(19) TZZ ¥_T (11) EP 2 344 447 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 229/00 (2006.01) A61K 31/675 (2006.01) 08.06.2016 Bulletin 2016/23 A61K 31/191 (2006.01) A61P 25/00 (2006.01) (21) Application number: 09819911.0 (86) International application number: PCT/US2009/060058 (22) Date of filing: 08.10.2009 (87) International publication number: WO 2010/042759 (15.04.2010 Gazette 2010/15) (54) GABA CONJUGATES AND METHODS OF USE THEREOF GABA-KONJUGATE UND VERFAHREN ZU IHRER VERWENDUNG CONJUGUÉS GABA ET PROCÉDÉS D’UTILISATION DE CEUX-CI (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A2-2005/092392 WO-A2-2005/092392 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL WO-A2-2008/010222 US-A1- 2003 087 803 PT RO SE SI SK SM TR US-A1- 2004 242 570 (30) Priority: 08.10.2008 US 103800 P • SHI W ET AL: "DESIGN, SYNTHESIS, AND PRELIMINARY EVALUATION OF (43) Date of publication of application: GABAPENTIN-PREGABALIN MUTUAL 20.07.2011 Bulletin 2011/29 PRODRUGS IN RELIEVING NEUROPATHIC PAIN", ARCHIV DER PHARMAZIE, WILEY - VCH (60) Divisional application: VERLAG GMBH & CO. KGAA, DE, vol. 338, no. 8, 16159660.6 1 January 2005 (2005-01-01), pages 358-364, XP008067446, ISSN: 0365-6233 (73) Proprietor: Xgene Pharmaceutical Inc • SHI W ET AL: "DESIGN, SYNTHESIS, AND Grand Cayman KY1-1112 (KY) PRELIMINARY EVALUATION OF GABAPENTIN-PREGABALIN MUTUAL (72) Inventor: XU, Feng PRODRUGS IN RELIEVING NEUROPATHIC Palo Alto PAIN", ARCHIV DER PHARMAZIE, WILEY - VCH CA 94303 (US) VERLAG GMBH & CO. KGAA, DE, vol. 338, no. 8, 1 January 2005 (2005-01-01), pages 358-364, (74) Representative: Cole, William Gwyn XP008067446, ISSN: 0365-6233 Avidity IP Broers Building Remarks: Hauser Forum Thefile contains technical information submitted after 21 J J Thomson Ave the application was filed and not included in this Cambridge CB3 0FA (GB) 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 2 344 447 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 344 447 B1 Description BACKGROUND OF THE INVENTION 5 [0001] A number of treatments involving the administration of single drugs are currently recommended for relief of pain including neurological pain. The single administration of narcotic analgesics, gamma ( γ)-aminobutyric acid (GABA) analogs such as gabapentin, pregabalin and baclofen, antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to display pain alleviating properties in the clinic and in various animal models. [0002] Despite the benefits derived from the current single drug pain relief regimens, these regimens have disadvan- 10 tages. One area of concern relates to the incidence of unwanted side effects caused by many of the pain treatment regimens available today. Narcotic analgesics, such as morphine, are sparingly prescribed for chronic pain because of the well-known addictive effects and central nervous system (CNS) side effects and gastrointestinal side effects resulting from their single administration. [0003] Another concern of the current pain treatment regimens relates to their effectiveness. Many single active in- 15 gredients such as antidepressant agents or GABA analogs employed in current pain relief regimens cannot achieve adequate pain alleviation even at their maximum approved therapeutic doses in certain severe pain states. In addition to not achieving adequate pain alleviation, increasing the drug dose may produce an increase in unwanted side effects such as cognitive impairment, nausea, and constipation. [0004] Furthermore, other concerns of GABA analogs and many narcotic analgesics relate to their less favorable 20 pharmacokinetic and physiological properties. Many orally administrated opioid molecules are extensively metabolized by digestive organs before reaching systemic circulation. Rapid systemic clearance and saturable absorption of some of the GABA analogs have limited these drugs to reach their full potential in treatment of pain and other CNS disorders. These sub-optimal properties often lead to less than adequate efficacy and unwanted side effects in patients. [0005] Sustained released formulations are a conventional method to address the issue of rapid systemic clearance, 25 as it is well known to those skilled in the art (e.g., "Remingtion’s Pharmaceutical Sciences," Philadelphia College of Pharmacy and Science, 17th Edition, 1985). GABA analogs, such as baclofen, gabapentin and pregabalin are not absorbed through the large intestine. Rather, these compounds are typically absorbed in the small intestine by the neutral amino transporter systems (Jezyk et al., Pharm. Res., 1999, 16, 519-526). The rapid passage of conventional tract has prevented the successful application of sustained release approach to these GABA analogs. 30 [0006] In view of these concerns, it is evident that there is a need for an improved pain regimen that provides an improved therapeutic benefit (i.e., reduced severity and/or frequency of pain) and/or reduces the incidence of unwanted side effects caused by many of the current regimens. In addition, improving pharmacokinetic profile of GABA analogs will also lead to more customized dosing regimens according to patients’ need. [0007] WO 2005/092392 describes conjugates of a psychotropic drug and an organic acid. WO 2008/010222 described 35 conjugates of GABA with an analgesic drug. Shi W. et al, Arch. Der Pharmazie, 338, 358-364 (2005), describes conjugates of gabapentin and pregabalin. SUMMARY 40 [0008] There is described a compound comprising a first moiety and a second moiety, the first moiety being covalently linked via an amino terminus or an acidic terminus other than a carboxylic acid group to the second moiety, wherein the first moiety is γ-aminobytyric acid (GABA) or an analog or derivative of GABA. In another case there is described a compound comprising a first moiety and a second moiety, the first moiety being covalently linked via a carboxylic acid group to the second moiety, and an amino terminus of the first moiety is linked to a protection group, wherein the first 45 moiety is GABA or an analog or derivative of GABA. Also described is a pharmaceutical composition comprising the compound of the invention disclosed herein and a pharmaceutically acceptable carrier. [0009] Also described is a method of preventing or treating a disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. The compound used in the described method of treatment may comprise a first moiety and a second moiety, the first moiety being covalently linked 50 via an amino terminus or an acidic terminus other than a carboxylic acid group to the second moiety, wherein the first moiety is GABA or an analog or derivative of GABA. The compound used in the described method of treatment may comprise a first moiety and a second moiety, the first moiety being covalently linked via a carboxylic acid group to the second moiety, and an amino terminus of the first moiety is linked to a protection group, wherein the first moiety is GABA or an analog or derivative of GABA. The method may comprise administering to a subject in need thereof a therapeutically 55 effective amount of a pharmaceutical composition of the invention. Such pharmaceutical composition comprises a com- pound described herein and a pharmaceutically acceptable carrier. [0010] Described herein is a method for reducing an adverse effect associated with a treatment of a disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the 2 EP 2 344 447 B1 invention. The compound may comprise a first moiety and a second moiety, the first moiety being covalently linked via an amino terminus or an acidic terminus other than a carboxylic acid group to the second moiety, wherein the first moiety is GABA or an analog or derivative of GABA. The compound may comprise a first moiety and a second moiety, the first moiety being covalently linked via a carboxylic acid group to the second moiety, and an amino terminus of the first moiety 5 is linked to a protection group, wherein the first moiety is GABA or an analog or derivative of GABA. The method for reducing an adverse effect associated with a treatment of a disorder may comprise administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention. Such pharmaceutical com- position may comprise the compound described herein and a pharmaceutically acceptable carrier. [0011] Also described is a method for enhancing the therapeutic efficacy of a treatment of a disorder, the method 10 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. The compound may comprise a first moiety and a second moiety, the first moiety being covalently linked via an amino terminus or an acidic terminus other than a carboxylic acid group to the second moiety, wherein the first moiety is GABA or an analog or derivative of GABA. The compound may comprise a first moiety and a second moiety, the first moiety being covalently linked via a carboxylic acid group to the second moiety, and an amino terminus of the first moiety is 15 linked to a protection group, wherein the first moiety is GABA or an analog or derivative of GABA.