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Huperzine for Use in the Treatment of Neuropathic

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Huperzine for Use in the Treatment of Neuropathic (19) TZZ_Z_¥¥_T (11) EP 1 901 733 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/215 (2006.01) A61K 31/74 (2006.01) 06.04.2016 Bulletin 2016/14 A61K 9/20 (2006.01) (21) Application number: 06770999.8 (86) International application number: PCT/US2006/019985 (22) Date of filing: 23.05.2006 (87) International publication number: WO 2006/127748 (30.11.2006 Gazette 2006/48) (54) HUPERZINE FOR USE IN THE TREATMENT OF NEUROPATHIC PAIN HUPERZIN ZUR VERWENDUNG BEI DER BEHANDLUNG VON NEUROPATHISCHEN SCHMERZEN HUPERZINE POUR SON UTILISATION DANS LE TRAITEMENT DE LA DOULEUR NEUROPATHIQUE (84) Designated Contracting States: US-A1- 2004 214 863 US-A1- 2005 065 176 AT BE BG CH CY CZ DE DK EE ES FI FR GB GR US-A1- 2005 129 783 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR • GALEOTTI, NICOLETTA ET AL: "Antinociceptive profile of the natural cholinesterase inhibitor (30) Priority: 23.05.2005 US 683745 P huperzine A", DRUG DEVELOPMENT 04.01.2006 US 756141 P RESEARCH , 54(1), 19-26 CODEN: DDREDK; ISSN: 0272-4391, 2001, XP002632199, (43) Date of publication of application: • RAJENDRAN V ET AL: "Synthesis of more potent 26.03.2008 Bulletin 2008/13 analogues of the acetylcholinesterase inhibitor, huperzine B", BIOORGANIC AND MEDICINAL (73) Proprietor: President and Fellows of Harvard CHEMISTRY LETTERS, vol. 12, no. 11, 3 June College 2002 (2002-06-03), pages 1521-1523, Cambridge, MA 02138-3805 (US) XP002632200, ISSN: 0960-894X • DATABASECA [Online] CHEMICAL ABSTRACTS (72) Inventor: SCHACHTER, Steven, C. SERVICE, COLUMBUS, OHIO, US; GUO, LIHE ET Sharon, MA 02067 (US) AL: "New acetylcholinesterase inhibitors in medicine for treating diabetes mellitus", (74) Representative: Lahrtz, Fritz et al XP002632201, retrieved from STN Database Isenbruck Bösl Hörschler LLP accession no. 2006:1073198 Patentanwälte • TONDULI L S ET AL: "Effects of huperzine used Prinzregentenstraße 68 as pre-treatment against soman-induced 81675 München (DE) seizures",NEUROTOXICOLOGY (LITTLE ROCK), vol. 22, no. 1, February 2001 (2001-02), pages (56) References cited: 29-37, XP002632202, ISSN: 0161-813X WO-A1-2007/014498 US-A- 5 104 880 US-A- 5 547 960 US-A1- 2003 158 147 Remarks: Thefile contains technical information submitted after the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 901 733 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 901 733 B1 Description Background Of The Invention 5 [0001] The technical field of this invention relates to using NMDA antagonists and acetylcholinesterase (AChE) inhib- itors in neurologic syndromes and disorders. [0002] Pain management remains a ubiquitous clinical problem. In addition to injury, nearly every disease or patho- logical condition from arthritis to cancer to HIV infection and diabetes has a major pain component. Pain management for some conditions such as nerve injuries and chronic inflammatory disease has been poor. While a number of drugs 10 exist to alleviate pain, the use of many of them is limited by safety issues and side effects. Summary Of The Invention [0003] Huperzine has been found to be useful to reduce the severity and perception of pain as well as to reduce the 15 severity or duration of a neurologic disorder such as a seizure disorder. A purified huperzine compound or an analogue thereof that interferes with an action of an excitatory amino acid at the N-methyl-D-aspartate (NMDA) receptor is ad- ministered to a subject that has been diagnosed as suffering from or at risk of developing such one or more of such conditions. Huperzine compounds are used to treat both acute and chronic pain indications. Major categories of pain to be treated include post-operative and post trauma pain; non-malignant chronic pain disorders such as osteoarthritis and 20 rheumatoid arthritis, fibromyalgia, multiple sclerosis and headache; neuropathic pain such as that associated with pe- ripheral nerve damage, diabetes, and Human Immunodeficiency Virus (e.g., HIV-1, AIDS) infection; back pain such as that associated with disc avulsion or nerve compression; and cancer pain, including pain secondary to chemotherapy. Neuropathic pain includes chronic pain resulting from injury to the nervous system, e.g., an injury to the central nervous system (brain and spinal cord) or the peripheral nervous system (nerves outside the brain and spinal cord). In some 25 cases, neuropathic pain occurs after trauma and is associated with pathologic conditions such as multiple sclerosis and stroke. Neuropathic pain is also associated with shingles (post-herpetic neuralgia due to Varicella-zoster virus). [0004] In accordance with the invention there is provided a pharmaceutical composition comprising as sole therapeutic agent or agents a huperzine compound or combination of huperzine compounds for use in reducing or preventing neuropathic pain, wherein said huperzine compound has the Formula I: 30 35 40 45 where: 50 R1 is hydrogen, C1-C8 alkyl, halo, pyridoyl, or benzoyl substituted by C1 -C5 lower alkoxy or C1 -C5 alkyl-OH; R2 is hydrogen, C1-C8 alkyl, or halo; R3 is hydrogen, C1-C8 alkyl, halo, NO 2, or OH; R4 is hydrogen, C1-C8 alkyl, halo, NO 2, or OH; R5 is CO2R’, where R’ is H, (C1 -C4)alkyl or phenyl, optionally substituted by one or two X, wherein X is halo, CF 3, 55 OR12, SR12, CN, NO2, CO2R12, C(O)N(R12)2, S(O)R12 or SO2R12, wherein each R12 is H, CF3, phenyl or (C1 -C4)alkyl; or R5 is (CH2)pNRaRb, where p is 0 or 1 and R a and Rb are individually H, (C1 - C8)alkyl, aryl, aralkyl, or one of R a and Rb is -CH=CH-G, where G is phenyl, furanyl, naphthyl, pyridyl, or dihydro or tetrahydropyridyl substituted by 2 EP 1 901 733 B1 C1 -C5 alkyl at the nitrogen atom, and G is optionally substituted with 1, 2, or 3 B, where B is C1 -C5 alkyl; C1 -C5 alkoxy; C1 -C5 alkyl-OH; nitro; halo; carboxy; alkyloxycarbonyl; hydroxymethyl; hydroxy; amino, or amino substituted by bis-C1 -C5 alkyl (the alkyl groups may be the same or different), and the other of R a and Rb is hydrogen or (C1 -C8)alkyl; or one of R a and R b is C(O)R 14 and the other of R a and R b is R 15, where R 14 is (C1 -C8)alkyl, -(CH 2)qCOOY, 5 where q is 0, 1, 2, 3, 4, or 5 and Y is hydrogen or C1 -C5 alkyl; (CH 2)m-G where m is 0 or 1 and G is phenyl, furanyl, naphthyl, pyridyl, or dihydro or tetrahydropyridyl substituted by C1 -C5 alkyl at the nitrogen atom, and G is optionally substituted with 1, 2, or 3 B, where B is C1 -C5 alkyl; C1 -C5 alkoxy; C1 -C5 alkyl-OH; nitro; halo; carboxy; alky- loxycarbonyl; hydroxymethyl; hydroxy; amino, or amino substituted by bis-C1 -C5 alkyl (the alkyl groups may be the same or different); R15 is hydrogen or (C1 -C8)alkyl; or 10 R5 is (CH2)pN=R16, where R16 is CH(CH2)m-G, where m is 0 or 1 and G is phenyl, furanyl, naphthyl, pyridyl, or dihydro or tetrahydropyridyl substituted by C1 -C5 alkyl at the nitrogen atom G is optionally substituted with 1, 2, or 3 B, where B is C1 -C5 alkyl; C1 -C5 alkoxy; C1 -C5 alkyl-OH; nitro; halo; carboxy; alkyloxycarbonyl; hydroxymethyl; hydroxy; amino, or amino substituted by bis-C1 -C5 alkyl (the alkyl groups may be the same or different); R6 is CRcRdRe, where Rc is H, halo or (C1 -C8)alkyl, R d is halo or (C1 -C8)alkyl; R e is H or is absent when a double 15 bond is present; one of R7a, and R7b is hydrogen or (C1 -C8)alkyl and the other of R 7a and R7b is hydrogen, (C1 -C8)alkyl, vinyl, (C3 -C8)alkenyl, ethynyl, CN, NO2, halo, OR’, SR’, CO2R’, C(O)N(R’)2, C(O)R’, S(O)R’ or SO2R’, wherein R’ is H, (C1 -C4)alkyl or phenyl, optionally substituted by 1 or 2 X, wherein X is halo, CF3, OR12, SR12, CN, NO2, CO2R12, C(O)N(R12)2, S(O)R12 or SO2R12, wherein each R12 is H, CF3, phenyl or (C1 -C4)alkyl; or R7a, and R7b together 20 are connected to form carbonyl (=O) or =C(R10)(R11) wherein each of R10 and R11 is H, X or (C1 -C4)alkyl; optionally R5 and R6 are connected to form a saturated 6, 7, or 8 membered ring, optionally containing 1 or 2 heteroatoms selected from O, NR13, and S, where R13 is hydrogen or C1 -C8 alkyl; R8 is hydrogen, C1-C8 alkyl, or hydroxyl; R9 is hydrogen, C 1 -C8 alkyl, or hydroxyl; 25 n is 1, 2, 3, or 4 ; C1-C8 alkyl includes both linear and branched alkyl, and wherein a dashed line indicates the presence or absence of a double bond, as consistent with the laws of chemical bonding, and wherein if a double bond is present between CR1 and CR9, then there is no double bond between CR1 and CR8, 30 or if a double bond is present between CR1 and CR8, then there is no double bond between CR 1 and CR9.
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