Loxapine analogs and methods of use thereof
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:
- 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, where 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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Abstract
The invention relates to novel compounds and methods of using them for modulating sleep.
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Citations
38 Claims
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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:
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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, where 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
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23. A compound of Formula I:
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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, 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, and C1-C6 alkoxy;
any hydrogen in the CH2 groups in the linker is optionally substituted with H, F, Cl, Br, OH, 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)2N-heteroalkyl, CONHS(O)2N-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, where R13 is C1-C6 alkyl, and R14 and R15 are, independently, hydrogen or lower alkyl, provided that when Z is COOH or COOR13 and R6 is H or halogen, then R1-R5, and R7-R12 are not each hydrogen;
further provided that when m is zero, X is absent.- View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)
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- 37. A compound selected from Compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, and 88.
Specification