US 20070265293A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0265293 A1 Boyd et al. (43) Pub. Date: Nov. 15, 2007 (54) (S)-N-METHYLNALTREXONE Publication Classification (76) Inventors: Thomas A. Boyd, Grandview, NY (51) Int. Cl. (US); Howard Wagoner, Warwick, NY A6II 3L/4355 (2006.01) (US); Suketu P. Sanghvi, Kendall Park, A6M II/00 (2006.01) NJ (US); Christopher Verbicky, A6M I5/08 (2006.01) Broadalbin, NY (US); Stephen 39t. 35O C Andruski, Clifton Park, NY (US) (2006.01) A6IP 3L/00 (2006.01) Correspondence Address: St. 4. CR WOLF GREENFIELD & SACKS, P.C. (2006.01) 6OO ATLANTIC AVENUE 3G (i. 308: BOSTON, MA 02210-2206 (US) A6IP 33/02 (2006.01) C07D 489/00 (2006.01) (21) Appl. No.: 11/441,452 (52) U.S. Cl. .............. 514/282; 128/200.23; 128/202.17; (22) Filed: May 25, 2006 546/45 Related U.S. Application Data (57) ABSTRACT This invention relates to S-MNTX, methods of producing (60) Provisional application No. 60/684,570, filed on May S-MNTX, pharmaceutical preparations comprising 25, 2005. S-MNTX and methods for their use. O G M Br Br e (pH OH N N Me O YO O YO OH OH R-MNTX S-MNTX Patent Application Publication Nov. 15, 2007 Sheet 1 of 6 US 2007/0265293 A1 Fig. 1 OH OH Me-N Me-N D / O O -----BBr, O O CHCI NMP, 3 AUTOCLAVE, 70'C OMe OH 1 2 Br OH As GE) G As 69 GOH Me-N ION Me-N -lass O SO EXCHANGE O SO OH OH 3 S-MNTX 1 - OXYCODONE 2 - OXYMORPHONE 3 - ODIDE SALT OF S-MNTX Fig. 2 Patent Application Publication Nov. 15, 2007 Sheet 2 of 6 US 2007/0265293 A1 ·6998./'7 SSNSN426% B ppm Fig. 3 Patent Application Publication Nov. 15, 2007 Sheet 3 of 6 US 2007/0265293 A1 100 SO 3. S. & R S 2 S. g & 3 40 g ov g S. s S g Š 3 O a : s S 4OOO 3OOO 2000 1500 1000 600 WAVENUMBERS (cm-1) NUMBER OF SAMPLE SCANS:32 NUMBER OF BACKGROUND SCANS: 32 RESOLUTION: 4000 DETECTOR: DTGS KBr SAMPLE GAIN: 4.0 BEAMSPLTTER: KBr MIRRORVELOCITY: O.6329 SOURCE: R APERTURE: 100.00 Fig. 4 Patent Application Publication Nov. 15, 2007 Sheet 4 of 6 US 2007/0265293 A1 METHOD NOTES LUNA Cl3(2), 5a 4.6 x 150 mm FLOW 10 ml/min. MONITORED (a 230 nm A-0.1% Aq TFA B-0.1%TFAIN MeOH NJECTION METHOD: 0.0 start3814 ura el8(2) long uv TIME N/A PEAKMEASUREMENT: PEAKAREA O:00 95 5 8:00 65 35 NJECTIONNOTES: S-MNTX 12:00 25 65 15:00 O 100 16:00 95 5 18:00 95 5 O.75 sM O.50. D 0.25 O.OO-- -O.10 2.5 5.0 7.5 1 O.O. 12.5 MINUTES RET TIME AREA WDTH PEAKNO. (MIN) (COUNTS) SEP. CODE 1/2 (SEC) RESULTO 1 8.025 26O31 BB 6.6 O.26O7 2 9.478 9551 224 BB 8.3 95.6377 3 9,995 259922 BB 5.8 2,6026 4. 10.728 1497O2 BB 5.5 14990 998.6879 100,0000 Fig.5 Patent Application Publication Nov. 15, 2007 Sheet 5 of 6 US 2007/0265293 A1 se N o f n 100 90 8O 70 60 50 40 3O 2O 10 1 OO 2OO 300 4OO 500 600 7OO 800 900 1000 m/z Fig. Patent Application Publication Nov. 15, 2007 Sheet 6 of 6 US 2007/0265293 A1 10 20 ? US 2007/0265293 A1 Nov. 15, 2007 (S)-N-METHYLNALTREXONE levomethorphan, is a potent narcotic. R.R-methylphenidate is a drug to treat attention deficit hyperactivity disorder RELATED APPLICATION (ADHD), whereas its enantiomer, S.S.-methylphenidate is an antidepressant. S-fluoxetine is active against migraine, 0001) This application claims benefit under 35 U.S.C. whereas its enantiomer, R-fluoxetine is used to treat depres 119(e) of the filing date of U.S. Ser. No. 60/684.570, filed on Sion. The S enantiomer of citalopram is therapeutically May 25, 2005, the entire disclosure of which is incorporated active isomer for treatment of depression. The Renantiomer herein by reference. is inactive. The Senantiomer of omeprazole is more potent FIELD OF THE INVENTION for the treatment of heartburn than the Renantiomer. 0006 Bianchetti et al., 1983 Life Science 33 (Sup I):415 0002 This invention relates to (S)-N-methylmaltrexone 418 studied three pairs of diastereoisomers of quaternary (S-MNTX), stereoselective synthetic methods for the prepa narcotic antagonist and their parent tertiary amines, leval ration of S-MNTX, pharmaceutical preparations comprising lorphan, nalorphine, and naloxone, to see how the configu S-MNTX and methods for their use. ration about the chiral nitrogen affected in vitro and in vivo activity. It was found that the activity varied considerably BACKGROUND OF INVENTION depending on how the quaternary derivatives were prepared. 0003 Methylmaltrexone (MNTX) is a quaternary deriva In each series, only the diastereomer obtained by methyla tive of the pure opioid antagonist, naltrexone. It exists as a tion of the N-allyl-substituted tertiary amine (referred to as salt. Names used for the bromide salt of MNTX in the “N-methyl diastereomer') was potent in displacing H-nal literature include: Methylnaltrexone bromide: N-Methyln trexone from rat brain membranes, and acting as a morphine altrexone bromide; Naltrexone methobromide; Naltrexone antagonist in the guinea-pig ileum. Conversely, diastereoi methyl bromide: MRZ 2663BR. MNTX was first reported in somers obtained by reacting N-methyl-substituted tertiary the mid-70s by Goldberg et all as described in U.S. Pat. No. amines with allyl halide (referred to as "N-allyl diastere 4,176,186. It is believed that addition of the methyl group to omers') did not displace 3H-naltrexone and had negligible the ring nitrogen forms a charged compound with greater antagonist activity and slight agonist action in the guinea-pig polarity and less liposolubility than naltrexone. This feature ileum. In vivo findings were generally consistent with those of MNTX prevents it from crossing the blood-brain barrier in vitro. Thus only the “N-methyl” but not the “N-allyl in humans. As a consequence, MNTX exerts its effects in the diastereomers’ inhibited morphine-induced constipation in periphery rather than in the central nervous system with the rats and behaved as antagonists. The author stated that the advantage that it does not counteract the analgesic effects of prepared materials appeared to be pure by H and 'C opioids on the central nervous system. nuclear magnetic resonance (NMR) analysis, but these methods are not accurate. The author cites a literature 0004 MNTX is a chiral molecule and the quaternary reference for the assignment of the R configuration to the nitrogen can be in R or S configuration. (See FIG. 1.) It is “N-methyl diastereomer of nalorphine. No assignment is unknown whether the different stereoisomers of MNTX proposed for the levallorphan and naloxone diastereomers. It exhibit different biological and chemical properties. All of would be adventurous to extrapolate the configuration to the reported functions of MNTX described in the literature these diastereomers (R. J. Kobylecki et al., J. Med. Chem. 25. indicate that MNTX is a peripheral opioid antagonist. Some 1278-1280, 1982). of these antagonist functions are described in U.S. Pat. Nos. 4,176, 186, 4,719,215, 4,861,781, 5,102,887, 5,972,954, 0007 Goldberget al.'s U.S. Pat. No. 4,176,186, and more 6.274,591, 6,559,158, and 6,608,075, and in U.S. patent recently Cantrell et al.'s WO 2004/043964 A2 describe a application Ser. No. 10/163,482 (2003/0022909A1), Ser. protocol for the synthesis of MNTX. Both describe a syn No. 10/821,811 (20040266806), Ser. No. 10/821,813 thesis of MNTX by quatemizing a tertiary N-substituted (20040259899) and Ser. No. 10/821,809 (20050004155). morphinan alkaloid with a methylating agent. Both Gold These uses include reducing the side-effects of opioids berg et al. and Cantrell et al. are silent as to the stereoiso without reducing the analgesic effect of opioids. Such side mer(s) produced by the synthesis. The authors remained effects include nausea, emesis, dysphoria, pruritus, urinary cautiously silent about the stereochemistry because the retention, bowel hypomotility, constipation, gastric hypo stereochemistry could not be determined based on prior art. motility, delayed gastric emptying and immune Suppression. The cyclopropylmethyl side-chain in naltrexone is different The art discloses that MNTX not only reduces the side from the prior art side-chains and may have affected the effects Stemming from opioid analgesic treatment but also stereochemical outcome in the synthesis of MNTX, as may reduces the side-effects mediated by endogenous opioids other reaction parameters such as temperature and pressure. alone or in conjunction with exogenous opioid treatment. Based on the method of synthesis described in each, it is Such side-effects include inhibition of gastrointestinal motil unknown whether the MNTX so produced was R, S or a ity, post-operative gastrointestinal dysfunction, idiopathic mixture of both. constipation and other Such conditions including, but not 0008 S-MNTX in pure form, and a method of making limited to, those mentioned above. However, it is unclear pure S-MNTX have not been described in the literature. from the art whether the MNTX used in these studies was a Researchers would have been unable to definitively charac mixture of R and S Stereoisomers or a single stereoisomer. terize and distinguish the stereoisomer(s) obtained by the Goldberg et al.