US008877753B2 (12) United States Patent (10) Patent No.: US 8,877,753 B2 Buschmann et al. (45) Date of Patent: Nov. 4, 2014 (54) 1-ARYL-3-AMNOALKOXY PYRAZOLES AS (56) References Cited SIGMA LGANDSENHANCING ANALGESC EFFECT OF OPODS AND ATTENUATING FOREIGN PATENT DOCUMENTS THE DEPENDENCY THEREOF EP 1130018 A1 9, 2001 EP 1634872 A1 3, 2006 (75) Inventors: Helmut Heinrich Buschmann, Aachen EP 1829875 A1 9, 2007 (DE); Jose Miguel Vela Hernandez, WO 96.16063 A1 5, 1996 Barcelona (ES); Daniel WO 98.46618 A1 10, 1998 WO 9959409 A1 11, 1999 Zamanillo-Castanedo, Barcelona (ES) WO 2006021462 A1 3, 2006 WO 2006027221 A1 3, 2006 (73) Assignee: Laboratorios Del Dr. Esteve, S.A., Barcelona (ES) OTHER PUBLICATIONS Chih-Cheng Chien et al., “Sigma antagonists potentiate opioid anal (*) Notice: Subject to any disclaimer, the term of this gesia in rats'. Neuroscience Letters, vol. 190, No. 2, 1995, pp. 137 patent is extended or adjusted under 35 139. U.S.C. 154(b) by 629 days. International Search Report for PCT/EP2009/054974, dated Jun. 17, 2009. (21) Appl. No.: 12/988,951 Chien et al., “Selective Antagonism of Opioid Analgesia by a Sigma System”. J. Pharmacol. Exp. Ther: 1994; 271; pp. 1583-1590. Meiet al., “Receptor Modulation of Opioid Analgesia in the Mouse'. (22) PCT Fled: Apr. 24, 2009 J. Pharmacol Exp. Ther.; 2002; 300(4); pp. 1070-1074. Carlsson et al., “Interaction of pentobarbital and morphine in the (86) PCT NO.: PCT/EP2009/054974 tail-flick test performed on rats: Synergism at the spinal and antago nism at the Supraspinal level”, NeuroSci. Lett.; 1986; 71; pp. 356 S371 (c)(1), 360. (2), (4) Date: Dec. 17, 2010 Janicki et al., “Detection of Antagonist Activity for Narcotic Anal gesics in Mouse Hot-Plate Test'. Pharmacol. Biochem. Behavior, 1979; 10(4); pp. 623-626. (87) PCT Pub. No.: WO2009/130310 Jianjing Cao, et al "Dual Probes for the Dopamine Transporter and PCT Pub. Date: Oct. 29, 2009 sigmal Receptors: Novel Piperazinyl Alkyl-bis (4-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents'. J. Med. Chem, No. 13, Mar. 20, 1946, pp. (65) Prior Publication Data 2589-2598. US 2011 FO112095 A1 May 12, 2011 (Continued) (30) Foreign Application Priority Data Primary Examiner — Sreeni Padmanabhan Assistant Examiner — Sahar Javanmard Apr. 25, 2008 (EP) ..................................... O838O122 (74) Attorney, Agent, or Firm — Hoffmann & Baron LLP (57) ABSTRACT (51) Int. C. A6 IK3 L/452 (2006.01) The invention relates to the use of a group of sigma receptor A6 IK3I/4I55 (2006.01) ligands of formula (I) A6 IK3I/485 (2006.01) A 6LX3/5377 (2006.01) A6IP 25/36 (2006.01) Rs CO7D 23L/22 (2006.01) N CO7D 40/12 (2006.01) R.1 Y(CH3)-O R CO7D 403/2 (2006.01) CO7D 47L/04 (2006.01) A6 IK 45/06 (2006.01) ( ) (52) U.S. C. N R2 CPC .......... C07D 231/22 (2013.01); A61 K31/4152 (2013.01); C07D 471/04 (2013.01); C07D N 403/12 (2013.01); C07D401/12 (2013.01); -HR A6 IK3I/485 (2013.01); A61K 45/06 a (2013.01); A61K 31/4155 (2013.01) R4 USPC .................. 514/236.5: 514/231.5; 514/239.2: 514/282; 544/106; 544/111; 544/140; 546/44 for the potentiation of the analgesic effect of opioids and (58) Field of Classification Search opiates and at the same time for decreasing the dependency USPC ......... 514/236.5, 282,231.5, 239.2:544/106, induced by them. 544/111, 140; 546/44 See application file for complete search history. 19 Claims, 7 Drawing Sheets US 8,877,753 B2 Page 2 (56) References Cited Medicinal Journal), Feb. 25, 2003, No. 4. Sections: Pulmonology: Selected Lectures for Family Physicians (Retrieved from the OTHER PUBLICATIONS Internet: URL-rm.ru/number 36.htm). D.G. Grahame-Smith et al. Oxford textbook on clinical pharmacol Nomura Mutsuko et al: "Studies on drug dependence (Rept. 322): ogy and drug therapy M.. “Meditsina', 2000, pp. 658-661, Chapter Attenuation of morphine- and psychoStimulants-induced place pref “Narcotic analgesics'. Drug encyclopedia M., RLS, 2001, pp. 572-573, articles “Mor erence by sigmal receptor agonist SA4503, Japanese Journal of phine”, “Morphine Sulfate”. Pharmacology, The Japanese Pharmacological Society, Kyoto, JP, Consilium MedSigma-receptors: new potentials of the treatment of vol. 79, No. suppl. 1, Jan. 1, 1999, p. 224P. depressions. Consilium Medicumicum 2012, vol. 14, No. 2 (found in Sari IZenwasser et al: "Characterization of kappa-opioid receptor the Internet: URLs new.consiliummedicum.com/magazines/cm/ binding in human insular cortex', Life Sciences, Pergamon Press, medicum/article/21505, paragraphs 4-8. Oxford, GB, vol. 65, No. 9, Jul. 23, 1999, pp. 857-862. Pirim. A et al.: "Addiction of ketamine infusion to patient controlled Osipova, N.A., “Tramadol (Tramal) in the Treatment of Acute and analgesia with intravenous morphine after abdominal hysterectomy Chronic Pain Syndromes.” Russky Meditsinsky Zhurnal (Russian Agri Jan. 2006; 18(I):52-8 Abstract. U.S. Patent Nov. 4, 2014 Sheet 1 of 7 US 8,877,753 B2 a-flick test i C(ii (kari 8.3 g (g pi 3. i-flick test Caripoing $3 {3:3kg. ip; FRE U.S. Patent Nov. 4, 2014 Sheet 2 of 7 US 8,877,753 B2 Tai-fick test worphine dose (mg/kg, sc) FGURE 2 ai-fick test ki C 2 { - 25,a--- 4.-25 . 5. 8. vio. 388 i388 gig, SC G. RE 3 U.S. Patent Nov. 4, 2014 Sheet 3 of 7 US 8,877,753 B2 ai-ick test O WT (ED50-35) { 2: 8. viorphine dose mg/kg, sc) FE 4 U.S. Patent Nov. 4, 2014 Sheet 4 of 7 US 8,877,753 B2 A Tai-fick test |- it is i 8. s 4 k MS f 8 :. ..: s . ; : 4.: f; Compound 83 gig, B ai-fick test 3: 2 2 *::::::::::::::::::::::g: kg, i.) FORES U.S. Patent Nov. 4, 2014 Sheet 5 Of 7 US 8,877,753 B2 a-fick test it. FGRE 6 ai-Fick Test i nam w-- ..., w FGRE 7 U.S. Patent Nov. 4, 2014 Sheet 6 of 7 US 8,877,753 B2 S.C. S.S.S F & E 8 Saline Morphine 1.5 mg/kg i $orphine 5 mg/kg Saire (Coin prairi 33 xx - s ::::: ; ws &3:3s; it 3:3 Ss:ii g : 3:3: ::::::::::: test FGURE 9 U.S. Patent Nov. 4, 2014 Sheet 7 Of 7 US 8,877,753 B2 8. w s x e --- Frecor: k P < 3.05 xk . ; ws F ?econcision fig Stude :-t tes FEGURE US 8,877,753 B2 1. 2 1-ARYL-3-AMNOALKOXY PYRAZOLES AS receptors as a modulatory system on the analgesic activity of SIGMA LGANDSENHANCING ANALGESC opioid drugs Sigma1 receptor modulation of opioid analge EFFECT OF OPODS AND ATTENUATING sia in the mouse, J Pharmacol Exp. Ther (2002), 30003), THE DEPENDENCY THEREOF 1070-1074. Notwithstanding, in all of this cases the problem of dependence induced by opioids and opiates remain to be CROSS-REFERENCE TO RELATED present. APPLICATIONS One of the pharmacological approaches to solve the prob lem of opioid and opiate dependency has been the co-admin This application is the National Stage of International istration of opioids or opiates and sigma ligands. For instance, Application No. PCT/EP2009/054974, filed Apr. 24, 2009, 10 sigma-1 receptor agonist SA4503 has been shown to have a which claims the benefit of European Application No. modulatory effect on addiction to morphine Nomura, M. et EP0838.0122.5, filed Apr. 25, 2008, the contents of which are al: Studies on drug dependence (Rept. 322): Attenuation of incorporated by reference herein. morphine- and psychoStimulants-induced place preference by sigma1 receptoragonist SA4503, 72nd Annual Meeting of FIELD OF THE INVENTION 15 the Japanese Pharmacological Society (Sapporo, Japan March 1999). Also, sigma-1 agonist DHEA has shown some The present invention relates to potentiation of the analge capacity to attenuate the development of morphine depen sic effect of opioids and opiates as well as to attenuation of the dence Noda, Y. et al: A neuroactive steroid, dehydroepi addiction thereof. More specifically, the present invention androsterone sulfate, attenuates the development of morphine relates to the use of a group of sigma receptor ligands for the dependence: an association with sigmal receptors, 31 potentiation of the analgesic effect of opioids and opiates and Annual Meeting of the Society of Neuroscience (San Diego for decreasing the dependency induced by them at the same November 2001). EP1130018 teaches the use of sigma time. ligands for the treatment of drug addiction to morphine, cocaine and methamphetamine. However, none of these BACKGROUND OF THE INVENTION 25 approaches show an enhancement of the analgesic effect of morphine. Opioids and opiates are potent analgesics widely used in Therefore, it is desirable to find sigma ligands capable of clinical practice. Opioid and opiates drugs are classified typi synergistically potentiate the analgesic effect of opioids or cally by their binding selectivity in respect of the cellular and opiates while attenuating at the same time the dependency differentiated tissue receptors to which specific drug specie 30 binds as a ligand. These receptors include mu (LL), delta (Ö). thereof. kappa (K) and the nociceptive receptors. SUMMARY OF THE INVENTION The well-known narcotic opiates, such as morphine and its analogues, are selective for the opioid mu receptors. Mu The inventors of the present invention have Surprisingly receptors mediate analgesia, respiratory depression, and inhi 35 found that some specific sigma ligands show the capacity to bition of gastrointestinal transit. Kappa receptors mediate potentiate synergistically the analgesic effects of opioids or analgesia and sedation.