EP0763053A1 - Derives steroidiens pour inhiber la 5-alpha-reductase - Google Patents

Derives steroidiens pour inhiber la 5-alpha-reductase

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Publication number
EP0763053A1
EP0763053A1 EP95922906A EP95922906A EP0763053A1 EP 0763053 A1 EP0763053 A1 EP 0763053A1 EP 95922906 A EP95922906 A EP 95922906A EP 95922906 A EP95922906 A EP 95922906A EP 0763053 A1 EP0763053 A1 EP 0763053A1
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EP
European Patent Office
Prior art keywords
groups
group
carbon atoms
methyl
substituted
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP95922906A
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German (de)
English (en)
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EP0763053A4 (fr
Inventor
Dennis Alan Holt
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0763053A1 publication Critical patent/EP0763053A1/fr
Publication of EP0763053A4 publication Critical patent/EP0763053A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Definitions

  • the present invention relates to certain novel 17 ⁇ and 17 ⁇ substituted aromatic A ring steroidal compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5- ⁇ -reductase.
  • the class of steroidal hormones known as androgens is responsible for the physical characteristics that differentiate males from females. Of the several organs that produce androgens, the testes produce these hormones in the greatest amounts. Centers in the brain exert primary control over the level of androgen production. Numerous physical manifestations and disease states result when ineffective control results in excessive androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, male pattern baldness and prostate diseases such as benign prostatic hypertropy are correlated with elevated androgen levels. Additionally, the reduction of androgen levels has been shown to have a therapeutic effect on prostate cancer.
  • Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5- ⁇ -reduced androgens are the active hormones in some tissues such as the prostate and sebaceous gland. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5- ⁇ -reduced analogue, in these tissues but not in others such as muscle and testes.
  • DHT dihydrotestosterone
  • Steroid 5- ⁇ -reductase is a nicotinamide adenine dinucleotide phosphate (NADPH) dependent enzyme that converts testosterone to DHT.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • Metcalf, et al. describes the effect of inhibitors of steroid 5 ⁇ -reductase in benign prostatic hyperplasia, male pattern baldness and acne;
  • This invention relates to a compound of Formula (I).
  • Rl represents: a hydrogen atom; an alkyl group having from 1 to 6 carbon atoms; or a substituted alkyl group having from 1 to 6 carbon atoms and having at least one substituent selected from aryl groups as defined below and aromatic heterocyclic groups as defined below;
  • R2 represents: a substituted alkyl group having from 1 to 6 carbon atoms and having at least one substituent selected from aryl groups as defined below and aromatic heterocyclic groups as defined below, and said alkyl group further optionally having a single hydroxy or carboxy substituent; adamantyl; or a ⁇ arylamino group in which the two aryl parts are the same or different and each is as defined below;
  • R3 represents a carboxy group or a group of formula - CONHS ⁇ 2 ⁇ wherein R ⁇ represents an alkyl group having from 1 to 6 carbon atoms; said aryl groups are carbocyclic aromatic groups having from 6 to 14 ring carbon atoms and which are unsubstituted or are substituted by at least one substituent selected from substituents A, defined below; said aromatic heterocyclic groups have 5 or 6 ring atoms of which from 1 to 3 are hetero-atoms selected from nitrogen, oxygen and sulphur hetero- atoms and the remainder are carbon atoms, said group being unsubstituted or being substituted by at least one substituent selected from substituents B, defined below; said substituents A are selected from: alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; alkoxycarbonyl groups having from 2 to 7 carbon atoms; hydroxy groups; halogen atoms; amino groups; alkylamino groups having from 1 to 6 carbon
  • the invention also is a method for inhibiting 5- ⁇ -reductase activity in mammals, including humans, that comprises administering to a subject an effective amount of a presently invented 5- ⁇ -reductase inhibiting compound.
  • a presently invented 5- ⁇ -reductase inhibiting compound included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention. Also included in the present invention are methods of co-administering the presently invented 5- ⁇ -reductase inhibiting compounds with further active ingredients.
  • Rl represents: a hydrogen atom; an alkyl group having from 1 to 6 carbon atoms; or a substituted alkyl group having from 1 to 6 carbon atoms and having at least on substituent selected from aryl groups as defined below and aromatic heterocyclic groups as defined below;
  • 2 represents: a substituted alkyl group having from 1 to 6 carbon atoms and having at least one substituent selected from aryl groups as defined below and aromatic heterocyclic groups as designed below, and said alkyl group further optionally having a single hydroxy or carboxy substituent; adamantyl; or a diarylamino group in which the two aryl parts are the same or different and each is as defined below;
  • R3 represents a carboxy group or a group of formula - CONHS02R wherein R ⁇ represents an alkyl group having from 1 to 6 carbon atoms; said aryl groups are carbocyclic aromatic groups having from 6 to 14 ring carbon atoms and which are unsubstituted or are substituted by at least one substituent selected from substituents A, defined below; said aromatic heterocyclic groups have 5 or 6 ring atoms of which from 1 to 3 are hetero-atoms selected from nitrogen, oxygen a nd sulphur hetero-atoms and the remainder are carbon atoms, said group being unsubstituted or being substituted by at least one substituent selected from substituents B, defined below; said substituents A are selected from: alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; alkoxycarbonyl groups having from 2 to 7 carbon atoms; hydroxy groups; halogen atoms; amino groups alkylamino groups having from 1 to 6 carbon atom
  • the invention also provides a pharmaceutical composition for the treatment of prophylaxis of disorders arising from high levels of 5- ⁇ - reductase, notably prostatic hypertrophy, which composition comprises an effective amount of an active compound in admixture with a pharmaceutically acceptable carrier or diluent; wherein said active compound is selected from compounds of formula (I), defined above, and pharmaceutically acceptable salts and esters thereof.
  • the invention still further provides the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt or ester thereof, as a pharmaceutical.
  • the invention also provides processes for the preparation of the compounds of the present invention, which processes are described in more detail hereafter.
  • R* represents an alkyl group having from 1 to 6 carbon atoms
  • this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms
  • examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1- methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups, especially the methyl, ethyl, propyl, iso
  • alkyl groups having from 1 to 4 carbon atoms more preferably from 1 to 3 carbon atoms
  • the methyl, ethyl isopropyl and isobutyl groups being more preferred
  • the methyl group being most preferred.
  • R* and R ⁇ represents a substituted alkyl group, this may be a straight or branched chain group as defined and exemplified above in relation to the unsubstituted alkyl groups which may be represented by Rl, such as the methyl, ethyl, propyl, isopropyl, t-butyl and 1- methylpentyl groups.
  • Particularly preferred alkyl groups which may be represented by R* and R2 include the alkyl groups having from 1 to 4 carbon atoms, more preferably alkyl groups having from 1 to 3 carbon atoms, and most preferably the methyl, ethyl and isopropyl groups.
  • substituents selected from aryl groups and aromatic heterocyclic groups, defined above and exemplified in more detail below.
  • R ⁇ there may optionally be a further substituent selected from hydroxy groups and carboxy groups.
  • substituents There is no particular limitation on the number of such substituents except such as may be imposed by the number of substitutable positions or by steric constraints. In general, however, from 1 to 3 such substituents are preferred, 1 or 2 being more preferred and 1 being most preferred. Where there are two or more substituents, these may be the same as each other or they may be different from each other.
  • substituent on the substituted alkyl groups represented by Rl and R ⁇ is an aryl group
  • this is a carboxcyclic aromatic group (i.e. an aromatic group containing one or more rings, in which all ring atoms are carbon atoms) having from 6 to 14 ring carbon atoms, preferably from 6 to 10 carbon atoms, and more preferably 6 to 10 carbon atoms.
  • Such groups include the phenyl, indeyl, 1-naphthyl, 2- naphthyl, biphenylenyl, acenaphthylenyl, fluoroenyl, phenanthryl and anthryl groups, of which the phenyl and naphthyl groups are preferred, the phenyl group being most preferred.
  • aryl groups may be unsubstituted or they may be substituted by one or more of substituents A, defined above and exemplified below. In the case of the substituted groups, there is no particular limitation on the number of such substituents A except such as may be imposed by the number of substitutable positions or possibly by steric constraints.
  • substituents A include: alkyl groups having from 1 to 6 carbon atoms, such as those exemplified above in relation to the unsubstituted groups which may be represented by R 1 ; alkoxy groups having from 1 to 6 carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopehtyloxy, neopentyloxy, 2-methoxypentyloxy, 3,3- dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2- dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy,
  • substituents C examples are the same as the corresponding groups and atoms included in substituents A and given above.
  • substituents A we prefer alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups having 2 or 3 carbon atoms, hydroxy groups, halogen atoms, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups in which each alkyl part has from 1 to 4 carbon atoms, and aUphatic acylamino groups having from 1 to 3 carbon atoms, more preferably the methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, hydroxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, formylamino and acetylamino
  • substituent on the substituted alkyl groups represented by Rl or R2 is an aromatic heterocycUc group
  • this is a heterocycUc group having 5 or 6 ring atoms in an aromatic ring.
  • the group also has from 1 to 3 hetero-atoms selected from nitrogen atoms, oxygen atoms and sulphur atoms, the remaining ring atoms being carbon atoms.
  • 1, 2 or 3, preferably 2 or 3, are nitrogen atoms and, correspondingly, 2, 1 or 0, preferably 1 or 0, are oxygen and/or sulphur atoms.
  • there are 1 or 2 hetero-atoms they may be freely selected from nitrogen, oxygen and sulphur atoms.
  • Such groups include the furyl, thienyl, pyridyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups.
  • furyl, thienyl and pyridyl groups more preferably the furyl and thienyl groups, and most preferably the thienyl group.
  • Such aromatic heterocycUc groups may be unsubstituted or they may be substituted by one or more substituents B, defined above.
  • substituents B there is no particular limitation on the umber of such substituents B except such as may be imposed by the number of substitutable positions or possibly by steric constraints. In general, however, from 1 to 3 such substituents are preferred, 1 or 2 being most preferred. Where there are two or more substituents, these may be the same as each other or they may be different from each other.
  • substituents B include the corresponding groups and atoms exemplified above in relation to substituents A and aryl groups having from 6 to 10 ring carbon atoms such as those exemplified above and included in the aryl groups which may be represented by R*.
  • preferred substituents include alkyl groups having from 1 to 6 carbon atoms (such as those exemplified above in relation to R*) and halogen atoms (such as the fluorine, chlorine, bromine and iodine atoms). More preferred substituents are alkyl groups having from 1 to 4 carbon atoms, fluorine atoms and chlorine atoms, still more preferably a methyl or ethyl group, and most preferably a methyl group.
  • substituents A, B or C may represent carboxy groups, and the group represented by R2 may include a carboxy group, and the compounds of the present invention may therefore form salts and esters as weU as other derivatives, which are well known in the art, such as amides.
  • salts, esters and other derivatives There is no restriction on the nature of such salts, esters and other derivatives, provided that, where they are to be used for therapeutic purposes, they are pharmaceutically acceptable, that is they are not less active (or unacceptably less active) pr more toxic (or unacceptably more toxic) than the parent compound.
  • the compounds are to be used for other purposes, for example as intermediates in the preparation of other compounds, even this restriction may not apply.
  • ester groups are those that can be converted to a carboxy group in vivo.
  • ester groups include: alkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms, such as those exemplified above in relation to R*; haloalkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms, such as the trifluoromethyl, 2,2,-trifluoroethyl, 2,2,2- trichloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-iodoethyl, 3-chloropropyl, 40fluorobutyl and 6-iodohyxyl groups, preferably the 2,2,2-trichloroethyl and 2-chloroethyl groups; hydroxyalkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms, such as the 2-hydroxyethyl, 2,3-dihydroxypropyl, 3- hydroxypropyl, 3,4-
  • alkoxycarbonyloxyalkyl groups in which the alkyl and alkoxy groups each have from 1 to 6, preferably from 1 to 4, carbon atoms, such as the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propocarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloycarbonyloxymethyl, 1- methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1- propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1- butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1- ethoxycarbonyloxypropyl, 1-propoxycarbon
  • alkyl groups having from 1 to 4 carbon atoms benzyl groups; substituted benzyl groups having from 1 to 3 substituents selected from methyl, ethyl, methoxy and ehtoxy groups and fluorine and chlorine atoms; the diphenylmethyl group; the naphthylmethyl groups; alkanoyloxylalkyl groups in which the alkanoyl part has from 1 to 5 carbon atoms and the alkyl part has from 1 to 4 carbon atoms; cycloalkanecarbonyloxyalkyl groups in which the cycloalkyl part has from 5 to 7 ring carbon atoms and the alkyl part has from 1 to 4 carbon atoms; alkoxycarbonyloxyalkyl groups in which the alkoxy and alkyl parts each have from 1 to 4 carbon atoms; cylcoalkyloxycarbonyloxyalkyl groups in which the cycloalkyl part has from 5 to 7
  • More preferred ester groups include: alkyl groups having from 1 to 4 carbon atoms; benzyl groups; alkanoyloxyalkyl groups in which the alkanoyl part has from 1 to 5 carbon atoms and the alkyl part has 1 or 2 carbon atoms; cycloalkanecarbonyloxyalkyl groupsi n which teh cydoalkyl part has from 5 to 7 ring carbon atoms and the alkyl part has 1 or 2 carbon atoms; alkoxycarbonyloxyalkyl groups in which the alkoxy part has from 1 to 4 carbon atoms and the alkyl part has 1 or 2 carbon atoms; cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl part has from 5 to 7 ring carbon atoms and the alkyl part has 1 or 2 carbon atoms; [5-phenyl-, 5-methyl- or 5-ehtyl-2-oxo-l,3-dioxolen
  • ester groups include methyl groups, ethyl groups, pivaloyloxymethyl groups, ethoxycarbonyloxymethyl groups, 1- (ethoxycarbonyloxy)ethyl groups, isopropoxycarbonyloxymethyl groups, l-(isopropoxycarbonyloxy)ethyl groups, (5-methyl-2-oxo- l,3-dioxolen-4- yl)methyl group and phthaUdyl groups.
  • ester groups include methyl groups, ethyl groups, pivaloyloxymethyl groups, ethoxycarbonyloxymethyl groups, 1- (ethoxycarbonyloxy)ethyl groups, isopropoxycarbonyloxymethyl groups, l-(isopropoxycarbonyloxy)ethyl groups, (5-methyl-2-oxo-l,3-dioxolen-4- yl)methyl group and phthaUdyl groups.
  • salts with an alkaU metal such as sodium, potassium or lithium
  • salts with an alkaline earth metal such as barium or calrium
  • salts with another metal such as magnesium or aluminium
  • ammonium salts organic base salts, such as a salt with triethylamine, diisopropylamine, cydohexylamine, dicydohexylamine and guanidine
  • salts with a basic amino add such as lysine or arginine.
  • the compound o the present invention contains a basic group, such as an amino group, in its molecule, it can form add addition salts.
  • add addition salts include: salts with mineral adds, espedally hydrohalic adds (such as hydrofluoric add, hydrobromic add, hydroiodic add or hydrochloric add), nitric add, carbonic add, sulphuric add or phosphoric add; salts with lower alkylsulphonic adds, such as methanesulphonic add triffuoromethanesulphonic add or ethanesulphonic add; salts with arylsulphonic adds, such as benzenesulphonic add or p- toluenesulphonic add; salts with organic carboxylic adds, such as acetic add, fumaric add, tartaric add,oxalic add, maleic add, malic add, sucdnic add, benzoic add, mandelic add, ascorbic add, lactic add,
  • alkyl groups which may be represented by R ⁇ indude the alkyl groups exemplified above in relation to R , espedally the methyl and ethyl groups.
  • R1 represents a hydrogen atom and R ⁇ is as defined above.
  • Preferred groups of formula -NR ⁇ R ⁇ include: the benzylamino, (2-, 3- or 4-methylbenzyl)amino, (2-, 3- or 4-methoxybenzyl)amino, (2-, 3- or 4-fluorobenzyl)amino, (2, 3- or 4-chlorobenzyl)amino, phenethylamino, (2-, 3- or 4-methylphenethyl)amino, (2-, 3- or 4- methoxyphenethyDamino, (2-, 3- or 4-fluorophenethyl)amino, (2-, 3- or 4- chlorophenethyl)-unino, (3-phenylpropyl)amino, (1-methyl-l- phenylethyDamino, [l-methyl-l-(2-, 3- or 4- methylphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4-methoxyphenyl)ethyl]amino
  • More preferred groups of formula -NR1R2 include: the (1-methyl- l-phenylethyl)amino, [l-methyl-l-(2-, 3- or 4-methylphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4-methoxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4-fluorophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- chlorophenyl)ethyl]amino, [-methyl-l-(2-, 3- or 4- hydroxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- aminophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- dimethylaminophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or -4- acetamidophenyl
  • Still more preferred groups of formula -NR1R2 include: the (1- methyl-l-phenylethyl)amino, [l-methyl-l-(2-, 3- or 4- methylphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- methoxyphenyl)ethyl]amino, [l-methyl-l-(3,4- or 3,5- dimethoxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- fluorophenyl)ethyl]amino, [l-methyl-l(2-, 3- or 4- chlorophenyl)ethyl]amino,[l-methyl-l(2-, 3- or 4- hydroxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- cnmethylammophenyl)ethyl]amino, (l,l-dimethyl-2-phenylethyl)
  • the most preferred groups of formula -NR1R2 include: the (1- methyl-l-phenylethyl)amino, [l-methyl-l-(2-, 3- or 4- methylphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- methoxyphenyl)ethyl]amino, [l-methyl-l-(3,4-or 3,5- dimethoxyphenyl)eti ⁇ yl]amino, [l-mehyl-l-(2-, 3- or 4- fluorophenyl)ethyl]amino, [l-methyl-l-(2-,3- or 4- chlorophenyl)ethyl]a ⁇ nino, [l-methyl-l-(2-, 3- or 4- hydroxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- cUmethylaminophenyl)ethyl]amino, (l,l-di
  • the compounds of the present invention may, depending upon the nature of the substituent groups, contain one or more asymmetric carbon atoms in their molecules, and in this case can form optical isomers. Although these are all represented herein by a single molecular formula, the present invention includes both the individual, isolated isomers and mixtures, including racemates thereof. Where stero spedfic synthesis techniques are employed or optically active compounds are employed as starting materials, individual isomers may be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques. Also induded within the scope of this invention are compounds in which the 17 position substituent is in the ⁇ position.
  • Preferred classes of compounds of the present invention are those compounds of formula (I) and salts, esters and other functional derivatives thereof, in which:
  • Rl represents: a hydrogen atom; an alkyl group having 3 carbon atoms; a benzyl group; a substituted benzyl group having at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups in which each alkyl part has from 1 to 4 carbon atoms, hydroxy groups, alkoxy carbonyl groups having from 2 to 5 carbon atoms and aliphatic acylamino groups having from 1 to 5 carbon atoms; a furylmethyl group; or a thienylmethyl group;
  • R2 represents; a substituted alkyl group having from 1 to 4 carbon atoms and substituted by 1 or 2 substituents selected from phenyl groups, substituted phenyl groups, thienyl groups, furyl groups, substituted thienyl groups and substituted furyl groups, wherein the substituent or substituents on the phenyl group are selected from: alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, hydroxy groups, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups in which each alkyl part has from 1 to 4 carbon atoms, alkoxycarbonyl groups having from 2 to 5 carbon atoms and aliphatic acylamino groups having from 1 to 5 carbon atoms; and the substituent or substituents on the thienyl and furyl groups are selected from alkyl groups having from 1 to 4 carbon atoms; or a diaryla
  • More preferred compounds of the present invention are those compounds of formula (I) and salts, esters and other functional derivatives thereof, in which:
  • (D) R! represents: a hydrogen atom; an isopropyl group; a benzyl group; a substituted benzyl group having at least one sustituent selected from methyl, ethyl, methoxy, ethoxy, hydroxy, ethoxycarbonyl, methoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, /3
  • R represents: a substituted alkyl group having from 1 to 4 carbon atoms and having 1 or 2 substituents selected from: phenyl groups; substituted pehnyl groups having at least one substituent selected from methyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, cUmethylamino, diethylamino, formamido and acetamido groups and fluorine, chlorine and bromine atoms; furyl groups; methyl-substituted furyl groups thienyl groups; and a diphenylamino group; or a substituted diphenylamino group having at least one substituent selected from methyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethyla
  • R3 represents: a carboxy group; an alkoxycarbonyl group having from 2 to 5 carbon atoms; a benzyloxycarbonyl group; an alkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from
  • the alkoxy part has 1 or 2 carbon atoms; a methoxycarbonyl or ethoxycarbonyl group which is substituted by an alkoxycarbonloxy group having from 2 to 5 carbon atoms; a cycloalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloaklyl part has from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbon atoms; a (5-phenyl-, 5-methyl- or 5-ethyl-2-oxo-l,3-dioxolen-4- yDmethoxycarbonyl group; a phthaUdyloxycarbonyl group; or a group of formula -CONHS02R ⁇ , wherein R ⁇ represents a methyl group or an ethyl group.
  • StiU more preferred compounds of the present invention are those compounds of formuls (I) and salts, esters and other functional derivatives thereof, in which:
  • (G)Rl and 2 are independently selected from benzyl groups and substituted benzyl geroups having at least one substituent selected from methyl, methoxy, hydroxy and acetamido groups and fluorine and chlorine atoms; or
  • R! represents a hydrogen atom
  • R2 represents: a substituted alkyl group having from 1 to 4 carbon atoms and having 1 or 2 substituents selected from: phenyl groups; substituted phenyl groups having at least one substituent selected from methyl, methoxy, hydroxy, dimethylamino and acetamido groups and fluorine and chlorine atoms; furyl groups and thienyl groups; a diphenylamino group; or a substituted diphenylamino group having at least one substitutent selected from methyl, methyoxy, hydroxy, dimethylamino and acetamido anf fluorine and chlorine atoms.
  • R represent a carboxy group, a methoxycarbonyl group, an ethyxycarbonyl group, a pivaloyloxymethoxycarbonyl group, an ethyoxycarbonyl group, a l-(ethoxycarbonyloxy)ethoxycarbonyl group, an isopropoxycarbonyloxymethoxycarbonyl group, a 1- (isopropoxycarbonyloxy)ethoxycarbonyl group, a (5-methyl-2-oxo-l,3- dioxolen-4-yl)methoxycarbonyl group, a phthaUdyloxycarbonyl group or a group of formula -CONHS ⁇ 2R ⁇ , wherein R ⁇ represents a methyl group.
  • Rl represents a hydrogen atom
  • R2 represents adamantyl or an alkyl group having from 1 to 3 carbon atoms and substituted with 1 or 2 substituents selected from: phenyl, benzyl, substituted phenyl groups having at least one substituent selected from methyl, methoxy ad hydroxy groups and fluorine and chlorine atoms; furyl groups and thienyl groups;
  • R represents a carboxy group, a methoxycarbonyl group or an ethoxycarbonyl group
  • (L) R represents a 2-hydroxyisopropyl group or a 1-carboxyethyl group having at least one substituent selected from aryl groups as defined above and aromatic heterocyclic groups as defined above.
  • Specific examples of the compounds of the present invention include those of formula (I) in which Rl, and R3 are as shown in the foUowing Table 1. In the Table, the following abbreviations are used:
  • preferred compounds are Compounds No. 1, 2, 4, 5, 8, 9, 12, 14, 17, 19, 22, 27, 28, 29, 31, 33, 45, 48, 50, 64, 66, 67, 69, 73, 76, 78, 79, 82, 86, 88, 127, 130, 140, 142, 149, 152, 157, 159, 166, 168, 178, 180, 182, 190, 191, 192, 193, 194, 195, 196, 197, 200, 201, 202, 203, 204 and 205 and more preferred compounds are Compounds No.
  • ⁇ -receptor antagonist refers to a known ensemble of alpha-andrenergic receptor antagonist comounds, such as described in Lafferty, et al. U.S. Patent No.4,963,547, which are utilized in treating vascular disorders such as diabetes, cardiovascular disease, benign prostatic hypertrophy and ocular hypertension.
  • Preferred alpha-andrenergic receptor antagonists for use in the compositions and methods of the invention indude amsulosin, terazosin, doxazosin, alfuzosin, indoramin, prazosin, 7-chloro-2-ethyl-3,4,5,6- tetrahydro ⁇ -methylthieno[4,3,2-efJ[3]-benzazepine and 8- ⁇ 3-[4-(2- methoxyphenyl)-l-piperazinyl]-propylcarbamoyl ⁇ -3-methyl-4-oxo-2- phenyl-4H-l-benzopyran.
  • amsulosin as used herein is meant a compound of the structure
  • amsulosin is designated as (-)-(R)-5-[2-[[2-(0- ethoxyphenoxy)ethyl]am o]propyl]-2-methoxybenzenesuffonamide.
  • terazosin as used herein is meant a compound of the structure
  • terazosin is designated as l-(4-amino-6,7-dimethoxy- 2 qu-Lnazolinyl)-4-[(tetrahydro-2-furoyl)carbonyl]piperazine.
  • Terazosin is disdosed in U.S. Patent Number 4,251,532.
  • doxazosin as used herein is meant a compound of the structure
  • doxazosin is designated as l-(4-amino-6,7- dimethoxy-2-quinazolinyl)-4-[(2,3-cUhydro-l,4-benzo ⁇ ioxin-2- yl)carbonyl]-piperazine.
  • alfuzosin as used herein is meant a compound of the structure
  • ChemicaUy alfuzosin is designated as N-[3-[(4-amino-6,7- dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2- furancarboxamide.
  • prazosin as used herein is meant a compound of the structure
  • Chemically prazosin is designated as l-(4-amino-6,7-dimethoxy-2- qumazolinyl)-4-(2-furanylcarbonyl)piperazine.
  • Prazosin is disclosed in U.S. Patent Number 3,511,836.
  • alpha-adrenergic receptor antagonists are preferred alpha- adrenergic receptor antagonists as used herein.
  • minoxidir as used herein is meant the compound of the structure:
  • Minoxidil is the active ingredient in Rogaine® which is sold as topical solution for stimulating hair growth by the Upjohn Company, Kalamazoo, Michigan.
  • aromatase inhibitor refers to a known ensemble of compounds, steroidal and non-steroidal, which prevent the conversion of androgens to estrogens, such as described in Gormley et al. International Publication Number WO 92 18132.
  • Aromatase inhibitors are disdosed in Gormley et al. as having utility in treating benign prostatic hyperplasia when used in combination with a 5- ⁇ -reductase inhibitor.
  • a preferred aromatase inhibitor for use in the compositions and methods of the invention 4-(5,6,7,8-tetrahydroimidazo-[l,5- ⁇ ]pyridin-5- yDbenzonitrile (fadrazole).
  • Fadrazole is disclosed in U.S. Patent No. 4,728,645. Additionally, all compounds disclosed in Gormley, et al. International Publication No. WO 92/18132 as having aromatase inhibiting activity are preferred aromatase inhibitors as used herein. As used herein, when a 5- ⁇ -reductase inhibitor, as described herein and a further active ingredient or ingredients are utilized together, said 5- ⁇ -reductase inhibitor can be co-administered with said further active ingredient or ingredients.
  • co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a 5- ⁇ -reductase inhibiting compound, as described herein, and a further active ingredient or ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocardnoma or compounds known to have utiUty when used in combination with 5- ⁇ -reductase inhibitors.
  • the administration is not simultaneous, the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • the compounds of the present invention may be prepared by a variety of methods well known for the preparation of known compounds of this type.
  • formula (I) compounds can be prepared as shown in Schemes I through IV.
  • B ⁇ is N 1R or moieties which can be converted to those of NR1R2 by chemical reactions readily is known to those of skill in the art, such as described in Arthur Barton and U.D. Ollis, Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds. Pub: Pergamon Press (1979), provided that R * does not include any such moieties that render inoperative the Schemes I through IV processes.
  • NR1R2 are performed on products of the synthetic pathways of Schemes
  • methylthio substituents can be converted to the methylsulfonyl by oxidation.
  • Methoxy substituents can be converted to the hydroxy by treatment with boron tribromide. Hydroxy substituents can be converted to the carboxy by reaction with a trihaloalkylsulfonic anhydride, such as trifluoromethanesulfonic anhydride, foUowed by a metal catalyzed coupling reaction.
  • a trihaloalkylsulfonic anhydride such as trifluoromethanesulfonic anhydride
  • novel compounds of Formula (I) of the present invention can be prepared by methods outlined in schemes 1-4 below and in the
  • estrone which has the formula:
  • estrone or from the 17 ⁇ -carboxylic add analogue of estrone, which is known and readily available.
  • Scheme I outlines formation of Formula I compounds.
  • compound (b) is prepared from compound (a) according to the procedure of Baldwin, et al., J. Chem. Soc. (c), 1968, 2283-2289.
  • Compound (b) is then stirred in an appropriate organic solvent, preferably methanol, with a base, preferably sodium hydroxide, and then addified to yield compound (c).
  • Compound (c) is next treated with a Grignard reagent, described hereinbelow, in an appropriate organic solvent, preferably tetrahydrofuran or diethylether solvent, preferably at reflux temperature to yield formula (d) compounds.
  • a Grignard reagent described hereinbelow
  • a base preferably 2,5-di-t-butyl-3- methyl-pyridine in an appropriate organic solvent, preferably dichloromethane
  • Formula (f) compounds are prepared by reacting a formula(e) compound in a metal catalyzed coupling reaction.
  • a formula (e) compound dissolved in dimethylformide (DMF) an organic base preferably, triethylamine, a phosphine, preferably bis(diphenylphosphino)propane, a palladium(II) compound, preferably, palladium( ⁇ ) acetate, and a Ci.galkyl alcohol (Ci.galkOH), foUowed by addition of carbon monoxide (CO).
  • a suitable base preferably potassium carbonate
  • the sulphonylamidation reaction may be carried out by reacting the corresponding carboxylic add, compounds of formula (g) in each of Schemes (I)-(IV), with an active esterifying agent to prepare an active ester, and then reacting this active ester with a compound of formula (LX):
  • R 4 represents an alkyl group in which the alkyl part has 1 to 4 carbons
  • M represents an alkali metal, such as sodium or potassium.
  • the compound of formula (IX) may be prepared by conventional procedures, for example by reacting the corresponding sulphonamide with an alkali metal alkoxide, such as sodium methoxide, sodium ethoxide or potassium t-butoxide, at a suitable temperature, e.g. at a bout room temperature, for an appropriate period, e.g. from 10 minutes to 3 hours, normally in an inert solvent, such as one of those suggested hereafter for the reaction between the active ester and the compound of formula (IX).
  • an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide
  • the reaction between the active ester and the compound of formula (IX) may be carried out by reactin these compounds in an inert solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction and that it can dissolve the reagents, at least to some extet.
  • suitable solvents include: amides, such as N.,H-dimeti ⁇ ytformamide, H ⁇ -dimethylacetamide or hexamethylphosphoric tramide; sulphoxides, such as dimethyl sulphoxide; and ethers, such as tetrahydrofuran and dioxane.
  • the reaction will take place over a wide range of temperatures, and the predse reaction temperature chosed is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature in the range of from -20 to 100°C, more preferably from 0 to 50°C.
  • the time required for the reaction may likewise vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, in most cases, a period of from 5 minutes to 10 hours, more preferably from 10 minutes to 3 hours, will normally suffice.
  • the desired compound can be coUected from the reaction mixture by conventional means.
  • one suitable recovery procedure comprises; removing the solvent by distillation under reduced pressure; adding water to the residue; and extracting the resulting mixture with a water-immisphate, the solvent may be distilled off, to give the desired compound.
  • the resulting compounds can be further purified by conventional means, such as recrystallisation or the various chromatography techniques, notably column chromatography.
  • Scheme II outlines formation of Formula I compounds.
  • the starting materials in Scheme II are formula (d) compounds prepared as described in Scheme I.
  • a formula (d) compound and a base preferably 2,5-di-t-butyl-3-methyl-pyridine in an appropriate organic solvent, preferably dichloromethane, is cooled to -20°C to 20°C, preferably 0°, and reacted with fluorosuUbnic anhydride to form compounds (h).
  • Formula (f) compounds are prepared by reacting a Formula (h) compound in a metal-catalyzed coupling reaction.
  • a Formula (h) compound is dissolved in dimethylformide (DMF) an organic base preferably triethylamine, a phosphine preferably bis (diphenylphospine)propane, a palladium(II) compound, preferably, palladium(II) acetate, and a Ci.galkyl alcohol (C ⁇ galkOH), foUowed by addition of carbon monoxide (CO).
  • DMF dimethylformide
  • a phosphine preferably bis (diphenylphospine)propane
  • a palladium(II) compound preferably, palladium(II) acetate
  • C ⁇ galkOH Ci.galkyl alcohol
  • Scheme III outlines formation of Formula I compounds.
  • R 8 are as described above
  • R 5 is CF3O2SO- or FO2SO-.
  • the 3-hydroxyl add (i) is converted to the 3- trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (j) (step A) by treating (i) with trifluoromethylsulfonyl anhydride or fluorosulfonic anhydride and an amine base, such as pyridine, preferably 2,5 di-t- butyl-3-methyl-pyridine, in an appropriate organic solvent, preferably dichloromethane at about -20°C to 20°C, preferably 0°.
  • the activated ester (k) is produced (step B) by treating (j) with
  • 2,2-dithiopyridyl and triphenylphosphine in an appropriate organic solvent solution preferably, tetrahydrofuran/toluene at room temperature for about 8-14 hours.
  • the 17-acyl derivative (1) is produced (step C) by treating (k) with a Grignard reagent, described hereinbelow, in tetrahydrofuran or diethyl ether solvent, at a temperature of about -50 to -70°C, for 1-16 hours.
  • the 3-alkyl ester (f) is produced (step D) by treating G) under carbonylation conditions, preferably by bubbling carbon monoxide gas through a solution of G) in an appropriate organic solvent, preferably methanol, containing palladium acetate catalyst, triphenylphosphine, and a tertiary organic amine preferably triethylamine at about room temperature for 1-16 hours.
  • an appropriate organic solvent preferably methanol, containing palladium acetate catalyst, triphenylphosphine, and a tertiary organic amine preferably triethylamine at about room temperature for 1-16 hours.
  • Compound (f) next are reacted with a suitable base, preferably potassium carbonate and addified to yield compounds (g).
  • Compounds (g) can also be produced (step G) by treating G) under carboxylation conditions, preferably by bubbling carbon monoxide gas through a solution of G) in an an appropriate non-alcoholic solvent, preferably DMSO, containing a paUadium catalyst, preferably paUadium (II) diacetate and l,l-Bis(diphenylphosphino)ferrocene (DPPF); and a base, preferably potassium acetate, preferably at increased temperatures.
  • an an appropriate non-alcoholic solvent preferably DMSO
  • a paUadium catalyst preferably paUadium (II) diacetate and l,l-Bis(diphenylphosphino)ferrocene (DPPF)
  • DPPF diphenylphosphino)ferrocene
  • Route 2 involves converting the starting steroidal add (i) to the 3- trifluoromethylsulfonylate or the 3-fluorosulfonylate derivative (j) by the above-described step A; carbonylating (j) to (m) by step D; forming the activated 2-pyridylthio ester (n) by step B; forming the 17-acyl compound (f) by step C; and hydrolyzing the 3-ester to the 3 add final product (g) by step F.
  • Route 3 involves converting the starting add (i) to the activated ester (o) by the above-described step B; forming the 17-acyl compound (d) by reacting (o) by the above described step C; converting (d) to the 3- trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (1) by the above-described step A; and converting (1) to the final product (g) by the above described step G or by the above-described step D followed by the above described step F.
  • a Formula (c) compound and a base preferably 2,5-di-t-butyl-3-methyl-pyridine in an appropriate organic solvent, preferably dichloromethane, is cooled to -20°C to 20°C, preferably 0°C, and reacted with a trihaloalkyl sulfonic anhydride, preferably trifluoromethanesulfonic anhydride to form compounds (p).
  • Formula (q) compounds are prepared by reacting a Formula (p) compound in a metal catalyzed coupling reaction.
  • Formula (p) compound dissolved in d ⁇ nethylfo ⁇ nide (DMF) and organic base preferably, triethylamine, a phosphine, preferably bis(diphenylphosphino)propane, a palladium( ⁇ ) compound, preferably, paUadium( ⁇ ) acetate, and a Cj-Cgalkyl alcohol (Ci-CgalkOH), followed by addition of carbon monoxide (CO).
  • Formula (q) compounds are reacted with a redudng agent, preferably dn ⁇ obutylaluminum hydride, to yield Formula (r) compounds.
  • Formula (s) compounds are produced by treating Formula (r) compounds with a Grignard Reagent (as described in Scheme HI) in tetrahydrofuran or diethylether solvent, at a temperature of about -50° to -70°C, for 1-16 hours.
  • Formula (g) compounds are prepared by oxidation of Formula (s) compounds. Preferably said oxidation will utilize a Jones reagent or tetrapropylamonium perruthenate followed by sodium chlorite.
  • Grignard reagents of the type, XMgR 8 , for aU of the spedes included within the scope of this invention are available or can be made readily by one skilled in the art.
  • Formula I compounds in which the 17 position substitutent is in the ⁇ position are prepared from compounds which contain the corresponding ⁇ substituent by the General Method below.
  • a base such as a hydroxide or alkoxide base, preferably sodium hydroxide, potassium hydroxide or sodium methoxide, at a temperature over 100°C preferably at reflux temperatures to yield the corresponding ⁇ epimer, after isolation and work up.
  • dimethyl sulfoxide or other non-reactive high boiling solvents are preferred when the starting 17B 5 ⁇ -reductase inhibiting steroidal compound contains reactive substituents or reactive unsaturated bonds that are, for example, subject to nucleophilic attack and ethylene glycol, or other reactive high boiling solvents can be used when the reactivity of the substituents or any unsaturated bonds of the starting 17B 5 ⁇ -reductase inhibiting steroidal compound is not a consideration.
  • solvent or "appropriate solvent” as used herein and the in the claims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, hexane, dimethylsulfoxide (DMSO), N,N'-dimethyl-N,N'-propylene urea, N- methyl-2-pyrroUdinone, methanol, isopropylalcohol, dimethylformamide
  • Formula (I) compounds are formed, where appropriate, by methods well known to those of sk-LU in the art.
  • the presently invented pharmaceutically active compounds inhibit steroid 5- ⁇ -reductase activity, they have therapeutic utiUty in treating diseases and conditions wherein decreases in DHT activity produces the desired therapeutic effect.
  • diseases and conditions include acne vulgaris, seborrhea, female hirsutism, male pattern baldness, prostate diseases such as benign prostatic hypertrophy, and prostatic adenocardnoma.
  • Membrane particulates are isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol, and 50 uM NADPH (buffer B). The suspended particulate solution is stored at -80°C.
  • Frozen human prostates are thawed and minced into small pieces ( Brinkmann Polytron (Sybron Corp., Westbury, New York). The solution is sonicated for 3 to 5 minutes with a Sonifier (Branson Sonic Power Co.) followed by hand homogenization in a Dounce hand homogenizer.
  • Prostatic particles are obtained by differential centrifugation at 600 or 1000 x g for 20 minutes and 140,000 x g for 60 minutes at 4°C.
  • the peUet obtained from the 140,000 x g centrifugation was washed with 5 to 10 tissue volumes of the buffer described above and centrifuged at 140,000 x g. The resulting pellet is suspended in buffer B and the particulate suspension was stored at -80°C.
  • Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5- ⁇ -reductase isozyme 2 are homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, ImM dithiothreitol, and 50 ⁇ M NADPH (buffer A) using a Douce hand homogenizer.
  • Membrane particulates containing the recombinant human enzyme are isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, ImM dithiothreitol, and 50 uM NADPH (buffer B). The suspended particulate solution is stored at -80°C until used.
  • a constant amount of [ C]testosterone (50 to 55 mCi/mmol) in ethanol and varying amounts of potential inhibitor in ethanol are deposited in test tubes and concentrated to dryness in vacuo.
  • buffer 10 uL (recombinant isoenzyme 1 or isoenzyme 2) or 20 uL (isoenzyme 2 from human prostate tissue) of 10 mM NADPH and an aliquot of a steroid 5 ⁇ -reductase preparation to a final volume of 0.5 mL.
  • Assays for human steroid 5 ⁇ -reductase isoenzyme 1 are conducted with a sample of the recombinant protein expressed in CHO cells in 50 mM phosphate buffer, pH 7.5 while assays of isoenzyme 2 are conducted with a suspension of human prostatic particulates and/or recombinant protein expressed in CHO cells in 50 mM ritrate buffer at pH 5.0. After incubating the solution at 37°C for 20 or 30 minutes the reaction is quenched by the addition of 4 mL ethyl acetate and 0.25 umol each of testosterone, 5 ⁇ -dihydrotestosterone, androstanediol, and androstanedione as carriers.
  • the organic layer is removed to a second test tube and evaporated to dryness in a Speed Vac.
  • the residue is dissolved in 40 uL chloroform, spotted on an individual lane of a 20 x 20 cm prechannelled siUca gel TLC plate (Si 250F-PA, Baker Chemical) and developed twice with acetonexhloroform (1:9).
  • the radiochemical content in the bands of the substrate and the products are determined with a BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C.). The percent of recovered radiolabel converted to product is calculated, from which enzyme activity is determined. All incubations are conducted such that no more than 20% of the substrate (testosterone) is consumed.
  • the experimentaUy obtained data is computer fit to a linear function by plotting the redprocal of the enzyme activity (1/velodty) against the variable inhibitor concentration; apparent inhibition constants (Kj a pp) are determined by the Dixon analysis (Dixon, M. (1953).
  • the value for the inhibition constant Ki is calculated from known procedures (Levy, M. (1989), Biochemistry.22:2815-2824).
  • the pharmaceutically active compounds of the present invention are preferably incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calrium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acada, magnesium stearate, and stearic add.
  • Liquid carriers include syrup, peanut oil, oUve oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • soUd carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation wfll preferably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous Uquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingreidents, as appropriate, to give the desired oral or parenteral products.
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficadous, nontoxic quantity preferably selected from the range of 0.01 - 1000 mg/kg of active compound, preferably 0.1 - 100 mg/kg.
  • the selected dose is administered preferably from 1-6 times daily, orally or parenteraUy.
  • Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion.
  • Oral dosage units for human administration preferably contain from 0.1 to 500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • the method of this invention of inhibiting steroid 5- ⁇ -reductase activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective steroid 5- ⁇ -reductase inhibiting amount of a pharmaceutically active compound of the present invention.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in the inhibition of steroid 5- ⁇ -reductase.
  • the invention also provides for a pharmaceutical composition for use in the treatment of benign prostate hypertrophy which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in the treatment of prostatic adenocarcinoma which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • the invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises bringing the compound of Formula I into assodation with the pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocardnoma or compounds known to have utility when used in combination with 5- ⁇ -reductase inhibitors.
  • further active ingredients such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocardnoma or compounds known to have utility when used in combination with 5- ⁇ -reductase inhibitors.
  • Particularly preferred is the co-administration of a 5- ⁇ -reductase inhibitor, as disclosed herein, and minoxidil for use in the treatment of male pattern baldness.
  • Particularly preferred is the co-administration of a 5 ⁇ -reductase inhibitor, as disclosed herein, and a ⁇ -recept
  • Oxalyl chloride (1.42 g, 11.22 mmol) was added to a solution of 17 ⁇ -(carboxyl)-estra-l,3,5(10)-3-(acetoxymethyl) triene (400 mg, 1.12 mmol) in CH2CI2 at 0°C.
  • Example 2 Preparation of 17(V(N-nHflmantvlcarbamovD-estra-1.3.5(10)-triene-3- carboxylic add a) 17 ⁇ -(N-adamantylcarbamoyl)-estra-l,3,5(10)-3- (acetoxymethyl) triene 1-aminoadamantane hydrochloride (93.9 mg, 0.5 mmol), triethylamine (101.2 mg, 1.0 mL), and 4-dimethylaminopyridine (3 mg, 0.025 mmo) were added to a solution of 17 ⁇ -(chlorocarboxyl)-estra- l,3,5(10 3-(acetoxymethyl) triene ( 189.7 mg, 0.5 mmol) in CH2CI2 (15 mL) at room temperature under argon.
  • CH2CI2 15 mL
  • 1,3-dicyclohexylcarbodiimide (20.9 mg, 0.1 mmol), 1- hydroxybenzotriazole (13.7 mg, 0.1 mmol), and benzylamine (10.8 mg, 0.1 mmol) were added to a solution of 17 ⁇ -(carboxyl)-estra-l,3,5(10)-3- (tert-butyl dimethyl silyloxymethyl) triene (39.3 mg, 0.029 mmol) in CH2CI2 (10 mL) and stirred at ambient temperature for 24 h under argon.
  • FORMULATION Scored tablets for oral use eachcontaining 250 mg of the active substance, are manufactured as follows:
  • composition for 10,000 tablets
  • the active substance is granulated with a 4%w/v aqueous solution of methyl ceUulose.

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Abstract

L'invention concerne des composés stéroïdiens de synthèse avec des substituants 17 α et 17 β sur le noyau aromatique A, des compositions pharmaceutiques contenant ces composés et des méthodes d'utilisation des ces composés pour inhiber la 5-α-réductase active sur les composés stéroïdiens.
EP95922906A 1994-06-03 1995-05-26 Derives steroidiens pour inhiber la 5-alpha-reductase Withdrawn EP0763053A4 (fr)

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PCT/US1995/006734 WO1995033761A1 (fr) 1994-06-03 1995-05-26 Derives steroidiens pour inhiber la 5-alpha-reductase

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WO1991013550A1 (fr) * 1990-03-16 1991-09-19 Smithkline Beecham Corporation Compositions synergiques

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US5091380A (en) * 1990-06-28 1992-02-25 Merck & Co., Inc. N-monosubstituted adamantyl/norbornanyl 17β-carbamides of 3-carboxy-androst-3,5-dienes as testosterone 5α-reductase inhibitors
ZA938B (en) * 1992-01-06 1994-06-16 Smithkline Beecham Corp Preparation of benzo esters and benzo acids
DK0567271T3 (da) * 1992-04-20 1998-02-16 Sankyo Co Steroidderivater til behandling af prostatahypertrofi, fremgangsmåde til fremstilling heraf og anvendelser heraf

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013550A1 (fr) * 1990-03-16 1991-09-19 Smithkline Beecham Corporation Compositions synergiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEVY M A ET AL: "3-PHOSPHINIC ACID AND 3-PHOSPHONIC ACID STEROIDS AS INHIBITORS OF STEROID 5 -REDUCTASE: SPECIES COMPARISON AND MECHANISTIC STUDIES" BIOORGANIC CHEMISTRY, vol. 19, no. 3, 1 September 1991, pages 245-260, XP000562186 *
See also references of WO9533761A1 *

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