Cyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase

A method of treating female sexual dysfunction comprising administering a therapeutically effective amount of a compound of formula (I), pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof:

• 203
• 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, C2-6hydroxyalkoxy, C1-6alkoxy(C1-6alkoxy), C3-7cycloalkyl, C3-7cycloalkenyl, aryl, aryloxy, (C1-4alkoxy)aryloxy, heterocyclyl, heterocyclyloxy, —NR2R3, —NR4COR5, —NR4S2R5, —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, —NR2R3 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, (C1-4alkyl)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;
• p is 0, 1, 2 or 3;
• n is 0, 1 or 2;
• 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
• 204
• 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)NR11R12 wherein R11 and R12 are as previously defined except that R11 and R12 are not both H;
• or
• Y is the group,
• 205
• 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 C1-4alkyl;
• or
• Y is the group
• 206
• 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, C16 haloalkoxy, 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, C1-6 haloalkoxy, 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 C 4alkyl;
• R19 is aryl, arylC1-4alkyl or heterocyclyl;
• and u is 0, 1, 2 or 3.