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  Anxiolytic agents with reduced sedative and ataxic effectsUSPTO Application #: 20070299058Title: Anxiolytic agents with reduced sedative and ataxic effects Abstract: Orally active benzodiazepine derivatives and their salts are disclosed. These compounds and their salts have anxiolytic and anticonvulsant activity with reduced sedative/hypnotic/muscle relaxant/ataxic effects. (end of abstract) Agent: Wisys Technology Foundation, Inc. C/o Mirick, O'connell, Demallie & Lougee, LLP - Westborough, MA, US Inventors: Xiaohui He, Xiaoyan Li, Jianming Yu, Dongmei Han, James M. Cook, Qi Huang USPTO Applicaton #: 20070299058 - Class: 514220000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of Two Nitrogens And Five Carbon Atoms, Polycyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos, Tricyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos The Patent Description & Claims data below is from USPTO Patent Application 20070299058. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. application Ser. No. 11/458,855 filed on Jul. 20, 2006, which is a Continuation of U.S. application Ser. No. 10/402,538 filed on Mar. 28, 2003, now U.S. Pat. No. 7,119,196, which claims benefit of U.S. Provisional Patent Application No. 60/368,408 filed Mar. 28, 2002, and is related to U.S. application Ser. No. 11/458,739 filed on Jul. 20, 2006, now U.S. Pat. No. 7,235,656, which is a divisional of U.S. application Ser. No. 10/402,538 filed on Mar. 28, 2003, now U.S. Pat. No. 7,119,196, all of which are incorporated herein in their entirety as if fully set forth herein. BACKGROUND OF THE INVENTION [0003] The present invention relates to a class of benzodiazepine derivatives which possess anxiolytic activity with decreased sedative, hypnotic, and ataxic side effects. [0004] The most frequently prescribed medication for treatment of anxiety disorders (such as phobias, obsessive compulsive disorders) and seizure disorders are benzodiazepines such as diazepam (Valium), triazolam (Halcion), midazolam (Versed), lorazepam (Ativan), chlordiazepoxide (Librium), alprazolam (Xanax), and other benzodiazepine-based medications. However, these benzodiazepine-based medications have side effects such as drowsiness, sedation, motor incoordination, memory impairment, potentiation of effects of alcohol, tolerance and dependence, and abuse potential. Buspirone, tandospirone, and other serotonergic agents have been developed as anxiolytics with a potentially reduced profile of side effects. However, while these medications do show a reduced profile of side effects, they have other characteristics which make them less than ideal for treatment of anxiety disorders. In some cases, these agents cause anxiety before a therapeutic dose can be obtained or require dosing of the drug for several days before a therapeutic effect is seen. Development of anxiolytics with even fewer side effects is desired. [0005] Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into three main classes: (1) GABA.sub.A receptors, which are members of the ligand-gated ion channel superfamily; (2) GABA.sub.B receptors, which may be members of the G-protein linked receptor superfamily; and (3) GABA.sub.C receptors, also members of the ligand-gated ion channel superfamily, but their distribution is confined to the retina. Benzodiazepine receptor ligands do not bind to GABA.sub.B and GABA.sub.C receptors. Since the first cDNAs encoding individual GABA.sub.A receptor subunits were cloned the number of known members of the mammalian family has grown to 21 including .alpha., .beta., and .gamma. subunits (6.alpha., 4.beta., 4.gamma., 1.delta., 1.epsilon., 1.pi., 1.theta., and 3.rho.). [0006] Subtype assemblies containing an .alpha.1 subunit (.alpha.1.beta.2.gamma.2) are present in most areas of the brain and are thought to account for 40-50% of GABA.sub.A receptors in the rat. Subtype assemblies containing .alpha.2 and .alpha.3 subunits respectively are thought to account for about 25% and 17% GABA.sub.A receptors in the rat. Subtype assemblies containing an .alpha.5 subunit (.alpha.5.beta.3.gamma.2) are expressed predominately in the hippocampus and cortex and are thought to represent about 4% of GABA.sub.A receptors in the rat. [0007] A characteristic property of all known GABA.sub.A receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine binding site. The benzodiazepine binding site is the most explored of the GABA.sub.A receptor modulatory sites, and is the site through which benzodiazepine-based anxiolytic drugs exert their effect. Before the cloning of the GABA.sub.A receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BENZODIAZEPINE1 and BENZODIAZEPINE2, on the basis of radioligand binding studies on synaptosomal rat membranes. The BENZODIAZEPINE1 subtype has been shown to be pharmacologically equivalent to a GABA.sub.A receptor comprising the .alpha.1 subunit in combination with a .beta. subunit and .gamma.2. This is the most abundant GABA.sub.A receptor subtype, and is believed to represent almost half of all GABA.sub.A receptors in the brain, as stated. [0008] Two other major populations are the .alpha.2.beta.2/3.gamma.2 and .alpha.3.beta.2/3.gamma.2/3 subtypes. Together these constitute approximately a further 35% of the total GABA.sub.A receptor population. Pharmacologically this combination appears to be equivalent to the BENZODIAZEPINE2 subtype as defined previously by radioligand binding, although the BENZODIAZEPINE2 subtype may also include certain .alpha.5-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known. [0009] It is now believed that agents acting as benzodiazepine agonists at GABA.sub.A/.alpha.2, GABA.sub.A/.alpha.3, and/or GABA.sub.A/.alpha.5 receptors, will possess desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABA.sub.A receptor by acting as benzodiazepine agonists are referred to hereinafter as "GABA.sub.A receptor agonists." The GABA.sub.A/.alpha.1-selective (.alpha.1.beta.2.gamma.2) agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BENZODIAZEPINE1 binding site is mediated through GABA.sub.A receptors containing the .alpha.1 subunit. Accordingly, it is considered that GABA.sub.A/.alpha.2, GABA.sub.A/.alpha.3, and/or GABA.sub.A/.alpha.5 receptor agonists rather than GABA.sub.A/.alpha.1 receptors will be effective in the treatment of anxiety with a reduced propensity to cause sedation. For example, QH-ii-066 binds with high affinity to GABA.sub.A/.alpha.5 receptors (Ki<10 nM), intermediate affinity to GABA.sub.A/.alpha.2 and GABA.sub.A/.alpha.3 (Ki<50 nM), and lower affinity to GABA.sub.A/.alpha.1 receptors (Ki>70 nM), unlike diazepam which binds with high affinity to all four diazepam-sensitive GABA.sub.A receptors (Ki<25 nM), as disclosed in Huang, et al., J. Med. Chem. 2000, 43, 71-95. Also, agents which are antagonists or inverse agonists at al receptors might be employed to reverse sedation or hypnosis caused by .alpha.1 agonists. [0010] Since the compounds of the present invention exhibit increased agonist efficacy at only a few GABA.sub.A types of receptors and/or selective efficacy at one or more ion channels and have been shown to be effective in animal models of anxiety and seizures, with reduced severity and/or incidence of side effects, they are useful in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, general anxiety disorder, attention deficit disorders, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder, neuroses, convulsions; migraine; depressive or bipolar disorders, for example single episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder, psychotic disorders including schizophrenia. SUMMARY OF THE INVENTION [0011] In consideration of this situation, the problem to be solved by the present invention is to provide a medication which can be used for the treatment of anxiety neurosis, general anxiety disorder, panic disorder, phobias, obsessive-compulsive disorders, schizophrenia, post-cardiac trauma stress disorders, depression disorders, psychosomatic disorders, and other psychoneurotic disorders, eating disorders, menopausal disorders, infantile autism and other disorders, and also emesis with fewer side effects. [0012] The present inventors engaged in repeated extensive studies to develop a superior medication free from the above problems. They found that the compounds of the present invention, that is, the novel benzodiazepine derivatives and their salts, have beneficial pharmacological and behavioral effects, that is, the compounds of the present invention show anxiolytic and anticonvulsant activity with greatly decreased or no sedative/hypnotic/muscle relaxant/ataxic side effects. [0013] The compounds described in the present invention have been synthesized based on a modified version of the computer modeling disclosed in Cook, et al J. Med. Chem., 1996, 39, 1928-1934. These compounds obtained by modifying elements, described herein, of the known benzodiazepine agents, have increased binding selectivity for the GABA.sub.A/.alpha.2, GABA.sub.A/.alpha.3, and/or GABA.sub.A/.alpha.5 receptors described above, and/or altered efficacy at one or more GABA.sub.A receptors described above, and/or altered selectivity at one or more ion channels. These compounds, which have been tested in animal models of anxiety in rats and seizures in mice, and side effect models in rats, have been found to be orally active and have anxiolytic and anticonvulsant activity, with reduced severity and/or incidence of side effects. [0014] One object of the present invention is to identify medications containing these benzodiazepine derivatives or their pharmaceutically acceptable salts as essential ingredients that are usable for the treatment of anxiety neurosis, phobias, obsessive-compulsive disorders, panic disorder, generalized anxiety disorder, schizophrenia, post-cardiac trauma stress disorders, depression disorders, psychosomatic disorders, and other psychoneurotic disorders, eating disorders, menopausal disorders, infantile autism, and other disorders. [0015] The present invention describes a class of benzodiazepine derivatives which possess desirable enhanced agonist efficacy at various GABA.sub.A receptors and desirable behavioral profile with respect to anxiolytic and anticonvulsant efficacy and reduced side effect efficacy. The compounds in accordance with the present invention have agonist efficacy at the GABA.sub.A/.alpha.2, GABA.sub.A/.alpha.3, and GABA.sub.A/.alpha.5 receptors. The compounds of this invention have anxiolytic and anticonvulsant effects with decreased sedative-hypnotic activity. [0016] The present invention provides a compound of formula I, or a salt or prodrug thereof, wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at least the substituent --C.ident.C--R, where R is H, Si (CH.sub.3).sub.3, t-butyl, isopropyl, methyl, or cyclopropyl; R.sub.1 is one of H, CH.sub.3, C.sub.2H.sub.4N(C.sub.2H.sub.5).sub.2, CH.sub.2CF.sub.3, CH.sub.2C.ident.CH, or an alkyl cyclopropyl; R.sub.2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heteorcyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO.sub.2 at the 2'-position; and R.sub.3 is one of H, OH, OCON(CH.sub.3).sub.2, COOCH.sub.3, or COOC.sub.2H.sub.5. Preferred compounds according to formula I include: [0017] The invention provides in another aspect a compound of formula II, or a salt or prodrug thereof, wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at least the substituent --C.ident.C--R, where R is H, Si (CH.sub.3).sub.3, t-butyl, isopropyl, methyl, or cyclopropyl; R.sub.1 is one of H, CH.sub.3, C.sub.2H.sub.4N(C.sub.2H.sub.5).sub.2, CH.sub.2CF.sub.3, CH.sub.2C.ident.CH, or an alkyl cyclopropyl; and R.sub.2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO.sub.2 at the 2'-position. Preferred compounds according to formula II include: [0018] The present invention provides in yet another aspect a compound of formula III, or a salt or prodrug thereof, wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at least the substituent --C.ident.C--R, where R is H, Si (CH.sub.3).sub.3, t-butyl, isopropyl, methyl, or cyclopropyl; and R.sub.2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO.sub.2 at the 2'-position. Preferred compounds according to the formula III include: [0019] Further, the present invention provides a compound of formula IV, or a salt or prodrug thereof, wherein R is H, Si (CH.sub.3).sub.3, t-butyl, isopropyl, methyl, or cyclopropyl; R.sub.1 is one of H, CH.sub.3, C.sub.2H.sub.4N(C.sub.2H.sub.5).sub.2, CH.sub.2CF.sub.3, CH.sub.2C.ident.CH, or an alkyl cyclopropyl; R.sub.2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO.sub.2 at the 2'-position; and A is an ethoxide or a propoxide. Preferred compounds according to the formula IV include: [0020] In a still further aspect, the present invention provides a compound of formula V, or a salt or prodrug thereof, wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent --C.ident.C--R, where R is H, Si (CH.sub.3).sub.3, t-butyl, isopropyl, methyl, or cyclopropyl; R.sub.1 is one of H, CH.sub.3, CF.sub.3, CH.sub.2CH.sub.3, CH.sub.2CF.sub.3, CH.sub.2C.ident.CH, an alkyl, or cyclopropyl; R.sub.2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO.sub.2 at the 2'-position; and R.sub.5 is a branched or straight chain C.sub.1 to C.sub.4 halogenated or unhalogenated alkyl or a methyl cyclopropyl. Preferred compounds according to formula V include: [0021] In yet another aspect, the present invention provides a compound of formula VI, or a salt or prodrug thereof, wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent --C.ident.C--R, where R is H, Si (CH.sub.3).sub.3, t-butyl, isopropyl, methyl, or cyclopropyl; R.sub.1 is one of H, CH.sub.3, CF.sub.3, CH.sub.2CH.sub.3, CH.sub.2CF.sub.3, or cyclopropyl; R.sub.2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO.sub.2 at the 2'-position; and R.sub.6 is a branched or straight chain C.sub.1 to C.sub.4 alkyl or a methyl cyclopropyl. Preferred compounds according to formula VI include: [0022] The present invention also provides a compound of formula VII, or a salt or prodrug thereof, wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent --C.ident.C--R, where R is H, Si (CH.sub.3).sub.3, t-butyl, isopropyl, methyl, or cyclopropyl; and R.sub.2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO.sub.2 at the 2'-position. Preferred compounds according to formula VII include: Continue reading... 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