Aminoindane compounds and use thereof in treating pain

1. A compound of formula (I) or (II):

wherein:

A is phenyl or heteroaryl;

R 1 and R 4 are, independently, C 1 to C 6 alkyl or CH 2 CH 2 OH; or

R 1 and R 4 are joined to form a 4- or 6-membered carbocyclic or heterocyclic ring;

R 2 is independently selected from the group consisting of hydrogen, halogen, NO 2 , OH, and C 1 to C 6 alkoxy;

R 3 is independently selected from the group consisting of hydrogen, halogen, CN, NO 2 , NH 2 , optionally substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, OH, CF 3 , OCF 3 , SCF 3 , optionally substituted C 1 to C 6 alkoxy, C 2 to C 6 alkynyloxy, heterocyclyloxy, heteroaryloxy, optionally substituted C 1 to C 6 alkylthio, heteroarylthio, C(O)O(C 1 to C 6 alkyl), C(O)(C 1 to C 6 alkyl), C(O)(aryl), C(O)(heterocycle), C(O)NH 2 , C(O)NH(C 1 to C 6 alkyl), C(O)NH(aryl), C(O)NH(heterocycle), C(O)NH(heteroaryl), C(O)N(C 1 to C 6 alkyl)(C 1 to C 6 alkyl), C(O)N(aryl)(C 1 to C 6 alkyl), C(S)NH 2 , optionally substituted aryl, heteroaryl, heterocycle, NHC(O)(C 1 to C 6 alkyl), NHC(O)(aryl), NHC(O)(heteroaryl), NHC(O)O(C 1 to C 6 alkyl), N(C 1 to C 6 alkyl)C(O)(C 1 to C 6 alkyl), N(C 1 to C 6 alkyl)C(O)O(C 1 to C 6 alkyl), NHC(O)NH 2 , NHC(O)NH(C 1 to C 6 alkyl), NHC(O)NH(heteroaryl), NHSO 2 (C 1 to C 6 alkyl), SO 2 (C 1 to C 6 alkyl), SO 2 NH 2 , SO 2 NH(C 1 to C 6 alkyl), SO 2 NH(C 2 to C 6 alkynyl), SO 2 N(C 1 to C 6 alkyl)(C 1 to C 6 alkyl), SO 2 NH(heteroaryl), NH(C 1 to C 6 alkyl), N(C 1 to C 6 alkyl)(C 1 to C 6 alkyl), N(C 1 to C 6 alkyl)(C 2 to C 6 alkenyl), and N(C 1 to C 6 alkyl)(heterocycle); or

q is 2 and two R 3 groups are joined to form an optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered carbocyclic ring, or optionally substituted 5- or 6-membered heterocycle or heteroaryl containing 1 to 3 oxygen, nitrogen, or sulfur atoms and 4 or 5 carbon atoms;

m is 1 to 5;

n is 1 to 3;

p is 0 to 2;

q is 0 to 4; and

X − is a halogen ion, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, citrate, pyruvate, succinate, oxalate, bisulfate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate, edisylate, isethionate, D-mandelate, L-mandelate, propionate, tartarate, phthalate, hydrochlorate, hydrobromate, nitrate, methanesulfonate, ethanesulfonate, napthalenesulfonate, benzenesulfonate, toluenesulfonate, mesitylenesulfonate, camphorsulfonate or trifluoromethanesulfonate.

2. The compound according to claim 1 , wherein two hydrogen atoms attached to a carbon atom are replaced with a double bond to an oxygen atom to form a carbonyl.

3. The compound according to claim 1 , which contains at least 1 chiral center.

4. The compound according to claim 1 , which is a mixture of enantiomers.

5. The compound according to claim 1 , which is an R-enantiomer.

6. The compound according to claim 1 , which is an S-enantiomer.

7. The compound according to claim 1 , wherein p is 0.

8. The compound according to claim 1 , wherein q is 0.

9. The compound according to claim 1 , wherein n is 1.

10. The compound according to claim 1 , wherein n is 2.

11. The compound according to claim 1 , wherein n is 3.

12. The compound according to claim 1 , wherein m is 3.

13. The compound according to claim 1 , wherein m is 2.

14. The compound according to claim 1 which has the structure:

15. The compound according to claim 1 which has the structure:

16. The compound according to claim 1 which has the structure:

17. The compound according to claim 16 which has the structure:

18. The compound according to claim 1 which is:

19. The compound according to claim 1 which is:

20. The compound according to claim 19 which is:

21. The compound according to claim 1 which is:

22. The compound according to claim 1 which is:

a racemic mixture of

23. The compound according to claim 1 which is selected from the group consisting of

(S)-1,1-dimethyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]piperidinium iodide,

(R)-1,1-dimethyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]piperidinium iodide,

(S)-1,1-diethyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]piperidinium iodide,

(R)-1,1-diethyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]piperidinium iodide,

(S)-1,1-dipropyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]piperidinium iodide,

(R)-1,1-dipropyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]piperidinium iodide,

(S)-1,1-dimethyl-2-[((indan-2-yl)(phenyl)amino)methyl]piperidinium iodide,

(R)-1,1-dimethyl-2-[((indan-2-yl)(phenyl)amino)methyl]piperidinium iodide,

(S)-1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium iodide,

(R)-1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-2-[((indan-2-yl)(phenyl)amino)methyl]piperidinium iodide,

1,1-dimethyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]pyrrolidinium iodide,

1,1-diethyl-2-[((indan-2-yl)(phenyl)amino)methyl]piperidinium iodide,

1,1-dimethyl-2-[2-((2-fluorophenyl)(indan-2-yl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-2-[2-((3-fluorophenyl)(indan-2-yl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-2-[2-((4-fluorophenyl)(indan-2-yl)amino)ethyl]piperidinium iodide,

1,1-diethyl-2-[2-((2-fluorophenyl)(indan-2-yl)amino)ethyl]piperidinium iodide,

1,1-diethyl-2-[2-((3-fluorophenyl)(indan-2-yl)amino)ethyl]piperidinium iodide,

1,1-diethyl-2-[2-((4-fluorophenyl)(indan-2-yl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-2-[2-((indan-2-yl)(3-methylphenyl)amino)ethyl]piperidinium iodide,

1,1-diethyl-2-[2-((indan-2-yl)(3-methylphenyl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-2-[2-((indan-2-yl)(4-methylphenyl)amino)ethyl]piperidinium iodide,

1,1-diethyl-2-[2-((indan-2-yl)(4-methylphenyl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium iodide,

1,1-diethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium iodide,

6-[2-((indan-2-yl)(phenyl)amino)ethyl]-5-azoniaspiro[4.5]decane bromide,

1,1-dimethyl-2-[3-((indan-2-yl)(phenyl)amino)propyl]piperidinium iodide,

1,1-diethyl-2-[3-((indan-2-yl)(phenyl)amino)propyl]piperidinium iodide,

1,1-dimethyl-2-[((indan-2-yl)(4-methylphenyl)amino)methyl]piperidinium iodide,

1,1-dimethyl-2-[((4-fluorophenyl)(indan-2-yl)amino)methyl]piperidinium iodide,

1,1-dimethyl-2-[((indan-2-yl)(3-methylphenyl)amino)methyl]piperidinium iodide,

1,1-diethyl-2-[((indan-2-yl)(4-methylphenyl)amino)methyl]piperidinium iodide,

1,1-dimethyl-2-[(3-fluorophenyl)(indan-2-yl)amino)methyl]piperidinium iodide,

1,1-dimethyl-2-[((indan-2-yl)(phenyl)amino)methyl]pyrrolidinium iodide,

1,1-diethyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]pyrrolidinium iodide,

1,1-dimethyl-2-[2-((indan-2-yl)(pyridine-2-yl)amino)ethyl]piperidinium iodide.

1,1-dimethyl-2-[2-((indan-2-yl)(pyrimidine-2-yl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-2-[2-((indan-2-yl)(thiazol-2-yl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-4-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium bromide,

7-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]-3-oxa-6-azaspiro[5.5]undecan-6-ium chloride,

1,1-dimethyl-2-[2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)(indan-2-yl)amino)ethyl]piperidinium iodide,

(R)-1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium bromide,

(S)-1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium chloride,

1,1-dimethyl-4-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium iodide,

1,1-bis(2-hydroxyethyl)-2-[2-((indan-2-yl)(2-methylphenyl)amino) ethyl]piperidinium bromide,

1,1-dimethyl-2-[2-((indan-2-yl)(6-methylpyridine-2-yl)amino)ethyl]piperidinium iodide,

1,1-dimethyl-2-[2-((indan-2-yl)(6-methylpyridine-2-yl)amino)ethyl]piperidinium bromide,

(S)-1,1-diethyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]piperidinium bromide,

1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium chloride,

(R)-1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium chloride, and

1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl]piperidinium bromide.

24. A composition comprising said compound of formula (I) or formula (II) of claim 1 , or a combination thereof, and a carrier.

25. A method for treating pain or itch in a patient, said method comprising administering to said patient said compound of formula (I) or formula (II) of claim 1 , or a combination thereof.

26. A method for preparing said compound (I) of claim 1 , wherein A is phenyl, said method comprising:

(i) converting

 to

(ii) converting said compound 2a to

(iii) reducing said compound 4a to

(iv) chlorinating said compound 5a to form

(v) coupling said compound 6a with

 to form

(vi) removing the benzyl group of compound 8a via hydrogenation to form

(vii) R 1 substituting compound 9a to form

and

(viii) R 4 substituting compound 11a.

27. The method according to claim 26 , wherein said compound 1a is

compound 2a is

compound 4a is

compound 5a is

compound 6a is

compound 8a is

compound 9a is

and compound 11a is

28. A method for preparing said compound of claim 1 , wherein A is phenyl, said method comprising:

(vii) R 1 and R 4 substituting compound 9c:

29. The method according to claim 28 , wherein said compound 9c is

30. A method for preparing said compound of claim 1 , wherein A is phenyl, said method comprising:

(i) protecting the nitrogen atom of

 to form

(ii) chlorinating said compound 13a to form

(iii) coupling said compound 14a with

 to form

(iv) deprotecting compound 15a to form

(v) R 1 substituting said compound 16a to form

 and

(vi) R 4 substituting compound 17a.

31. The method according to claim 30 , wherein said compound 12a is piperidine-2-methanol, compound 13a is

compound 14a is

compound 15a is

compound 16a is

and compound 17a is

32. A method for preparing said compound of claim 1 , wherein A is phenyl, R 3 is 2-F, m is 2, and q is 1, said method comprising:

(vi) R 1 and R 4 substituting compound 9d:

33. The method according to claim 32 , wherein compound 9d has the following structure:

34. A method for preparing said compound of claim 1 , wherein A is phenyl, said method comprising:

(i) coupling

 and

 to form

 and

(ii) R 4 substituting compound 17a.

35. The method according to claim 34 , wherein said compound 18a is

and compound 17a is

36. A method for preparing said compound of claim 1 , wherein m is 3, said method comprising:

(i) reducing

 using an acid to form

(ii) protecting compound 21a with a benzyl group to provide

(iii) oxidizing compound 22a to provide

(iv) coupling compound 23a with

 to provide

(v) substituting the nitrogen atom of said compound 24a with a R 3 -substituted phenyl group to form

(vi) deprotecting said compound 25a to provide

 and

(v) R 1 and R 4 substituting said compound 26a.

37. The method according to claim 36 , wherein said compound 20a is

compound 21a is

compound 22a is

compound 23a is

compound 24a is

compound 25a is

and compound 26a is

38. A method for preparing said compound of claim 1 , wherein A is phenyl, said method comprising:

(i) converting

 to

(ii) converting said compound 2a to

(iii) reducing said compound 4a to

(iv) oxidizing compound 5a to provide

(v) coupling said compound 23a with

 to provide

(v) substituting the nitrogen atom of compound 24c with an R 3 -substituted phenyl group to provide

 and

(vi) deprotecting compound 8c to form

 and

(vii) R 1 and R 4 substituting the nitrogen ring.

39. The method according to claim 38 , wherein said compound 1a is

compound 2c is

compound 4c is

compound 5c is

compound 31 is

compound 24c is

compound 8c is

and compound 9f is

40. A method for preparing said compound of claim 1 , said method comprising:

(i) converting

 to

(ii) reducing compound 2b to

(iii) oxidizing compound 37a to

(iv) coupling compound 38a with

 to

(v) coupling compound 39a with an A-(R 3 ) q group to form

(vi) deprotecting compound 40a to form

 and

(vii) R 1 and R 4 substituting compound 41a.

41. The method according to claim 40 , wherein:

compound 1a is

 compound 2b is

 compound 37a is

 compound 38a is

 compound 39a is

 compound 40a is

 and compound 41a is

42. A method for preparing said compound of claim 1 , said method comprising:

(i) BOC protecting

 to form

(ii) oxidizing compound 37a to form

(iii) coupling compound 38a with

 to form

(iv) substituting compound 39a with A-(R 3 ) q to form

(v) deprotecting compound 40a to form

 and

(vi) R 1 and R 4 substituting compound 41a.

43. The method according to claim 42 , wherein:

compound 12b is

 compound 37a is

 compound 38a is

 compound 39a is

 compound 40a is

 and compound 41a is

44. A method for preparing said compound of claim 1 , wherein n is 2, said method comprising:

(i) substituting

 with A-(R 3 ) q to form

(ii) deprotecting compound 40a to form

and

(iii) R 1 and R 4 substituting compound 41a.

45. The method according to claim 44 , wherein:

compound 39a is

compound 40a is

and compound 41a is

46. A method for preparing said compound of claim 1 , said method comprising:

(i) protecting

 to form

(ii) oxidizing compound 5a to form

(iii) coupling compound 23a with

 to form

(iv) substituting compound 24f with A-(R 3 ) q to form

(v) deprotecting compound 8e to form

(vi) R 1 substituting compound 41a to form

 and

(vii) R 4 substituting compound 61c.

47. The method according to claim 46 , wherein:

compound 12b is

 compound 5a is

 compound 23c is

 compound 24f is

 compound 8e is

 compound 41a is

 and compound 61c is

48. A method for preparing said compound of claim 1 , said method comprising reacting

with X″—(CH 2 ) r —Y—(CH 2 ) s —X″, wherein:

r is 1 to 4;

s is 1 to 4;

Y is CH 2 , O, or S; and

X″ is a leaving group.

49. The method according to claim 48 , wherein compound 41a is

and X″—(CH 2 ) r —Y—(CH 2 ) s —X″ is C1CH 2 CH 2 OCH 2 CH 2 Cl.

50. A method for preparing said compound of claim 1 , said method comprising:

(i) reacting

 with H 2 N-A-(R 3 ) q to form

(ii) coupling compound 7c with

 to form

(iii) deprotecting compound 8f to form

(iv) R 1 substituting compound 9h to form

 and

(v) R 4 substituting compound 61a.

51. The method according to claim 50 , wherein H 2 N-A-(R 3 ) q is

compound 7c is

compound 58a is

compound 8f is

compound 9h is

and compound 61a is

52. A method for preparing said compound of claim 1 , wherein R 4 is CH 3 , said method comprising:

(i) oxidizing

 to form

(ii) coupling compound 38a with

 to form

(iii) reducing compound 40a to form

 and

(iv) R 1 substituting compound 41c.

53. The method according to claim 52 , wherein compound 40a is prepared by adding compound 38a to a solution comprising compound 7c and a mild reducing agent.

54. The method according to claim 53 , wherein said mild reducing agent is Na(OAc) 3 BH.

55. The method according to claim 52 , wherein the % ee of compound 40a is at least about 97% ee.