) p C(O)]—, R 6 —, R 6 C(O)— and R 6 OC(O)—;

R 2 is —OR 7 or —[NR 8 (CHR 9 ) q C(O)OR 7 ];

p and q are independently 1 or 2;

R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl;

each R 4 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, when R 4 and R 5 are attached to adjacent atoms then R 4 and R 5 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R 5 is selected from the group consisting of hydrogen, R 6 —, R 6 C(O)— and R 6 C(O)—;

R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl;

R 7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl;

R 8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl;

each R 9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, when R 8 and R 9 are attached to adjacent atoms then R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R 11 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl;

with the provisos that:

when R 1 is [R 5 NH(CHR 4 ) p C(O)]-then R 2 is —OR 7 ; and

when R 2 is —[NR 8 (CHR 9 ) q C(O)OR 7 ] then R 1 is not [R 5 NH(CHR 4 ) p C(O)]—.

2. The compound of claim 1 , wherein n is 0.

3. The compound of claim 1 having structural Formula (III):

wherein R 4 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl and substituted heteroarylalkanyl.

4. The compound of claim 3 , wherein R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH2, —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

5. The compound of claim 1 having structural Formula (IV):

6. The compound of claim 5 , wherein R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

7. The compound of claim 1 having structural Formula (V):

8. The compound of claim 7 , wherein R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

9. The compound of claim 1 having structural Formula (VI):

10. The compound of claim 9 , wherein R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

11. The compound of claim 1 having structural Formula (VII):

wherein R 3 is hydrogen or methyl; and

R 4 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl and substituted heteroarylalkanyl.

12. The compound of claim 11 , wherein R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

13. A compound of Formula (VIII):

wherein R 3 is hydrogen or methyl; and

14. The compound of claim 13 , wherein R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

15. The compound of claim 1 having structural Formula (IX):

wherein R 8 is hydrogen or methyl; and

R 9 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl and substituted heteroarylalkanyl, or optionally R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

16. The compound of claim 15 , wherein R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

17. The compound of claim 15 , wherein R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.

18. The compound of claim 1 having structural Formula (X):

wherein R 8 is hydrogen or methyl; and

19. The compound of claim 18 , wherein R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

20. The compound of claim 19 , wherein R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.

21. The compound of claim 1 having structural Formula (XI):

wherein R 3 is hydrogen or methyl;

R 8 is hydrogen or methyl; and

22. The compound of claim 21 , wherein R 3 is hydrogen.

23. The compound of claim 22 , wherein R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

24. The compound of claim 22 , wherein R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.

25. The compound of claim 1 having structural Formula (XII):

26. The compound of claim 1 having structural Formula (XIII):

27. The compound of claim 1 having structural Formula (XIV):

wherein R 3 is hydrogen or methyl.

28. The compound of claim 1 having Formula (XV):

wherein R 3 is hydrogen or methyl.

29. A compound of Formula (II):

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, wherein:

n is 0 or 1;

R 10 is hydrogen or [R 5 NH(CHR 4 ) p C(O)]—;

p and q are independently 1 or 2;

R 5 is selected from the group consisting of hydrogen, R 6 —, R 6 C(O)— and R 10 C(O)—;

with the proviso that:

when R 10 is hydrogen then n is 1.

30. The compound of claim 29 , wherein n is 0.

31. The compound of claim 29 having structural Formula (XVI):

R 8 is hydrogen or methyl; and

R 9 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl and substituted heteroarylalkanyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

32. The compound of claim 31 , wherein R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

33. The compound of claim 31 , wherein R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.

34. The compound of claim 31 , wherein R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

35. The compound of claim 32 or 33 , wherein both the N— and C-terminal amino acid residues are of the L-configuration.

36. The compound of claim 35 , wherein R 9 is hydrogen, R 9 is methyl and R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

37. The compound of claim 35 , wherein R 8 is hydrogen, R 9 is —CH 2 CONH 2 and R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

38. The compound of claim 35 , wherein R 8 is hydrogen, R 9 is benzyl and R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

39. The compound of claim 35 , wherein R 8 is hydrogen, R 9 is 4-hydroxybenzyl and R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

40. The compound of claim 29 having structural Formula (XVII):

wherein R 3 is hydrogen or methyl;

R 9 is hydrogen or methyl; and

41. The compound of claim 40 , wherein R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

42. The compound of claim 40 , wherein R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.

43. The compound of claim 29 having structural Formula (XVIII):

wherein R 3 is hydrogen or methyl;

R 8 is hydrogen or methyl; and

R 9 is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl and substituted heteroarylalkanyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

44. The compound of claim 43 , wherein R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

45. The compound of claim 43 , wherein R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.

46. The compound of claim 44 or 45 , wherein R 4 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.

47. A method for treating or reducing risk of acquiring migraine, nausea, vomiting, anxiety, seizures, convulsions, trauma of the central nervous system, and neurodegenerative conditions selected from the group consisting of Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Pick disease in a patient, comprising administering to a patient in need of such treatment or reduction in risk a therapeutically effective amount of a compound according to claim 1 or 29 .

48. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or 29 and a pharmaceutically acceptable vehicle.

Assignments (6)

RELEASE OF SECURITY INTEREST Recorded Oct 20, 2021

From: DEUTSCHE BANK AG NEW YORK BRANCH

To: ARBOR PHARMACEUTICALS, LLC; WILSHIRE PHARMACEUTICALS, INC.; XENOPORT, INC.

Reel/Frame 057880/0174 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 25, 2018

From: XENOPORT, INC.

To: ARBOR PHARMACEUTICALS, LLC

Reel/Frame 046633/0753 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 20, 2018

From: ARBOR PHARMACEUTICALS, LLC

To: XENOPORT, INC.