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(12) United States Patent (10) Patent No.: US 9,181.237 B2 Grote (45) Date of Patent: Nov

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(12) United States Patent (10) Patent No.: US 9,181.237 B2 Grote (45) Date of Patent: Nov US009181237B2 (12) United States Patent (10) Patent No.: US 9,181.237 B2 Grote (45) Date of Patent: Nov. 10, 2015 (54) SUBSTITUTED BERBINES AND THEIR OTHER PUBLICATIONS SYNTHESIS Jiaranaikulwanitch, J. et al.: Triazolyl tryptoline derivatives as beta (71) Applicant: MALLINCKRODT LLC, Hazelwood, Secretase inhibitors. Biorg. & medicinal Chem. letters, vol. 20, pp. MO (US) 6572-6576, 2010.* Kobayashi, J. et al.: Theoneberine; The first brominated (72) Inventor: Christopher W. Grote, Webster Groves, benzyltetrahydroberberine alkaloid from the Okinawan marine MO (US) sponge TheOnella sp., vol. 57, pp. 6680-6682, 1992.* Rastrelli, L. et al.: New Protopine and (73) Assignee: Mallinckrodt LLC, Hazelwood, MI benzyltetrahydroprotoberberine alkaloids from Aristolochia (US) constricta and their activity on isolated guinea-pig ileum.J. of Natu ral Prod., vol. 60, pp. 1065-1069, 1997.* (*) Notice: Subject to any disclaimer, the term of this Grycova et al., Quaternary protoberberine alkaloids, Phytochem. patent is extended or adjusted under 35 2007, 68(2): 150-175. U.S.C. 154(b) by 0 days. Mali et al., Novel syntheses of 1-substituted-7,8-dialkoxyisochro man-3-ones and 8-substituted.-2,3,9,10-tetramethoxyberbines, Tetra (21) Appl. No.: 14/504,906 hedron (1986), 42(7), 2075-82. Memetzidis, et al., Synthesis of Aromatic Chloroberbines, Hetero (22) Filed: Oct. 2, 2014 cycles (1990), 31(2), 341-51. Memetzidis, et al., Structure-affinity relationships of berbines or (65) Prior Publication Data 5,6,13,13a-tetrahydro-8H-dibenzoa, gduinolizines at O-adrenocep tors, Eur, J. Med. Chem., 1991, 26: 605-611. US 2015/OO99772 A1 Apr. 9, 2015 Nagubandietal. The mechanism of the Bischler-Napierski reaction, J. Heterocyclic Chem., 1980, 17: 1457-1463. Related U.S. Application Data Sotomayor et al., Bischler-Napieralski Cyclization-N/C-Alkylation Sequences for the Construction of Isoquinoline Alkaloids. Synthesis (60) Provisional application No. 61/886,695, filed on Oct. of Protoberberines and Benzocphenanthridines via C-2'- 4, 2013. Functionalized 3-Arylisoquinolines, Journal of Organic Chemistry (1996), 61(12), 4062-4072. (51) Int. Cl. Valpuesta et al., Regio-and Stereoselective Stevens Rearrangement CO7D 22/8 (2006.01) of Benzyltetrahydroprotoberberinium Salts, Eur, J. Org. Chem. 2004, CO7D 22/04 (2006.01) 4313-4318. CO7D 455/03 (2006.01) Yamamoto et al., Total synthesis of 8-epi-javaberine A and javaberine (52) U.S. Cl. A, Heterocycles 2014, 88(2): 1311-1321. CPC .................................... C07D455/03 (2013.01) Zhang, et al., A Novel Analgesic Isolated from a Traditional Chinese (58) Field of Classification Search Medicine, Current Biology, 2014, vol. 24(2), pp. 1-7. USPC ...................................................... 546/73, 71 International Search Report and Written Opinion dated Jan. 14, 2015 See application file for complete search history. from related international application No. PCT/US2014/058806, 11 pg.S. (56) References Cited PubChem. Compound Summary for CID 6342, Acetonitrile, Create Date: Sep. 16, 2004. retrieved on 20.22.2014 from the Internet U.S. PATENT DOCUMENTS pubchem.ncbi.nlm.nih.gov/6342. PubChem. Compound Summary for CID 8025, Ethyl formate, Create 4.013,666 A 3, 1977 Lenz ............................... 546,71 Date: Mar. 26, 2005. retrieved on Nov. 21, 2014 from the Internet 4,052,389 A 10, 1977 Monkovic pubchem.ncbi.nlm.nih.gov/8025. 6.255,317 B1 7, 2001 Kim 8,003,795 B2 8, 2011 Liu 8,163,912 B2 4/2012 Grote * cited by examiner 8,431,705 B2 4/2013 Grote 2010.0113494 A1 5, 2010 Hu Primary Examiner — Charanjit Aulakh 2010, 0120810 A1* 5, 2010 Leblond et al. ............... 514,280 2012,0004223 A1 1/2012 Liu 2012/0059026 A1 3/2012 LaVoie (57) ABSTRACT The present invention provides substituted berbines, pro FOREIGN PATENT DOCUMENTS cesses for the synthesis of substituted berbine compounds, as EP 0 028959 5, 1981 well as intermediates used in the synthesis of substituted WO 2009/007457 1, 2009 berbine compounds. Also provided are methods for using the WO 2010.075469 T 2010 substituted berbines to inhibit cancer cell growth. WO 2010, 128061 11, 2010 WO 2012, 1631 79 12/2012 5 Claims, No Drawings US 9, 181,237 B2 1. 2 SUBSTITUTED BERBINES AND THEIR SUMMARY OF THE INVENTION SYNTHESIS Among the various aspects of the present invention is a compound comprising Formula (V-1): CROSS-REFERENCE TO RELATED APPLICATIONS (V-1) R1 R12 R11 This application claims the priority of U.S. provisional application Ser. No. 61/886,696, filed Oct. 4, 2013, which is hereby incorporated by reference in its entirety. 10 15 FIELD OF THE INVENTION The present invention generally relates to substituted ber wherein: bines, processes for the synthesis of substituted berbines, R. R. R., and Rindependently are hydrogen, halogen, OR',NR'N', nitro, cyano, thiol, hydrocarbyl, sub intermediate compounds used in the preparation of Substi stituted hydrocarbyl, or together RandR along with tuted berbines, and methods of using substituted berbines. the ring carbons to which they are attached form a ring comprising { }O(CH2)O{-}; R. R. R', and Rindependently are hydrogen, halogen, 25 OR', NR'N', nitro, cyano, thiol, hydrocarbyl, sub stituted hydrocarbyl, or together RandR along with the ring carbons to which they are attached form a ring comprising { }O(CH2).O—}; provided that at BACKGROUND OF THE INVENTION least two of R. R. and Rare other than methoxy; 30 R. R', R', and R' independently are hydrogen, The berbine class of heterocyclic compounds is structur hydrocarbyl, or substituted hydrocarbyl, R',R,R,R, and Rindependently are hydrogen, ally related to the plant alkaloid berberine. Berbine com halogen, OR, NR'N', nitro, cyano, thiol, hydro pounds have been reported to have numerous therapeutic carbyl, or substituted hydrocarbyl; effects. For example, they have been found to have antibac 35 R" and R' independently are hydrogen, hydrocarbyl, terial, antifungal, antiparasitic, antipyretic, antihypertensive, or substituted hydrocarbyl, m is an integer of 0 or greater; antidepressant, antiemetic, tranquilizing, and analgesic n is an integer from 1 to 3; and activities. Because of the potential therapeutic value of ber the dashed lines represent optional double bonds. Another aspect of the disclosure encompasses a process for bine compounds and derivatives thereof, there is a need for 40 preparing a compound comprising Formula (V). The process new derivatives than may be more potent and/or efficacious. comprises contacting a compound comprising Formula (II) Moreover, there is a need for efficient synthesis processes for with a cyclizing agent to form a compound comprising For mula (IV), and contacting the compound comprising Formula the preparation of pure preparations of specific enantiomers (IV) with a reducing agent to form the compound comprising of these substituted berbines. Formula (V) according to the following reaction scheme: RI R12 R11 Cyclizing agent US 9, 181,237 B2 -continued Reducting agent a wherein: the ring carbons to which they are attached form a ring R is hydrogen, hydrocarbyl, or substituted hydrocarbyl, comprising { }O(CH2)O{-}; R. R. R., and Rindependently are hydrogen, halogen, R. R', R'', R', R', and Rindependently are hydro OR', NR'N', nitro, cyano, thiol, hydrocarbyl, sub gen, hydrocarbyl, or substituted hydrocarbyl; stituted hydrocarbyl, or together RandR along with n is an integer from 1 to 3; and the ring carbons to which they are attached form a ring comprising { }O(CH2)O{-}; 25 the dashed lines represent optional double bonds. R. R. R', and Rindependently are hydrogen, halogen, Other aspects and features of the invention will be in part OR', NRN nitro, cyano, thiol, hydrocarbyl, substi apparent and in part pointed out hereinafter. tuted hydrocarbyl, or together RandR along with the ring carbons to which they are attached form a ring DETAILED DESCRIPTION comprising { }O(CH), O—}; 30 R. R', R'', R', R', and R' independently are hydro The present invention provides new substituted berbine gen, hydrocarbyl, or substituted hydrocarbyl; compounds and processes for preparing Substituted berbines, n is an integer from 1 to 3: as well as intermediate compounds for use in the preparation X is halogen, { }OSOR", or {-}OCOR', wherein 35 of substituted berbines. The processes disclosed herein allow R" is hydrocarbyl or substituted hydrocarbyl; and for regiochemical and stereochemical synthesis of substituted the dashed lines represent optional double bonds. berbines. For example, Syn diastereomers may be prepared A further aspect of the present disclosure provides a using the processes disclosed herein. Furthermore, the pro method for inhibiting growth of a cancer cell. The method cesses disclosed herein are more efficient, more specific, and comprises contacting the cancer cell with an effective amount 40 provide greater yields than currently available synthesis pro of a compound comprising Formula (V): cesses. Additionally, it has been discovered that substituted berbine compounds inhibit cancer cell growth. (V) For ease of discussion, the ring atoms of berbine com RI pounds are numbered as diagrammed below. 45 50 55 wherein: Substituted berbine compounds may have at least two chiral R is hydrogen, hydrocarbyl, or substituted hydrocarbyl, carbons, namely, C-14 and C-8, as indicated above with aster R. R. R. and Rindependently are hydrogen, halogen, 60 isks. OR', NR'N', nitro, cyano, thiol, hydrocarbyl, sub stituted hydrocarbyl, or together RandR along with (I) Compounds the ring carbons to which they are attached form a ring (a) Compounds Comprising Formula (III) comprising { }O(CH2)O{-}; One aspect of the present disclosure encompasses com R. R. R', and Rindependently are hydrogen, halogen, 65 pounds that may be used as intermediates in the preparation of OR', NRN nitro, cyano, thiol, hydrocarbyl, substi Substituted berbine compounds. In general, the intermediate tuted hydrocarbyl, or together RandR along with compounds comprise Formula (III): US 9, 181,237 B2 6 In one alternative of this embodiment, the compound com (III) prising Formula (III) may be a compound comprising For mula (IIIa): (IIIa) 10 15 wherein: R is hydrogen, hydrocarbyl, or substituted hydrocarbyl, R.
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