Preparation of 4-aza-17-substituted-5଱-androstan-3-ones useful as 5଱-reductase inhibitors

Patent 4220775 Issued on September 2, 1980. Estimated Expiration Date:

March 15, 1999. Estimated Expiration Date is calculated based on simple USPTO term provisions. It does not account for terminal disclaimers, term adjustments, failure to pay maintenance fees, or other factors which might affect the term of a patent.

Abstract Claims Description Full Text

Patent References

2227876

2897202

3022312

3239417

3264301

3285918

Inventors

Assignee

Merck & Co., Inc.

Application

No. 06/020372 filed on 03/15/1979

US Classes:

546/77, The six-membered hetero ring shares ring members with one other cyclo only514/859, Acne540/519, Polycyclo ring system which contains the hetero ring as one of the cyclos546/15, Spiro549/39, Chalcogen attached indirectly to the hetero ring by nonionic bonding552/510, The cyclopentanohydrophenanthrene ring system is part of a polycyclo ring system having at least five cyclos552/519, Oxygen bonded directly to the nitrogen (e.g., oximes, isonitrosos, etc.)552/611, Exactly one oxygen bonded directly to the cyclopentanohydrophenanthrene ring system (e.g., 3-keto-etiocholanic acids, etc.)552/641, The cyclopentanohydrophenanthrene ring system is fully saturated (e.g., androstandiols, androsterones, dihydrotestosterones, etc.)552/650Oxygen bonded directly at the 16- or 17-position of the cyclopentanohydrophenanthrene ring system

Examiners

Primary: Ford, John M.
Assistant: Bond, Robert T.

Attorney, Agent or Firm

International Classes

C07J 73/00 (20060101)
C07C 62/24 (20060101)
C07J 33/00 (20060101)
C07J 1/00 (20060101)
C07J 21/00 (20060101)
C07J 43/00 (20060101)
C07C 62/00 (20060101)
C07J 3/00 (20060101)
C07J 41/00 (20060101)

Abstract

A method of preparing a compound of the formula: ##STR1## where Formula (I) may also have the structure of partial Formula (III); wherein, ##STR2## R' is hydrogen or methyl; R" is hydrogen or ଲ-methyl;R'" is ଲ-methyl or hydroxy;Z is (1) oxo;(2) ଲ-hydrogen and ଱-hydroxy; or ଱-hydrogen or ଱-hydroxyl and(3) (Y)n Q where n=0 or 1, Y is a straight or branched hydrocarbon chain of 1 to 12 carbon atoms andQ is ##STR3## where R8 is, ##STR4## where the dashed bond replaces the 17଱ hydrogen; (6) cyano; or(7) tetrazolyl;and pharmaceutically acceptable salts of the above compounds;CHARACTERIZED IN THAT(I.) a compound of the formula: ##STR5## , where A has the meanings above except --CH=CH--, is (1) treated with an oxidizing agent at reduced temperatures to form the corresponding 5-oxo-3,5-seco-androstan-3-oic acid compound;(2) treating the product of step (1) with an amine of formula: R1 NH2 to form the corresponding 4-aza-5-androsten-3-one compound substituted in the 4-position with R1 ; and(3) treating the product of step (2) with hydrogen under catalytic conditions to form the compound of Formula I and I & II wherein B is ##STR6## (II.) and where it is desired to prepare compounds of Formula I wherein B is ##STR7## additionally carrying out the following steps on the products prepared by the procedures in (I.) above:(1) alkylating the lactim carbonyl by treating it with trialkyloxonium tetrafluoroborate to form the corresponding alkyl iminium ether, i.e., the compound of Formula I where B is as above and R4 =OR5 ;(2) treating the product of step (1) with an amine of formula HNR6 R7 followed by treatment with a mineral acid to form the compound of Formula I where B is as above and R4 =NR6 R7 ;(III.) and where it is desired to prepare compounds of Formula I wherein A is --CH=CH--, additionally carrying out the following steps on the products prepared by the procedures in (I.) above:(1) treating the 1,2 saturated compound with lithium diisopropyl amide to form the corresponding enolate;(2) treating the enolate of step (1) in situ with diphenyldisulfide to form the corresponding ଱-phenylthio compound;(3) oxidizing the product of step (2) to form the corresponding sulfoxide compound; and(4) heating the product of step (3) to form the compound of Formula I wherein A is --CH=CH--.