5-Aryl-indan-1-one oximes and analogs useful as progesterone receptor modulators
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Abstract
Compounds of formula I, wherein R1-R9 and n are defined herein, and pharmaceutical compositions and kits containing these compounds are provided.
Also provided are methods of inducing contraception, providing hormone replacement therapy, treating cycle-related symptoms, or treating or preventing benign or malignant neoplastic disease using the compounds of formula I or formula II, wherein R3-R5, R10, and R11 are defined herein.
75 Citations
20 Claims
- 1. A compound of formula I:
- 15. A method of inducing contraception, providing hormone replacement therapy, treating cycle-related symptoms, and treating or preventing benign or malignant neoplastic disease comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula II:
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19. A method of contraception which comprises administering to a female of child bearing age for 28 consecutive days:
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(a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μ
g levonorgestrel;
(b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of a compound of (i) or (ii);
(i) a compound of formula I;
wherein R1 and R2 are, independently, selected from the group consisting of H, halogen, C1 to C6 alkyl, CF3, CF2CF3, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
provided both of R1 and R2 are not H;
orR1 and R2 are fused to form (a), (b), or (c);
(a) a carbon-based 3 to 6 membered saturated spirocyclic ring;
(b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds;
or(c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO2, and NRC;
wherein rings (a)-(c) are optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C1 to C3 alkyl;
R3 is a 5 or 6 membered heteroayl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NRC and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO2, OH, amino, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 alkylamino, C═
NORC, CORD, and NRCCORD;
RC is absent, H, C1 to C4 alkyl, substituted C1 to C4 alkyl, CN, or CORD;
RD is H, C1 to C3 alkyl, C1 to C3 alkoxy, or C1 to C3 alkylamino;
R4 is H, halogen, CN, OH, NO2, alkoxy, or lower alkyl;
R5 is H or lower alkyl;
R6, R7, R8, and R9 are, independently, H, F, or C1 to C3 lower alkyl;
n is 0 or 1;
or(ii) a compound of formula II;
wherein;
R3 is aryl, substituted aryl, or a 5 or 6 membered heteroayl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NRC and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO2, OH, amino, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 alkylamino, C═
NORC, CORD, and NRCCORD;
R4 is H, halogen, CN, OH, NO2, or alkoxy;
R5 is H or lower alkyl;
R10 and R11 are, independently, H, F, or C1 to C3 lower alkyl; and
(c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered;
wherein the total daily dosage units of the first, second and third phases equals 28.
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20. A pharmaceutically useful kit adapted for daily oral administration which comprises:
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(a) a first phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μ
g levonorgestrel;
(b) a second phase of from 1 to 11 daily dosage units of a compound of formula I or II, each daily dosage unit containing said compound at a daily dosage of from about 2 to 50 mg, wherein said compound is (i) or (ii);
(i) a compound of formula I;
wherein R1 and R2 are, independently, selected from the group consisting of H, halogen, C1 to C6 alkyl, CF3, CF2CF3, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
provided both of R1 and R2 are not H;
orR1 and R2 are fused to form (a), (b), or (c);
(a) a carbon-based 3 to 6 membered saturated spirocyclic ring;
(b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds;
or(c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO2, and NRC;
wherein rings (a)-(c) are optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C1 to C3 alkyl;
R3 is a 5 or 6 membered heteroayl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NRC and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO2, OH, amino, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 alkylamino, C═
NORC, CORD, and NRCCORD;
RC is absent, H, C1 to C4 alkyl, substituted C1 to C4 alkyl, CN, or CORD;
RD is H, C1 to C3 alkyl, C1 to C3 alkoxy, or C1 to C3 alkylamino;
R4 is H, halogen, CN, OH, NO2, alkoxy, or lower alkyl;
R5 is H or lower alkyl;
R6, R7, R8, and R9 are, independently, H, F, or C1 to C3 lower alkyl;
n is 0 or 1;
or(ii) a compound of formula II;
wherein;
R3 is aryl, substituted aryl, or a 5 or 6 membered heteroayl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NRC and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO2, OH, amino, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 alkylamino, C═
NORC, CORD, and NRCCORD;
R4 is H, halogen, CN, OH, NO2, or alkoxy;
R5 is H or lower alkyl;
R10 and R11 are, independently, H, F, or C1 to C3 lower alkyl; and
(c) a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo;
wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28.
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Specification