(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 24 January 2008 (24.01.2008) WO 2008/011483 A2 (51) International Patent Classification: Not classified (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, PCT/US2007/073813 CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, (22) International Filing Date: 18 July 2007 (18.07.2007) IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, (25) Filing Language: English MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, (26) Publication Language: English TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (30) Priority Data: 60/807,799 19 July 2006 (19.07.2006) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): ALLER- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, GAN, INC. [US/US]; 2525 Dupont Drive, Irvine, CA ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 92612 (US). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (72) Inventors; and PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, (75) Inventors/Applicants (for US only): DONELLO, John, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). E. [US/US]; 34041 Pequito Drive, Dana Point, CA 92629 (US). SCHWEIGHOFFER, Fabien, J. [FR/FR]; 36 Published: avenue du VaI de Beaute, F-94120 Nogent surMarne (FR). — without international search report and to be republished LEBLOND, Bertrand [FR/FR]; 17 allee des Dahlias, upon receipt of that report F-92320 Chatillon (FR). For two-letter codes and other abbreviations, refer to the "G uid (74) Agents: GERMAN, Joel et al.; c/o Allergan, Inc., 2525 ance Notes on Codes and Abbreviations" appearing at the beg in Dupont Drive, Irvine, CA 92612 (US). ning of each regular issue of the PCT Gazette. (54) Title: METHODS FOR TREAHNG CHRONIC PAIN USING 1-ARYL-I -HYDROXY 2,3-DIAMINO-PROPYL AMINES, 1-HETEROARYL- 1-HYDROX Y-2,3-DIAMINO-PROPYL AMINES AND RELATED COMPOUNDS (57) Abstract: Disclosed herein are methods of treating a pa tient suffering from one or more types of chronic pain using com pounds of the following formula II wherein the variables have the meaning defined in the specification. METHODS FOR TREATING CHRONIC PAiN USING 1-ARYL-1 -HYDROXY- 2,3-DIAMINO-PROPYL AMINES, 1-HETEROARYL-1 -HYDROXY-2,3- DIAMINO-PROPYL AMINES AND RELATED COMPOUNDS BACKGROUND OF THE INVENTION Field of the Invention The present invention is directed to methods of treating a patient suffering from one or more types of chronic pain using derivatives of 1-aryi-1 - hydroxy-2,3-diamino-propyl amines, 1-heteroaryl-1 -hydroxy-2,3-diamino- propyl amines and related compounds. Background Art 1-Phenyl-2-decanoylamino-3-morpholtno-1 -propanol (PDMP) was discovered by Vunam, R. R . and Radin, N., Chem Phys. Lipids, 26, 265-278, 1980. Preparation of PDMP is described in Inokuchi, J. et ai., J. Lipid Res. 28, 565-571 , 1987; Radin, A. et ai., NeuroProtocois, 3(2), 145-55, 1993; Radin, A. et at., J . Lipid Res. 36, 6 11-621 , 1995 and US 591 691 1. POMP mixture of DL-erythro and DL-threo isomers These derivatives inhibit glucosylceramide (GlcCer) formation by inhibiting the enzyme GlcCer synthase, thereby lowering the level of glycosphingolipids.) The isomers most active have the f?,R-(D-tf7reo)-configuration. Four enantiomers are produced during the synthesis. Because only the O-threo enantiomers are active in inhibiting the glucosylceramide synthase, resolution of the active D-threo inhibitors was performed bychiral chromatography. Moreover, D-threo-PDMP has antitumor activity via inhibition of glycosphingolipid biosynthesis as described by lnokuchi J., Cancer Letters 38(1 -2), 23-30, 1987. L-threo-PDMP D-f/)reø-PDMP Furthermore, it was also reported that D-threo-PDMP suppresses synaptic function by Mizutani A. et al., Biochem. Biophys. Res Commun., 222, 494-498, 1996 Preparation of enantiomericaily pure D-threo-PDMP has been reported by Mitchell, Scott A.[ J. Org Chem., 63 (24), 8837-8842, 1998]; Miura, T. et at, [Bioorg. Med. Chem., 6 , 1481 -1498, 1998]; Shin, S. et al., [Tetrahedron asymmetry, 11, 3293-3301 , 2000]; VVO 200201 2 185 L-f/ireoPDMP is an agent for treating neuronal diseases WO 95/05177. This compound is also described to be an agent for protecting brain in US 6407064. Moreover treatment with L-threo-PDMP after transient forebrain ischemia in rats ameliorated the deficit of a well learned spatial memory by an 8-arm maze task, suggesting a potential for neurodegenerative disorders as described by lnokuchi et al., Ann. N.Y. Acad. ScL, 845(1 ) , 2 19- 224, 1998 and JP 10324671 (Seikagaku Kogyo Co.). A stereoselective synthesis of enantiomericaily pure D-threo-PDMP has also been described by Shin, S. et al., Tetrahedron asymmetry, 11, 3293- 3301 , 2000 and WO 200201 2185 the key step is the regioselective cleavage by nitrogen nucleophiles, as morpholine, of the C(3)-N-bond of non-activated enantiomericaily pure aziridine-2-methanoIs. 99 % D-threo-PDMP 8 1 % ι ι ) TMS-I, CH3CN ii) a) morpholine ) HCI MI) Pd(OH)2 H AcOH, MeOH, 40 C v)1 0% NaOH, dacanoyl chioride 81% On the other hand, the synthesis of enantiomerically pure ( 1 S,2S)-1 -phenyl-2- decanoylamino-3-morpholino-1 -propanol (L-threo-PDMP) from L-serine has also been described by Mitchell, Scott A., J. Org. Chem., 63 (24), 8837-8842, 1998. O'Donnei SChiff base L-f/ireo-PDMP I) IBU5A I2 H II) PhMgBr Other known methods to obtain L-threo-PDMP are described by Miura, T. et al, Bioorg. Med Chem., 6, 1481 - 1498, 1998 and in JP-A-9-21 6858. L-f/ireo-PDMP is an agent for treating neuronal diseases WO 95/05177. This compound is also described to be an agent for protecting brain in US 6407064. Moreover treatment with L- ?reσ-PDMP after transient forebrain ischemia in rats ameliorated the deficit of a well learned spatial memory by an 8-arm maze task, suggesting a potential for neurodegenerative disorders as described by lnokuchi et al., Ann. N. Y. Acad. ScL, 845(1 ), 2 19-224, 1998 and J P 10324671 (Seikagaku Kogyo Co .) Synthesis of ( 1 S,2S)- threo- and ( 1 fl,2S)-e/yf/7rø-1 -phenyl-2- palmitoyiamino-3- Λ/-morpho!ino-1 -propanol (PPMP) were described starting from Garner aldehyde of L-serine, by Nishida, A., Synlett, 4 , 389-390, 1998. L-f/?reoPPMP D-erythro-PPMP Compounds with longer chain fatty acyl groups (than decanoyl) have been found to be substancially more effective as inhibitor of GCS. D-fftreo-1 - phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4 or PPPP) analogues were first obtained by a Mannich reaction as described Abe, A . et al., J. Biochem., 111, 19 1-196, 1992 or US 591691 1 and WO 2001 004108. O-threoPA Preparation of D-tf?reø-4'-hydroxy-P4, one of the most potent inhibitor of 10 GCS, was described by Lee, L et al., J. Biol. Chem., 27A, 2 1, 14662-14669, 1999. In addition, a series of dioxane substitutions was designed and tested. These included 3\4'-methyienedioxypheny!-3',4'- ethylenedioxyphenyl-, and 3',4'-trimethy!enedioxyphenyI-substituted homologues. , r D-?/ireo-4'-hydroxy-P4 Synthesis of enantiomerically pure D-tf?reo-1 -pheny!-2- benzyioxycarbonylamino-3-pyrrolidino-1 -propanol (PBPP) and D-threo-P4 and its analogues from Λ/-benzyloxycarbonyl-D-serine, was described by Jimbo M . 0 et al, J . Biochem., 127(3), 485-91 , 2000 and EP 782992 (Seikagaku Kogyo Co.). PBPP is described as a potent GCS inhibitor. D-threo-PBPP Novel prodrugs of P4 derivatives were described in US 200201 98240 and WO 2002062777 Synthesis of enantiomericaliy pure of D-tf?reoethylenedioxy-P4 and D- #7røo-p-nnethoxy-P4 were described by Husain A and Ganem B., Tetrahedron Lett, 43. 8621 -8623, 2002. The key step is a highly syn-selective additions of aryl Grignard reagents to Garner aldehyde. Garner Aldehyde m) D ff>reo-ethylenedioxy-P4 ι) 3,4-ethylen βdιoxyphe πylmagnes ιum bromide, 78 C CuI THF Me2S 64 % n) 0 1 N HC!, THF 82%, MsCI Et3N DCM O C 85 % in) pyrrolidine, DMF, 45°C 58 % ιv) 3 N HCI, O C, to RT then Ci 5H3 1COCI, Et3N DMAP, DCM -20°C, 87% Dtastereoselective synthesis of PA analogues were described in U S 03/0153768 and W O 2003045928 (Genzyme Corp.); Oxazolines I [R1 = (un)substituted aryl; R 2 R 3 = H , (un)substituted aliphatic; N R 2R 3 = heterocyclic] are prepared a s intermediates for P 4 glucosyltransferase 1 2 3 inhibitors from R CHO and R R NCOCH 2CN. Thus, methyl isocyanoacetate CNCH 2C O 2 M e was treated with pyrrolidine and the amide was treated with 1,4-benzodioxane- θ-carboxaldehyde, followed by hydrolysis o f the oxazoline using HCI in methanol, reduction of the keto group of amide Il using LiAIH 4 , and acylation with palmitoyl chloride to give D,L-tf?reoethylenedioxy-P4 111.