Claims
- 1. A compound of the formula ##STR8## wherein the dotted line represents an optional double bond;
- R.sub.1 is hydrogen, C.sub.1 -C.sub.6 alkyl/cycloalkyl or --(CH.sub.2).sub.x -Ar-(M).sub.y, wherein x is 0, 1 or 2, Ar is phenyl, y is 0, 1 or 2, and M is C.sub.1 -C.sub.6 alkoxy, halogen, C.sub.1 -C.sub.6 alkyl/cycloalkyl, or --S(O).sub.z R.sub.5 wherein R.sub.5 is a C.sub.1 -C.sub.6 alkyl/cycloalkyl and z is 0, 1 or 2; and
- R.sub.2 is C.sub.1 -C.sub.6 alkyl alcohol; C.sub.1 -C.sub.6 alkyl aldehyde/ketone; CON(R.sub.3)(R.sub.4), wherein R.sub.3 and R.sub.4 are each independently, hydrogen or C.sub.1 -C.sub.6 alkyl/cycloalkyl, or --(CH.sub.2).sub.x -Ar-(M).sub.y, wherein x is 0, 1 or 2, Ar is phenyl, y is 0, 1 or 2, and M is C.sub.1 -C.sub.6 alkoxy, halogen, C.sub.1 -C.sup.6 alkyl, or --S(O).sub.z R.sub.5 wherein R.sub.5 is a C.sub.1 -C.sub.6 alkyl/cycloalkyl and z is 0, 1 or 2.
- 2. A compound of claim 1 wherein R.sub.1 is hydrogen.
- 3. A compound of claim 2 wherein R.sub.2 is 1-(hydroxymethyl)ethyl.
- 4. A compound of claim 2 wherein R.sub.2 is N,N-diisopropylcarboxamide.
- 5. A compound of claim 2 wherein R.sub.2 is N-tertiarybutylcarboxamide.
- 6. A method of treating a patient afflicted with a DHT-mediated disease or condition comprising administering to said patient an effective 5-.alpha.-reductase inhibitory amount of a compound of claim 1.
- 7. A pharmaceutical composition comprising an effective 5-.alpha.-reductase inhibitory amount of a compound of claim 1 in admixture with one or more pharmaceutically acceptable carriers or excipients.
- 8. A compound of claim 1 wherein the compound is 17.beta.-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3.alpha.-carboxylic acid.
- 9. A compound of claim 1 wherein the compound is 2 17.beta.-(N,N-diisopropylcarboxamide)-A-nor-androst-3,6-diene-3-carboxylic acid.
- 10. A compound of claim 1 wherein the compound is 17.beta.-(N,N-diisopropylcarboxamide)-A-nor-androst-2,5-diene-3-carboxylic acid.
- 11. A compound of claim 1 wherein the compound is 17.beta.-(N,N-diisopropylcarboxamide)-A-nor-androst-3-ene-3-carboxylic acid.
- 12. A compound of claim 1 wherein the compound is 17.beta.-(N-tertiarybutylcarboxamide)-A-nor-androst-5-ene-3.alpha.-carboxylic acid.
- 13. A compound of claim 1 wherein the compound is 17.beta.-(N-tertiarybutylcarboxamide)-A-nor-androst-3,6-diene-3-carboxylic acid.
- 14. A compound of claim 1 wherein the compound is 17.beta.-(N-tertiarybutylcarboxamide)-A-nor-androst-2,5-diene-3-carboxylic acid.
- 15. A compound of claim 1 wherein the compound is 17.beta.-(N-tertiarybutylcarboxamide)-A-nor-androst-3-ene-3-carboxylic acid.
BACKGROUND OF THE INVENTION
This is a continuation-in-part of application Ser. No. 458,869, filed Dec. 29, 1989, now abandoned. The present invention relates to novel A-nor-steroid-3-carboxylic acid derivatives and to their use as inhibitors of mammalian steroid 5-.alpha.-reductase.
Mammalian steroid 5-.alpha.-reductase is an enzyme present in mammalian tissues, including skin, male genitalia and prostate gland, which catalyzes the conversion of the steroidal hormone testosterone to the steroidal hormone dihydrotestosterone (5-.alpha.-androstane-17-.beta.-ol-3-one). Testosterone and dihydrotestosterone (DHT) are members of the class of hormones called androgens which are primarily responsible for producing the physical characteristics which differentiate males from females. Testosterone and DHT are the primary androgenic steroids in males. However DHT, rather than testosterone, is the most potent androgen end-organ effector in certain tissues, particularly in mediating growth. Furthermore, DHT is formed mostly in the target cells themselves by reduction of testosterone by 5-.alpha.-reductase.
It is known that skin responds to androgens and is an active site of androgen metabolism. In particular, testosterone is metabolized in the skin to DHT by the action of 5-.alpha.-reductase. Testosterone metabolism in the skin may at times be abnormally excessive and have undesirable effects. There is considerable evidence that DHT is involved in the pathogenesis of acne, including acne vulgaris, as well as other androgen associated conditions [See Price, Arch. Dermatol. 111, 1496 (1975)]. Agents which are capable of blocking the formation of DHT from testosterone in skin, such as by inhibiting the activity of 5-.alpha.-reductase, would therefore be effective in the treatment of acne.
In addition, other physical conditions and disease states, including benign prostatic hypertrophy, androgenetic alopecia (common baldness caused by androgen in genetically susceptible men and women), seborrhea and female hirsutism, are associated with elevated androgen activity. Agents which are capable of blocking the formation of DHT from testosterone would also be effective in the treatment of these conditions.
The present invention provides novel A-nor-steroid-3-carboxylic acid derivatives of the formula (A), (B), (C) or (D) ##STR1## wherein the dotted line represents an optional double bond;
R.sub.2 is C.sub.1 -C.sub.6 alkanol; C.sub.1 -C.sub.6 alkanone, CON(R.sub.3)(R.sub.4), wherein R.sub.3 and R.sub.4 are each independently, hydrogen or C.sub.1 -C.sub.6 alkyl, or --(CH.sub.2).sub.x -Ar-(M).sub.y, wherein x is 0, 1 or 2, Ar is phenyl, y is 0, 1 or 2, and M is C.sub.1 -C.sub.6 alkoxy, halogen, C.sub.1 -C.sub.6 alkyl, or --Si(O).sub.z R.sub.5 wherein R.sub.5 is a C.sub.1 -C.sub.6 alkyl and z is 0, 1 or 2.
The present invention also provides a method of inhibiting 5-.alpha.-reductase in a patient in need thereof, comprising administering to said patient a therapeutically effective 5-.alpha.-reductase inhibiting amount of a compound of formula (A), (B), (C), (D).
US Referenced Citations (6)
Foreign Referenced Citations (1)
| Number |
Date |
Country |
| 0289327 |
Nov 1988 |
EPX |
Non-Patent Literature Citations (1)
| Entry |
| "Hackh's Chemical Dictionary," 4th Ed., p. 27 (1969). |
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
458869 |
Dec 1989 |
|
Patent Grant
5100917
