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(12) United States Patent (10) Patent No.: US 7,119,196 B2 Cook Et Al

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(12) United States Patent (10) Patent No.: US 7,119,196 B2 Cook Et Al US007 119196B2 (12) United States Patent (10) Patent No.: US 7,119,196 B2 Cook et al. (45) Date of Patent: Oct. 10, 2006 (54) ANXIOLYTIC AGENTS WITH REDUCED Armin Walser, et al., “Triazolobenzo- and Triazolothienodiazepines SEDATIVE AND ATAXC EFFECTS as Potent Antagonists of Platelet Activating Factor,” “Journal of Medicinal Chemistry,” 1991, pp. 1209-1221, vol. 34, No. 3, Ameri (75) Inventors: James M. Cook, Whitefish Bay, WI can Chemistry Society. (US); Qi Huang, Moorpark, CA (US); Qi Huang, “Part One: A Chemical and Computer Assisted Approach to Pharmacophore/Receptor Models for GABAaBZ Receptor Sub Xiaohui He, San Diego, CA (US); types; Part Two: Predictive Models for GABAaBZR Subtypes Via Xioayan Li, Milwaukee, WI (US); Comparative Molecular Field Analysis.” DISSERTATION, UW Jianming Yu, Princeton, NJ (US); Milwaukee, 1998, pp. 1-296. Dongmei Han, Milwaukee, WI (US); Shu Yu, et al., “Studies in the Search for a5 Subtype Selective Snjezana Lelas, Middletown, CT (US); Agonists for GABAaBZR Sites,” “Medicinal Chemistry Research.” John F. McElroy, Wilmington, DE 1999, pp. 71-88, Birkhauser Boston. (US) Qi Huang, et al., “Pharmacophore Receptor Models for GABAa? BZR Subtypes (alB3y2, aSB3y2, and aoB3y2) via a Comprehensive (73) Assignee: Wisys Technology Foundation, Inc., Ligand Mapping Approach.” “J. Med. Chem.” 2000, pp. 71-95, Madison, WI (US) American Chemical Society. Xiaohui He, et al., “Pharmacophore/Receptor Models for GABAa? (*) Notice: Subject to any disclaimer, the term of this BZRa2B3y2, a3B3y2 and a4B3y2 Recombinant Subtypes. Induced patent is extended or adjusted under 35 Volume Analysis and Comparison to alB3y2, aSB3y2 and aoB3y2 U.S.C. 154(b) by 198 days. Subtypes,” “Drug Design and Discovery,” 2000, pp. 131-171, vol. 17, Overseas Publishers Association. (21) Appl. No.: 10/402,538 Xiaohui He, “Studies of Molecular Phamracophore/Receptor Mod els for GABAaBZR Subtypes: Chemical and Computer Assisted Approach in Search of Selective Ligands for GABAaBZR Sub (22) Filed: Mar. 28, 2003 types.” DISSERTATION, UW-Milwaukee, 2000, pp. 1-300. (65) Prior Publication Data Le Solleu, et al., “Determination of a PAF Antagonist Pharmacophore Using Combined Molecular Electrostatic Potential US 2004/0082573 A1 Apr. 29, 2004 and Molecular Lipophilicity Potential.” “Drug Design and Discov ery,” 1994, pp. 149-167, vol. 12, Harwood Academic Publishers Related U.S. Application Data GmbH. Yu, et al., “Studies in Search of alpha2 Selective Ligands for (60) Provisional application No. 60/368,408, filed on Mar. GABAaBZR Receptor Subtypes. Part I. Evidence for the Conser 28, 2002. vation of Pharmacophoric Desciptors for DS Subtypes”, “Med. Chem. Res.” 1999, pp. 186-202, vol. 9, No. 3, Birkhauser, Boston. (51) Int. Cl. Bundgaard, H., “Design of prodrugs: Bioreversible derivatives for CO7D 487/12 (2006.01) various functional groups and chemical entities, pp. 1-92 in (52) U.S. Cl. ...................................................... 54.0/S62 Bundgaard, H., ed., Design of Prodrugs, Elsevier Science Publishers B.V., Amsterdam 1985. (58) Field of Classification Search ................. 54O7562 Chambon, J.P. et al., Ethyl loflazepate: a prodrug from the See application file for complete search history. benzodiazepine series designed to dissociate anxiolytic and sedative (56) References Cited activities. Arzneimittelforschung. 1985:35(10): 1573-7. Cho, M.J., et al., Sequentially labile water-soluble prodrugs of U.S. PATENT DOCUMENTS alprazolam. J Med Chem. Aug. 1986; 29(8): 1346-50. Han, K.-Y., & Amidon, G.L., Targeted prodrug design to optimize 2,893,992 A 7, 1959 Sternbach drug delivery, AAPS Pharmsci. 2000; 2(1): 1-11, article 6, http:// 4,280,957 A 7, 1981 Walser et al. www.pharmsci.org/. 4,401,597 A 8, 1983 Walser et al. Mussini, E., et al., Hydroxylation of three benzodiazepines in vitro. 4.959,361 A 9, 1990 Walser J. Pharm Sci. Oct. 1977;66(10): 1482-3. Simon-Trompler, E., et al., Lorazepam and oxazepam esters. Hydro phobicity, hydrolysis rates and brain appearance. Arzneimit FOREIGN PATENT DOCUMENTS telforschung. 1982:32(2):102-5. Tegyey, Z. et al., Comparison of dihydrodiazepam enantiomers: EP O 320992 6, 1989 metabolism, serum binding and brain receptor binding. Experientia. WO WO O2/O83652 A1 10, 2002 Sep. 15, 1980:36(9): 103.1-2. Primary Examiner Bruck Kifle OTHER PUBLICATIONS (74) Attorney, Agent, or Firm Godfrey & Kahn, S.C.; Sonali S. Srivastava Camille G. Wermuth, “Molecular Variations Based on Isosteric Replacements.” “The Practice of Medicinal Chemistry.” 1996, pp. 203-237, Academic Press Limited. (57) ABSTRACT Qi Huang, et al., “BenZo-fused Benzodiazepines Employed as Topological Probes for the Study of Benzodiazepine Receptor Orally active benzodiazepine derivatives and their salts are Subtypes,” “Medicinal Chemistry Research.” 1996, pp. 384-391. Birkhauser Boston. disclosed. These compounds and their salts have anxiolytic Ruiyan Liu, et al., “Synthesis and Pharmacological Properties of and anticonvulsant activity with reduced sedative/hypnotic/ Novel 8-Substituted Imidazobenzodiazepines: High-Affinity, Selec muscle relaxant/ataxic effects. tive Probes for a5-Containing GABAa Receptors,” “J. Med. Chem.” 1996, pp. 1928-1934. 5 Claims, No Drawings US 7,119,196 B2 1. 2 ANXOLYTIC AGENTS WITH REDUCED receptor modulatory sites, and is the site through which SEDATIVE AND ATAXC EFFECTS benzodiazepine-based anxiolytic drugs exert their effect. Before the cloning of the GABA receptor gene family, the CROSS-REFERENCE TO RELATED benzodiazepine binding site was historically subdivided into APPLICATIONS two subtypes, BENZODIAZEPINE1 and BENZODIAZ EPINE2, on the basis of radioligand binding studies on This application claims benefit of U.S. Provisional Patent synaptosomal rat membranes. The BENZODIAZEPINE1 Application No. 60/368,408 filed Mar. 28, 2002. Subtype has been shown to be pharmacologically equivalent to a GABA receptor comprising the C.1 subunit in combi STATEMENT REGARDING FEDERALLY 10 nation with a B subunit and Y2. This is the most abundant SPONSORED RESEARCH OR DEVELOPMENT GABA receptor subtype, and is believed to represent almost This invention was made with Government support under half of all GABA receptors in the brain, as stated. NIMH grant number MH46851. The Government has cer Two other major populations are the C.232/3y2 and C3f2/ tain rights to this invention. 15 3y2/3 subtypes. Together these constitute approximately a further 35% of the total GABA receptor population. Phar BACKGROUND OF THE INVENTION macologically this combination appears to be equivalent to the BENZODIAZEPINE2 subtype as defined previously by The present invention relates to a class of benzodiazepine radioligand binding, although the BENZODIAZEPINE2 derivatives which possess anxiolytic activity with decreased Subtype may also include certain C5-containing Subtype sedative, hypnotic, and ataxic side effects. assemblies. The physiological role of these subtypes has The most frequently prescribed medication for treatment hitherto been unclear because no sufficiently selective ago of anxiety disorders (such as phobias, obsessive compulsive nists or antagonists were known. disorders) and seizure disorders are benzodiazepines such as It is now believed that agents acting as benzodiazepine diazepam (Valium), triazolam (Halcion), midazolam 25 agonists at GABA/C2, GABA/o3, and/or GABA/O5 (Versed), lorazepam (Ativan), chlordiazepoxide (Librium), receptors, will possess desirable anxiolytic properties. Com alprazolam (Xanax), and other benzodiazepine-based medi pounds which are modulators of the benzodiazepine binding cations. However, these benzodiazepine-based medications site of the GABA receptor by acting as benzodiazepine have side effects such as drowsiness, sedation, motor inco agonists are referred to hereinafter as “GABA receptor ordination, memory impairment, potentiation of effects of 30 agonists.” The GABA/O. 1-selective (C.132y2) agonists alpi alcohol, tolerance and dependence, and abuse potential. dem and Zolpidem are clinically prescribed as hypnotic Buspirone, tandospirone, and other serotonergic agents have agents, Suggesting that at least Some of the sedation asso been developed as anxiolytics with a potentially reduced ciated with known anxiolytic drugs which act at the BEN profile of side effects. However, while these medications do ZODIAZEPINE1 binding site is mediated through GABA show a reduced profile of side effects, they have other 35 receptors containing the C.1 Subunit. Accordingly, it is con characteristics which make them less than ideal for treat sidered that GABA/C2, GABA/C3, and/or GABA/O.5 ment of anxiety disorders. In some cases, these agents cause receptor agonists rather than GABA/O.1 receptors will be anxiety before a therapeutic dose can be obtained or require effective in the treatment of anxiety with a reduced propen dosing of the drug for several days before a therapeutic sity to cause sedation. For example, QH-ii-066 binds with effect is seen. Development of anxiolytics with even fewer 40 high affinity to GABA/O.5 receptors (Ki-10 nM), interme side effects is desired. diate affinity to GABA/C2 and GABA/C3 (Ki-S0 nM), Receptors for the major inhibitory neurotransmitter, and lower affinity to GABA/O.1 receptors (Ki>70 nM), gamma-aminobutyric acid (GABA), are divided into three unlike diazepam which binds with high affinity to all four main classes: (1) GABA receptors, which are members of diazepam-sensitive GABA receptors (Ki-25 nM), as dis the ligand-gated ion channel Superfamily; (2) GABA recep 45 closed in
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