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WO1997015305A1 - Traitement des pathologies hyperandrogeniques - Google Patents

Traitement des pathologies hyperandrogeniques Download PDF

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Publication number
WO1997015305A1
WO1997015305A1 PCT/US1996/016871 US9616871W WO9715305A1 WO 1997015305 A1 WO1997015305 A1 WO 1997015305A1 US 9616871 W US9616871 W US 9616871W WO 9715305 A1 WO9715305 A1 WO 9715305A1
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WIPO (PCT)
Prior art keywords
androst
carboxamide
oxa
oxo
compound
Prior art date
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PCT/US1996/016871
Other languages
English (en)
Inventor
Herb G. Bull
Georgianna Harris
Robert W. Myers
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9602853.5A external-priority patent/GB9602853D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to US09/051,948 priority Critical patent/US5932559A/en
Priority to AU74637/96A priority patent/AU7463796A/en
Publication of WO1997015305A1 publication Critical patent/WO1997015305A1/fr

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    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/006—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by sulfur as hetero atom
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    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the invention concerns the treatment of hyperandrogenic conditions in humans by the formation of a novel mechanism-based irreversible inhibitor of human 5 ⁇ -reductase enzymes from 3-oxo-4- oxa and 4-thiasteroids having a 1 ,2-double bond and the pyridine- nucleotide cofactor of the 5 ⁇ -reductase enzyme, NADPH.
  • the invention further relates to the isolated inhibitor-cofactor complex.
  • Certain undesirable physiological manifestations such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hype ⁇ lasia, are the result of hyperandrogenic stimulation caused by excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Androgenic alopecia is also known as androgenetic alopecia.
  • T testosterone
  • Androgenic alopecia is also known as androgenetic alopecia.
  • Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own.
  • the estrogens for example, not only counteract the effect of the androgens but have a feminizing effect as well.
  • Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neri. et al., Endocrinol. 1972, 91 (2).
  • these products though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
  • DHT 5 ⁇ -dihydrotestosterone
  • Inhibitors of testosterone-5oc-reducta.se will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs.
  • the enzyme 5 ⁇ -reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown below:
  • Finasteride ( 17 ⁇ -(N-tert-butylcarbamoyl)-3-oxo-4-aza-5 ⁇ - androst- l -ene-3-one) as shown below, is a potent inhibitor of the human prostate enzyme.
  • finasteride is known to be useful in the treatment of hyperandrogenic conditions; see eg. U.S. 4.760,071. Finasteride is currently prescribed for the treatment of benign prostatic hype ⁇ lasia (BPH), a condition afflicting to some degree the majority of men over age 55. Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published 5 October 1988; EP 0 285,383, published 5 October 1988; Canadian Patent no. 1.302,277: and Canadian Patent no. 1 ,302,276.
  • BPH benign prostatic hype ⁇ lasia
  • Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published 5 October 1988; EP 0 285,383, published 5 October 1988; Canadian Patent no. 1.302,277: and Canadian Patent no. 1 ,302,276.
  • isozymes of 5 ⁇ -reductase there are two isozymes of 5 ⁇ -reductase in humans.
  • One isozyme (type 1 ) predominates in sebaceous glands of most regions of skin tissue and is relatively insensitive to finasteride; the other (type 2) predominates in the prostate and is potently inhibited by finasteride.
  • type 1 predominates in sebaceous glands of most regions of skin tissue and is relatively insensitive to finasteride
  • type 2 predominates in the prostate and is potently inhibited by finasteride.
  • finasteride and certain analogs thereof are slow- binding inhibitors, such that their potency had been mistakenly underrated in standard fixed-time assays (Harris et al., Proc. Natl. Acad. Sci. U.S.A., 89: 10787- 10791 ( 1992)). Independently. Faller et al., also recognized the inconsistency.
  • finasteride is not a significant inhibitor of human skin (type 1 ) isozyme at doses employed in the treatment of BPH, finasteride does slowly form a comparable high affinity complex with this isozyme.
  • the second-order rate constant for formation of this complex is 4.0 x 10 ⁇ M ⁇ l s"' . which is about 1 % of the rate constant against the prostate isozyme.
  • Tian et al. proposed that finasteride binds to the enzyme covalently as a Michael acceptor.
  • 3-oxo-4-oxa and 4-thiasteroids having a 1.2-double bond are recognized as a substrate by the human 5 ⁇ -reductase type I and type 2 enzymes, and in the course of the enzymatic reduction, the 3- oxo-4-oxa and 4-thiasteroid having a 1 ,2-double bond forms a covalent adduct with the pyridine-nucleotide cofactor (NADPH).
  • NADPH pyridine-nucleotide cofactor
  • the covalent inhibitor-cofactor complex formed between the 3-oxo-4-oxasteroid anion and the oxidized nicotinamide cofactor is bound by the enzyme as a potent collected-product inhibitor.
  • Novel mechanism-based irreversible inhibitors of human 5 ⁇ -reductase enzymes are formed from 3-oxo-4-oxa and 4-thiasteroids having a 1 ,2-double bond and the pyridine-nucleotide cofactor of the 5 ⁇ -reductase enzyme NADPH.
  • the structure of the covalent NADP- inhibitor complex is represented below as structural formula (I):
  • AH + In the scheme above, AH and BH represent proton donors in the enzyme active site and (P)ADPR represents 2-phospho-adenosine- diphospho-ribose.
  • 3-oxo-4-oxa and 4-thiasteroids having a 1 ,2-double bond are selectively activated by the enzyme 5 -reductase to produce the novel covalent adduct with the cofactor NADPH of structural formula (I):
  • 3-oxo-4-oxa and 4- thiasteroids having a 1 ,2-double bond useful in the present invention are the compounds of structural formula III, below:
  • the C5-C6 bond designated with a dotted line independently represents a single or double bond, provided that when the C5-C6 is a double bond, Ha is absent and when the C5-C6 bond is a single bond H a is present and represents hydrogen;
  • X is selected from oxygen and sulfur
  • R is selected from hydrogen and Cl-5 alkyl
  • R 2 is selected from CH3, CH2OR 3 , and H;
  • R3 is selected from: Cl-5 alkyl
  • a 1 is selected from:
  • Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
  • (a) protected hydroxy is selected from: dimethyl-t-butyl silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri- isopropylsilyloxy. and triphenylsilyloxy ;
  • Cl-10 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl, 5- methylhexyl, and l-methyl-4-isopropylhexyl;
  • substituted or unsubstituted C2-10alkenyl is selected from: phenylmethylene, chlorophenylmethylene.
  • ethoxycarbonylphenylmethylene carboxyphenylmethylene, (((1 ,1 -dimethylethyl) amino) carbonyOphenylmethylene, trimethoxyphenyl methylene, methoxyphenylmethylene, methylsulfonylphenylmethylene, biphenylmethylene, nitrophenylmethylene, aminophenylmethylene, acetylaminophenylmethylene, pivaloylaminophenylmethylene, phenoxyphenylmethylene, 2-imidazolyl methylene. 2-thiazolylmethylene.
  • aryl substituted Cl - 10 alkyl is selected from omega- phenylpropyl and l -(chlorophenoxy)ethyl;
  • aryl is selected from phenyl, and naphthyl
  • substituted aryl or heteroaryl is selected from phenyl, pyridyl and pyrimidinyl substituted with one to three substituents independently selected from:
  • aryl or heteroaryl carbamoyl substituted C l _ 10 alkyl is selected from 2-(4-pyridyl-carbamoyl)ethyl and 2-phenyl- ethyl;
  • Cl - l ⁇ alkylcarbonyl is selected from isobutylcarbonvl and isopropylcarbonyl;
  • aryl or heteroaryl carbonyl is selected from phenylcarbonyl and pyridyl carbonyl;
  • ether-substituted Cl - l ⁇ alkyl is selected from 1 -methoxy ⁇ ethyl and 1 -ethoxy-ethyl;
  • thioether-substituted C i - l ⁇ alkyl is selected from I - methylthio-ethyl, and 1 -ethylthio-ethyl;
  • keto-substituted Cl - l ⁇ alkyl is 1 -keto-ethyl, ketomethyl, 1 - ketopropyl, and ketobutyl;
  • heteroaryl-substituted Cl - 10 alkyl is omega-(4-pyridyl)- butyl;
  • carboxylic esters are Cl - 10 alkylcarboxylic esters selected from carbomethoxy and carboethoxy;
  • (p) carboxamides are selected from N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide.
  • N-isobutyramidophenyl carboxamide N- (methyl),N-(diphenylmethyl) carboxamide, N- (diphenylmethyl)-carboxamide, N-t-butyl carboxamide.
  • Ci -i ⁇ alkanoyloxyCl -2alkyl is selected from acetyloxymethyl, trimethylacetyioxymethyl, and (2- ethy Ihexanoy loxy )methy 1 ;
  • urea is t-butylcarbonylamino urea;
  • C l - i o alkylureido C ⁇ -5 alkyl is selected from: N-t- butylureidomethyl, N-n-propylureidomethyl, N-n- octylureidomethyl, N-isopropylureido, allylureido,
  • substituted or unsubstituted arylureidoC ⁇ -5 alkyl is selected from: N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl, N-phenylureidomethyl
  • alkanoylamidoalkyl is selected from: trimethylacetamidomethyl, carbomethoxyoctanoylamidomethyl,
  • ether is selected from ethylene ketal, and
  • (x) thioether is selected from: C i -8alkylthio. phenylthio.
  • X is oxygen.
  • N-phenylcarboxamide N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N- (methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl- carboxamide.
  • R l is hydrogen.
  • R 2 is selected from H and CH3, the C5-C6 bond designated with a dotted line is a single bond.
  • Ha is present and represents hydrogen, and
  • a l is selected from: carboxamide. including substituted and unsubstituted anilide derivatives.
  • carboxamide is selected from: N.N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N- (hydroxyphenyl) carboxamide.
  • R 1 is hydrogen
  • R 2 is selected from H and CH3
  • the C5-C6 bond designated with a dotted line is a double bond
  • Ha is absent
  • Al is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
  • carboxamide is selected from: N.N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N- (hydroxyphenyl) carboxamide.
  • (methoxycarboxy) phenyl carboxamide N-acetamidophenyl-N-acetyl- carboxamide, N-acetamidophenyl-carboxamide, N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide, N-(methyl),N- (diphenylmethyl) carboxamide, N-(diphenylmethyI)-carboxamide, N-t- butyl carboxamide, N-isopropyl carboxamide, 1 -adamantyl carboxamide, 2-adamantyl carboxamide and N-(substituted phenyl) carboxamides, wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
  • R 1 is CH3, R 2 is selected from H and CH3, and A l is a selected from: carboxamide, including substituted and unsubstituted anilide derivatives, and Cl -i o alkyl.
  • Rl is H or CH3
  • R 2 is selected from H and CH3
  • a 2 is selected from: substituted and unsubstituted aryl or heteroaryl ether.
  • substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3- pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.
  • carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N- (hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N- (methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl- carboxamide, N-acetamidophenyl-carboxamide, N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide, N-(methyl),N- (diphenylmethyl) carboxamide, N-(diphenylmethyl)-carboxamide, N-t- butyl carboxamide, N-isopropyl carboxamide, N-(
  • R l is CH3, R 2 is selected from H and CH3, and A l is a selected from: carboxamide, including substituted and unsubstituted anilide derivatives, and C l -10 alkyl.
  • Z is
  • Rl is H or CH3
  • R 2 is selected from H and CH3
  • a 2 is selected from: substituted and unsubstituted aryl or heteroaryl ether.
  • substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3- pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.
  • substituted or unsubstituted aryl or heteroaryl ether is selected from 4-methyl-phenoxy, 4-chlorophenoxy, and 2- pyrimidinyloxy.
  • variable e.g., aryl, heterocyde, R l , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentane, isohexane, etc.
  • Alkyloxy (or “alkoxy”) represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propyloxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and the like.
  • aryl includes phenyl and naphthyl.
  • aryl is phenyl.
  • Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
  • Heterocyclic rings may be attached to structural formula I at any heteroatom (N, O or S) or carbon atom in the ring which results in the creation of a stable, uncharged structure.
  • Hydroxy and amino protecting groups are known to those of ordinary skill in the art, and any such groups may be used.
  • acetate, benzoate, ether and silyl protecting groups are suitable hydroxy protecting groups.
  • Standard silyl protecting groups have the general formula -Si(Xa)3, wherein each Xa group is independently an alkyl or aryl group, and include, e.g. trimethylsilyl, tri-ethylsilyl, tri-i- propylsilyl, triphenylsilyl as well as t-butyl-di-(Xb)-silyl where Xb is methyl, ethyl, i-propyl or phenyl (Ph).
  • Standard amino protecting groups have the general formula -C(0)-Xc, wherein Xc is alkyl, aryl, O-alkyl or O-aryl, and include, e.g. N-t-butoxycarbonyl. See also Protective Groups in Organic Synthesis, T. W. Green et ai- (John Wiley and Sons, 1991 ) for descriptions of protecting groups.
  • Scheme 2 outlines the synthesis of the novel oxasteroids of the present invention.
  • the appropriately substituted seco-acid may be prepared by methods known in the art.
  • PCT publication WO 95/1 1254 describes procedures for the synthesis of compounds having various substituents at the 16-position of the azasteroid. Starting with a 3-keto- delta4- 17-one precursor and following the procedures of WO 95/1 1254, the appropriate A 2 substitution may be obtained. To obtain the appropriate Al substitution, the procedures of the following publications are followed starting with a 3-keto-delta4-17-one precursor: for ether or thioether WO 93/23040; for anilide WO 94/07861 , EP 0 663 924; for unsubstituted.
  • R 2 is H or CH2 ⁇ R ⁇
  • Scheme 2 the seco-acid (1 ) is treated with a dehydrating agent such as acetic anhydride, methyl ortho-formate, ethyl ortho-formate, in a nonpolar aprotic solvent such as toluene, xylene, dichloroethane, chlorobenzene and the like optionally in the presence of an acidic catalyst, such as PTSA (paratoluenesulfonic acid), or sodium acetate to form the ⁇ -oxasteroid (2).
  • a dehydrating agent such as acetic anhydride, methyl ortho-formate, ethyl ortho-formate
  • a nonpolar aprotic solvent such as toluene, xylene, dichloroethane, chlorobenzene and the like
  • an acidic catalyst such as PTSA (paratoluenesulfonic acid), or sodium acetate
  • the seco-acid (1 ) is treated with acetic anhydride in acetic anhydride in the presence of sodium acetate at an elevated temperature, preferably at about 140°C.
  • Hydrogenation of the double bond to form the oxasteroid (3) may be carried out in the presence of an appropriate catalyst such as Rh/C, Pd/C, etc., preferably Rh/C in a solvent such as tetrahydrofuran (THF) or ethyl acetate.
  • an appropriate catalyst such as Rh/C, Pd/C, etc., preferably Rh/C in a solvent such as tetrahydrofuran (THF) or ethyl acetate.
  • THF tetrahydrofuran
  • ethyl acetate ethyl acetate
  • the lactone is opened to form the hydroxamide (5).
  • the lactone may be opened by various means such as treatment with dimethylalumino-3-aminopyridine (which may be prepared in situ by treating trimethyl aluminum with 3-amino pyridine), chlorobenzene or dichloroethane in a nonpolar, aprotic solvent such as toluene.
  • the hydroxamide (5) is treated with alkyl- or aryl sulfonyl chloride in a solvent such as methylene chloride, toluene or dichloroethane in the presence of a base such as pyridine, dimethylaminopyridine (DMAP), or N-methylpyrolidine (NMP), to give the corresponding alkyl- or aryl sulfonate (6).
  • a base such as pyridine, dimethylaminopyridine (DMAP), or N-methylpyrolidine (NMP)
  • the iodide is treated with thioacetic acid in a nonpolar solvent such as toluene or dichloroethane in the presence of cesium carbonate or other base such as potassium carbonate or sodium carbonate to give the thioacetate (8).
  • the thioacetate (8) is hydrolyzed to form the thialactone (9), preferably by treatment with acid in a polar solvent such as methanol or ethanol, preferably by treatment with hydrochloric acid in methanol.
  • the thialactone (9) may be dehydrogenated to form the ⁇ l - thiasteroid (10) as described above, preferably by treatment with benzeneselenic anhydride in chlorobenzene at reflux.
  • the 4-oxa and 4-thia steroids of the structural formula (III) include the 1 ,2-5,6 diene which may be prepared by treating the compound of structural formula (2) with benzeneselenic anhydride in chlorobenzene with refluxing to obtain the ⁇ l , ⁇ 5-oxasteroid derivative.
  • the corresponding thiasteroid derivative may be obtained by following the procedures of Scheme 2, starting with (2), the ⁇ -oxasteroid.
  • the present invention relates to a method for treating hyperandrogenic conditions in a human being in need of such treatment by irreversibly inhibiting the human 5oc-reductase enzyme without covalently modifying the 5oc-reductase enzyme.
  • This method comprises the administration to the human in need of such treatment of a 3-oxo-4-oxa and 4-thiasteroid having a 1 ,2-double bond.
  • the 3-oxo-4-oxa and 4-thiasteroid having a 1 ,2-double bond is selectively activated by 5 ⁇ -reductase to produce the covalent adduct with the cofactor NADPH of structural formula (I).
  • X is selected from oxygen and sulfur.
  • This covalent adduct is released so slowly from the 5 ⁇ -reductase enzyme that the inhibition of the enzyme is effectively irreversible.
  • the method of the present invention provides for an inhibitor which displays the characteristics of a suicide inhibitor without covalently modifying the enzyme.
  • suicide inhibitors are inhibitors that deactivate the enzyme by covalent modification of the enzyme protein.
  • Such "suicide inhibitors” are not favored as pharmaceutical agents because the covalently-modified enzyme may be recognized by the immune system of the treated organism as foreign matter and trigger an undesirable immunological response.
  • the non- protein bound adduct of the present invention eliminates the possibility of such an undesirable immunological response.
  • the long-lived enzyme-bound 3-oxo-4-oxasteroid-NADP adduct and 3-oxo-4-thiasteroid NADP adduct of the present invention provides further advantages in clinical settings.
  • the method of the present invention provides for sustained inhibition of 5cx-reductase even when the dose regimen is interrupted and the levels of the 3-oxo-4- oxasteroid or 3-oxo-4-thiasteroid drug having a 1 ,2-double bond drop, as when the patient misses a dose. In this situation of interrupted dosing, 5 ⁇ -reductase that had been inhibited cannot recover from the inhibition and additional drug is required to inhibit only the 5 ⁇ - reductase that has been newly synthesized by the patient.
  • Hyperandrogenic conditions treatable by the method of the present invention include benign prostatic hype ⁇ lasia, androgenic alopecia, acne vulgaris, seborrhea, female hirsutism, prostatitis and prostatic carcinoma.
  • the 3-oxo-4-oxa and 4-thiasteroids having a 1 ,2-double bond useful in the present invention are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices may be administered systemically, by oral administration or by intravenous or intramuscular injection or topically.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Capsules containing the product of this invention can be prepared by mixing an active compound of the present invention with lactose and magnesium stearate, calcium stearate, starch, talc, or other carriers, and placing the mixture in gelatin capsules.
  • Tablets may be prepared by mixing the active ingredient with conventional tableting ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents which may be employed include glycerin and the like.
  • glycerin for parenteral administration, sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • Topical pharmaceutical compositions may be, e.g., in the form of a solution, cream, ointment, gel, lotion, shampoo or aerosol formulation adapted for application to the skin.
  • Topical pharmaceutical compositions useful in the method of treatment of the present invention may include about 0.001 % to 0.1 % of the active compound in admixture with a pharmaceutically acceptable carrier.
  • Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. See, e.g., EP 0 285 382.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol. or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacryla.es and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacryla.es and cross-linked or amphipathic block copolymers of hydrogels.
  • the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
  • doses of the 3-oxo-4-oxa and 4-thiasteroid having a 1 ,2- double bond useful in the method of the present invention range from 0.001 to 100 mg per day, preferably 0.05 to 50 mg per day and as provided by the advantage of the present invention, doses inadvertently missed will not compromise the therapeutic efficacy. Most preferably, dosages range from 0.01 to 10 mg/day.
  • the ⁇ l -3-oxo-4-oxa and 4-thiasteroids of the present invention may be administered on a cyclical regimen.
  • the details of the effective regimen depend on the particular ⁇ l -3-oxo-4-oxa and 4- thiasteroid administered.
  • These cyclical regimens provide an advantage over classical drugs, i.e., pharmaceutically active agents that do not function as an irreversible inhibitor.
  • the ⁇ l -3-oxo-4-oxa and 4-thiasteroids of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as hydrochloride, hydrobromide.
  • acetate, panoate and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate. laurate. benzoate. malate. bicarbonate, maleate. bisulfate. mandelate, bitartrate. mesvlate. borate. methylbromide, bromide, methylnitrate. calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate. chloride, nitrate, clavulanate.
  • sulfate hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate. isothionate. triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro ⁇ drug formulations.
  • salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine. arginine. ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine.
  • bases such as ammonia, ethylenediamine, N-methyl-glu
  • esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formulae I. II and III, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as mixtures thereof.
  • some of the crystalline forms for compounds of the present invention may exist as polymo ⁇ hs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • the compounds of the instant invention can be combined with a therapeutically effective amount of another 5 ⁇ - reductase inhibitor, such as finasteride or ep ⁇ steride, or other 5 - reductase inhibitor compounds having type 2 activity, type 1 activity or dual activity for both isozymes, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
  • another 5 ⁇ - reductase inhibitor such as finasteride or ep ⁇ steride, or other 5 - reductase inhibitor compounds having type 2 activity, type 1 activity or dual activity for both isozymes
  • a combined therapy can be employed wherein the compound of formula I and the other 5 ⁇ -reductase inhibitor are administered in separate oral, systemic, or parenteral dosage formulations.
  • the compounds of the instant invention and another 5 ⁇ -reductase inhibitor such as finasteride or epristeride can be formulated for topical administration.
  • a compound of formula I and finasteride can be administered in a single oral or topical dosage formulation, or each active agent can be administered in a separate dosage formulation, e.g., in separate oral dosage formulations, or an oral dosage formulation of finasteride in combination with a topical dosage formulation of a compound of formula I.
  • a compound of the present invention in combination with a therapeutically effective amount of a potassium channel opener, such as minoxidil. cromakahn, pinacidil, a compound selected from the classes of S- t ⁇ azine.
  • th ⁇ ane- 1 -oxide th ⁇ ane- 1 -oxide
  • benzopyran. and pyridinopyran derivatives or a pharmaceutically acceptable salt thereof may be used for the treatment of androgenic alopecia including male pattern baldness.
  • Therapy may further comprise the administration of a 5 ⁇ -reductase type 2 inhibitor such as finasteride or epristeride, or a 5 ⁇ -reductase type 1 inhibitor, or a type 1 and type 2 dual inhibitor, in combination with a compound of the present invention and a potassium channel opener such as minoxidil.
  • the active agents can be administered in a single topical dosage formulation, or each active agent can be administered in a separate dosage formulation, e.g., in separate topical dosage formulations, or an oral dosage formulation of a compound of formula I in combination with a topical dosage formulation of, e.g., minoxidil, or a single oral dosage formulation of a compound of formula I and another 5 ⁇ -reductase inhibitor, in combination with a topical dosage formulation of, e.g., minoxidil. See, e.g., U.S. Patent No.'s 4,596,812, 4,139,619 and WO 92/02225, published 20 February 1992, for dosages and formulations of calcium channel openers.
  • a combined therapy can be used by administering a therapeutically effective amount of a compound of formula I in combination with a therapeutically effective amount of retinoic acid or a derivative thereof, e.g. an ester or amide derivative thereof, such as e.g., tretinoin or isotretinoin.
  • this combined therapy for acne vulgaris may further include a 5 ⁇ -reductase type 2 inhibitor such as finasteride or epristeride, or a 5cx-reductase type 1 inhibitor, or a dual type 1 and type 2 inhibitory compound.
  • a combined therapy comprising a administration of a compound of formula I with a 5 -reductase type 2 inhibitor, such as e.g., finasteride, and an alpha- 1 adrenergic receptor antagonist, such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin, may be employed.
  • a 5 -reductase type 2 inhibitor such as e.g., finasteride
  • an alpha- 1 adrenergic receptor antagonist such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin
  • the combined therapy can comprise administering a compound of formula I with a 5 ⁇ -reductase type 2 inhibitor, such as e.g., finasteride, and an alpha- l a adrenergic receptor antagonist (formerly called an alpha- l c adrenergic receptor antagonist).
  • a 5 ⁇ -reductase type 2 inhibitor such as e.g., finasteride
  • an alpha- l a adrenergic receptor antagonist previously called an alpha- l c adrenergic receptor antagonist
  • a combined therapy can be used by administering a therapeutically effective amount of a compound of formula I with a therapeutically effective amount of an anti-androgen, such as, e.g., flutamide. spironolactone or casodex.
  • an anti-androgen such as, e.g., flutamide. spironolactone or casodex.
  • the active agents can be administered concomitantly, or they each can be administered at separately staggered times.
  • the standard assay contains 100 pM membrane-bound enzyme suspended in a solution of 25 nM [ ⁇ Hltestosterone ( 139,000 dpm, carrier free) and 500 ⁇ M NADPH in a buffer consisting of 0.1 M MOPS. ImM EDTA, and 0.1 % BSA, at pH 7.20 and 37°C, in a total volume of 100 ⁇ L. Ethanol is included at 1 % final concentration as the vehicle for introduction of inhibitors. The rate of production of Hjdihydrotestosterone is approximately constant for up to 2 hours or 10% consumption of substrate. A unit of enzyme activity was defined as 1 pmol product/min, and is equal to 444 fmol enzyme under these conditions.
  • measurements may be conducted under conditions that have more traditionally been employed for this enzyme at pH 5.50 and 37°C.
  • the PH]dihydrotestosterone is isolated by direct injection onto a reverse phase C-18 column (Vydac. 4.6 x 250 mm, 300 A, 5 micron), which is run in an isocratic system of 40% water (containing 0.1 % trifluoroacetic acid) and 60% methanol at 1 mL/min.
  • tissue extracts are the source of enzyme, the quenched reactions are clarified by centrifugation at 10,000 x g before analysis.
  • Retention times are - 13 min for testosterone and -20 min for dihydrotestosterone.
  • the effluent containing the [ ⁇ Hldihydrotestosterone peak (6 mL) is collected in a liquid scintillation vial and counted with AQL ⁇ SOL 2 ( 14 mL, New England Nuclear) with an efficiency of 0.309.
  • the assay is completely automated using a SUN SPARKSTATION 2 computer interfaced to a ZYMARK robot and ancillary equipment.
  • the native human enzyme was from prostate (type 2) or scalp (type 1 ) tissue, and the recombinant human enzymes were produced by the baculovirus expression system of Andersson, et al. (Chan, HK. Geissler, WM, Andersson, S, Sex Hormones and
  • the Km for NADPH was found to be - 1 ⁇ M under the assay conditions and 10 x K m testosterone.
  • k C at/K m 2.99 + 0.32 x 106 M- l s- l .
  • the K m for the type 1 5 ⁇ -reductase was 7 ⁇ M. and the kcat for the type 1 enzyme was 1.4 sec- ' .
  • the molecular weight was taken to be about 30,000 in estimating enzyme purity.
  • IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM. Representative compounds of this invention were tested in the above described assay for 5o - reductase type 1 and type 2 inhibition.
  • a compound referred to herein as a 5 -reductase 1 inhibitor is a compound that shows inhibition of the 5 ⁇ -reductase 1 isozyme in the above-described assay, having an IC50 value of about or under 100 nM.
  • a compound referred to herein as a 5 -reductase 2 inhibitor is a compound that shows inhibition of the 5 ⁇ -reductase 2 isozyme in the above-described assay, having an IC50 value of about or under 100 nM.
  • the loss of the ⁇ H from the enzyme could be used to determine the rate of release of the inhibitor from the type 1 or 2 5 ⁇ -reductase.
  • Either native or recombinantly-expressed 5 - reductase may be incubated with the [ 1 ,2- ⁇ Hl-inhibitor and NADPH. If necessary, excess ⁇ H-inhibitor not bound to the enzyme may be removed by dialysis prior to determination of the radioactivity bound to the enzyme.
  • the concentrations of bound and free radioactivity could be determined by ultrafiltration on 10,000 Da cutoff membranes (AMICON, Centricon- 10), which would be centrifuged for several hours at 4°C. Typically, 100 ⁇ L samples would be diluted to 1 mL with water before ultrafiltration, and the 3H in the total solution and the filtrate determined by scintillation counting.
  • Type 1 or 2 5 ⁇ -reductase (native or recombinantly produced) could be incubated with radiolabeled inhibitor and NADPH to produce the enzyme ⁇ nhibitor complex. Excess inhibitor could be removed by dialysis of the enzyme solution. Release of the reduced inhibitor from the enzyme:inhibitor complex can be accomplished by heat denaturation in a boiling water bath for 90 min. The denatured protein can be removed by centrifugation or ultrafiltration through a 10,000 Da cutoff membrane (AMICON, YM-10). The identity of the radioactive species could be determined by reverse phase high pressure liquid chromatography, for example a C column with a linear gradient of 1 mL/minute of water to 100% methanol over 30 minutes.
  • the material released from the enzyme will no longer comigrate with the parent ⁇ l - 4-oxa or 4-thia inhibitor. This process could be scaled up to produce sufficient material for structure identification by mass spectrometry.
  • enzyme inhibitor complex could be prepared by incubation of the labeled inhibitor, NADPH and recombinantly produced or native type 1 or 2 5 ⁇ -reductase. Denaturation of the enzyme-inhibitor complex with an equal volume of 95% ethanol containing 20 mM ammonium bicarbonate, pH 9.0 would liberate the NADP-inhibitor covalent adduct (structure 1 ). The suspension should be stirred for 30 min at room temperature, then centrifuged at 10,000 x g for 45 min to remove the insoluble matter. Alternatively, 6M guanidine:HCl or other organic solvents could be used to liberate the adduct.
  • radiolabeled adduct After release of the adduct from the enzyme, all solutions should contain ammonium bicarbonate adjusted to pH 9 with ammonium hydroxide to buffer the free adduct.
  • the radiolabeled adduct could be purified by using anion exchange chromatography such as a Pharmacia Mono 0 anion exchange column HCO'3 form equilibrated to 0.01 M ammonium bicarbonate, pH 9, and 50% methanol.
  • Step 1 Benzotriazol- 1 '-yl-3-oxo-androst-4-ene- 17 ⁇ -carboxamide.
  • Step 2 N-t-Butyl-3-oxo-androst-4-ene- 17 ⁇ -carboxamide.
  • Step 3 N-t-Butyl-5-oxo-3,5-secoandrostan-3-oic-17 ⁇ - carboxamide.
  • Step 4 N-t-Butyl-4-oxa-androst-5-en-3-one- 17 ⁇ -carhoxamide.
  • Step 5 N-t-Butyl-4-oxa-5 ⁇ -androstan-3-one- 17 ⁇ -carboxamide.
  • Step 6 N-t-Butyl-4-oxa-5oc-androst- 1 -en-3-one- 17 ⁇ -carboxamide
  • Step 3 7 ⁇ -Methyl-4-oxa-5 -Cholest- 1 -en-3-one
  • Step 2 N-(2',5'-Bistrifluoromethy Ipheny l)-3-oxo-androst-4-ene- 17 ⁇ -carboxamide
  • Step 4 N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-5-en-3- one- 17 ⁇ -carboxamide
  • Step 6 N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst- 1 -en-3- one- 17 ⁇ -carboxamide
  • Step 2 (N-Pyrid-3-yl)-5-p-toluenesulfonyloxy-3,5-secoandrostan-
  • step 1 3-carboxamide- 17 ⁇ -(N-t-butyl)carboxamide.
  • pyridine solution 50 mL
  • 1.2 equivalents of p-toluenesulfonyl chloride is added.
  • the reaction is warmed to ambient temperature, partitioned between water and dichloromethane and washed with dilute bicarbonate solution to remove residual sulfonyl chloride.
  • the organic layer is dried and evaporated to a residue, which is immediately taken on to the iodide displacement.
  • Step 3 (N-Pyrid-3-yl)-5-(epi)iodo-3,5-secoandrostan-3- carboxamide- 17 ⁇ -(N-t-butyl)carboxamide.
  • the tosyl derivative of step 2 is stirred at ambient temperature with 3 equivalents of dry tetrabutylammonium iodide in toluene for 30 min. and then heated at reflux for another 2 hrs.
  • the reaction mixture is cooled, partitioned with dichloromethane and water, and washed to remove ammonium salts. After drying and solvent removal under reduced pressure, the residual amo ⁇ hous material is chromatographed to provide the pure iodo compound.
  • Step 4 (N-Pyrid-3-yl)-5-acetylthio-3,5-secoandrostan-3- carboxamide- 17 ⁇ -(N-t-butyPcarboxamide.
  • step 3 The iodo compound of step 3 is stirred at ambient temperature with 10 equivalents of thioacetic acid in toluene for 30 min. and then heated at reflux for another 2 hrs. The reaction mixture is cooled, solvents and volatile reactants evaporated under reduced pressure, and the residual amo ⁇ hous material chromatographed.
  • Step 5 N-t-Butyl-4-thia-5 -androstan-3-one- 17 ⁇ -carboxamide.
  • step 4 The thioacetyl derivative of step 4 is treated at ambient temperature with methanolic HCl (3%) until the starting material is gone by thin-layer chromatography or hplc. Product is isolated by chromatography and recrystallized.
  • Step 6 N-t-Butyl-4-thia-5 -androst- 1 -en-3-one- 17 ⁇ -carboxamide.
  • an oral composition of a compound of this invention 5 mg of a compound of stmctural formula
  • I of the present invention is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.

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Abstract

Cette invention concerne le traitement des pathologies hyperandrogéniques chez l'homme au moyen de la formation d'un inhibiteur irréversible fondé sur un nouveau mécanisme des enzymes 5α-réductase humaines à partir de stéroïdes 3-oxo et 4-thia comprenant une liaison doube 1,2 et le cofacteur pyridine-nucléotide de l'enzyme 5α-réductase, NADPH. Cette invention concerne également le complexe isolé inhibiteur-cofacteur.
PCT/US1996/016871 1995-10-26 1996-10-22 Traitement des pathologies hyperandrogeniques WO1997015305A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/051,948 US5932559A (en) 1995-10-27 1996-10-22 Treatment of hyperandrogenic conditions
AU74637/96A AU7463796A (en) 1995-10-26 1996-10-22 Treatment of hyperandrogenic conditions

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US586995P 1995-10-26 1995-10-26
US60/005,869 1995-10-26
GBGB9602853.5A GB9602853D0 (en) 1996-02-13 1996-02-13 Treatment of hyperandrogenic conditions
GB9602853.5 1996-02-13

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760071A (en) * 1984-02-27 1988-07-26 Merck & Co., Inc. 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760071A (en) * 1984-02-27 1988-07-26 Merck & Co., Inc. 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors

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