(19) & (11) EP 1 598 339 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 211/04 (2006.01) C07D 211/06 (2006.01) 24.06.2009 Bulletin 2009/26 C07D 235/24 (2006.01) C07D 413/04 (2006.01) C07D 235/26 (2006.01) C07D 401/04 (2006.01) (2006.01) (2006.01) (21) Application number: 05014116.7 C07D 401/06 C07D 403/04 C07D 403/06 (2006.01) A61K 31/44 (2006.01) A61K 31/48 (2006.01) A61K 31/415 (2006.01) (22) Date of filing: 18.04.2002 A61K 31/445 (2006.01) A61P 25/04 (2006.01) (54) 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ONE DERIVATIVES AND RELATED COMPOUNDS AS NOCICEPTIN ANALOGS AND ORL1 LIGANDS FOR THE TREATMENT OF PAIN 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ON DERIVATE UND VERWANDTE VERBINDUNGEN ALS NOCICEPTIN ANALOGE UND ORL1 LIGANDEN ZUR BEHANDLUNG VON SCHMERZ DERIVÉS DE LA 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ONE ET COMPOSÉS SIMILAIRES POUR L’UTILISATION COMME ANALOGUES DU NOCICEPTIN ET LIGANDES DU ORL1 POUR LE TRAITEMENT DE LA DOULEUR (84) Designated Contracting States: • Victory, Sam AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Oak Ridge, NC 27310 (US) MC NL PT SE TR • Whitehead, John Designated Extension States: Newtown, PA 18940 (US) AL LT LV MK RO SI (74) Representative: Maiwald, Walter (30) Priority: 18.04.2001 US 284666 P Maiwald Patentanwalts GmbH 18.04.2001 US 284667 P Elisenhof 18.04.2001 US 284668 P Elisenstrasse 3 18.04.2001 US 284669 P 80335 München (DE) (43) Date of publication of application: (56) References cited: 23.11.2005 Bulletin 2005/47 EP-A- 0 636 614 EP-A- 0 990 653 EP-A- 1 142 587 WO-A-00/06545 (62) Document number(s) of the earlier application(s) in WO-A-00/08013 WO-A-01/05770 accordance with Art. 76 EPC: WO-A-01/39775 WO-A-01/68604 02764236.2 / 1 379 246 WO-A-95/28397 WO-A-96/05166 WO-A-96/13262 WO-A-96/25934 (73) Proprietor: EURO-CELTIQUE S.A. WO-A-97/23216 WO-A-98/44922 1653 Luxembourg (LU) WO-A-99/09984 WO-A-99/32481 WO-A-99/36421 JP-A- 10 330 377 (72) Inventors: US-A- 4 410 528 US-A- 5 661 169 • Sun, Qun US-A- 5 760 054 Belle Mead, NJ 08502 (US) • Goehring, Richard R. • OBASE ET AL: "Synthesis of (1-substituted Pipersville, PA 18947 (US) piperidin-4-yl)-1H-benzimidazoles and (1- • Kyle, Donald substituted piperidin-4-yl)-3,4- Newton, PA 18940 (US) dihydroquinazolines as possible • Chen, Zhengming antihypertensive agents" JOURNAL OF Belle Mead, NJ 08502 (US) HETEROCYCLIC CHEMISTRY, vol. 20, no. 3, 1983, pages 565-573, XP002333375 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 598 339 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 598 339 B1 • NERENBERG ET AL: "Design and Synthesis of • DATABASE CAPLUS CHEMICAL ABSTRACTS N-Alkylated Saccharins as Selective alpha-1A SERVICE, COLUMBUS, OHIO, US; 1970, Adrenergic Receptor Antagonists" BIOORGANIC XP002951914 Database accession no. AN: 1970: AND MEDICINAL CHEMISTRY LETTERS, vol. 8, 445405 & OGATA MASARU ET AL: "ORGANIC 1998, pages 2467-2472, XP004138253 PHOTOCHEMICAL REACTIONS. VII. • BIANCHI M ET AL: "Compounds with antiulcer PHOTOLYSIS OF 1-BENZYL-2- and antisecretory activity. I. 3-Aryl- ETHYLBENZIMIDAZOLE 3-OXIDE" CHEMICAL benzimidazolin-2-ones and -thiones" PHARMACEUTICAL BULLETIN, vol. 18, no. 5, EUROPEAN JOURNAL OF MEDICINAL 1970, pages 964-969, CHEMISTRY, EDITIONS SCIENTIFIQUE • NAKAMURA SEIKOU ET AL: "SYNTHESIS OF A ELSEVIER, PARIS, FR, vol. 16, no. 4, 1981, pages REGIO-ISOMER OF KEALIIQUINONE, A MARINE 321-326, XP002148863 ISSN: 0223-5234 BENZIMIDAZOLE ALKALOID" JOURNAL OF THE • DATABASE CAPLUS CHEMICAL ABSTRACTS CHEMICAL SOCIETY, PERKIN TRANSACTIONS SERVICE, COLUMBUS, OHIO, US; 1981, 1, vol. 4, 2001, pages 429-436, XP002345381 XP002951913 Database accession no. AN: 1981: 577993 & GUILIANO M ET AL: "SPECTROSCOPIC STUDIES OF 2-OXO-2,3- DIHYDROBENZIMIDAZOLE AND SOME N- MONOSUBSTITUTED OR N,N’-DISUBSTITUTED DERIVATIVES" APPLIED SPECTOSCOPY, vol. 35, no. 5, 1981, pages 486-488, 2 EP 1 598 339 B1 Description [0001] This application claims priority from U.S. Provisional Application Serial Nos. 60/284,666; 60/284,667; 60/284,668; 60/284,669 all filed April 18, 2001. 5 BACKGROUND OF THE INVENTION [0002] Chronic pain is a major contributor to disability and is the cause of an untold amount of suffering. The successful treatment of severe and chronic pain is a primary goal of the physician with opioid analgesics being preferred drugs. 10 [0003] Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes were designated as P, δ and κ. As opiates had a high affinity to these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as enkephalins, endorphins and dynor- phins. 15 [0004] Recent experimentation has led to the identification of a cDNA encoding an opioid receptor-like (ORL1) receptor with a high degree of homology to the known receptor classes. This newly discovered receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for P, δ and κ receptors had low affinity for the ORL1. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term 20 "orphan receptor". [0005] Subsequent research led to the isolation and structure of the endogenous ligand of the ORL1 receptor. This ligand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family. [0006] The discovery of the ORL1 receptor presents an opportunity in drug discovery for novel compounds which can be administered for pain management or other syndromes modulated by this receptor. 25 [0007] WO 01/05770 A in the name of Fujisawa Pharmaceutical Co., LTD describes benzimidazolone derivatives and their use as phosphodiesterase (PDE) inhibitors. Pharmaceutical compositions comprising said derivatives can inter alia be used for the treatment or prevention of diseases mediated by cGMP-PDE. [0008] EP 0 990 653 in the name of Banyu Pharmaceutical Co., LTD discloses 2-oxoimidazole derivatives which may be used in the medical field as they inhibit nociceptin from binding to the nociceptin receptor ORL1 and may thus be 30 useful inter alia as analgesic. [0009] WO 00/06545 A in the name of Schering Corporation also describes compounds as high affinity ligands for the nociceptin receptor ORL1. Said nociceptin receptor inhibitors may be used in the manufacture of medicaments for the treatment of pain, anxiety, cough, asthma, depression and alcohol abuse. [0010] WO 99/36421 A in the name of Pfizer Pharmaceuticals Inc. discloses 4-(2-keto-1-benzimidazolinyl)piperidine 35 compounds or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds have activity as ORL1-receptor agonists and as such are useful as analgesics, anti-inflammatories, diuretics, anesthetics, neuroprotectives, anti-hypertensives, anti-anxiety agents, or as agents for appetite control or hearing regulation. [0011] WO 99/32481 A in the name of Alcon Laboratories, Inc. discloses a group of compounds having muscarinic 40 activity. Said compounds may be used in the manufacture of a medicament for treating glaucoma, myopia, psychosis and various other conditions involving muscarinic receptors. [0012] WO 99/09984 A in the name of Merck & Co., Inc. describes pyrrolidine and piperidine compounds which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4. 45 [0013] JP 10 330377 A in the name of Kyowa Hakko Kogyo Co., LTD discloses compounds having muscarinic activity. Such compounds have useful pharmacological activity. [0014] US 5 661 169 in the name of Sanofi describes 1-benzyl-1,3-dihydro-2H-benzimidazol-2-one derivatives and possible salts thereof as well as a process for their preparation and to pharmaceutical compositions containing them. Said compounds have an affinity for the vasopressin and/or oxytocin receptors. 50 [0015] WO 97/23216 A in the name of Warner-Lambert Company and Cocensys, Inc. discloses 4-substituted piperidine analogs, pharmaceutical compositions containing the same and methods of using 4-substituted piperidine analogs. Said analogs are selective antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. They may be used in the man- ufacture of medicaments for the treatment of inter alia stroke, anxiety, chronic pain, opioid tolerance or withdrawal. [0016] WO 96/25934 A in the name of Merck & Co., Inc. relates to alpha la adrenergic receptors antagonists. It 55 describes their synthesis and use, such as in the manufacture of a medicament for the treatment of benign prostatic hyperplasia. Compounds according to the invention are selective in their ability to relax smooth muscle tissue enriched in the alpha la receptor subtype without at the same time inducing hypotension.