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WO1995031453A1 - Derives d'indole a titre d'inhibiteurs de la 5-alpha-reductase 1 - Google Patents

Derives d'indole a titre d'inhibiteurs de la 5-alpha-reductase 1 Download PDF

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Publication number
WO1995031453A1
WO1995031453A1 PCT/EP1995/001574 EP9501574W WO9531453A1 WO 1995031453 A1 WO1995031453 A1 WO 1995031453A1 EP 9501574 W EP9501574 W EP 9501574W WO 9531453 A1 WO9531453 A1 WO 9531453A1
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alkyl
compound according
halo
pharmaceutically acceptable
compound
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PCT/EP1995/001574
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English (en)
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David James Rawson
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Pfizer Limited
Pfizer Research And Development Company, N.V./S.A.
Pfizer Inc.
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Publication of WO1995031453A1 publication Critical patent/WO1995031453A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to indole derivatives which have steroid 5 ⁇ -reductase inhibitory activity.
  • the androgen class of steroidal hormones is responsible for the difference in the physical characteristics of males and females. Of all the organs that produce androgens, the testes produce these hormones in the greatest amounts. Androgens have a permissive or stimulatory role in many undesirable physical manifestations and disease states, e.g. acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.
  • Testosterone is the prohormone of DHT which is formed locally in the above organs by the action of testosterone 5 ⁇ -reductase inhibitors.
  • the enzyme 5 ⁇ -reductase mediates the conversion of testosterone to the more potent androgen DHT locally, in the target organ. It has been postulated, and demonstrated, that inhibitors of 5 ⁇ -reductase block the formation of DHT and should bring about amelioration of the above undesirable physiological conditions. Testosterone 5 ⁇ -reductase inhibitors may also be useful in the treatment of human prostate adenocarcinomas. Recently, two 5 -reductase isozymes has been described jn humans, (Andersson et al., Proc. Natl. Acad. Sci.
  • Compounds reportedly useful for inhibiting 5 ⁇ -reductase are generally steroid derivatives such as the azosteroids in Rasmusson, et al., J. Med. Chem.. 29, (11), 2298-2315 (1986); and benzoylaminophenoxy-butanoic acid derivatives such as those disclosed in EPO 291 245.
  • European Patent Application 0532190 discloses certain benzo[f] quinolinones as 5 ⁇ -reductase inhibitors. Certain indole derivatives having steroid 5 -reductase inhibitory activity are generally disclosed by International Patent Applications No. PCT/EP93/00380 (WO93/17014), PCT/EP92/01625 (WO93/02050) and PCT/EP92/01626 (WO93/02051).
  • the present compounds are potent and selective inhibitors of human 5 ⁇ -reductase 1 with minimal activity against 5 ⁇ -reductase 2, which leads to the therapeutic advantages over hitherto known 5 ⁇ -reductase inhibitors that the compounds have reduced side effects.
  • the compounds may be used for the treatment of male pattern baldness which is known to be primarily responsible for hairloss in the human scalp as well as female hirsutism, acne vulgaris, seborrhoea and prostatic cancer.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are each .ndependently selected from H, C C 4 alkyl, halo(C ⁇ -C 4 )alkyl, d-C 4 alkoxy and halo,
  • R 5 is H or C1-C4 alkyl, m is O or 1 , n is 2, 3 or 4,
  • Z is tetrazol-5-yl or C0 2 R 13 where R 13 i ⁇ H or a biolabile ester-forming group,
  • X is methylene, S, O, -SO or -S0 2 -,
  • R 9 and R 10 are independently H or C C . alkyl
  • W is S, O, H/H, H/C C 4 alkyl or C r C ⁇ lkyl/C r C 4 alkyl wherein the alkyl groups are the same or different, and R 11 and R 12 are independently H, Ci-Ce alkyl, halo(C ⁇ -C 6 )alkyl, or optionally substituted C 3 -C 8 cycloalkyl, or aryl or heteroaryl.
  • R, R 1 -R 8 , R 11 , R 12 , m, n and Z are as defined for formula (I).
  • a further aspect of the invention provides a compound of formula (III):
  • R, R 1 -R 8 , m, n and Z are as defined above and R 15 is H or d-C 4 alkyl.
  • aryl used above means phenyl optionally substituted by CrC 6 alkyl, C ⁇ -C 6 alkoxy, halo or halo(C ⁇ -C 6 )alkyl.
  • Heteroaryl means a 5- or 6- membered heteroaryl ring containing 1 or 2 heteroatoms each independently selected from N, O and S, said ring being optionally substituted by C ⁇ -C 6 alkyl, Ci- Ce alkoxy, halo(C C 6 )alkyl or halo. Cycloalkyl groups may similarly be substituted.
  • Alkyl and alkoxy groups containing three or more carbon atoms and alkenyl, alkanamido and alkanoyl groups containing four or more carbon atoms may be straight- or branched-chain.
  • halo means fluoro, chloro, bromo or iodo.
  • biolabile ester-forming group is well understood in medicinal chemistry as meaning a group which forms an ester which can be readily cleaved in vivo to liberate the corresponding acid of the formula (I) wherein Z is -COOH.
  • a number of such ester groups are well-known, for example in the penicillin area or in the case of the angiotensin-converting enzyme (ACE) inhibitor antihypertensive agents.
  • ACE angiotensin-converting enzyme
  • Esters of the formula (I), (II) and (III) wherein Z is -COOR 13 and R 13 is C C 6 alkyl are steroid 5 ⁇ -reductase inhibitors per se but, in general, esters wherein R 13 is a biolabile ester-forming group are useful as pro-drugs to provide compounds of the formula (I), (II) and (III) wherein Z is -COOH in vivo following oral administration.
  • Such esters are also useful as intermediates for the preparation of compounds of the formula (I), (II) and (III) wherein Z is -COOH.
  • biolabile ester-forming groups are alkyl, alkanoyloxyalkyl (including alkyl, cycloalkyl or aryl substituted derivatives thereof), arylcarbonyl- oxyalkyl (including aryl substituted derivatives thereof), aryl, arylalkyl, indanyl and haloalkyl: wherein alkanoyl groups have from 2 to 8 carbon atoms, alkyl groups have from 1 to 8 carbon atoms and aryl means phenyl or naphthyl, both of which may be optionally substituted by C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy or halo.
  • Alkyl, alkanoyl and alkoxy groups can, where appropriate, be straight- or branched-chain.
  • biolabile ester-forming groups are CrC 6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), benzyl, 1-(2,2-diethylbutyryloxy)ethyl, 2-ethyl-propionyloxymethyl, 1 -(2-ethylpropionyloxy)ethyl, 1 -(benzoyloxy)ethyl, 2-methyl-1 -propionyloxy-1 -propyl, 2,4,6-trimethylbenzoyloxymethyl, 1-(2,4,6-trimethyl-benzoyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4 dimethylphenyl, 4-t-buty I phenyl and 5-indanyl.
  • CrC 6 alkyl e.g. methyl, ethyl,
  • the pharmaceutically acceptable salts of the compounds of the invention include suitable acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts and examples thereof are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and ⁇ -toluenesulphonate salts.
  • Suitable base salts are formed from bases which form non-toxic salts and examples thereof are the calcium, lithium, magnesium, potassium, sodium, zinc, N-benzyl-N-(2-phenylethyl)amine, 1-adamantylamine and diethanolamine salts.
  • Preferred base salts are the sodium and potassium salts.
  • R is H or methyl. Radicals -R ⁇ R 10 are preferably H, m is preferably 1 and n is preferably 3.
  • Groups R 11 and R 2 may be phenyl substituted at the 4-position by chloro, ethyl, propyl or butyl groups or alkyl groups such as methyl, n-butyl and ⁇ -propyl. Compounds in which at least one of R 11 and R 12 is substituted phenyi are preferred.
  • Compounds of the invention may contain one or more asymmetric carbon atoms and/or one or more non-aromatic carbon-carbon double bonds and may therefore exist in two or more stereoisomeric forms.
  • the present invention includes both the individual stereoisomers of the compounds together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.LC. of a stereoisomeric mixture of a compound of the invention or a suitable salt or derivative thereof.
  • An individual enantiomer of a compound may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.LC. of a racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of a racemate with a suitable optically active acid or base.
  • R, R 1 -R 12 , m, n, W and X are as defined above and R 14 is a suitable ester- forming group.
  • R 14 is a suitable ester- forming group.
  • ester-forming groups which may be cleaved to form the corresponding carboxylic acid are known, see for example T.W. Greene, "Protective Groups in Organic Synthesis", Wiley-lnterscience (1981).
  • R 14 is an ester-forming group that may be removed by hydrolysis, e.g. a biolabile ester-forming group as previously defined for R 13 (such as C Ce alkyl)
  • the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid or a suitable inorganic base.
  • the hydrolysis is carried out under basic conditions.
  • an ester of the formula (la) is treated with an aqueous solution of a suitable base, e.g. sodium or potassium hydroxide, in the presence of a suitable organic co-solvent, e.g. tetrahydrofuran or a C C alkanol (e.g. methanol or ethanol) or a combination thereof.
  • a suitable organic co-solvent e.g. tetrahydrofuran or a C C alkanol (e.g. methanol or ethanol) or a combination thereof.
  • the hydrolysis is typically carried out at from room temperature to the reflux temperature and preferably at room temperature.
  • the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
  • R 14 is an ester-forming group that may generally be removed by reduction, e.g. benzyl
  • the reduction may be carried out by catalytic hydrogenation using, e.g. palladium-on-charcoal, as the catalyst.
  • Compounds of formula (II) and (III) in which Z is COOH may be prepared similarly from corresponding esters in which Z is -COOR 14 , R 14 being as defined above.
  • the reaction may be carried out under classical esterification conditions such as by using an excess of the alcohol and with acid catalysis, e.g. using sulphuric acid or p-toluenesulphonic acid, at from room temperature to the reflux temperature.
  • acid catalysis e.g. using sulphuric acid or p-toluenesulphonic acid
  • the water generated during the reaction may be removed by azeotropic distillation or by the use of a dehydrating agent or a molecular sieve.
  • the esterification may also be carried out by reacting the acid with the alcohol in the presence of a suitable dehydrating agent, e.g. dicyclohexylcarbodiimide or diethylazodicarboxylate/triphenylphosphine (see O. Mitsunobu, Synthesis, 1981, 1).
  • a suitable dehydrating agent e.g. dicyclohexylcarbodiimide or diethylazodicarboxylate/triphenylphosphine (see O. Mitsunobu, Synthesis, 1981, 1).
  • esterification may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the alcohol of the formula R 13 OH.
  • An activated ester may be formed by reacting the carboxylic acid with 1- hydroxybenzotriazole in the presence of a suitable dehydrating agent, e.g. 1-(3- N,N-dimethylaminopropyl)-3-ethylcarbodiimide, and in a suitable solvent, e.g. dichloromethane, at room temperature.
  • An imidazolide may be formed by reacting the carboxylic acid with 1,1 1 -carbonyldiimidazole in a suitable solvent, e.g. dichloromethane, at room temperature.
  • the compounds of formula (I) and (la) may be prepared by reduction of the corresponding carbonyl compounds of formula (lb):
  • This reduction may be carried out by treating the carbonyl compound with a borane reducing agent, such as borane/tetrahydrofuran complex or sodium borohydride/borontrifluoride etherate in a solvent such as tetrahydrofuran.
  • a borane reducing agent such as borane/tetrahydrofuran complex or sodium borohydride/borontrifluoride etherate in a solvent such as tetrahydrofuran.
  • the starting materials of formula (lb) may be prepared from known starting materials by several different methods.
  • the compounds of formula (lb) in which X is O or S, m, n and groups R, R 1 -R 12 and W are as defined above for formula (I) may be prepared by intramolecular cyclisation of a base salt (phenoxide or thiophenoxide) of a compound of formula (lc):
  • the base salt may be the sodium or potassium salt.
  • the reaction may be carried out in a solvent such as tetrahydrofuran or N,N-dimethylformamide and the base salt may be generated in situ by reaction of the phenol or thiophenyl with a base such as sodium hydride.
  • the phenol or thiophenol starting material may generally be prepared by known methods.
  • the compound of formu'a (lb) may be prepared by reaction of compound (Id):
  • Z 1 may be a C ⁇ -C 4 alkoxy or benzyloxy group or halo (e.g. chloro or bromo) and Z 2 may be halo or a methanesulphonyloxy or ⁇ -toluenesulphonyloxy group.
  • the reaction may be carried out in the presence of an acid acceptor such as triethylamine and in a solvent such as dichloromethane.
  • Compounds of formula (Id) may be made by conventional methods.
  • Z 3 is a leaving group such as halo (preferably Cl or Br), C ⁇ -C 4 ethoxy (such as methoxy or ethoxy) or benzyloxy, optionally in the presence of an acid acceptor such as triethylamine.
  • the reaction may be carried out in an organic solvent such as dichloromethane, conveniently at reflux temperature.
  • Compound (le) may be prepared by conventional methods.
  • the compounds of formula (lb) may be prepared by acylation of an indole of formula (IV):
  • R, R 1 -R 4 and n are as defined above and Z is tetrazoyl or C0 2 R 14 , R 14 being an ester-forming group, or of a base salt such as the sodium or potassium salt of an indole of formula (V):
  • R -R , X, W, and m are as defined for formula (I) and Z 4 is a leaving group such as halo (preferably chloro) in the presence of a Lewis acid such as aluminium chloride or diethylaluminium chloride.
  • a Lewis acid such as aluminium chloride or diethylaluminium chloride.
  • the reaction may be performed at reflux in a solvent such as toluene.
  • the product obtained as a base salt by the above procedure may be converted to the carboxylic acid by acidification during the work-up procedure.
  • the compound of formula (lb) may alternatively be prepared by oxidation of a compound of formula (VII):
  • R, R 1 -R 12 , m, n and Z are as defined above for formulae (II) and (III).
  • Suitable reducing agents are the borane/tetrahydrofuran and the sodium borohydride/borontrifluoride/ether complexes.
  • Compounds of formula (II) and (III) in which Z is COOH or C0 2 R 14 , R 14 being an ester-forming group, may be made by methods analogous to those described above for compounds of formula (I).
  • a pharmaceutically acceptable base salt of a compound of the formula (I), (II) or (III) may be readily prepared by mixing together solutions of a compound of the formula (I), (II) or (III) and the desired base.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the compounds of the invention are steroid 5 ⁇ -reductase inhibitors and therefore they are useful in the curative or prophylactic treatment of diseases or conditions such as acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness. These compounds are also useful for the treatment of human prostate adenocarcinomas.
  • the compounds of the invention may be tested in vitro for testosterone 5 ⁇ - reductase inhibitory activity using prostate tissue from rats or humans as follows:-
  • the compounds may be tested for their potency in inhibiting rat testosterone 5 ⁇ -reductase using ventral prostate tissue from male rats. In determining inhibitory potency against rat prostatic 5 ⁇ - reductase the following procedure was employed:-
  • Rat prostates were minced into small pieces.
  • the tissue was homogenised in Buffer A (20mM sodium phosphate, pH 6.5, buffer containing 0.32M sucrose and 1mM dithiothreitol) with a Brinkman Polytron (Kinematica GmBH, Luzern), and then homogenised with a motor-driven (lOOOrpm) Potter Elvehjem (teflon-to-glass) homogeniser.
  • Prostate particles were obtained by centrifugation at 105.000G for 60 minutes.
  • the pellet was washed in 4 volumes of Buffer A and recentrifuged at 105.000G.
  • the resulting pellet was dispersed in Buffer A (1ml per g of prostate tissue originally used) with a motor-driven Potter Elvehjem homogeniser as described above.
  • the paniculate suspension was stored as 1ml samples at -70°C.
  • reaction mixture was incubated at 37°C for 30 minutes and then quenched by addition with vigorous mixing of 2ml of ethyl acetate containing 20 ⁇ g each of testosterone and 5 ⁇ -dihydrotestosterone as carriers.
  • the aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes.
  • the organic layer was transferred to a second test tube and evaporated to dryness under nitrogen.
  • the residue was dissolved in 50-80 ⁇ l of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in dichloromethane:acetone (185:15).
  • the radiochemical content in the bands of the substrate (testosterone) and the product (5 ⁇ -dihydrotestosterone) were determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5 ⁇ -dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.
  • the compounds may be tested for their potency in inhibiting human testosterone 5 ⁇ -reductase-2 using tissue from hyperplastic human prostates.
  • tissue from hyperplastic human prostates In determining inhibitory potency against human prostatic 5 ⁇ - reductase-2 the following procedure was employed:- Frozen human prostate tissue was pulverised in liquid nitrogen using a steel mortar and pestle. The powdered tissue was homogenised in 4 volumes of Buffer A (20mM sodium phosphate, pH 6.5, containing 0.32M sucrose, 1 mM dithiothreitol and 50 ⁇ M NADPH) with an Ultra-Turrax homogeniser (Janke and Kunkel GmBH & Co., Staufen i.BR., Germany).
  • the homogenate was centrifuged at 500G for 5 minutes to remove large particles of tissue, and the supernatant was then centrifuged at 100,000G for 1 hour.
  • the resulting pellet was dispersed in Buffer A (1 ml per -g of prostate tissue originally used) with the Ultra-Turrax homogeniser. This paniculate preparation was then filtered through 2 layers of cheesecloth and the filtrate was stored as 2ml samples at -70°C.
  • reaction mixture was incubated at 37°C for 30 minutes and was then quenched by addition, with vigorous mixing, of 2ml of ethyl acetate containing 20 ⁇ g each of testosterone and 5 ⁇ -dihydrotestosterone as carriers.
  • the aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes.
  • the organic layer was transferred to a second test tube and evaporated to dryness under nitrogen.
  • the residue was dissolved in 50-80 ⁇ l of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in dichloromethane:acetone (185:15).
  • the radiochemical content in the bands of the substrate (testosterone) and the product (5 ⁇ -dihydrotestosterone) were determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5 ⁇ -dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.
  • the compounds of the formula (I) may be tested for potency in inhibiting steroid 5 ⁇ -reductase activity in human prostate adenocarcinomas using cell lines DU145 and HPC36M. In determining inhibitory potency against 5 ⁇ - reductase the following procedure was employed:-
  • Human prostate adenocarcinoma cell lines were grown in Dulbecco's Modified Eagles medium (DMEM) containing 5% serum. The cells were recovered from the medium by centrifugation, washed in serum-free DMEM and suspended at 5-10 x 10 s cells/ml. in serum-free medium.
  • DMEM Dulbecco's Modified Eagles medium
  • test tube 10 ⁇ l of [ 3 H]- testosterone (1 ⁇ Ci, 20 pmol) dissolved in ethanol (Du Pont, NEN Research Products, Stevenage, U.K.) and 5 ⁇ l of an ethanol solution of a compound of the formula (I).
  • the ethanol was evaporated under nitrogen and the testosterone and the compound were redissolved in 0.25ml of serum-free medium containing 0.25 ⁇ mol NADPH.
  • the mixture was warmed to 37°C and the reaction started by addition of 0.25ml of cell suspension (1.2-2.5 x 10 6 cells).
  • the reaction mixture was incubated at 37°C for 2 hours and then quenched by addition, with vigorous mixing, of 1.5ml of ethyl acetate containing 20 ⁇ g each of testosterone and 5 ⁇ -dihydrotestosterone as carriers.
  • the aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes.
  • the organic layer containing testosterone and its metabolites, was transferred to a second test tube and evaporated to dryness under nitrogen.
  • the residue was dissolved in 50-80 ⁇ l of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in dichloromethane: acetone (185:15).
  • the radiochemical content in the bands of the substrate (testosterone) and the product (5 ⁇ -dihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percentage of recovered radiolabel converted to 5 ⁇ -dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.
  • the compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practic o.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practic o.
  • they can be administered orally in the form of tablets contemning such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents.
  • They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the daily dosage level of the compounds of the forrnuia (i) wiil be from 0.01 to 20 mg/kg (in single or divided doses) and preferably will be from 0.1 to 10mg/kg except for the treatment of human prostate adenocarcinomas where doses of up to 20mg/kg may be used.
  • tablets or capsules of the compounds will contain from 5mg to 0.5g of active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
  • the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid oaraffin; or they can be incorporated, at a concentration between 1 and 1 C%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
  • the compounds may also be administered together with an ⁇ -antagonist (e.g. prazosin or doxazosin), an antiandrogen (e.g. flutamide) or an aromatase inhibitor (e.g. atamestane), particularly for the curative or prophylactic treatment of benign rostatic hypertrophy.
  • an ⁇ -antagonist e.g. prazosin or doxazosin
  • an antiandrogen e.g. flutamide
  • an aromatase inhibitor e.g. atamestane

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Abstract

Dérivés d'indole servant d'inhibiteurs de la 5-α-réductase stéroïde, et répondant aux formules (I), (II) et (III), ou leurs sels pharmaceutiquement acceptables, dans lesquelles R représente H ou alkyle C1-4; R?1, R2, R3, R4, R6, R7 et R8¿, indépendamment les uns des autres, représentent H, alkyle C¿1-4?, haloalkyle C1-4, alcoxy C1-4 ou halo; R?5¿ représente H ou alkyle C¿1-4?; m vaut 0 ou 1; n vaut 2, 3 ou 4; Z représente tétrazol-5-yle ou CO2R?13 où R13¿ représente H ou un groupe biologiquement labile de formation d'esters; X représente méthylène, S, O, -SO ou -SO¿2?-; R?9 et R10¿, indépendamment l'un de l'autre, représentent H ou alkyle C¿1-4?; W représente S, O, H/H, H/alkyle C1-4 ou alkyle C1-4/alkyle C1-4, où les groupes alkyle sont identiques ou différents; et R?11 et R12¿, indépendamment l'un de l'autre, représentent H, alkyle C¿1-6?, haloalkyle C1-6, cycloalkyle C3-8, aryle ou hétéroaryle, ledit cycloalkyle, aryle ou hétéroaryle étant éventuellement substitué par alkyle C1-6, alcoxy C1-6, haloalkyle C1-6 ou halo; et R?15¿ représente H ou alkyle C¿1-4?.
PCT/EP1995/001574 1994-05-13 1995-04-25 Derives d'indole a titre d'inhibiteurs de la 5-alpha-reductase 1 WO1995031453A1 (fr)

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GB9409583.3 1994-05-13

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PCT/EP1995/001574 WO1995031453A1 (fr) 1994-05-13 1995-04-25 Derives d'indole a titre d'inhibiteurs de la 5-alpha-reductase 1

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GB (1) GB9409583D0 (fr)
WO (1) WO1995031453A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7659269B2 (en) 1998-03-31 2010-02-09 The Institute For Pharmaceutical Discovery, Llc Substituted indolealkanoic acids
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0458207A2 (fr) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'indole
WO1993002050A1 (fr) * 1991-07-24 1993-02-04 Pfizer Limited Indoles
WO1993017014A1 (fr) * 1992-02-28 1993-09-02 Pfizer Limited DERIVES D'INDOLE SERVANT D'INHIBITEURS DE LA STEROIDE-5$(a)-REDUCTASE

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0458207A2 (fr) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'indole
WO1993002050A1 (fr) * 1991-07-24 1993-02-04 Pfizer Limited Indoles
WO1993002051A1 (fr) * 1991-07-24 1993-02-04 Pfizer Limited Indoles
WO1993017014A1 (fr) * 1992-02-28 1993-09-02 Pfizer Limited DERIVES D'INDOLE SERVANT D'INHIBITEURS DE LA STEROIDE-5$(a)-REDUCTASE

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7659269B2 (en) 1998-03-31 2010-02-09 The Institute For Pharmaceutical Discovery, Llc Substituted indolealkanoic acids
US8163932B2 (en) 1998-03-31 2012-04-24 Alinea Pharmaceuticals, Inc. Substituted indolealkanoic acids
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

Also Published As

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