USE OF SIGMA RECEPTOR LIGANDS IN OSTEOARTHRITIS

• US 20170273948A1
• Filed: 12/15/2015
• Published: 09/28/2017
• Est. Priority Date: 12/15/2014
• Status: Abandoned Application

• Current Assignee: Laboratories Del Dr Esteve SA (Corporation Quimico Farmaceutica Esteve SA)
• Original Assignee: Laboratories Del Dr Esteve SA (Corporation Quimico Farmaceutica Esteve SA)
• Inventors: VELA HERNNDEZ, Jos Miguel, MERLOS-ROCA, Manuel, ZAMANILLO-CASTANEDO, Daniel
• Application Number:
  US15/532,168
• Publication Number:
  US 20170273948A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to compounds of formula (I) or formula (II)

having pharmacological activity towards the sigma receptor, for use in the treatment or prevention of osteoarthritis and pain due to osteoarthritis.

Claims

1-15. -15. (canceled)

16. A method for the treatment or prevention of a condition selected from osteoarthritis and pain due to osteoarthritis in a subject in need thereof, comprising administration of a compound binding to the sigma-receptor.

17. The method according to claim 16, wherein the condition is pain due to osteoarthritis.

18. The method according to claim 17, wherein the pain is selected from acute and/or chronic pain due to osteoarthritis, including neuropathic pain, neuralgia, allodynia, causalgia, hyperalgesia, hyperesthesia, hyperpathia, neuritis or neuropathy secondary to surgical procedure.

19. The method according to claim 16, wherein the compound is selected from a sigma receptor antagonist, a neutral antagonist, an inverse agonist or a partial antagonist, and/or wherein the compound binds to the sigma-1 receptor subtype.

20. The method according to claim 16, wherein the compound is a compound of formula I:

21. The method according to claim 20, wherein R₁ is hydrogen.

22. The method according to claim 20, wherein R₂ is H or alkyl;

and/or

R₃ and R₄ together with the phenyl form a naphthyl group.

23. The method according to claim 22, wherein R₂ is H or methyl.

24. The method according to claim 20, wherein n is 2, 3, or 4;

and/or

R₅ and R₆, together with the nitrogen atom to which they are attached, form a morpholine-4-yl group.

25. The method according to claim 24, wherein n is 2.

26. The method according to claim 16, wherein the compound is selected from 4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine, or a pharmaceutically acceptable salt or solvate thereof, and 4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride or a solvate thereof.

27. The method according to claim 16, wherein the compound is a compound of formula II:

28. The method according to claim 27, wherein R′

¹ is selected from a 5- to 10 membered substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group which may contain N, O or S as a ring member;

a 5- to 10 membered substituted or unsubstituted aryl group, and a 5- to 10 membered substituted or unsubstituted cycloalkyl group.

29. The method according to claim 28, wherein R′

¹ is selected from substituted or unsubstituted cyclopentyl, substituted or =substituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzofuran, substituted or unsubstituted pyridine, and substituted or unsubstituted quinoline.

30. The method according to claim 27, wherein R′

² and R′

³ are independently selected from H and substituted or unsubstituted C_1-6 alkyl.

32. The method according to claim 27, wherein R′

⁴ and R′

⁵, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclyl group.

33. The method according to claim 32, wherein R′

⁴ and R′

³, together with the nitrogen atom to which they are attached, form a morpholine-4-yl group, a piperidine-4-yl group, pyrrolidine-4-yl group or a piperazine-4-yl group.

34. The method according to claim 27, wherein m′

and n′

are independently selected from 1 and 2; and

/or

X represents an oxygen atom or a —

CH₂—

group.

35. The method according to claim 27, wherein the compound is selected from 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone, or a pharmaceutically acceptable salt or solvate thereof, and 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone hydrochloride or a solvate thereof.

36. The method according to claim 16, wherein the compound is selected from 1-(4-(2-((1-(3-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone, or a pharmaceutically acceptable salt or solvate thereof;

1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone hydrochloride or a solvate thereof;

4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine, or a pharmaceutically acceptable salt or solvate thereof; and

4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride or a solvate thereof.

31. The method according to claim 31, wherein R′

² and R′

³ are independently selected from H and methyl.