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  Loxapine analogs and methods of use thereofUSPTO Application #: 20060063755Title: Loxapine analogs and methods of use thereof Abstract: The invention relates to novel compounds and methods of using them for modulating sleep. (end of abstract) Agent: Mintz, Levin, Cohn, Ferris, Glovsky And Popeo, P.C. - Boston, MA, US Inventors: Dale M. Edgar, David G. Hangauer, Kazumi Shiosaki, Michael Solomon, James F. White USPTO Applicaton #: 20060063755 - Class: 514211130 (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 Contains Seven Members Including Nitrogen, Carbon And Chalcogen, Polycyclo Ring System Which Contains The Seven-membered Hetero Ring As One Of The Cyclos, Tricyclo Ring System Having The Seven-mmbered Hetero Ring As One Of The Cyclos, Nitrogen Bonded Directly To Ring Carbon Of The Seven-membered Hetero Ring The Patent Description & Claims data below is from USPTO Patent Application 20060063755. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This non-provisional patent application claims priority under 35 U.S.C. .sctn. 119(e) to U.S. Provisional Patent Application Ser. Nos. 60/611,849, filed Sep. 21, 2004, and 60/673,198, filed Apr. 19, 2005, each of which is herein incorporated by reference in its entirety. This application is also related to copending application entitled "Loxapine Analogs and Methods of use Thereof", Attorney Docket Number 20712-510A, filed on Sep. 21, 2005. FIELD OF THE INVENTION [0002] The invention relates to methods for treating sleep disorders and compositions useful in such methods. BACKGROUND OF THE INVENTION [0003] Difficulty falling asleep or remaining asleep is a significant medical issue that arises for a variety of reasons. Sometimes, these problems arise from endogenous conditions such as sleep apnea or insomnia. Other times, these problems arise from exogenous stresses such as the disruptive effect of shift work schedules and "jet lag." Whether caused by an endogenous or exogenous source, difficulty falling asleep or remaining asleep can result in problem sleepiness, which impairs the health, quality of life, and safety of those affected. [0004] Existing pharmaceutical treatments for inducing sleep include sedatives or hypnotics such as benzodiazepine and barbiturate derivatives. These treatments have numerous drawbacks, including rebound insomnia, delayed onset of desired sedative effects, persistence of sedative effects after the desired sleep period, and side effects due to nonspecific activity such as psychomotor and memory deficits, myorelaxation, and disturbed sleep architecture, including REM sleep inhibition. Additionally, sedatives and hypnotics can be habit forming, can lose their effectiveness after extended use, and may be metabolized more slowly by some people. [0005] Consequently, physicians often recommend or prescribe antihistamines as a milder treatment for sleep disorders when hypnotics are less appropriate. However, many antihistamines suffer from a number of side effects. These side effects include prolongation of the QT interval in a subject's electrocardiogram, as well as central nervous system (CNS) side effects such as decreased muscle tone and drooping eyelids. Finally, such compounds can bind to muscarinic receptors, which leads to anti-cholinergic side effects such as blurred vision, dry mouth, constipation, urinary problems, dizziness and anxiety. [0006] As a result, there is a need for sleep-promoting treatments with reduced side effects. Additionally, while known sleep-inducing compounds are effective for treating sleep-onset insomnia, i.e., a subject's difficulty in falling asleep, there are no drugs currently indicated for treating sleep maintenance insomnia, i.e., maintaining a subject's sleep throughout a normal sleep period after falling asleep. Therefore, there is also a need for improved pharmaceutical treatments for maintaining sleep in subjects in need of such treatment. SUMMARY OF THE INVENTION [0007] The present invention relates to loxapine analogs and their use to modulate sleep. Loxapine (LOXAPAC.TM., LOXITANE.TM.) is a tricyclic dibenzoxazepine antipsychotic agent used in the management of the manifestations of schizophrenia. Loxapine (2-chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][1,4]oxazepine) has the following structure: [0008] In one aspect, the invention relates to a method of modulating sleep in a subject by administering to the subject a therapeutically effective amount of a compound of Formula I: [0009] or a pharmaceutically effective salt thereof, wherein: m, n, o, p, and q are, independently, an integer 0, 1, 2, 3, 4, 5, or 6; X and Y are, independently, absent, O, S, C(O), SO, or SO.sub.2; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are, independently, H, F, Cl, Br, OH, CF.sub.3, CH.sub.3, C.sub.2-C.sub.6 straight chain alkyl, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7 heterocyclyl, OCH.sub.3, OCF.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, C.sub.1-C.sub.6 hydroxyalkyl, or C.sub.1-C.sub.6 alkoxy; any hydrogen in the CH.sub.2 groups in the linker is optionally substituted with H, F, Cl, OH, Br, CF.sub.3, CH.sub.3, C.sub.2-C.sub.6 straight chain alkyl, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7 heterocyclyl, OCH.sub.3, OCF.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, C.sub.1-C.sub.6 hydroxyalkyl, or C.sub.1-C.sub.6 alkoxy; R.sub.9, R.sub.10, R.sub.11, and R.sub.12 are, independently, H, C.sub.1-C.sub.6 straight chain alkyl, C.sub.2-C.sub.6 branched alkyl, or R.sub.9 and R.sub.10 together with the carbon to which they are attached are absent or are connected to form a spiro ring of size 3, 4, 5, 6, or 7 atoms, or R.sub.11 and R.sub.12 together with the carbon to which they are attached are connected to form a spiro ring of size 3, 4, 5, 6, or 7 atoms, or substituents on two different carbon atoms are connected to form a ring of size 3, 4, 5, 6, or 7; Z is selected from CO.sub.2H, CO.sub.2R.sub.13 (where R.sub.13 is C.sub.1-C.sub.6 alkyl) CONR.sub.14R.sub.15 (where R.sub.14 and R.sub.15 are, independently, hydrogen or lower alkyl) CONHS(O).sub.2-alkyl, CONHS(O).sub.2-cycloalkyl, CONHS(O).sub.2-heteroalkyl, CONHS(O).sub.2-aryl, CONHS(O).sub.2-heteroaryl, S(O).sub.2NHCO-alkyl, S(O).sub.2NHCO-cycloalkyl, S(O).sub.2NHCO-heteroalkyl, S(O).sub.2NHCO-aryl, S(O).sub.2NHCO-heteroaryl, CONHS(O).sub.2NH-alkyl, CONHS(O).sub.2NH-cycloalkyl, CONHS(O).sub.2NH-heteroalkyl, CONHS(O).sub.2NH-aryl, CONHS(O).sub.2NH-heteroaryl, SO.sub.3H, SO.sub.2H, S(O)NHCO-alkyl, S(O)NHCO-aryl, S(O)NHCO-heteroaryl, P(O)(OH).sub.2, P(O)OH, provided that when Z is COOH or COOR.sub.13, and R.sub.6 is H or halogen, R.sub.1-R.sub.5 and R.sub.7-R.sub.12 are not each hydrogen, further provided that when m is zero, X is absent. [0010] In one embodiment, Z is a sulfonamide. Examples of sulfonamides include acyl sulfonamides. For example, Z can have the formula where W is a substituent chosen as needed to modulate the effects of the polar surface area of the Z moiety such that the desired level of oral absorption, CNS penetration, and rate of excretion into urine or bile is obtained. Examples of useful W substituents for this purpose include an alkyl group (optionally containing a double or triple bond or heteroatom substituted e.g., CH.sub.2OCH.sub.3 or CH.sub.2OCH.sub.2CH.sub.3), a cycloalkyl group (optionally containing a double bond), a heterocyclyl group, an aryl group or a heteroaryl group, both optionally substituted, such as those shown below where V is one or more side chains selected to modulate the pKa of the acylsulfonamide moiety, or to affect the physical or metabolic properties of the compound. Examples of V side chains include halogens such as F, Cl, or Br; C.sub.1-C.sub.6 alkoxy groups such as OCH.sub.3 or OCH.sub.2CH.sub.3; C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.8 cycloalkyl groups such as CH.sub.3, CF.sub.3, or cyclopropyl; heteroatom substituted C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.8 cycloalkyl, such as CH.sub.2OCH.sub.3, or CH.sub.2OCH.sub.2CH.sub.3; electron withdrawing groups such as CN, a ketone, an amide, or a sulfone, (and pyridyl isomers), (and pyrimidine isomers), and [0011] In one embodiment, Z is a sulfamide. Examples of sulfamides include acyl sulfamides. For example, Z can have the formula where R.sub.a and R.sub.b are, independently, for example an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, optionally substituted. Examples include the following: (where V is a halogen such as F, Cl, or Br; C.sub.1-C.sub.6 alkoxy such as OCH.sub.3 or OCH.sub.2CH.sub.3; C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.8 cycloalkyl, such as CH.sub.3, CF.sub.3, or cyclopropyl; heteroatom substituted C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.8 cycloalkyl, such as CH.sub.2OCH.sub.3, or CH.sub.2OCH.sub.2CH.sub.3; an electron withdrawing group such as CN, a ketone, an amide, or a sulfone), (and pyridyl isomers), or (and pyrimidine isomers). [0012] In one embodiment, the compounds of Formula I for use in the methods of the invention have one or more of the following characteristics: an inhibition constant (K.sub.i) with regard to H1 receptor binding of less than 500 nM; a K.sub.i with regard to off target binding to an off target selected from M1, M2, M3, D1, D2, .alpha.1 and .alpha.2 that is greater than 500 nM and/or more than 5 times greater than the K.sub.i with regard to the H1 receptor; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. [0013] In another embodiment, the compound of Formula I for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (K.sub.i) with regard to H1 receptor binding of less than 300 nM; a K.sub.i with regard to off target binding to an off target selected from M1, M2, M3, D1, D2, .alpha.1 and .alpha.2 that is greater than 1 .mu.m; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 13 minutes in duration; net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep. [0014] In another embodiment, the compound of Formula I for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (K.sub.i) with regard to H1 receptor binding of less than 150 nM; a K.sub.i with regard to off target binding to an off target selected from M1, M2, and M3, that is greater than 10 .mu.M; a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after the compound is administered to a subject; a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longest sleep bout that is greater than 17 minutes in duration; net longest sleep bout post treatment is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep bout that is greater than 6 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of rebound insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep. [0015] In one embodiment, in the compound of Formula I used in the method of the invention, R.sub.6 is not hydrogen or halogen. In another embodiment, in the compound used in the method of the invention, R.sub.6 is methyl, methoxy, methoxymethylene (CH.sub.2OCH.sub.3), or hydroxy. In another embodiment, in the compound used in the method of the invention, R.sub.6 is methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. [0016] In another embodiment, in the compound of Formula I used in the method of the invention, R.sub.1-R.sub.5 and R.sub.7-R.sub.8 are each hydrogen. [0017] In another embodiment, in the compound of Formula I used in the method of the invention, at least one of R.sub.1-R.sub.8 is a non-hydrogen substituent and the remaining R.sub.1-R.sub.8 are hydrogen. In another embodiment, in the compound used in the method of the invention, at least one non-hydrogen R.sub.1-R.sub.8 is independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. [0018] In another embodiment, in the compound of Formula I used in the method of the invention, at least two of R.sub.1-R.sub.8 are non-hydrogen substituents, and the remaining R.sub.1-R.sub.8 are hydrogen. In another embodiment, in the compound used in the method of the invention, at least 2 non-hydrogen R.sub.1-R.sub.8 are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. [0019] In another embodiment, in the compound of Formula I used in the method of the invention, at least three of R.sub.1-R.sub.8 are non-hydrogen substituents, and the remaining R.sub.1-R.sub.8 are hydrogen. In another embodiment, in the compound used in the method of the invention, at least 3 non-hydrogen R.sub.1-R.sub.8 are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. [0020] In another embodiment, in the compound of Formula I used in the method of the invention, R.sub.2 is a non-hydrogen substituent. For example, R.sub.2 is, e.g., methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. Continue reading... Full patent description for Loxapine analogs and methods of use thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Loxapine analogs and methods of use thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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