Combinations

• US 20050065176A1
• Filed: 09/08/2004
• Published: 03/24/2005
• Est. Priority Date: 09/22/2003
• Status: Abandoned Application

• Current Assignee: Mark John Field, Richard Griffith Williams
• Original Assignee: Mark John Field, Richard Griffith Williams
• Inventors: Williams, Richard Griffith, Field, Mark John
• Application Number:
  US10/936,416
• Publication Number:
  US 20050065176A1
• Time in Patent Office: Days
• US Class Current: 514/291
• 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 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The instant invention relates to a combination of an alpha-2-delta ligand and an AChE inhibitor for use in therapy, particularly in the treatment of pain, particularly neuropathic pain. Particularly preferred alpha-2-delta ligands are gabapentin and pregabalin. Particularly preferred ACHE inhibitors are donepezil (Aricept®), tacrine (cognex®), rivastigmine (Exelon®), physostgmine (Synapton®), galantamine (Reminyl), metrifonate (Promem), neostigmine (Prostigmin) and icopezil.

Claims

1. A combination comprising an alpha-2-delta ligand and an AChE inhibitor or a pharmaceutically acceptable salt or solvate of either thereof.

2. A combination according to claim 1, wherein the components are in a synergistic ratio.

3. A combination according to claim 1, wherein the alpha-2-delta ligand is selected from gabapentin, pregabalin, [(1R,5R,6S)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-Aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-Tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (1α

,3α

,5α

)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid and (3S,5R)-3-Amino-5-methyl-octanoic acid, or a pharmaceutically acceptable salt thereof.

4. A combination according to claim 1, wherein the AChE inhibitor is selected from donepezil (Aricept®

), tacrine (cognex®

), rivastigmine (Exelon®

), physostgmine (Synapton®

), galantamine (Reminyl), metrifonate (Promem), neostigmine (Prostigmin), icopezil, hupazine A, zanapezil (TAK

     147), stacofylline, phenserine, (5R,9R)-5-(r-chloro-2-hydroxy-3-methoxybenzylidene-amino)-11-ethlidene-7-methyl-1,2,5,6,9,10-hexahydro-5,9-methanocycloocta[b]pyridin-2-one (ZT

     1), the galantamine derivatives SPH 1371, SPH 1373 and SPH 1375, tolserine, 1-(3-fluorobenzyl)-4-[(2-fluoro-5,6-dimethoxy-1-indanone-2-yl)methyl]piperidine hydrochloride (ER127528), thiatolserine, (−

)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride (huperine X), N,N-dimethylcarbamic acid 4-[1(S)-(methylamino)-3-(4 nitrophenoxy)propyl]phenyl ester hemifumarate (RS

     1259), ipidacrine (Amiridin), velnacrine (Mentane®

), eptastigmine (heptylphysostigmine), zifrosilone (2,2,2-trifluoro-1-[3-(trimethylsilyl)phenyl]ethanone), 2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinolin-1-one hemifumerate (T

     82), 1,3-dichloro-6,7,8,9,10,12-hexahydroazepino[2,1-b]-quinazoline (CI

     1002), N-heptylcarbamic acid 2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1,2-oxazino[6,5-b]indol-6-yl ester-L-tartrate (CHF

     2060), 3-(2-[1-(1,3-dioxolan-2-ylmethyl)piperidin-4-yl]ethyl)-3,4-dihydro-2H-1,3-benzoxazine-2,4-dione hydrochloride (E

     2030), N-[10-(diethylamino)decyl]carbamic acid (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester (MF

     247), 5-amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thiopyrano-[3,4-b]quinoline (MF

     8615), N-[8-(cis-2,6-dimethylmorpholin-4-yl)octyl]carbamic acid (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester L-bitartrate hydrate (MF

     268), (−

)N-(3-piperidinopropyl)-N-demethylgalantamine (SPH

     1286) and N-propargyl-3R-aminoindan-5-yl-ethyl methyl carbamate (TV

     3326), or a pharmaceutically acceptable salt thereof.

5. A combination according to claim 1, wherein the AChE inhibitor is selected from:

Donepezil

Tacrine;

Rivastigmine;

Physostigmine;

Galantamine;

Metrifonate;

Neostigmine; and

Icopezil;

or a pharmaceutically acceptable salt thereof.

6. A combination according to claim 1, wherein the AChE inhibitor is donepezil or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a therapeutically effective amount of a combination according to claim 1.

8. A method for the curative, prophylactic or palliative treatment of pain, comprising simuHaneous, sequential or separate administration of a therapeutically effective amount of an alpha-2delta ligand and an AchE inhibitor, or pharmaceutically acceptable salt thereof, to a a mammal in need of said treatment.

9. A method according to claim 8 where the pain is neuropathic pain.

10. A combination comprising gabapentin, or a pharmaceutically acceptable salt thereof, and a AChE inhibitor selected from donepezil (Aricept®

), tacrine (cognex®

), rivastigmine (Exelon®

), physostgmine (Synapton®

), galantamine (Reminyl), metrifonate (Promem), neostigmine (Prostigmin), icopezil, hupazine A, zanapezil (TAK

     147), stacofylline, phenserine, (5R,9R)-5-(r-chloro-2-hydroxy-3-methoxybenzylidene-amino)-11-ethlidene-7-methyl-1,2,5,6,9,10-hexahydro-5,methanocycloocta[b]pyridin-2-one (ZT

     1), the galantamine derivatives SPH 1371, SPH 1373 and SPH 1375, tolserine, 1-(3-fluorobenzyl)-4-[(2-fluoro-5,6-dimethoxy-1-indanone-2-yl)methyl]piperidine hydrochloride (ER

     127528), thiatolserine, (−

)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride (huperine X), N,N-dimethylcarbamic acid 4-[1 (S)-(methylamino)-3-(4-nitrophenoxy)propyl]phenyl ester hemifumarate (RS

     1259), ipidacrine (Amiridin), velnacrine (Mentane®

), eptastigmine (heptylphysostigmine), zifrosilone (2,2,2-trifluoro-1-[3-(trimethylsilyl)phenyl]ethanone), 2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinolin-1-one hemifumerate (T

     82), 1,3-dichloro-6,7,8,9,10,12-hexahydroazepino[2,1-b]-quinazoline (CI

     1002), N-heptylcarbamic acid 2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1,2-oxazino[6,5-b]indol-6-yl ester-L-tartrate (CHF

     2060), 3-(2-[1-(1,3-dioxolan-2-ylmethyl)piperidin-4-yl]ethyl)-3,4-dihydro-2H-1,3-benzoxazine-2,4-dione hydrochloride (E

     2030), N-[10-(diethylamino)decyl]carbamic acid (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester (MF

     247), 5-amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thiopyrano-[3,4-b]quinoline (MF

     8615), N-[8-(cis-2,6-dimethylmorpholin-4-yl)octyl]carbamic acid (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester L-bitartrate hydrate (MF

     268), (−

)N-(3-piperidinopropyl)-N-demethylgalantamine (SPH

     1286) and N-propargyl-3R-aminoindan-5-yl-ethyl methyl carbamate (TV

     3326), or a pharmaceutically acceptable salt thereof.

11. A combination according to claim 10 comprising gabapentin and donepezil or pharmaceutically acceptable salts thereof.

12. A combination comprising pregabalin and a AChE inhibitor selected from donepezil (Aricept®

), tacrine (cognex®

), rivastigmine (Exelon®

), physostgmine (Synapton®

), galantamine (Reminyl), metrifonate (Promem), neostigmine (Prostigmin), icopezil, hupazine A, zanapezil (TAK

     147), stacofylline, phenserine, (5R,9R)-5-(r-chloro-2-hydroxy-3-methoxybenzylidene-amino)-11-ethlidene-7-methyl-1,2,5,6,9,10-hexahydro-5,9-methanocycloocta[b]pyridin-2-one (ZT

     1), the galantamine derivatives SPH 1371, SPH 1373 and SPH 1375, tolserine, 1-(3-fluorobenzyl)-4-[(2-fluoro-5,6-dimethoxy-1-indanone-2-yl)methyl]piperidine hydrochloride (ER

     127528), thiatolserine, (−

)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11 methanocycloocta[b]quinoline hydrochloride (huperine X), N,N-dimethylcarbamic acid 4-[1(S)-(methylamino)-3-(4-nitrophenoxy)propyl]phenyl ester hemifumarate (RS

     1259), ipidacrine (Amiridin), velnacrine (Mentane®

), eptastigmine (heptylphysostigmine), zifrosilone (2,2,2-trifluoro-1-[3-(trimethylsilyl)phenyl]ethanone), 2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinolin-1-one hemifumerate (T

     82), 1,3-dichloro-6,7,8,9,10,12-hexahydroazepino[2,1-b]-quinazoline (CI

     1002), N-heptylcarbamic acid 2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1,2-oxazino[6,5-b]indol-6-yl ester-L-tartrate (CHF

     2060), 3-(2-[1-(1,3-dioxolan-2-ylmethyl)piperidin-4-yl]ethyl)-3,4-dihydro-2H-1,3-benzoxazine-2,4-dione hydrochloride (E

     2030), N-[10-(diethylamino)decyl]carbamic acid (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester (MF

     247), 5-amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thiopyrano-[3,4-b]quinoline (MF

     8615), N-[8-(cis-2,6-dimethylmorpholin-4-yl)octyl]carbamic acid (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester L-bitartrate hydrate (MF

     268), (−

)N-(3-piperidinopropyl)-N-demethylgalantamine (SPH

     1286) and N-propargyl-3R-aminoindan-5-yl-ethyl methyl carbamate (TV

     3326), or a pharmaceutically acceptable salt thereof.

13. A combination according to claim 12 comprising pregabalin and donepezil or pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition for the curative, prophylactic or palliative treatment of pain, comprising an alpha-2-delta ligand selected from pregabalin or gabapentin and a AChE inhibitor selected from donepezil (Aricept®

), tacrine (cognex®

), rivastigmine (Exelon®

), physostgmine (Synapton®

), galantamine (Reminyl), metrifonate (Promem), neostigmine (Prostigmin), icopezil, hupazine A, zanapezil (TAK

     147), stacofylline, phenserine, (5R,9R)-5-(r-chloro-2-hydroxy-3-methoxybenzylidene-amino)-11-ethlidene-7-methyl-1,2,5,6,9,10-hexahydro-5,9-methanocycloocta[b]pyridin-2-one (ZT

     1), the galantamine derivatives SPH 1371, SPH 1373 and SPH 1375, tolserine, 1-(3-fluorobenzyl)-4-[(2-fluoro-5,6-dimethoxy-1-indanone-2-yl)methyl]piperidine hydrochloride (ER

     127528), thiatolserine, (−

)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride (huperine X), N,N-dimethylcarbamic acid 4-[1 (S)-(methylamino)-3-(4-nitrophenoxy)propyl]phenyl ester hemifumarate (RS

     1259), ipidacrine (Amiridin), velnacrine (Mentane®

), eptastigmine (heptylphysostigmine), zifrosilone (2,2,2-trifluoro-1-[3-(trimethylsilyl)phenyl]ethanone), 2-[2-(1 benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinolin-1-one hemifumerate (T

     82), 1,3-dichloro-6,7,8,9,10,12-hexahydroazepino[2,1-b]-quinazoline (CI

     1002), N-heptylcarbamic acid 2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1,2-oxazino[6,5-b]indol-6-yl ester-L-tartrate (CHF

     2060), 3-(2-[1-(1,3-dioxolan-2-ylmethyl)piperidin-4-yl]ethyl)-3,4-dihydro-2H-1,3-benzoxazine-2,4-dione hydrochloride (E

     2030), N-[10-(diethylamino)decyl]carbamic acid (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester (MF

     247), 5-amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thiopyrano-[3,4-b]quinoline (MF

     8615), N-[8-(cis-2,6-dimethylmorpholin-4-yl)octyl]carbamic acid (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester L-bitartrate hydrate (MF 268), (−

)N-(3-piperidinopropyl)-N-demethylgalantamine (SPH

     1286) and N-propargyl-3R-aminoindan-5-yl-ethyl methyl carbamate (TV

     3326), or a pharmaceutically acceptable salt thereof.