Acyloxyalkyl carbamate prodrugs of α-amino acids, methods of synthesis and use

• US 7,531,572 B2
• Filed: 07/26/2007
• Issued: 05/12/2009
• Est. Priority Date: 07/28/2006
• Status: Expired due to Fees

• Current Assignee: XenoPort, Inc. (Arbor Pharmaceuticals LLC)
• Original Assignee: XenoPort, Inc. (Arbor Pharmaceuticals LLC)
• Inventors: Dai, Xuedong, Xiang, Jia-Ning, Gangakhedkar, Archana, Gallop, Mark A
• Primary Examiner(s): Zucker; Paul A
• Application Number:
  US11/878,661
• Publication Number:
  US 20080051458A1
• Time in Patent Office: 656 Days
• Field of Search: None
• US Class Current: 514/476
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/24 with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 271/34 with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 271/36 with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring

Abstract

Acyloxyalkyl carbamate prodrugs of α-amino acids, pharmaceutical compositions thereof, methods of making acyloxyalkyl carbamate prodrugs of α-amino acids and methods of using acyloxyalkyl carbamate prodrugs of α-amino acids, and pharmaceutical compositions thereof to treat a disease are disclosed. Acyloxyalkyl carbamate prodrugs of α-amino acids suitable for oral administration using sustained release dosage forms are also disclosed.

Claims

1. A compound of Formula (I):

5. The compound of claim 1, wherein R⁴ is hydrogen;

R⁵ is methyl; and

R⁶ is hydrogen.

6. The compound of claim 1, wherein R⁴ is hydrogen;

and R⁵ and R⁶ together with the carbon atom to which they are bonded form a 1,1-cyclopropane ring.

7. The compound of claim 6, wherein R¹ is chosen from C_1-6 alkyl, phenyl, substituted phenyl, cyclohexyl, substituted cyclohexyl, C_7-9 phenylalkyl, and adamantyl;

R² is chosen from hydrogen and C_1-4 alkyl; and

R³ is hydrogen.

8. The compound of claim 6, wherein the compound is chosen from:

1-(1-isobutyryloxy-ethoxycarbonylamino)-cyclopropanecarboxylic acid;

1-(1-Isobutyryloxy-2-methyl-propoxycarbonylamino)-cyclopropanecarboxylic acid;

1-{[(2-methylphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic acid;

1-[(phenylcarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylic acid;

1-[(3-methyl-butyryloxy)-ethoxycarbonylamino]-cyclopropanecarboxylic acid;

1-[(2,2-dimethyl-propionyloxy)-ethoxycarbonylamino]-cyclopropanecarboxylic acid;

1-(1-butyryloxy-ethoxycarbonylamino)-cyclopropanecarboxylic acid;

1-(1-pentanoyloxy-ethoxycarbonylamino)-cyclopropanecarboxylic acid;

1-[(cyclohexylcarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylic acid;

1-[(1-cyclohexylcarbonyloxy-2-methylpropoxy)carbonylamino]cyclopropanecarboxylic acid;

1-[(2-methyl-1-phenylcarbonyloxypropoxy)carbonylamino]cyclopropanecarboxylic acid;

1-[(heptanoyloxyethoxy)carbonylamino]cyclopropanecarboxylic acid;

1-{[(3,4-dimethoxyphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic acid;

1-{[(4-phenylbutanoyloxy)ethoxy]carbonylamino }cyclopropanecarboxylic acid;

1-{[((2E)-3-phenylprop-2-enoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic acid;

1-{[2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}sodium cyclopropanoate;

1-{[(2-phenylacetyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic acid;

1-{[(4-methylphenylcarbonyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic acid;

1-[(adamantanecarbonyloxyethoxy)carbonylamino]cyclopropanecarboxylic acid;

1-{[(3-phenylpropanoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic acid;

1-{[2-methyl-1-(3-phenylpropanoyloxy)propoxy]carbonylamino}cyclopropanecarboxylic acid;

and a pharmaceutically acceptable salt of any of the foregoing.

12. The compound of claim 1, wherein R¹ is chosen from C_1-6 alkyl, substituted C_1-6 alkyl, C_6-10 aryl, substituted C_6-10 aryl, C_3-7 cycloalkyl, substituted C_3-7 cycloalkyl, C_6-10 arylalkyl, and C_6-10 substituted arylalkyl.

13. The compound of claim 1, wherein R¹ is chosen from C_1-4 alkyl, phenyl, substituted phenyl, cyclohexyl, substituted cyclohexyl, styryl, and substituted styryl.

14. The compound of claim 1, wherein R¹ is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl.

15. The compound of any one of claims 1, 2, 9, 12, and 13, wherein each substituent group is independently chosen from halogen, C_1-3 alkyl, —

OH, —

NH₂, —

SH, C_1-3 alkoxy, C_1-3 acyl, C_1-3 thioalkyl, C_1-3 alkoxycarbonyl, C_1-3 alkylamino, and C_1-3 dialkylamino.

16. The compound of any one of claims 1, 2, and 9, wherein R² and R³ are independently chosen from hydrogen, C_1-6 alkyl, substituted C_1-6 alkyl, C_6-10 aryl, substituted C_6-10 aryl, C_3-7 cycloalkyl, and substituted C_3-7 cycloalkyl.

17. The compound of any one of claims 1, 2, and 9, wherein R² and R³ are independently chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl.

18. The compound of any one of claims 1, 2, and 9, wherein R² is hydrogen;

and R³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl.

19. The compound of any one of claims 1 and 9, wherein R¹ is chosen from C_1-6 alkyl, substituted C_1-6 alkyl, C_6-10 aryl, substituted C_6-10 aryl, C_3-7 cycloalkyl, substituted C_3-7 cycloalkyl, C_6-10 arylalkyl, and C_6-10 substituted arylalkyl;

and R² and R³ are independently chosen from hydrogen, C_1-6 alkyl, substituted C_1-6 alkyl, C_6-10 aryl, substituted C_6-10 aryl, C_3-7 cycloalkyl, and substituted C_3-7 cycloalkyl.

20. The compound of any one of claims 1 and 9, wherein R¹ is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl;

R² is hydrogen; and

R³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl.

21. The compound of claim 1, wherein R¹ is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl;

R² is hydrogen;

R³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl; and

R⁴ is hydrogen.

23. A pharmaceutical composition comprising at least one pharmaceutically acceptable vehicle and at least one compound of any one of claims 1, 2, and 9.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is formulated for oral administration.

25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is a sustained release oral formulation.

26. The pharmaceutical composition of claim 24, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment of a disease in a patient, wherein the disease is chosen from post-partum depression, premenstrual syndrome, premenstrual dysphoric disorder, a learning disorder, autistic disorder, attention-deficit hyperactivity disorder, Tourette'"'"'s syndrome, phobia, post-traumatic stress disorder, dementia, AIDS dementia, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, spasticity, myoclonus, muscle spasm, depression, anxiety, bipolar disorder, a substance abuse disorder, and urinary incontinence.

27. The pharmaceutical composition of claim 23, wherein the disease is schizophrenia.

28. A method of treating a disease in a patient, wherein the disease is chosen from post-partum depression, premenstrual syndrome, premenstrual dysphoric disorder, a learning disorder, autistic disorder, attention-deficit hyperactivity disorder, Tourette'"'"'s syndrome, phobia, post-traumatic stress disorder, dementia, AIDS dementia, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, spasticity, myoclonus, muscle spasm, depression, anxiety, bipolar disorder, a substance abuse disorder, and urinary incontinence, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1, 2, and 9;

and at least on pharmaceutically acceptable vehicle.

29. The method of claim 28, wherein the disease is schizophrenia.

30. The method of claim 28, wherein the pharmaceutical composition is a sustained release oral dosage form.

31. The method of claim 28, wherein the pharmaceutical composition is administered to the patient once or twice per day.

32. The method of claim 28, comprising administering a therapeutically effective amount of at least one additional therapeutic agent.

33. The method of claim 32, wherein the at least one additional therapeutic agent is chosen from an antipsychotic, an antidepressant, an anxiolytic, an anti-anxiety agent, a sedative, and a hypnotic.

2. A compound of Formula (I):

3. The compound of claim 2, wherein R¹ is chosen from C_2-4 alkyl, phenyl, substituted phenyl, cyclohexyl, and substituted cyclohexyl;

R² is chosen from hydrogen and C_1-4 alkyl; and

R³ is hydrogen.

4. The compound of claim 2, wherein the compound is chosen from:

(2R)-3-hydroxy-2-{[2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}propanoic acid;

(2R)-3-hydroxy-2-{[(2-methylpropanoyloxy)methoxy]carbonylamino}propanoic acid;

(2R)-3-hydroxy-2-[(pentanoyloxyethoxy)carbonylamino]propanoic acid;

(2R)-2-[(butanoyloxyethoxy)carbonylamino]-3-hydroxypropanoic acid;

(2R)-3-hydroxy-2-{[(2-methylpropanoyloxy)ethoxy]carbonylamino}propanoic acid;

(2R)-3-hydroxy-2-[(phenylcarbonyloxyethoxy)carbonylamino]propanoic acid;

(2R)-2-[(cyclohexylcarbonyloxyethoxy)carbonylamino]-3-hydroxypropanoic acid;

(2R)-3-hydroxy-2-{[(3-methylbutanoyloxy)ethoxy]carbonylamino}propanoic acid;

(2R)-3-hydroxy-2-{[(2-methylphenylcarbonyloxy)ethoxy]carbonylamino}propanoic acid;

(2R)-2-{[(2,2-dimethylpropanoyloxy)ethoxy]carbonylamino}-3-hydroxypropanoic acid;

(2R)-2-[(1-cyclohexylcarbonyloxy-2-methylpropoxy)carbonylamino]-3-hydroxypropanoic acid;

(2R)-3-hydroxy-2-[(2-methyl-1-phenylcarbonyloxypropoxy)carbonylamino]propanoic acid;

(2R)-2-[(heptanoyloxyethoxy)carbonylamino]-3-hydroxypropanoic acid;

and a pharmaceutically acceptable salt of any of the foregoing.

34. The compound of claim 2, wherein R¹ is chosen from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl;

R² is hydrogen; and

R³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl.

35. The compound of claim 2, wherein R¹ is chosen from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl;

R² is hydrogen; and

R³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl.

9. A compound of Formula (I), wherein:

10. The compound of claim 9, wherein R¹ is chosen from C_1-6 alkyl, phenyl, substituted phenyl, cyclohexyl, and substituted cyclohexyl;

R² is chosen from hydrogen, C_1-4 alkyl, phenyl, substituted phenyl, cyclohexyl, and substituted cyclohexyl; and

R³ is hydrogen.

11. The compound of claim 9, wherein the compound is chosen from:

2-{N-methyl[2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}acetic acid;

2-{N-methyl[(2-methylpropanoyloxy)ethoxy]carbonylamino}acetic acid;

2-{N-methyl[(2-methylphenylcarbonyloxy)ethoxy]carbonylamino}acetic acid;

2-[N-methyl(phenylcarbonyloxyethoxy)carbonylamino]acetic acid;

2-{[(2,2-dimethylpropanoyloxy)ethoxy]-N-methylcarbonylamino}acetic acid;

2-[(cyclohexylcarbonyloxyethoxy)-N-methylcarbonylamino]acetic acid;

2-[N-methyl(pentanoyloxyethoxy)carbonylamino]acetic acid;

2-[(butanoyloxyethoxy)-N-methylcarbonylamino]acetic acid;

2-{N-methyl[(3-methylbutanoyloxy)ethoxy]carbonylamino}acetic acid;

2-{N-methyl[(2-methylpropanoyloxy)methoxy]carbonylamino}acetic acid;

2-[N-methyl(phenylphenylcarbonyloxymethoxy)carbonylamino]acetic acid;

2-[(1-cyclohexylcarbonyloxy-2-methylpropoxy)-N-methylcarbonylamino]acetic acid;

2-[N-methyl(2-methyl-1-phenylcarbonyloxypropoxy)carbonylamino]acetic acid;

2-[(heptanoyloxyethoxy)-N-methylcarbonylamino]acetic acid;

and a pharmaceutically acceptable salt of any of the foregoing.

22. The compound of claim 9, wherein R¹ is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, o-tolyl, cyclohexyl, and styryl;

R² is hydrogen; and

R³ is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl.