Cannabinoid receptor mediating compounds

Patent metadata

Field	Value
Publication number	US-9765031-B2
Application number	US-201314442383-A
Country	US
Kind code	B2
Filing date	Nov 12, 2013
Priority date	Nov 13, 2012
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

A compound, or a pharmaceutically acceptable salt or ester thereof, comprising (i) a CB 1 receptor mediating scaffold conjugated to (ii) a second therapeutic scaffold.

First claim

What is claimed is:

1. A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein A is an amidino-containing moiety
having a structure of

wherein R 4 is selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino; and R 5 is selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, heterocycloalkyl, or imino;
R 1 , R 2 , and R 3 are each independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino;
X is SO 2 or C═O; and
a, b, and c are each independently 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1 , wherein R 4 is H, hydroxy, C 1 -C 6 alkyl, or acyl.

3. The compound of claim 2 , wherein X is SO 2 .

4. The compound of claim 1 , wherein R 5 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino, phenyl, heteroaryl, acyl or heterocycloalkyl.

5. The compound of claim 4 , wherein X is SO 2 .

6. The compound of claim 4 , wherein R 4 is H.

7. The compound of claim 6 , wherein R 5 is amino.

8. The compound of claim 6 , wherein R 5 is methyl.

9. The compound of claim 6 , wherein X is SO 2 .

10. The compound of claim 1 , wherein R 5 is amino.

11. The compound of claim 1 , wherein R 5 is —NH(alkyl).

12. The compound of claim 1 , wherein a and c are each one, R 1 is halogen, and R 3 is halogen.

13. The compound of claim 1 , wherein b is zero.

14. The compound of claim 1 , wherein X is SO 2 .

15. The compound of claim 1 , wherein a and c are each one, and b is zero.

16. The compound of claim 1 , wherein a is one, and R 1 is halogen.

17. The compound of claim 1 , wherein a is 1, b is zero, R 1 is halogen, and X is SO 2 .

18. The compound of claim 1 , wherein A is

wherein R 4 is H; R 5 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —N(alkyl) 2 , —NH(alkyl), phenyl, N-heteroaryl, or N-heterocycloalkyl; and X is SO 2 .

19. The compound of claim 1 , wherein the compound has a structure of:

20. The compound of claim 1 , wherein the compound has a structure of:

21. The compound of claim 20 , wherein R 5 is methyl, phenyl, —NHBoc, pyridinyl, cyclopropyl, tert-butyl, morpholinyl, pyrrolidinyl, or —N(methyl) 2 .

22. The compound of claim 20 , wherein R 5 is methyl.

23. The compound of claim 1 , wherein the compound is an S-enantiomer:

24. The compound of claim 1 , wherein the compound has a plasma half-life of 4 to 8 hours.

25. The compound of claim 1 , wherein the compound preferentially targets CB 1 receptors in peripheral tissue, while not interacting with CB 1 receptors in brain tissue.

26. A pharmaceutical composition comprising a compound of claim 1 , and at least one pharmaceutically acceptable additive.

27. A method for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, a co-morbidity of obesity, dyslipidemias that predispose to arteriosclerotic heart disease, diabetic nephropathy, or gout, in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1 , wherein the co-morbidity of obesity is selected from Metabolic Syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis; venous statis ulcers, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arterial sclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovaries, cervix, uterus, breasts, prostrate, or gallbladder.

28. The method of claim 27 , comprising treating obesity in the subject.

29. The method of claim 27 , comprising treating diabetes in the subject.

30. The method of claim 27 , wherein administering of the compound causes substantially no adverse neuropsychiatric effects.

31. The method of claim 27 , wherein administering of the compound results in a ratio of maximum concentration in the brain to maximum concentration in plasma which is less than 0.1.

32. A method for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, a co-morbidity of obesity, dyslipidemias that predispose to arteriosclerotic heart disease, diabetic neuropathy, or gout in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of claim 18 , wherein the co-morbidity of obesity is selected from Metabolic Syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis; venous statis ulcers, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arterial sclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovaries, cervix, uterus, breasts, prostrate, or gallbladder.

Assignees

• Us Health

Inventors

• Kunos George
• Iyer Malliga
• Cinar Resat
• Rice Kenner C

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title