Use of aminoindane compounds in treating overactive bladder and interstitial cystitis

1. A method of treating an overactive bladder, said method comprising administering to a patient in need thereof a therapeutically effective amount of 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 method according to claim 1 , wherein said compound contains at least 1 chiral center.

3. The method according to claim 1 , wherein said compound is a mixture of enantiomers.

4. The method according to claim 1 , wherein said compound is an R-enantiomer.

5. The method according to claim 1 , wherein said compound is an S-enantiomer.

6. The method according to claim 1 , wherein said compound has the structure:

7. The method according to claim 1 , wherein said compound 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.

8. The method according to claim 1 , further comprising administering a therapeutically effective amount of a TRPV1 receptor activator.

9. The method according to claim 8 , wherein said TRPV1 receptor activator is selected from the group consisting of capsaicin, dihydrocapsaicin, nordihydrocapsaicin, lidocaine, articaine, procaine, tetracaine, mepivicaine, bupivicaine, eugenol, camphor, clotrimazole, N-arachidonoylvanillamine, anandamide, 2-aminoethoxydiphenyl borate, AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate, olvanil, N-oleoyldopamine, N-arachidonyldopamine, 6′-iodoresiniferatoxin, a C 18 N-acylethanolamine, a lipoxygenase derivative, nonivamide, a fatty acyl amide of a tetrahydroisoquinoline inhibitor cysteine knot peptide, pipeline, N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide, N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea, hydroxy-α-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol, oleylgingerol, oleylshogaol, N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea, aprindine, benzocaine, butacaine, cocaine, dibucaine, encamide, mexiletine, oxetacaine, prilocalne, proparacaine, procainamide, n-acetylprocainamide, chloroprocaine, dyclonine, etidocaine, levobupivacaine, ropivacaine, cyclomethycaine, dimethocaine, propoxycaine, trimecaine, and sympocaine.

10. The method according to claim 8 , wherein said TRPV1 receptor activator and said compound of formula (I), formula (II), or a combination thereof are co-administered.

11. The method according to claim 10 , wherein the ratio of said TRPV1 receptor activator to said compound of formula (I), formula (II), or a combination thereof, is about 1:1 to about 10:1.

12. The method according to claim 1 , wherein said compound of formula (I) or (II) is administration by direct instillation into the bladder or urothelium.

13. The method according to claim 1 , wherein said compound of formula (I) or (II) is placed into the bladder or urothelium in an extended-release formulation.

14. The method according to claim 1 , wherein said compound of formula (I) or (II) is injected directly into the urothelium.