Substituted diketopiperazines as oxytocin antagonists

A process for the preparation of compounds of formula (I):

• wherein R1 is a 2-indanyl group;
• R2 represents C3-6cycloalkyl, C1-6alkyl optionally substituted by a C1-2alkoxy, a C1-2alkylthio, a di-C1-2alkyl-amino or a C3-6 cycloalkyl group, or a 5 or 6 membered heterocyclic group containing a single hetero atom selected from O, S or N, which nitrogen atom carries a hydrogen atom or a methyl or ethyl group;
• R3 represents an optionally substituted phenyl,
• a 5 membered heteroaryl group which is unsubstituted or substituted by one or more groups selected from halogen, trifluoromethyl, C1-4alkyl, cycloalkyl, heteroaryl, saturated heterocyclic, or phenyl,
• a 6 membered heteroaryl group which is unsubstituted or substituted by 1 to 3 C1-4alkyl, or trifluoromethyl, or alkoxy groups, or
• a fused bicyclic ring system containing 9-10 ring members which ring system contains a benzene and which ring members include 0 to 3 heteroatoms selected from O, S or N;
• R4 represents NR5R6,
• where,
• R5 represents hydrogen, C1-6alkyl optionally substituted with C1-4alkoxy, or C3-7cycloalkyl,
• R6 represents hydrogen, methyl, C1-4alkoxy, C3-7cycloalkyl, C2-4alkyl optionally substituted with one or more R50, or C2-4alkyl optionally substituted with one or more R55,
• or R6 represents a phenyl or benzyl group optionally substituted by one or more methoxy or benzyloxy groups, an optionally substituted heteroarylmethyl group, a heteroaryl group, C3-7 cycloalkyl, or the group CH2CONR9R10,
• or R5 and R6 together with the nitrogen to which they are attached form a 3 to 7 membered saturated heterocycle optionally substituted with one or more R60 which heterocycle optionally contains an additional heteroatom selected from oxygen, sulphur and nitrogen, wherein the sulphur atom may be in an oxidised form and the additional nitrogen atom either carries a hydrogen atom or a C1-4alkyl or a C1-4alkanoyl group or a C1-4alkylsulphonyl group or a C1-3 alkoxyC2-4 alkyl,
• where,
• R50 is selected from the group consisting of:
• carboxyl, C1-4alkylsulphonyl, or C1-4alkoxycarbonyl, and
• R55 is selected from the group consisting of:
• halogen, hydroxy, C1-4alkoxy, or NR7R8,
• where,
• R7 and R8 independently represent hydrogen or C1-4alkyl or together form a 3 to 7 membered saturated heterocyclic ring which optionally contains an additional heteroatom selected from O, S or N and which heterocyclic group may be substituted by 1 to 3 groups selected from C1-3alkyl, hydroxy, C1-3 alkoxy optionally substituted by C3-6 cycloalkyl or optionally substituted phenyl, C3-6cycloalkyl or NRcRd, wherein Rc and Rd each independently represent a group selected from C1-3alkyl optionally substituted by C3-6 cycloalkyl or optionally substituted phenyl, or C3-6 cycloalkyl,
• R9 represents hydrogen or C1-4alkyl, and
• R10 represents hydrogen, C1-4alkyl optionally substituted by a 5 or 6 membered heteroaryl group, or R9 and R10 together form a 5 or 6 membered saturated heterocyclic ring and wherein the 6 membered heterocyclic group optionally contains an additional heteroatom selected from oxygen, sulphur or nitrogen and the additional nitrogen atom either carries a hydrogen atom or a C1-4alkyl or C1-4alkanoyl group, and
• R60 is selected from the group consisting of:
• halogen, C1-3alkyl, hydroxy, oxo, C3-6cycloalkyl or NReRf wherein Re and Rf each independently represent a group selected from C1-3alkyl optionally substituted by C3-6 cycloalkyl or optionally substituted phenyl or C3-6 cycloalkyl,
• wherein the method comprises:
• (a) cyclisation of the compound of formula (II)
• wherein R11 is hydrogen and R12 is a C1-3alkyl group in a suitable solvent or
• (b) reacting a compound of formula (I) wherein R4 is hydroxyl or an activated derivative thereof with the amine NHR5R6 wherein R5 and R6 have the meaning defined in formula (I);
• (c) reacting a compound of formula (I) wherein R4 is the group NR5R6 and R5 is hydrogen and R6 is 2-hydroxyphenyl with carbonyldiimidazole or thiocarbonyldiimidazole in a suitable solvent and subsequent reaction of the product thus formed with amine NHR5R6.