4-amino-17.beta.-(cyclopropyloxy)androst-4-en-3-one, 4-amino-17.beta.-(cyclopropylamino)androst-4-en-3-one and related compounds as C.sub.17-20 lyase and 5.alpha.-reductase
First Claim
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1. A compound and the pharmaceutically acceptable salts of the formula:
- wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond.
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Abstract
This invention is directed to 4-amino-17β-(cyclopropyloxy)androst-4-en-3-one, 4-amino-17β-(cyclopropylylamino)androst-4-en-3-one and related compounds, a process for their synthesis, a pharmaceutical composition having C17-20 lyase and 5α-reductase inhibitory activity, the use of the present compounds as C17-20 lyase and 5α-reductase inhibitors and also to a method for using such compounds in the treatment of androgen and/or estrogen dependent disorders, including bengin prostatic hyperplasia, breast cancer and prostatic cancer. The 4-amino compounds are prepared by the reaction of the appropriate 4,5-epoxide with sodium azide in an inert solvent in the presence of a catalytic amount of strong acid under appropriate reaction conditions. Alternatively, the 4-amino compounds are prepared by first nitration and then reduction of the appropriate steroid under appropriate reaction conditions.
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Citations
38 Claims
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1. A compound and the pharmaceutically acceptable salts of the formula:
wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond.- View Dependent Claims (2, 3, 4)
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5. A pharmaceutical composition having C17-20 lyase and 5α
- -reductase inhibiting activity, in a dosage unit form, comprising a pharmaceutical carrier and a compound and the pharmaceutically acceptable salts of the formula ##STR9## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (6, 7, 8)
- -reductase inhibiting activity, in a dosage unit form, comprising a pharmaceutical carrier and a compound and the pharmaceutically acceptable salts of the formula ##STR9## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
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9. A method of inhibiting C17,20 lyase enzyme which comprises administering to a patient in need thereof an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula:
- ##STR10## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (10, 11, 12)
- ##STR10## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
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13. A method of inhibiting 5α
- -reductase enzyme which comprises administering to a patient in need thereof an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula;
##STR11## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (14, 15, 16)
- -reductase enzyme which comprises administering to a patient in need thereof an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula;
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17. A method for treating androgen-dependent disorders which comprises administering to a patient in need thereoff an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula:
- ##STR12## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1-4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (18, 19, 20)
- ##STR12## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1-4 lower alkyl;
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21. A method for treating estrogen-induced or estrogen-stimulated disorders, which comprises administering to a patient in need thereof an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula:
- ##STR13## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (22, 23, 24)
- ##STR13## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
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25. A method of treating a DHT-mediated disease which comprises administering to a patient in need thereof an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula:
- ##STR14## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (26, 27, 28)
- ##STR14## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
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29. A method of treating benign prostatic hyperplasia which comprises administering to a patient in need thereof an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula:
- ##STR15## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (30, 31, 32)
- ##STR15## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
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33. A method of treating breast cancer which comprises administering to a patient in need thereof an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula:
- ##STR16## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (34, 35)
- ##STR16## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
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36. A method of treating prostate cancer which comprises administering to a patient in need thereof an effective inhibitory amount of a compound and the pharmaceutically acceptable salts of the formula:
- ##STR17## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
each X is independently selected from the group consisting of hydrogen, halogen, and methyl; and
the dotted lines indicate the optional presence of a double bond. - View Dependent Claims (37, 38)
- ##STR17## wherein A is O or NH and each R is independently selected from the group consisting of hydrogen and C1 -C4 lower alkyl;
Specification
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Current AssigneeMerrell Dow Pharmaceuticals Inc (Dow, Inc.)
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Original AssigneeMerrell Dow Pharmaceuticals Inc (Dow, Inc.)
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InventorsJohnston, J. O'Neal, Angelastro, Michael R., Curran, Timothy T., Weintraub, Philip M., Gates, Cynthia A.
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Primary Examiner(s)PRIOR, KIMBERLY
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Application NumberUS08/231,434Time in Patent Office631 DaysField of Search552/515, 514/178, 514/181, 514/177, 514/180US Class Current514/178CPC Class CodesC07J 41/0011 Unsubstituted amino radicalsC07J 41/0027 AzidesC07J 71/001 Oxiranes
