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Loxapine analogs and methods of use thereof

  • US 20060063755A1
  • Filed: 09/21/2005
  • Published: 03/23/2006
  • Est. Priority Date: 09/21/2004
  • Status: Abandoned Application
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First Claim
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1. A method of modulating sleep in a subject, comprising administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof:

  • embedded image or a pharmaceutically effective salt thereof, wherein;

    m, n, o, p, q are, independently, an integer from 0, 1, 2, 3, 4, 5, or 6;

    X and Y are, independently, absent, O, S, C(O), SO, or SO2;

    R1, R2, R3, R4, R5, R6, R7, and R8 are, independently, selected from H, F, Cl, Br, OH, CH3, CF3, C2-C6 straight chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, OCH3, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

    any hydrogen in the CH2 groups in the linker is optionally substituted with H, F, Cl, OH, Br, CF3, CH3, C2-C6 straight chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, OCH3, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, C1-C6 hydroxyalkyl;

    or C1-C6 alkoxy;

    R9, R10, R11, and R12 are, independently, H, C1-C6 straight chain alkyl, C2-C6 branched alkyl, or R9 and R10 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 R11 and R12 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 atoms;

    Z is selected from CO2H, CO2R13, CONR14R15, CONHS(O)2-alkyl, CONHS(O)2-cycloalkyl, CONHS(O)2-heteroalkyl, CONHS(O)2-aryl, CONHS(O)2-heteroaryl, S(O)2NHCO-alkyl, S(O)2NHCO-cycloalkyl, S(O)2NHCO-heteroalkyl, S(O)2NHCO-aryl, S(O)2NHCO-heteroaryl, CONHS(O)2NH-alkyl, CONHS(O)2NH-cycloalkyl, CONHS(O)2NH-heteroalkyl, CONHS(O)2NH-aryl, CONHS(O)2N-heteroaryl, SO3H, SO2H, S(O)NHCO-alkyl, S(O)NHCO-aryl, S(O)NHCO-heteroaryl, P(O)(OH)2, P(O)OH, embedded imagewhere R13 is C1-C6 alkyl, and R14 and R15 are, independently, hydrogen or lower alkyl, further wherein the compound has one or more of the following characteristics;

    (i) an inhibition constant (Ki) with regard to H1 receptor binding of less than 500 nM;

    (ii) a Ki with regard to off target binding to an off target selected from M1, M2, M3, D1, D2, α

    1 and α

    2 that is more than 5 times greater than the Ki with regard to the H1 receptor;

    (iii) a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after said compound is administered to a subject;

    (iv) a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation;

    (v) a longest sleep bout that is greater than 13 minutes in duration;

    (vi) 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 said compound to a subject;

    (vii) an average sleep bout that is greater than 5 minutes at absolute peak;

    (viii) administration of said compound to a subject does not produce appreciable amounts of rebound insomnia;

    (ix) administration of said compound to a subject does not appreciably inhibit REM sleep; and

    (x) administration of said compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep, provided that when Z is COOH or COOR13 and R6 is H or halogen, R1-R5, and R7-R12 are not each hydrogen, further provided that when m is zero, X is absent.

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