Claims
- 1 The use of a neutral endopeptidase inhibitor (NEPi) compound in the preparation of a medicament for the treatment of male sexual dysfunction.
- 2. Use according to claim 1 for the treatment of ejaculatory disorders, desire disorders or male erectile dysfunction (MED).
- 3. Use according to claim 2 for the treatment of MED.
- 4. Use of a NEPi compound according to any one of claims 1 to 3 for the treatment of MED wherein the medicament is administered by mouth.
- 5. Use according to any one of the preceding claims wherein the NEPi has a selectivity for NEP over angiotensin converting enzyme (ACE) of greater than 100.
- 6. Use according to any of the preceding claims wherein the NEPi is a compound of formula I (or a pharmaceutically acceptable salt, solvate or prodrug thereof):
- 7. Use of a NEPi according to claim 6 wherein the NEPi is selected from the group consisting of:
2-[(1-{[(1-benzyl-6-oxo-1,6-dihydro-3-pyridinyl)amino]carbonyl}cyclopentyl)-methyl]-4-methoxybutanoic acid; 2-{[1-({[3-(2-oxo-1-pyrrolidinyl)propyl]amino}carbonylcyclopentyl]-methyl}-4-phenylbutanoic acid; (+)-2-{[1-({[2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)cyclopentyl]methyl}-4-phenylbutanoic acid; 2-[(1-{[(5-methyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]-4-phenylbutanoic acid; cis-3-(2-methoxyethoxy)-2-[(1-{[(4-{[(phenylsulfonyl)amino]carbonyl}cyclohexyl)-amino]carbonyl}cyclopentyl)methyl]propanoic acid; (+)-2-{[1-({[2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)cyclopentyl]-methyl}pentanoic acid; (2R)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl) methyl]pentanoic acid or (−)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]pentanoic acid; (2S)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)-methyl]pentanoic acid or (+)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)-methyl]pentanoic acid; and (S)-2-{[l -({[2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)-cyclopentyl]methyl}-4-methoxybutanoic acid.
- 8. Use of pharmaceutical combination comprising a combination of a NEPi according to any preceding claim and;
one or more naturally occurring or synthetic prostaglandins or esters thereof; and/or one or more α-adrenergic receptor antagonist compounds; and/or one or more NO-donor (NO-agonist) compounds; and/or one or more potassium channel openers or modulators; and/or one or more dopaminergic agents; and/or one or more vasodilator agents; and/or one or more thromboxane A2 agonists; and/or one or more ergot alkaloids; and/or one or more compounds which modulate the action of natruretic factors in particular atrial naturetic factor; and/or one or more angiotensin receptor antagonists; and/or one or more substrates for NO-synthase; and/or one or more calcium channel blockers; and/or one or more antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme; and/or one or more cholesterol lowering agents such as statins and fibrates; and/or one or more antiplatelet and antithrombotic agents; and/or one or more insulin sensitising agents; and/or one or more acetylcholinesterase inhibitors; and/or one or more estrogen receptor modulators, estrogen agonists or estrogen antagonists; and/or one or more of a PDE inhibitor, more particularly a PDE 2, 4, 5, 7 or 8 inhibitor; and/or one or more of an NPY (neuropeptide Y) inhibitor, more particularly NPY1 or NPY5 inhibitor; and/or one or more of vasoactive intestinal protein (VIP), VIP mimetic, VIP analogue; of a VIP receptor agonist or a VIP fragment, or a α-adrenoceptor antagonist with VIP combination; and/or one or more of a melanocortin receptor agonist or modulator or melanocortin ehancer; and/or one or more of a serotonin receptor agonist, antagonist or modulator; and/or one or more of a testosterone replacement agent, dihydrotestosterone or a testosterone implant; and/or one or more of estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (i.e. as a combination); and/or one or more of a modulator of transporters for noradrenaline, dopamine and/or serotonin; and/or one or more of a purinergic receptor agonist and/or modulator; and/or one or more of a neurokinin (NK) receptor antagonist; and/or one or more of an opioid receptor agonist, antagonist or modulator, preferably agonists for the ORL-1 receptor; and/or one or more of an agonist or modulator for oxytocin/vasopressin receptors,; and/or one or more modulators of cannabinoid receptors.
- 9. Use according to claim 8 wherein the combination is that of a NEPi and a PDE5i for the treatment of male sexual dysfunction.
- 10. Use of a combination according to claim 9 which is for the treatment of MED.
- 11. Use of a combination according to claims 8 to 10 which is adapted for administration by mouth.
- 12. Use according to claims 9 to 11 wherein the PDE5i is selected from the group consisting of:
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) also known as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine; 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known as 3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1 R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one; 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, also known as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine; 5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsu Iphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-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; (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 (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) also known as 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5, 1-f]-as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine; and the compound of example 11 of published international application WO93/07124 (EISAI).
- 13. Use according to claim 12 wherein the PDE5i is sildenafil.
- 14. A pharmaceutical composition comprising a NEPi and a PDE5i for the treatment of MED.
- 15. A kit comprising a first component and a second component adapted for the treatment of MED wherein the first component comprises a NEPi as defined in any of claims 1 to 7 and wherein the second component comprises a PDE5i as defined in any of claims 9 to 13.
- 16. The use of a pharmaceutical combination adapted for administering by mouth in the preparation of a medicament for the treatment of male sexual dysfunction, said combination comprising an inhibitor of neutral endopeptidase (NEP) having an IC50 against NEP of less than 100 nM and a selectivity for NEP over angiotensin converting enzyme of greater than 100, and an inhibitor of phosphodiesterase type 5 enzyme (PDE5) having an IC50 against PDE5 of less than 100 nM and a selectivity for PDE5 over PDE3 of greater than 100.
- 17. A method for the treatment of male sexual dysfunction comprising administering to the patient an effective amount of a neutral endopeptidase inhibitor.
- 18. A method for the treatment of male sexual dysfunction comprising administering to the patient an effective amount of a neutral endopeptidase inhibitor and a phosphodiesterase type 5 inhibitor (PDE5).
Priority Claims (4)
Number |
Date |
Country |
Kind |
0016684.3 |
Jul 2000 |
GB |
|
0030647.2 |
Dec 2000 |
GB |
|
0106167.0 |
Mar 2001 |
GB |
|
0108483.9 |
Apr 2001 |
GB |
|
Parent Case Info
[0001] This application claims priority from provisional application U.S. serial No. 60/219,100 filed Jul. 19, 2000 and from provisional application U.S. serial No. 60/265,358 filed Jan. 31, 2001 the benefit of which is hereby claimed under 37 C.F.R.§1 .78(a)(3).
Provisional Applications (2)
|
Number |
Date |
Country |
|
60219100 |
Jul 2000 |
US |
|
60265358 |
Jan 2001 |
US |