Synergistic combinations

• US 20040157847A1
• Filed: 02/03/2004
• Published: 08/12/2004
• Est. Priority Date: 08/15/2002
• Status: Active Grant

• Current Assignee: Mark John Field, Richard Griffith Williams
• Original Assignee: Mark John Field, Richard Griffith Williams
• Inventors: Williams, Richard Griffith, Field, Mark John
• Granted Patent: US 7,419,981 B2
• Time in Patent Office: Days
• US Class Current: 514/246
• 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 31/195 having an amino group
• 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 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495

Abstract

The instant invention relates to a combination of an alpha-2-delta ligand and a PDEV inhibitor for use in therapy, particularly in the curative, prophylactic or palliative treatment of pain, particularly neuropathic pain. Particularly preferred alpha-2-delta ligands are gabapentin and pregabalin. Particularly preferred PDEV inhibitors are sildenafil, vardenafil and tadalafil.

Claims

1. A combination comprising a synergistic ratio of an alpha-2-delta ligand and a PDEV inhibitor, or a pharmaceutically acceptable salt or solvate of any thereof.

2. 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 and 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 or solvate thereof.

3. A combination according to claim 1 or 2 where the alpha-2-delta ligand is gabapentin, or a pharmaceutically acceptable salt or solvate thereof.

4. A combination according to claim 1 or 2 where the alpha-2-delta ligand is pregabalin, or a pharmaceutically acceptable salt or solvate thereof.

5. A combination according to any one of claims 1-4 wherein the PDEV inhibitor is selected from:

5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil);

(6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2′

,1′

;

6,1]pyrido[3,4-b]indole-1,4-dione (tadalafil, IC-351);

2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil);

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and

1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine;

or a pharmaceutically acceptable salt or solvate thereof.

6. A combination according to any one of claims 1-5 wherein the PDEV inhibitor is sildenafil, or a pharmaceutically acceptable salt or solvate thereof.

7. A combination according to any one of claims 1-5 wherein the PDEV inhibitor is vardenafil, or a pharmaceutically acceptable salt or solvate thereof.

8. A combination according to any one of claims 1-5 wherein the PDEV inhibitor is tadalafil, or a pharmaceutically acceptable salt or solvate thereof.

9. A combination as claimed in any one of claims 1-8 for the curative, prophylactic or palliative treatment of pain.

10. A combination according to claim 9 where the pain is neuropathic pain.

12. Use of a combination as claimed in any one of claims 1-8 in the manufacture of a medicament for the curative, prophylactic or palliative treatment of pain.

13. Use according to claim 12 where the pain is neuropathic pain.

14. A pharmaceutical composition comprising a therapeutically effective amount of a combination as claimed in any one of claims 1-8 together with a suitable excipient or carrier.

16. A synergistic combination for administration to humans comprising an alpha-2-delta ligand and a PDEV inhibitor, or pharmaceutically acceptable salts or solvates thereof, according to any one of claims 1-8, where the dose ranges of the alpha-2-delta ligand and PDEV inhibitor correspond to a synergistic dose range of 1-10 mg/kg and 0.1-1 mg/kg respectively, in the rat model of CCI induced static allodynia.

11. A combination comprising an alpha-2-delta ligand, excluding gabapentin, pregabalin and compounds of formula (i)-(xxv) of PCT/IB02/01146 and a PDEV inhibitor.

15. A synergistic combination for human administration comprising an alpha-2-delta ligand and a PDEV inhibitor, or pharmaceutically acceptable salts or solvates thereof, in a w/w combination range which corresponds to a synergistic combination range of the order of 1:

1 to 10;

1 parts by weight in the rat model of CCI induced static allodynia.