IP Library Granted Patent US 8,314,096
Granted Patent B2
US 8,314,096 · App. 12/703,126 · Granted Nov 20, 2012

Sigma receptor inhibitors

Assignee: Laboratorios del Dr. Esteve, S.A.
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Quick Facts
Patent No.
US 8,314,096
App. No.
12/703,126
Granted
Nov 20, 2012
Kind
B2
Abstract

The invention relates to compounds of formula (I) having pharmacological activity towards the sigma receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which the sigma receptor is involved.

Claims (72)

1. A method for the treatment or prophylaxis of pain, comprising administering to a patient a therapeutically effective amount of a compound of formula (I)

wherein

R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —CH═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , and halogen;

R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —CH═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t —R 8 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , and halogen;

R 3 and R 4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —CH═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t —R 8 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , and halogen, or together they form a fused ring system,

R 5 and R 6 together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group;

n is 1, 2, 3, 4, 5, 6, 7 or 8;

t is 1, 2 or 3;

R 8 and R 9 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein the pain is neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia.

3. The method according to claim 1 wherein R 1 is H, —COR 8 , or substituted or unsubstituted alkyl.

4. The method according to claim 1 wherein R 1 is H, methyl or acetyl.

5. The method according to claim 1 wherein R 1 is hydrogen.

6. The method according to claim 1 wherein R 2 is H or alkyl.

7. The method according to claim 1 wherein R 2 is methyl or H.

8. The method according to claim 1 wherein R 3 and R 4 are situated in the meta and para positions of the phenyl group.

9. The method according to claim 1 wherein R 3 and R 4 are independently selected from the group consisting of halogen, and substituted or unsubstituted alkyl.

10. The method according to claim 1 wherein R 3 and R 4 are independently selected from the group consisting of halogen and haloalkyl.

11. The method according to claim 1 wherein n is selected from 2, 3, or 4.

12. The method according to claim 1 wherein n is 2.

13. The method according to claim 1 wherein R 5 and R 6 together form a morpholine-4-yl group.

14. The method according to claim 1 wherein the compound of formula (I) is selected from the group consisting of:

4-{2-(1-(3,4-dichlorophenyl)-5-methyl-1H pyrazol-3-yloxy)ethyl}morpholine;

1-(3,4-Dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;

1-(3,4-Dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;

1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperidine;

1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole;

3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine;

1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-4-methylpiperazine;

Ethyl 4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazine carboxylate;

1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone;

4-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine;

1-(4-Methoxyphenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;

1-(4-Methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;

1-[2-(1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidine;

1-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole;

4-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}morpholine;

1-(3,4-Dichlorophenyl)-5-methyl-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole;

1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}piperidine;

1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-4-methylpiperazine;

1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-1H-imidazole;

1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-4-phenylpiperidine;

1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-6,7-dihydro-1H-indol-4(5H)-one;

2-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-1,2,3,4-tetrahydroisoquinoline;

4-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}morpholine;

1-(3,4-Dichlorophenyl)-5-isopropyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;

1-(3,4-Dichlorophenyl)-5-isopropyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;

1-{2-[1-(3,4-Dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}piperidine;

2-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoquinoline;

4-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}morpholine;

1-(3,4-dichlorophenyl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;

1-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}piperidine;

1-(3,4-dichlorophenyl)-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;

1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazine;

1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine;

4-{2-[1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy]ethyl}morpholine;

1-(3,4-Dichlorophenyl)-4,5-dimethyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;

1-(3,4-Dichlorophenyl)-4,5-dimethyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;

1-{2-[1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy]ethyl}piperidine;

4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}morpholine;

(2S,6R)-4-{-4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}-2,6-dimethylmorpholine;

1-{4-[1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}piperidine;

1-(3,4-Dichlorophenyl)-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole;

4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}thiomorpholine;

1-[1-(3,4-Dichlorophenyl)-5-methyl-3-(2-morpholinoethoxy)-1H-pyrazol-4-yl]ethanone;

1-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazol-4-yl}ethanone;

1-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(piperidin-1-yl)ethoxy]-1H-pyrazol-4-yl}ethanone;

4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine;

1-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}piperidine; and

5-Methyl-1-(naphthalen-2-yl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole

or a pharmaceutically acceptable salt thereof.

Assignments (1)
CHANGE OF NAME Recorded Dec 17, 2018
From: LABORATORIOS DEL DR. ESTEVE S.A.
To: ESTEVE PHARMACEUTICALS, S.A.
Reel/Frame 047931/0001 →
Continuity (1)
Related Publication 20100190781A1 · Jul 29, 2010