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(12) Patent Application Publication (10) Pub. No.: US 2008/0234306 A1 Perez Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2008/0234306 A1 Perez Et Al US 200802343 06A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0234306 A1 Perez et al. (43) Pub. Date: Sep. 25, 2008 (54) N-OXIDES OF 4.5-EPOXY-MORPHINANIUM Related U.S. Application Data ANALOGS (60) Provisional application No. 60/867,104, filed on Nov. (75) Inventors: Julio Perez, Tarrytown, NY (US); 22, 2006. Amy Qi Han, Hockessin, DE (US); Publication Classification Yakov Rotshteyn, Monroe, NY (US); Govindaraj Kumaran, (51) Int. Cl. Woburn, MA (US) A63L/485 (2006.01) C07D 489/00 (2006.01) Correspondence Address: A6IP 25/00 (2006.01) KELLEY DRYE & WARREN LLP C07D 47L/00 (2006.01) 400 ALTLANTIC STREET, 13TH FLOOR (52) U.S. Cl. .............................. 514/282:546/44; 546/40 STAMFORD, CT 06901 (US) (57) ABSTRACT (73) Assignee: Progenics Pharmaceuticals, Inc., Novel N-oxides of 4.5-epoxy-morphinanium analogs are dis Tarrytown, NY (US) closed. Pharmaceutical compositions containing the N-ox ides of 4.5-epoxy-morphinanium analogs and methods of (21) Appl. No.: 11/944,300 their pharmaceutical uses are also disclosed. The compounds disclosed are useful, interalia, as modulators of opioid recep (22) Filed: Nov. 21, 2007 tOrS. COMPETITION CURVE OBTA NED WITH COMPOUND O-5720 AT THE HUMAN MU RECEPTOR CSO = 6. E. O9 M - O.9 75 S O 2. S .25 ... 3 - 2 -11 - 0 -9 -8 - 7 -6 - 5 - 4 Log O-5720 (M) Patent Application Publication Sep. 25, 2008 US 2008/0234306 A1 Figure l COMPETITION CURVE OBTANED WITH COMPOUND O-5720 AT THE HUMAN MU RECEPTOR CSO = 6. E-O9 M H - 0.9 100 SS 75 t) 50 M2, 25 3.210", "5" Log O-5720 (M) US 2008/023430.6 A1 Sep. 25, 2008 N-OXIDES OF 4.5-EPOXY-MORPHINANIUM excreted among the many metabolic pathways which have ANALOGS been identified in mammals administered various tertiary amines. J. D. Phillipson et al., Eur. J. Drug Metab. Pharma cokinetics 3, 119 (1978), report that morphine and codeine 0001. This application claims priority to Provisional are converted in part to the corresponding N-oxides by a Application Ser. No. 60/867,104, filed Nov. 22, 2006, which guinea pig liver microsomal preparation, and also that these is herein incorporated by reference in its entirety. two drugs are partially metabolized to the N-oxides when administered to rats. T. Ishida et al., Drug Metab. Dispos. 7, BACKGROUND OF THE INVENTION 162 (1979), and T. Ishida et al., J. Pharmacobio-Dyn. 5,521 0002 1. Field of the Invention (1982), report that oxycodone N-oxide is one of a number of 0003. The present invention generally relates to N-oxides identifiable metabolites found in the urine of rabbits admin of 4.5-epoxy-morphinanium analogs (hereinafter referenced istered oxycodone subcutaneously. While other metabolites as “4.5-epoxy-morphinaniums), and in particular isolated were found in both free and conjugated forms, oxycodone axial (hereinafter 'axial 4.5-epoxy-morphinaniums) and N-oxide was found only in the free, unconjugated form. The equatorial (hereinafter “equatorial 4.5-epoxy-morphinani analgesic activity of oxycodone is believed to be due to the ums) stereoisomers of the same, prodrugs, polymorphs, Syn unchanged drug rather than the metabolites. S.Y.Yeh et al., J. thetic methods for their preparation, pharmaceutical prepara Pharm. Sci. 68, 133 (1979), also report isolating morphine tions comprising the same, and methods for their use. N-oxide from the urine of guinea pigs administered morphine 0004 2. Description of the Related Art sulfate. 0005 Opioid activity of morphinoids has been shown to 0010. The art suggests that isolated stereoisomers of a be particularly sensitive to the nature of their nitrogen sub compound, whether enantiomers or diastereomers, some stituents. For example, replacement of the N-methyl group in times may have contrasting physical and functional proper morphine and related opioids by substituents rich in JL-elec ties, although it is unpredictable whether this is the case in any trons, such as allyl, cyclobutylmethyl, and propylmethyl, particular circumstance. Dextromethorphan is a cough Sup result in potent antagonists such as nalorphine, naloxone, pressant, whereas its enantiomer, levomethorphan, is a potent maltrexone and nalbuphine. narcotic. R.R-methylphenidate is a drug to treat attention 0006 N-oxides of certain morphinan derivatives are deficit hyperactivity disorder (ADHD), whereas its enanti known, e.g., Tiffany, U.S. Pat. No. 2,813,097 which discloses omer, S.S.-methylphenidate is an antidepressant. S-fluoxetine 3-hydroxy-N-methylmorphinan N-oxide and its utility as an is active against migraine, whereas its enantiomer, R-fluox analgesic. Tiffany, U.S. Pat. No. 2,813,098 further discloses etine is used to treat depression. The S-enantiomer of citalo 3-methoxy-N-methylmorphinan N-oxide and its utility as an pram is therapeutically active isomer for treatment of depres antitussive. It is stated that these N-oxides have a higher sion. The R-enantiomer is inactive. The S-enantiomer of therapeutic index than the corresponding tertiary amines. omeprazole is more potent for the treatment of heartburn than Bartels-Keith disclose in U.S. Pat. No. 3,299,072 certain the the Renantiomer. baine morphinan derivates (having a di-unsaturated cyclo 0011. The designations “R” and “S” are commonly used in hexanone ring in the backbone). The compounds are indi organic chemistry to denote specific configuration of a chiral cated to have analgesic and/or narcotic antagonist activity. center. The designations “R” refers to “right' and refers to U.S. Pat. Nos. 3,144,459 and 3,217,006 disclose N-oxide that configuration of a chiral center with a clockwise relation morphinan structures lacking the 4.5-epoxy. ship of group priorities (highest to second lowest) when 0007. The N-oxides of morphine and simple morphine viewed along the bond toward the lowest priority group. The derivatives such as codeine, hydromorphone (dihydromor term “S” or “left” refers to that configuration of a chiral center phinone), and hydrocodone (dihydro codeinone), are well with a counterclockwise relationship of group priorities known, having been reported by, among others: M. (highest to second lowest) when viewed along the bond Polonovski et al, Bull. Acad. Med. 103, 174 (1930); N. H. toward the lowest priority group. Chang et al., J. Org. Chem. 15, 634 (1950); B. Kelentei et al. 0012. The priority of groups for the R/S designation is Arzneimittel-Forsch. 7,594 (1957); K. Takagietal.Yakugaku based upon atomic number (heaviest isotope first). A partial Zasshi 83,381 (1963) (Chem. Abs. 59:9224b): L. Lafon, U.S. list of priorities and a discussion of Stereochemistry is con Pat. No. 3,131,185; M. R. Fennessy, Brit. J. Pharmacol. 34, tained in the book: The Vocabulary of Organic Chemistry, 337 (1968); M. R. Fennessy, Eur. J. Pharmacol. 8,261 (1969); Orchin, et al. John Wiley and Sons, Inc., page 126 (1980), and M. R. Fennessy, J. Pharm. Pharmacol. 21, 668 (1969). which is incorporated herein by reference in its entirety. Morphine N-oxide is variously reported to be either less When quaternary nitrogen morphinan structures are pro active or inactive as an analgesic but an effective antitussive, duced, such structures may be characterized as (R) or (S) as well as having somewhat lower toxicity than morphine. Stereoisomers. 0008 Boswell et al., U.S. Pat. No. 4,990,617, disclose the 0013 The pharmacology of the diastereomeric conform N-oxide derivatives of 3-hydroxymorphinans said to be use ers of N-oxide morphinans has not been elucidated. Given ful as prodrugs, agonist-antagonists, analgesics and narcotic that different stereoisomers of organic compounds have been antagonists. Among the compounds described are the N-ox found in the past to elicit significantly different pharmaco ide of naloxone, naltrexone, nalmefene, nalbuphine, pentazo logical profiles, it is possible that significant differences in cine, butorphanol, and buprenorphine. The reference Sug pharmacological activity might be seen with select N-oxide gests improved oral bioavailability for the N-oxide analogs, morphinans. that appears to result from the biotransformation of the N-ox ides to their parent amine forms. SUMMARY OF THE INVENTION 0009. It should be noted that N-oxide morphinan struc 0014. It is disclosed in equatorial/axial embodiments tures are also produced by oxidative metabolism which are herein that N-oxides of 4.5-epoxy-morphinaniums, and in US 2008/023430.6 A1 Sep. 25, 2008 particular 7.8-saturated-4,5-epoxy-morphinaniums, possess 0041 amine, amide, sulfonamide, ester, heterocycle, significant mu-opioid receptor antagonistic activity at physi cyclic carbohydride, aryl; ological concentrations when the N-oxide is in an axial plane with respect to the nitrogen (i.e., (S) configuration when N is R, is H, OH, OR, substituted with hydrocarbyl substituents). It is further dis 0.042 (C-C) alkyl substituted with 0-3 Ro: closed that equatorial/axial N-oxide compounds of the 0.043 (C-C) alkenyl substituted with 0-3 Ro: present invention having an axial oxygen Substitutent may be 0044 (C-C) alkynyl substituted with 0-3 Ro: found to display significantly greater antagonist activity than 0045 (C-C) cycloalkyl substituted with 0-3 Ro: their counterpart equatorial stereoisomers (wherein the oxy 0046 (C-C) carbocycle substituted with 0-3 Ro: gen is in an equatorial position). Equatorial-orientation of the 0047 aryl substituted with 0-3 Ro: oxygen Substitutent in Such 4.5-epoxy-morphinanium com 0.048 or R and R, are combined to form an O-fused pounds may diminish antagonistic activity. ring, a C-C carbocycle fused ring, a benzo fused ring, 0015. In an embodiment there are provided compounds of or a 5-6 membered heteroaryl fused ring or a bicyclic the formula (I): combination thereof Rs is H, OH, OR (I) 0049 (C-C) alkyl substituted with 0-3 Ro: 0050 (C-C) alkenyl substituted with 0-3 Ro: 0051 (C-C) alkynyl substituted with 0-3 Ro: equatorial 0.052 (C-C) cycloalkyl substituted with 0-3 Ro: 0053 (C-C) carbocycle substituted with 0-3 Ro: 0054) aryl substituted with 0-3 Ro: Ra is H, OH, OR, NHR, 0.055 (C-C) alkyl substituted with 0-3 Rs.
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