# US 8,541,579 B2 · Substituted diketopiperazines as oxytocin antagonists > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,541,579 B2 - Document ID: US8541579B2 - Status: Granted - Kind: B2 - Application number: 13/715,522 - Filed: 2012-12-14 - Published: 2013-05-23 - Granted: 2013-09-24 - Earliest claimed: 2001-12-21 - Assignees: Glaxo Group Limited - Applicants: Glaxo Group Limited - Inventors: Alan David Borthwick; Richard Jonathan Hatley; Deirdre Mary Bernadette Hickey; John Liddle; David George Hubert Livermore; Andrew McMurtrie Mason; Neil Derek Miller; Fabrizio Nerozzi; Steven Leslie Sollis; Anna Katrin Szardenings; Paul Graham Wyatt - Web page: https://patentgrep.com/patent/US8541579B2 ## CPC - A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - C07D 241/08: with oxygen atoms directly attached to ring carbon atoms - A61P 15/06: Antiabortive agents; Labour repressants - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 401/10: linked by a carbon chain containing aromatic rings - C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 413/10: linked by a carbon chain containing aromatic rings - C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms - C07K 5/06078: {and aromatic or cycloaliphatic} - C07K 5/06191: {containing heteroatoms different from O, S, or N} - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract A method of treating or preventing diseases or conditions mediated through the action of oxytocin which comprises administering to a human in need thereof of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. ## Claims ### Claim 1 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.