Treatment of male sexual dysfunction

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):

• wherein
• R1 is C1-6alkyl which may be substituted by one or more substituents, which may be the same or different, selected from the list:
• halo, hydroxy, C1-6 alkoxy, C2-6 hydroxyalkoxy, C1-6 alkoxy(C1-6alkoxy), C3-7cycloalkyl, C3-7cycloalkenyl, aryl, aryloxy, (C1-4alkoxy)aryloxy, heterocyclyl, heterocyclyloxy, —NR2R3, —NR4COR5, —NR4SO2R5, —CONR2R3, —S(O)pR6, —COR7 and —CO2(C1-4alkyl);
• or R1 is C3-7cycloalkyl, aryl or heterocyclyl, each of which may be substituted by one or more substituents from said list, which substituents may be the same or different, which list further includes C1-6alkyl;
• or R1 is C1-6 alkoxy, —NR2, R3 or —NR4SO2R5;
• wherein
• R2 and R3 are each independently H, C1-4alkyl, C3-7cycloalkyl (optionally substituted by hydroxy or C1-4alkoxy), aryl, (C1-4alkyl)aryl, C1-6alkoxyaryl or heterocyclyl;
• or R2 and R3 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N—(C1-4 alkyl)piperazinyl group;
• R4 is H or C1-4alkyl;
• R5 is C1-4alkyl, CF3, aryl, (C1-4 alkyl)aryl, (C1-4alkoxy)aryl, heterocyclyl, C1-4alkoxy or —NR2R3 wherein R2 and R3 are as previously defined;
• R6 is C1-4alkyl, aryl, heterocyclyl or NR2R3 wherein R2 and R3 are as previously defined;
• and
• R7 is C1-4alkyl, C3-7cycloalkyl, aryl or heterocyclyl;
• n is 0, 1 or 2;
• p is 0, 1, 2 or 3;
• the —(CH2)n— linkage is optionally substituted by C1-4alkyl, C1-4alkyl substituted with one or more fluoro groups or phenyl, C1-4alkoxy, hydroxy, hydroxy(C1-3alkyl), C3-7cycloalkyl, aryl or heterocyclyl;
• Y is the group
• wherein A is —(CH2)q— where q is 1, 2, 3 or 4 to complete a 3 to 7 membered carbocyclic ring which may be saturated or unsaturated;
• R8 is H, C1-6alkyl, —CH2OH, phenyl, phenyl(C1-4alkyl) or CONR11R12;
• R9 and R10 are each independently H, —CH2OH, —C(O)NR11R12, C1-6alkyl, phenyl (optionally substituted by C1-4alkyl, halo or C1-4alkoxy or phenyl(C1-4alkyl) wherein the phenyl group is optionally substituted by C1-4alkyl, halo or C1-4alkoxy, or R9 and R10 together form a dioxolane;
• R11 and R12 which may be the same or different are H, C1-4alkyl, R13 or S(O)rR13, where r is 0, 1 or 2 and R13 is phenyl optionally substituted by C1-4alkyl or phenylC1-4alkyl wherein the phenyl is optionally substituted by C1-4alkyl;
• or
• Y is the group, —C(O)NR11 R12 wherein R11 and R12 are as previously defined except that R11 and R12 are not both H;
• or
• Y is the group,
• wherein R14 is H, CH2OH, or C(O)NR11R12 wherein R11 and R12 are as previously defined;
• when present R15, which may be the same or different to any other R15, is OH, C1-4alkyl, C1-4alkoxy, halo or CF3;
• t is 0, 1, 2, 3 or 4;
• and R16 and R17 are independently H or C1-4 alkyl;
• or
• Y is the group
• wherein one or two of B, D, E or F is a nitrogen, the others being carbon;
• and
• R14 to R17 and t are as previously defined;
• or
• Y is an optionally substituted 5-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic and contains a nitrogen, oxygen or sulphur and optionally one, two or three further nitrogen atoms in the ring and which may be optionally benzofused and optionally substituted by:
• C1-6 alkoxy;
• hydroxy;
• oxo;
• amino;
• mono or di-(C1-4alkyl)amino;
• C1-4alkanoylamino;
• or
• C1-6alkyl which may be substituted by one or more substituents, which may be the same or different, selected from the list:
• C1-6alkoxy, C1-6haloalkoxy, C1-6alkylthio, halogen, C3-7cycloalkyl, heterocyclyl or phenyl;
• or
• C3-7cycloalkyl, aryl or heterocyclyl, each of which may be substituted by one or more substituents, which may be the same or different, selected from the list:
• C1-6alkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylthio, halogen, C3-7cycloalkyl, heterocyclyl or phenyl;
• wherein when there is an oxo substitution on the heterocyclic ring, the ring only contains one or two nitrogen atoms and the oxo substitution is adjacent a nitrogen atom in the ring;
• or Y is —NR18S(O)uR19, wherein R18 is H or C1-4alkyl;
• R19 is aryl, arylC1-4alkyl or heterocyclyl (preferably pyridyl);
• and
• u is 0, 1, 2 or 3.

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.