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(12) United States Patent (10) Patent No.: US 8.247,609 B2 Roques Et Al

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(12) United States Patent (10) Patent No.: US 8.247,609 B2 Roques Et Al USOO82476.09B2 (12) United States Patent (10) Patent No.: US 8.247,609 B2 Roques et al. (45) Date of Patent: Aug. 21, 2012 (54) AMINOACID DERIVATIVES CONTAININGA FOREIGN PATENT DOCUMENTS DSULFANYL GROUPIN THE FORM OF EP O262O53 3, 1988 MIXED DISULEANYLAND AMINOPEPTIDASEN INHIBITORS (Continued) (75) Inventors: Bernard Roques, Paris (FR): Marie-Claude Fournie-Zalluski, Paris OTHER PUBLICATIONS (FR) Silverman (The Organic Chemistry of Drug Design and Drug Action, (73) Assignee: Pharamleads, Paris (FR) 1992, Academic Press Inc.).* (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.S.C. 154(b) by 868 days. (21) Appl. No.: 12/146,941 Primary Examiner — Susanna Moore Assistant Examiner — Jennifer C Sawyer (22) Filed: Jun. 26, 2008 (74) Attorney, Agent, or Firm — Harness, Dickey & Pierce, (65) Prior Publication Data P.L.C. US 2009/OO12153 A1 Jan. 8, 2009 Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. 12/084,091, The invention relates to novel compounds of formula (I): filed as application No. PCT/EP2006/067711 on Oct. HN CH(R)-CH S S CH-CH(R) CONH 24, 2006. Rs, wherein R is a hydrocarbon chain, phenyl or benzyl (30) Foreign Application Priority Data radical, methylene radical substituted by a 5 or 6 atom het erocycle; R is a phenyl or benzyl radical, a 5 or 6 atom Oct. 25, 2005 (FR) ...................................... O5 10862 aromatic heterocycle, methylene group Substituted by a 5 or 6 May 5, 2006 (FR) ...................................... O6 O4030 atom heterocycle; Rs is a CH(R)—COOR radical, wherein R is hydrogen, an OH or OR group, a saturated hydrocarbon (51) Int. Cl. group, a phenyl or benzyl radical and OR is hydrophile ester, C07C32/00 (2006.01) or 5 or 6 membered heterocycle comprising several heteroa C07C323/00 (2006.01) toms selected from a group consisting of nitrogen, Sulphur C07C38L/00 (2006.01) and oxygen, with at least two nitrogene atoms, wherein said CD7C2II/00 (2006.01) heterocycle is substitutable by an alkyl C-C phenyl or A6 IK3I/38 (2006.01) benzyl radical. The use of the inventive compounds in the (52) U.S. Cl. ......................... 564/340; 564/463: 514/438 form of drugs, a pharmaceutical composition comprising said (58) Field of Classification Search ........................ None compounds, a pharmaceutically acceptable excipient, the use See application file for complete search history. in conjunction of at least one type of cannabinoid derivative for potentiating the analgesic and antidepressant effect of the (56) References Cited novel compounds of formula (I) and/or morphine or the U.S. PATENT DOCUMENTS derivatives thereof are also disclosed. 4,618,708 A 10/1986 Roques et al. (Continued) 35 Claims, 6 Drawing Sheets % analgesia 1 2.5 5 dose, mg/kg US 8,247.609 B2 Page 2 U.S. PATENT DOCUMENTS Marie-Claude Fournié-Zaluski et al. : "Analgesic Effects of 4,738,803 A 4, 1988 Roques et al. Kelatorphan, a New Highly Potent Inhibitor of Multiple Enkephalin 5,491,169 A * 2/1996 Roques et al. ................ 514,529 Degrading Enzymes'. European Journal of Pharmacology, 102 2004/0242576 A1 12, 2004 Flohr et al. (1984) pp. 525-528. 2005/0O25791 A1 2/2005 Remenar et al. Gilles Waksman et al. “In Vitro and in Vivo Effects of Kelatorphan on Enkephalin Metabolism in Rodent Brain'. European Journal of Phar FOREIGN PATENT DOCUMENTS macology, 117 (1985) 233-243. FR 2.518088 6, 1983 R. Maldonado et al.: “Comparison of Selective and Complete Inhibi FR 2 605 004 4f1988 tors of Enkephalin-Degrading Enzymes on Morphine Withdrawal FR 2651 229 A 3, 1991 Syndrome'. European Journal of Pharmacology, 165 pp. 199-207, OTHER PUBLICATIONS received Dec. 8, 1988, revised MS received Mar. 2, 1989, accepted Mar. 28, 1989, E.JP 50832. Marie-Claude Fournié-Zaluskiet al.: “Mixed Inhibitor-Prodrug As V. Kayser et al. : "Potent Antinociceptive Effects of Kelatorphan (a a New Approach Toward Systemically Active Inhibitors of Highly Efficient Inhibitor of Multiple Enkephalin-Degrading Enkephalin-Degrading Enzymes'. Journal of Medicinal Chemistry, Enzymes) Systemically Administered in Normal and Arthritic Rats'. American Chemical Society. Washington, US, vol. 35. No. 13, 1992, Brain Research, 497 (1989) pp. 94-101, BRES 14785. pp. 2473-2481, XPO020 19768, ISSN: 0022-2623. Huixiong Chen et al. : “Phosphinic Derivatives as New Dual Florence Noble et al.: “Inhibition of the Enkephalin-Metabolizing Enkephalin-Degrading Enzyme Inhibitors: Synthesis, Biological Enzymes by the First Systemically Active Mixed Inhibitor Prodrug Properties, and Antinociceptive Activities”, Journal of Medicinal RB 101-Induces Potent Analgesic Responses in Mice and Rats'. Chemistry, 2000, vol.43, pp. 1398-1408. Journal of Pharmacology and Experimental Therapeutics, American Huixiong Chen et al. : "Long Lasting Antinociceptive Properties of Society for Pharmacology and, US, vol. 261, No. 1, Jan. 1992, pp. Enkephalin Degrading Enzyme (NEP and APN) Inhibitor Prodrugs'. 181-190, XP000386321, ISSN: 0022-3565. Journal of Medicinal Chemistry, 2001, vol. 44, No. 21, pp. 3523 Florence Noble et al.: “Pain-Suppressive Effects on Various Nocicep 3530. tive Stimuli (Thermal, Chemical, Electrical and Inflammatory) of the Bernard P. Rogues et al.: “Neutral Endopeptidase 24.11: Structure, First Orally Active Enkephalin-Metabolizing Enzyme Inhibitor RB Inhibition, and Experimental and Clinical Pharmacology”. The 120”, Pain, 73 (1997) 383-391 Coden: PAINDB, ISSN: 0304-3959, American Society for Pharmacology and Experimental Therapeu 1997, XP002386725. tics, 1993, vol. 45, No. 1, pp. 87-133. C. Schmidt et al.: "Analgesic Responses Elicited by Endogenous B. Malfroyet al.:"High-Affinity Enkephalin-Degrading Peptidase in Enkephalins (protected by Mixed Peptidase Inhibitors) in a Variety of brain is Increased After Morphine”. Nature vol. 276, Nov.30, 1978, Morphine-Sensitive Noxious Tests”, European Journal of Pharma pp. 523-526. cology, 192 (1991), pp. 253-262, 1991 Elsevier Science Publishers B.V. (Biomedical Division) 0014-2999/91, E.JP51646. * cited by examiner U.S. Patent Aug. 21, 2012 Sheet 1 of 6 US 8,247,609 B2 % analgesia 1 2.5 5 dose, mg/kg FIG. 10 O B 8 O t ' i 6 O O 50 100 150 200 250 O 40 8O 120 Compound 15. ag/kg Tine, nin FIG. 2A and 2B U.S. Patent Aug. 21, 2012 Sheet 2 of 6 US 8,247,609 B2 30 i 0.4 0.375 (.44G.38 dose, Frigikg 5 THC 15/THC FIG. 3 U.S. Patent Aug. 21, 2012 Sheet 3 of 6 US 8,247,609 B2 25 O LEFT PAWS 20 O RIGHT PAWS Fig. 4A LEFT PAWS RIGHT PAWS (inoculated) 25 s O 12.5 25 50 0 12.5 2S 50 Fig. 4B U.S. Patent Aug. 21, 2012 Sheet 4 of 6 US 8.247,609 B2 25 20 LEFT PAWS RIGHT PAWS (inoculated) 15 10 5 O Compound 15-25 - 25 - 25 - 25 NAL-MET - - 2 2 - - 2 2 Fig. 5 U.S. Patent Aug. 21, 2012 Sheet 5 of 6 US 8,247,609 B2 25 20 15 10 -20 O 20 40 60 80 100 120 Fig. 6A Fig. 6B Left PawS Right Paws 25 (inoculated) 20 15 10 5 O O 6.2 12.5 25 O 6.2 12.525 U.S. Patent Aug. 21, 2012 Sheet 6 of 6 US 8,247,609 B2 15 10 Fig. 7A 12 Fig. 7B US 8,247,609 B2 1. 2 AMNOACD DERVATIVES CONTAINING A cutaneous, percutaneous, intrathecal or intra-articular injec DSULFANYL GROUPN THE FORM OF tion and by oral or nasal route. MIXED DISULEANYLAND It is generally understood that the hematoencephalic bar AMINOPEPTIDASEN INHIBITORS rier is more easily crossed by hydrophobic and non-polar molecules. However, unexpectedly, the hydrophilic mol CROSS REFERENCE TO RELATED ecules that have been synthesized exhibit powerful responses APPLICATIONS in central tests indicating the existence of a good capacity to reach cerebral structures by several administration routes (ex This application is a continuation-in-part application of cept for the local route). Another object of the invention is to U.S. Ser. No. 12/084,091, filed Apr. 24, 2008, which is a 10 provide novel compounds that exhibit the properties of mor National Phase Entry of PCT Application Serial No. PCT/ phine Substances, in particular analgesia, beneficial effects on EP2006/067711, filed Oct. 24, 2006, which claims priority to behavior (reduction in the emotional component of pain and French Application Serial No. 05/10862, filed Oct. 25, 2005 antidepressant responses) and peripheral effects (antidiar and French Application Serial No. 06/04030, filed May 5, rheal, antitussive, anti-inflammatory) without their major dis 2006. The entire disclosures of the above applications are 15 advantages (tolerance, physical and psychological depen incorporated herein by reference. dence, respiratory depression, constipation, nausea). BACKGROUND AND SUMMARY Moreover, inflammatory and neurogenic pain, whose peripheral component is significant, are reduced or even The invention relates to novel mixed inhibitors of the eliminated by the compounds according to the invention neprilysin and aminopeptidase N. administered by oral route and thus without such compounds It is known that natural opioid peptides or enkephalins— being constrained from reaching the central nervous system. (Tyr-Gly-Gly-Phe-Met or Tyr-Gly-Gly-Phe-Leu)—are pri This result, highly advantageous but unexpected, was for marily degraded by two Zinc metallopeptidases, neprilysin mally demonstrated by the use of an antagonist incapable of (EC 3.4.24.11) which cleaves the Gly3-Phe-4 bond (Nature 25 entering the brain. This completely reduces all of the effects 276 (1978) 523) and aminopeptidase N (EC 3.4.11.2) which due to stimulation of cerebral opioid receptors by the com cuts the Tyr1-Gly2 bond of these peptides (Eur. J. Pharmacol. pounds according to the invention, without altering the anal 117 (1985) 233; review in Pharmacological Review, 1993, gesics effects of the compounds on these types of pain, in 45, 87-146).
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