Combination regimens using progesterone receptor modulators

A method of contraception, which comprises administering to a female of child bearing age for 28 consecutive days:

• a) a first phase of from 14 to 24 daily dosage units of about 35 to about 100 μg of the progestational agent 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 an antiprogestin compound of Formula I:
• R1 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, and NRBCORA;
• R2 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, and NRBCORA;
• or R1 and R2 are fused to form:
• i) a 3 to 8 membered saturated spirocyclic carbon ring;
• ii) a 3 to 8 membered spirocyclic carbon ring having one or more carbon-carbon double bonds;
• or
• iii) a 3 to 8 membered heterocyclic ring containing one to three heteroatoms selected from the group consisting of O, S and N;
• the spirocyclic rings of i), ii), and iii) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 thioalkyl, CF3, OH, CN, NH2, NH(C1 to C6 alkyl), and N(C1 to C6 alkyl)2;
• RA is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
• RB is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• R3 is H OH NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C3 to C6 alkenyl, alkynyl, substituted alkynyl, or CORC;
• RC is H, C1 to C4 alkyl, substituted C1 to C4 alkyl, aryl, substituted aryl, C1 to C4 alkoxy, substituted C1 to C4 alkoxy, C1 to C4 aminoalkyl, or substituted C1 to C4 aminoalkyl;
• R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, alkynyl, substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
• R5 is selected from the group consisting of iv), v), vi), and vii):
• iv) a substituted benzene ring containing the substituents X, Y and Z as shown below:
• wherein:
• X is selected from the group consisting of H, halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C, to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, CORD, OCORD, and NRECORD;
• RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
• RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, and C1 to C3 thioalkoxy, wherein not all of X, Y and Z are H;
• v) a five membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, and SO2 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, amino, C1 to C3 alkyl, and C1 to C3 alkoxy;
• vi) a five membered ring having in its backbone 1, 2, or 3 NR6 heteroatoms and containing one or two independent substituents selected from the group consisting of H, halogen, NO2, amino, C1 to C3 alkyl, and C1 to C3 alkoxy;
• and
• vii) a six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, amino, C1 to C3 alkyl, and C1 to C3 alkoxy;
• R6 is H or C1 to C3 alkyl;
• or pharmaceutically acceptable salt thereof;
• 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.

A method of contraception, which comprises administering to a female of child bearing age for 28 consecutive days:

• a) a first phase of from 14 to 24 daily dosage units of about 35 to about 100 μg of the progestational agent 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 an antiprogestin compound of Formula I:
• R1=R2 and are selected from the group consisting of C1 to C3 alkyl and substituted C1 to C3 alkyl, or R1 and R2 are fused to form a 3 to 6 membered saturated spirocyclic carbon based ring;
• R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORC;
• RC is H, C1 to C4 alkyl, or C1 to C4 alkoxy;
• R4 is H, halogen, CN, NO2, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, or substituted C1 to C3 alkoxy;
• R5 is selected from the group consisting of (i), (ii), (iii), and (iv):
• (i) a substituted benzene ring of the structure:
• wherein:
• X is halogen, CN, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
• Y is H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkoxy;
• (ii) a five membered ring with the structure:
• wherein:
• U is O or S;
• X′ is selected from the group consisting of halogen, CN, NO2, C1 to C3 alkyl and C1 to C3 alkoxy;
• Y′ is selected from the group consisting of H and C1 to C4 alkyl;
• (iii) a five membered ring with the structure:
• wherein:
• U is NR6;
• X′ is selected from the group consisting of halogen, NO2, C1 to C3 alkyl and C1 to C3 alkoxy;
• Y′ is selected from the group consisting of H and C1 to C4 alkyl;
• (iv) a six membered ring with the structure:
• wherein:
• X1 is N or CX2;
• X2 is halogen, CN, alkoxy, or NO2,
• or pharmaceutically acceptable salt thereof.

A method of contraception, which comprises administering to a female of child bearing age for 28 consecutive days:

• a) a first phase of from 14 to 24 daily dosage units of about 35 to about 100 μg of the progestational agent 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 an antiprogestin compound of Formula I:
• R1 and R2 are CH3 or R1 and R2 are fused to form a 6 membered saturated spirocyclic carbon based ring
• R3 is H, OH, NH2, CH3, substituted CH3, or CORC;
• RC is H, C1 to C3 alkyl, or C1 to C4 alkoxy;
• R4 is H, halogen, NO2, CN, or C1 to C3 alkyl;
• R5 is (i) or (ii):
• (i) a substituted benzene ring of the formula:
• wherein:
• X is selected from the group consisting of halogen, CN, methoxy, NO2, and 5-membered heterocyclic ring;
• wherein said 5-membered heterocyclic ring is 2-thiazole;
• Y is H or halogen;
• wherein said halogen is F;
• or
• (ii) a five membered ring of the structure:
• wherein:
• U is O or S, or NH;
• X′ is halogen, CN, or NO2, provided that when U is NH, X is not CN;
• Y′ is H or C1 to C4 alkyl;
• or
• or a pharmaceutically acceptable salt thereof.