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(12) United States Patent (10) Patent No.: US 7,038,085 B2 Rariy Et Al

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(12) United States Patent (10) Patent No.: US 7,038,085 B2 Rariy Et Al US007038O85B2 (12) United States Patent (10) Patent No.: US 7,038,085 B2 Rariy et al. (45) Date of Patent: May 2, 2006 (54) STEREOISOMERS OF Gard, S., et al., “Enhancement of Second-Migrating P-HYDROXY-MILNACIPRAN, AND Enantiomer Peak Symmetry of Basic Drugs by Using Dual METHODS OF USE THEREOF Cyclodextrin System in Capillary Electrophoresis.” Electrophoresis 2000, N. 21, pp. 3028-3034, (2002). (75) Inventors: Roman V. Rariy, Allston, MA (US); Bonnaud, B., et al., “1-Aryl-2(Aminomethyl) Michael Heffernan, Hingham, MA cyclopropanecarboxylic Acid Derivatives. A New Series of (US); Stephen L. Buchwald, Newton, Potential Antidepressants.” J. Med. Chem. 1987, No. 30, pp. MA (US); Timothy M. Swager, 318-325 (1987). Newton, MA (US) Shuto, S., et al., “(+)-(Z)-2-(Aminomethyl)-1- phenylcyclopropanecarboxamide Derivatives as a New (73) Assignee: Collegium Pharmaceutical, Inc., Prototype of NMDA Receptor Antagonists.” U. Med. Chem, Cumberland, RI (US) 1995, No. 38, pp. 2964-2968, (1995). ViaZZo, P. et al. “Microbiological Transformations 34: (*) Notice: Subject to any disclaimer, the term of this Enantioselective Hydrolysis of a Key-Lactone Involved in patent is extended or adjusted under 35 the Synthesis of the Antidepressant MilnacipranR), U.S.C. 154(b) by 0 days. Tetrahedron Letters, vol. 37, No. 26, pp. 4519-4522 (1996). Shuto, S., et al., “Synthesis of (+)- and (-)-Milnaciprans and (21) Appl. No.: 10/691,465 Their Conformationally Restricted Analogs.” Tetrahedron Letters, vol. 37, No. 5, pp. 641-644 (1996). Shuto, S., et al., “Synthesis and Biological Activity of (22) Filed: Oct. 22, 2003 Conformationally Restricted Analogs of Milnacipran: (IS, 2R)-1-Phenyl-2-(S)-1-aminopropyl N,N- diethylcyclopropanecarboxamide, and Efficient (65) Prior Publication Data Noncompetitive N-Methyl-D-aspartic Acid Receptor US 2004/O142904 A1 Jul. 22, 2004 Antagonist, J. Med. Chem. 1996, No. 39, pp. 4844-4852, (1996). Related U.S. Application Data (Continued) (60) Provisional application No. 60/445,142, filed on Feb. 5, 2003, provisional application No. 60/423,062, filed Primary Examiner Shailendra Kumar on Nov. 1, 2002, provisional application No. 60/421, (74) Attorney, Agent, or Firm—Dana M. Gordon; Foley 640, filed on Oct. 25, 2002. Hoag LLP (51) Int. Cl. (57) ABSTRACT C07C 23.3/05 (2006.01) A6 IK3I/I65 (2006.01) The present invention relates generally to the enantiomers of para-hydroxy-milnacipran or congeners thereof. Biological (52) U.S. Cl. ...................... 564/165; 564/164: 564/171; assays revealed that racemic para-hydroxy-milnacipran is 564/190: 514/620: 514/624 approximately equipotent in inhibiting serotonin and nore (58) Field of Classification Search ................ 564/164, pinephrine uptake (IC.s 28.6 nM for norepinephrine, 564/165, 171, 190; 514/620, 624 ICso 21.7 nM for serotonin). Interestingly, (+)-para-hy See application file for complete search history. droxy-milnacipran is a more potent inhibitor of norepineph (56) References Cited rine uptake than serotonin uptake (ICso 10.3 nM for nore pinephrine, ICso 22 nM for serotonin). In contrast, (-)-para U.S. PATENT DOCUMENTS hydroxy-milnacipran is a more potent inhibitor of serotonin 4.478,836 A 10, 1984 Mouzin et al. uptake compared to norepinephrin uptake (ICso-88.5 nM 5,621,142 A 4/1997 Mochizuki et al. for norepinephrine, ICs, 40.3 nM for serotonin). The inven 6,602,911 B1* 8/2003 Kranzler et al. ............ 514,624 tion also relates to salts and prodrug forms of the aforemen tioned compounds. In certain embodiments, the compounds FOREIGN PATENT DOCUMENTS of the present invention and a pharmaceutically acceptable JP 3-56415 3, 1991 excipient are combined to prepare a formulation for admin istration to a patient. Finally, the present invention relates to OTHER PUBLICATIONS methods of treating mammals suffering from various afflic Registry No. 136091-14-0(Belongs to JP 3-56415), 1991.* tions, e.g., depression, chronic pain, or fibromyalgia, com Moret, C., et al., “Biochemical Profile of Midalcipran (F prising administering to a mammal in need thereof a thera 2207), 1-Phenyl-1-Diethyl-Aminocarbonyl-2- peutically effective amount of a compound of the present Aminomethyl-Cyclopropane (Z) Hydrochloride, A Potential invention. Fourth Generation Antidepressant Drug.” Neuropharmacol ogy, vol. 24, No. 12, pp. 1211-1219, (1985). 38 Claims, 63 Drawing Sheets US 7,038,085 B2 Page 2 OTHER PUBLICATIONS Class of NMDA-Receptor Antagonist: Molecular Design by Shuto, S., et al., “Synthesis and Biological Activity of a Novel Conformational Restriction Strategy.” Jpn. J. Conformationally Restricted Analogs of Milnacipran: (1S, Pharmacol. 85, pp. 207-213, (2001). 2R)-1-Phenyl-2-(R)-1-amino-2-propynyl-N,N-diethylcy Doyle, M., et al., “A New Enantioselective Synthesis of clopropanecarboxamide Is a Novel Class of NMDA Recep Milnacipran and an Analogue by Catalytic Asymmetric tor Channel Blocker,” J. Med. Chem. 1998, 41, pp. 3507 Cyclopropanatioin.” Adv. Synth. Catal. 2003, vol. 343, No. 3514, (1998). 3, pp. 299-302, (2001). Deprez, D., et al., “Which Bioeduivalence Study for a KaZuta, Y., et al., “Synthesis of (1S,2R)-1-Phenyl-2-(S)-1- Racemic Drug? Application to Milnacipran.” Eur: J. Drug aminopropyl-N,N-diethylcyclopropanecarboxamide Metab. Pharmacokinet, 23, pp. 166-171, (1998). (PPDC) Derivatives Modified at the Carbamoyl Moiety As Puzzo, C., et al., “Pharmacokinetics of Milnacipran in Liver a New Class of NMDA Receptor Antagonists. Bioorganic Impairment, Eur: J. Drug Metab. Pharmacokinet, 23, pp. & Medicinal Chemistry 10, pp. 1777-1791, (2002). 273-279, (1998). Labat, L., et al., “Separation of New Antidepressants and Puzzo, C., et al., “Pharmacokinetics of Milnacipran in Renal Their Metabolites by Micellar Electrokinetic Capillary Impairment, Eur: J. Drug Metab. Parmacokinet, 23, pp. Chromatography,” Journal of Chromatography B., 773 pp. 280-286, (1998). Shuto, S., et al., “(1S,2R)-1-Phenyl-2-(S)-1-aminopropyl 17-23, (2002). N,N-diethylcyclopropanecarboxamide (PPDC), a New * cited by examiner U.S. Patent May 2, 2006 Sheet 1 of 63 US 7,038,085 B2 Figure 1 CN OMe MeO S O agree O OMe C d o1 O O CSS90 CS1591 o CS OMe s"CM NE, NE, O NE, N N NE CSsos CS1809 CS12 CS1848 O t KS O N, N O NE, O NH, HN d -A. A.NE, --A.NEt, ANE CS1 cS18ss cSsss CS1 A. A O NE, N. c. cS713 CS1.4 U.S. Patent May 2, 2006 Sheet 2 of 63 US 7,038,085 B2 Figure 2 s U.S. Patent May 2, 2006 Sheet 3 of 63 US 7,038,085 B2 Figure 3 E ssg • 8. U.S. Patent May 2, 2006 Sheet 4 of 63 US 7,038,085 B2 Figure 4 serg g; U.S. Patent May 2, 2006 Sheet 5 of 63 US 7,038,085 B2 f U.S. Patent May 2, 2006 Sheet 6 of 63 US 7,038,085 B2 Figure 6 U.S. Patent May 2, 2006 Sheet 7 of 63 US 7,038,085 B2 Figure 7 : U.S. Patent May 2, 2006 Sheet 8 of 63 US 7,038,085 B2 Figure 8 U.S. Patent May 2, 2006 Sheet 9 of 63 US 7,038,085 B2 Figure 9 A. U.S. Patent May 2, 2006 Sheet 10 of 63 US 7,038,085 B2 Figure 10 U.S. Patent US 7,038,085 B2 Figure 11 100 SpectrumMassPositivºlan 133 164145 E+7ions424Intensi?y:PeakBase U.S. Patent May 2, 2006 Sheet 12 of 63 US 7,038,085 B2 Figure 12 e ; U.S. Patent May 2, 2006 Sheet 13 of 63 US 7,038,085 B2 Figure 13 S. U.S. Patent May 2, 2006 Sheet 14 of 63 US 7,038,085 B2 Figure 14 OH r CS17101 DAD1A, Sig-254,4Refeoff (030625012-03.01.D) i PMP1, Solwent B U.S. Patent May 2, 2006 Sheet 15 of 63 US 7,038,085 B2 Figure 15 100 133 1892044145157175 E+7ionsSpectrumBásePeakintensity:1.077MassNegativºlom 4.062E+7ionsSpectrumBasePeakIntensity.MassPositive?on OH U.S. Patent May 2, 2006 Sheet 16 of 63 US 7,038,085 B2 Figure 16 U.S. Patent May 2, 2006 Sheet 17 of 63 US 7,038,085 B2 U.S. Patent May 2, 2006 Sheet 18 of 63 US 7,038,085 B2 Figure 18 DADA, Sig-254,4 Ref-off (030630.001-0101.D) mAU 1000 3. 2 U.S. Patent May 2, 2006 Sheet 19 of 63 US 7,038,085 B2 Figure 19 100 95133183 SpectrumBasePeakIntensity:5.966E+5ionsNegativelonMass SpectrumBasePeakIntensity.5.158E+7ionsPositive?onMass CS1713/4 %. 100HO ONH, U.S. Patent May 2, 2006 Sheet 20 of 63 US 7,038,085 B2 U.S. Patent May 2, 2006 Sheet 21 of 63 US 7,038,085 B2 Figure 21 as ags if g ss s U.S. Patent May 2, 2006 Sheet 22 of 63 US 7,038,085 B2 Figure 22 xHC r CS1714/1 DAD1A, Sig-254,4Refeoff (030630.002-0201.0) TAU 1000 U.S. Patent May 2, 2006 Sheet 23 of 63 US 7,038,085 B2 Figure 23 100 SpectrumMassNegative?on 100 4.482E+7ionsIntensity.SpectrumBasePeakMassPositive?on 5.917E+5’ionsIntensity.BasePeak U.S. Patent May 2, 2006 Sheet 24 of 63 US 7.038,085 B2 Figure 24 U.S. Patent May 2, 2006 Sheet 25 of 63 US 7,038,085 B2 Figure 25 U.S. Patent May 2, 2006 Sheet 26 of 63 US 7,038,085 B2 Figure 26 DADA, Sig-2544 Ref=off (30804YO32-0101.9) U.S. Patent May 2, 2006 Sheet 27 of 63 US 7,038,085 B2 Figure 27 UVDetection2Orn. Smooth (SG, 1x4) R ES: MassChromatogram of 263 (FM-HD 42852(FMNa+304.2 (Mih-CH3CN Mat intensity 5,804 E47 ions Maintensity .748E48 ions U.S.
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