(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date PCT 24 January 2008 (24.01.2008) WO 2008/011487 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/40 (2006.01) A61P 29/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/5375 (2006.01) AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, (21) International Application Number: ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, PCT/US2007/073818 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, (22) International Filing Date: 18 July 2007 (18.07.2007) MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, (25) Filing Language: English PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (26) Publication Language: English ZM, ZW (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 60/807,796 19 July 2006 (19.07.2006) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): ALLER- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), GAN, INC. [US/US]; 2525 Dupont Drive, Irvine, CA European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, 92612 (US). 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 Av Published: enue Du VaI De Beaute, F-94120 Nogent Sur Marne (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: STATHAKIS,Dean, G. et al; C/o Allergan, Inc., ance Notes on Codes and Abbreviations" appearing at the beg in 2525 Dupont Drive, Irvine, CA 92612 (US). ning of each regular issue of the PCT Gazette. (54) Title: METHODS FOR TREATING CHRONIC PAIN USING 1-BENZYL-I -HYDROX Y-2,3-DIAMINO-PROPYL AMINES,3-BENZYL-3-HYDROXY-2-AMINO-PROPIONIC ACID AMIDES AND RELATED COMPOUNDS (57) Abstract: Disclosed herein are methods of treating a patient suffering from one or more types of chronic pain using the fol lowing compounds: METHODS FOR TREATING CHRONIC PAIN USING 1-BEN2YL-1 - HYDROXY-2,3-DIAMINO-PROPYL AMINES, 3-BENZYL-3-HYDROXY-2- AMINO-PROPIONIC ACID AMIDES 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 using 1-benzyl-1 - hydroxy-2,3~diamino-propyi amines, 3-benzyI-3-hydroxy-2-amino-propionic acid amides and related compounds. Background of the invention 1-Phenyl-2-decanoylamino-3-morpholino-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. etai., J Lipid Res. 28, 565-571 , 1987; Radin, A et ai., NeuroProtocols, 3(2), 145-55, 1993; Radin, A . et ai., J. Lipid Res. 36, 6 1 1-621 , 1995 and US 591 691 1. MP mixture of L-erythro and DL-th 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 Four enantiomers are produced during the synthesis. Because only the ϋ -threo enantiomers are active in inhibiting the glucosylceramide synthase, resolution of the active ϋ -threo inhibitors was performed by chiral chromatography. Moreover, D-threo-PDkλP has antitumor activity via inhibition of glycosphingolipid biosynthesis as described by Inokuchi J., Cancer Letters 38(1 -2), 23-30, 1987. L-thr βo-PDMP D-thr P 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 enantiomerically pure D-f/?reo-PDMP has been reported by Mitchell, Scott A.[ J. Org. Chem. 63 (24), 8837-8842, 1998]; Miura, T. et al, [Bioorg. Med. Chem., 6 , 1481-1498, 1998]; Shin, S. etal., [Tetrahedron asymmetry, 11, 3293-3301 , 2000]; WO 2002012185 L-threo-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-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 ScI., 845(1 ), 219- 224, 1998 and JP 10324671 (Seikagaku Kogyo Co.). A stereoselective synthesis of enantiomerically pure D- jr σ-PDMP has also been described by Shin, S. et al., Tetrahedron asymmetry, 11, 3293- 3301 , 2000 and WO 20020121 85 the key step is the regioselective cleavage by nitrogen nucleophiles, as morpholine, of the C(3)-N-bond of non-activated enantiomerically pure aziridine-2-methanols. 99 % D (I) ι i) TMS-I, C N a) morpboiine ) HCI in) Pd(OH)2 H AcOH, MeOH, 40°C v)10% NaOH, decanoyf chloride 8 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 Other known methods to obtain L-ihreo-PDMP are described by Miura, T et at, Bioorg. Med Chem., 6, 1481 - 1498, 1998 and in JP-A-9-216858. L-threo-PDMP is an agent for treating neuronal diseases WO 95/051 77. 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 at., Ann N. Y. Acad. Sci., 845(1 ), 2 19-224, 1998 and JP 10324671 (Setkagaku Kogyo Co.). Synthesis of ( 1 S.2S)- threo- and ( 1 fl,2S)-e/y07rø-1 -phenyl-2- palmitoylamino-3- Λ/-morpholino-1 -propanol (PPMP) were described starting from Garner aldehyde of L-serine, by Nishida, A .t Synlett, 4 , 389-390, 1998 L-threo-PPMP PPMP Compounds with longer chain fatty acyl groups (than decanoyl) have been found to be substancially more effective as inhibitor of GCS. D-threoA - phenyl-2-palmitoy!amino-3-pyrrolidino-1 -propanoi (P4 or pppp) analogues were first obtained by a Mannich reaction as described Abe, A et a!., J. Biochem., 111, 19 1- 196, 1992 or US 591 691 1 and WO 2001004108. D-threo-P4 Preparation of D-^reo-4'-hydroxy-P4, one of the most potent inhibitor of GCS, was described by Lee, L. et al., J. Biol. Chem , 274, 2 1, 14662-14669, 1999 In addition, a series of dioxane substitutions was designed and tested. These included 3',4'-methylenedioxyphenyl-3',4'- ethylenedioxypheny!-, and 3\4'- trimethylenedioxyphenyl-substituted homotogues. D-tf)reo-4'- y-P4 Synthesis of enantiomerically pure D- reo-1-phenyl-2- benzy!oxycarbonyiamino-3-pyrrolidino-1 -propanol (PBPP) and O-threo-PA and its analogues from /V-benzyloxycarbonyl-D-serine, was described by Jimbo M. et al, J. Biochem., 127(3), 485-91 , 2000 and EP 782992 (Seikagaku Kogyo Co.) PBPP is described as a potent GCS inhibitor. D- PBPP Novel prodrugs of P4 derivatives were described in US 200201 98240 and WO 2002062777. Synthesis of enantiomericatiy pure of D-tfjreoethy!enedioxy-P4 and D- tfjreo-p-methoxy~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 D- ϊreø-ethyienedioxy-P4 t) 3,4-ethylenedf θxyphenylmagnes ιum bromide, -78 64 % n) 0 1 N HCI, THF 82%, MsCI, Et3N, DCM, 0°C, 85 % in) pyrrolidine, DMF 4 I, 0°C, to RT then C16H3XOCI, Et3 N, DMAP, DCM, -20°C, 87% Diastereoselective synthesis of P4 analogues were described in US 03/01 53768 and W O 2003045928 (Genzyme Corp.); Oxazolines i [R1 = (un)substituted aryl; R2, R3 = H, (un)substituted aliphatic; NR2R3 = heterocyclic] are prepared as intermediates for P4 glucosyltransferase 1 2 3 inhibitors from R CHO and R R NCOCH 2CN. Thus, methyl isocyanoacetate CNCH CO2Me was treated with pyrrolidine and the amide was treated with 1,4-benzodioxane-6-carboxaldehyde, followed by hydrolysis of 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?røo-ethylenedioxy-P4 III. D,L- ylenedιoxy-P4 Synthesis of enantiopure P4 analogues were described in WO 2003008399 (Genzyrne Corp.). P4 derivatives, such as I [R1 R5 = un(substituted) aromatic; R2, R3 = H un(substituted) aliphatic; NR2R3 = (un)substituted non-aromatic heterocyclic 4 ring; R = O, H2] , were prepared for their therapeutic use as GCS inhibitors.