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WO1993002051A1 - Indoles - Google Patents

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Publication number
WO1993002051A1
WO1993002051A1 PCT/EP1992/001626 EP9201626W WO9302051A1 WO 1993002051 A1 WO1993002051 A1 WO 1993002051A1 EP 9201626 W EP9201626 W EP 9201626W WO 9302051 A1 WO9302051 A1 WO 9302051A1
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WIPO (PCT)
Prior art keywords
formula
alkyl
compound
aryl
group
Prior art date
Application number
PCT/EP1992/001626
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English (en)
Inventor
Julian Blagg
Kelvin Cooper
Peter Lionel Spargo
Original Assignee
Pfizer Limited
Pfizer 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
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Priority to JP5502592A priority Critical patent/JPH06511483A/ja
Priority to EP92915891A priority patent/EP0598754A1/fr
Publication of WO1993002051A1 publication Critical patent/WO1993002051A1/fr
Priority to FI940311A priority patent/FI940311A7/fi
Priority to NO940237A priority patent/NO940237L/no

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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

Definitions

  • This invention relates to indole derivatives which have steroid 5 ⁇ -reductase inhibitory activity.
  • this invention relates to indoles, their preparation and their use as testosterone-5 ⁇ - reductase inhibitors.
  • the androgen class of steroidal hormones which includes testosterone, 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. Over-production of these hormones in the body results in many undesirable physical, manifestations and disease states, e.g. acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.
  • the principal androgen secreted by the testes is testosterone and it is the primary androgen present in male plasma.
  • the principal mediator of androgenic activity in certain organs such as the prostate and sebaceous gland are the 5 ⁇ -reduced androgens.
  • Testosterone is therefore the prohormone of 5 ⁇ - dihydrotestosterone which is formed locally in the above organs by the action of testosterone-5 ⁇ -reductase.
  • the presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone 5 ⁇ -reductase inhibitors.
  • Testosterone 5 ⁇ -reductase inhibitors may also be useful in the treatment of human prostate
  • EP-A-0458207 discloses certain indole derivatives which have testosterone 5 ⁇ -reductase inhibitory activity.
  • the present invention provides compounds of the formula:-
  • X is O, NH, N(C 1 -C 4 alkyl), C 1 -C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkynylene, said alkylene, alkenylene and alkynylene groups being optionally substituted by C 1 -C 4 alkyl or aryl;
  • Y is C 1 -C 6 alkylene optionally substituted by C 1 -C 6 alkyl;
  • R is H, OH, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, OH, halo and CF 3 ;
  • R 6 , R 7 and R 8 is C 1 -C 15 alkyl or a group of the formula -Z(C 1 -C 15 alkyl), -Z(aryl) or
  • alkyl group being optionally interrupted by O, S(O) q , NH or N(C 1 - C 6 alkyl), and said alkyl group and the alkyl group of said -Z(C 1 -C 15 alkyl) group being optionally substituted by C 1 -C 10 alkoxy, aryl, C 3 -C 7 cycloalkyl or a group of the formula
  • R 6 , R 7 and R 8 and R 5 and R 9 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo and halo(C 1 -C 4 alkyl);
  • R 10 is COOH, COOR 11 or CONR 12 R 13 ;
  • R 11 is a biolabile ester-forming group
  • R 12 and R 13 are each independently selected from H and C 1 -C 4 alkyl
  • Z is O, S(O) q , NH or N(C 1 -C 6 alkyl);
  • q 0, 1 or 2;
  • aryl used in the definitions of X, R 6 , R 7 and R 8 , means phenyl optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, OH, halo, CF 3 , halo(C 1 -C 6 alkyl), nitro, amino, C 2 -C 6 alkanamido, C 2 -C 6 alkanoyl or phenyl.
  • 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 R 10 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) wherein R 10 is -CO 2 (C 1 -C 6 alkyl) are steroid 5 ⁇ -reductase inhibitors per se but, in general, where R 10 is COOR 11 such compounds are useful as pro-drugs to provide compounds of the formula (I) wherein R 10 is COOH in vivo following oral administration.
  • Such esters are also useful as intermediates for the
  • biolabile ester-forming groups are alkyl (e.g. C 1 -C 6 alkyl), alkanoyloxyalkyl(including alkyl, cycloalkyl or aryl substituted derivatives
  • arylcarbonyloxyalkyl including aryl
  • alkanoyl groups have from 2 to 8 carbon atoms and alkyl groups have from 1 to 8 carbon atoms, all of which may be straight- or branched- chain, and aryl means phenyl or naphthyl, both of which may be optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halo.
  • biolabile ester-forming groups are benzyl, 1-(2,2- diethylbutyryloxy) ethyl, 2-ethylpropionyloxymethyl, 1-(2- ethylpropionyloxy) ethyl, 1-(2,4-dimethylbenzoyloxy) ethyl, ⁇ -benzoyloxybenzyl, 1-(benzoyloxy) ethyl, 2-methyl-1- propionyloxy-1-propyl, 2,4,6-trimethylbenzoyloxymethyl, 1-(2,4,6-trimethylbenzoyloxy) ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2- naphthyl, 2,4-dimethylphenyl, 4-t-butylphenyl and 5- indanyl.
  • acids of the formula (I) are the acid addition and the base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the
  • hydrochloride hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and p- toluenesulphonate salts.
  • Suitable base salts are formed from bases which form non-toxic salts and examples are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and
  • X is O, NH, C 1 -C 4 alkylene or C 2 -C 4 alkenylene.
  • X is O, NH, methylene, ethylene or ethenylene.
  • X is methylene
  • Y is C 1 -C 6 alkylene.
  • Y is propylene
  • R is H or C 1 -C 4 alkyl.
  • R is H.
  • R 1 , R 2 , R 3 and R 4 are each H.
  • one of R 6 , R 7 and R 8 is -0 (C 1 -C 15 alkyl), the alkyl of said -0(C 1 -C 15 alkyl) group being optionally substituted by aryl, and the remainder of R 6 , R 7 and R 8 and R 5 and R 9 are each H.
  • R 6 , R 7 and R 8 is -OCH 2 (aryl) or -OCH(C 1 -C 4 alkyl) (aryl) and the remainder of R 6 , R 7 and R 8 and R 5 and R 9 are each H:
  • R 7 is -OCH(CH 3 ) (aryl) and R 5 , R 6 , R 8 and R 9 are each H.
  • R 10 is COOH or COOR 11 .
  • R 10 is COOH.
  • R 11 is C 1 -C 6 alkyl.
  • R 11 is ethyl
  • Z is O.
  • aryl means phenyl optionally
  • substituents and most preferably means phenyl optionally substituted by one substituent.
  • aryl means phenyl optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , nitro or phenyl and more
  • aryl means phenyl, 4-(n- propyl)phenyl, 4-isobutylphenyl, 4-methoxyphenyl, 2,4- dichlorophenyl, 3,4-dichlorophenyl, 4- trifluoromethylphenyl, 4-nitrophenyl or 4-phenylphenyl and most preferably means 4-isobutylphenyl.
  • a compound of the formula (I) may contain one or more asymmetric carbon atoms and/or one or more alkenyl groups and may therefore exist in two or more
  • the present invention includes both the individual stereoisomers of the compounds of the formula (I) 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.L.C. of a
  • stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of a racemate using a suitable chiral support or by fractional
  • R 14 is a suitable ester-forming group and X, Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I).
  • ester-forming groups that may be cleaved to provide the corresponding carboxylic acid are known to the skilled man, see, e.g., T.W. Greene and P.G. Wuts, "Protective Groups in Organic Synthesis", Wiley-Interscience (2nd edition, 1991).
  • R 14 is an ester-forming group that may be removed by hydrolysis, e.g. C 1 -C 6 alkyl or an
  • 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.
  • hydrolysis is carried out under basic conditions.
  • an ester of the formula (II) is treated with an aqueous solution of a suitable base, e.g. sodium or potassium hydroxide, and in the presence of a suitable organic co-solvent, e.g. tetrahydrofuran or a C 1 -C 4 alkanol such as methanol.
  • a suitable base e.g. sodium or potassium hydroxide
  • a suitable organic co-solvent e.g. tetrahydrofuran or a C 1 -C 4 alkanol
  • 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 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.
  • the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid, e.g. hydrochloric or sulphuric acid, or a suitable inorganic base, e.g. sodium or potassium hydroxide, at from room
  • a suitable mineral acid e.g. hydrochloric or sulphuric acid
  • a suitable inorganic base e.g. sodium or potassium hydroxide
  • X, Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) and R 15 is H or C 1 -C 4 alkyl.
  • the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid, e.g. hydrochloric or acetic acid, or a suitable inorganic base, e.g. sodium or potassium hydroxide, at from room temperature to the reflux temperature.
  • a suitable acid e.g. hydrochloric or acetic acid
  • a suitable inorganic base e.g. sodium or potassium hydroxide
  • the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
  • the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid, e.g. hydrochloric or
  • sulphuric acid or a suitable inorganic base, e.g. sodium or potassium hydroxide, at from room
  • R 17 taken together represent ethylene, said ethylene group being optionally substituted by phenyl or C 1 -C 4 alkyl (preferably methyl).
  • R 16 and R 17 taken together represent -CH 2 C(CH 3 ) 2 -.
  • the hydrolysis may be carried out using an aqueous solution of a suitable acid such as hydrochloric acid at from room temperature to the reflux
  • the compounds of the formula (I) wherein R 10 is CONH 2 and X, Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) may be prepared by partial hydrolysis of a compound of the formula (IV) wherein X, Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I). The hydrolysis may be carried out using concentrated sulphuric acid at from 0°C to room temperature.
  • 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. by sulphuric acid or p-toluenesulphonic acid, at from room temperature to the reflux temperature.
  • acid catalysis e.g. by sulphuric acid or p-toluenesulphonic acid
  • the water generated during the reaction may be removed by azeotropi ⁇ distillation or by the use of a
  • the esterification may also be carried out by
  • 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 11 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.
  • An imidazolide may be formed by reacting the carboxylic acid with 1,1'- carbonyldiimidazole in a suitable solvent, e.g.
  • X, Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) and Z 1 is a suitable leaving group, e.g. chloro or bromo, with an alcohol of the formula R 11 OH wherein R 11 is as previously defined for this method.
  • the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0°C to room temperature.
  • an acid acceptor e.g. pyridine
  • a suitable solvent e.g. dichloromethane
  • the compounds of the formula (I) wherein R 10 is COOR 11 wherein X, Y, R, R 1 to R 9 and R 11 are as previously defined for a compound of the formula (I) may be prepared by reaction of a base salt of a compound of the formula (I) wherein R 10 is COOH and X, Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) (i.e. a carboxylate base salt) with a compound of the formula R 11 Z 2 wherein R 11 is as previously defined for a compound of the formula (I) and Z 2 is a suitable leaving group, e.g. halo, preferably bromo or iodo, or p-toluenesulphonyloxy.
  • Preferred base salts of the compounds of the formula (I) for use in this method are the sodium and
  • reaction may be carried out in a suitable solvent, e.g. dimethylformamide or
  • CONR 12 R 13 and X, Y, R, R 1 to R 9 , R 12 and R 13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (I) wherein R 10 is COOH and X, Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I), with an amine of the formula R 12 R 13 NH wherein R 12 and R 13 are as previously defined for this method, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide.
  • the reaction may be carried out in a suitable organic solvent, e.g.
  • reaction 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 amine of the formula R 12 R 13 NH. Suitable procedures for the formation of an activated ester or imidazolide are described in method (7).
  • CONR 12 R 13 and X, Y, R, R 1 to R 9 , R 12 and R 13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (VI) wherein X, Y, R, R 1 to R 9 and Z 1 are as previously defined for a compound of the formula (VI), with an amine of the formula R 1Z R 13 NH wherein R 12 and R 13 are as previously defined for this method.
  • the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0°C to room temperature.
  • CONR 12 R 13 and X, Y, R, R 1 to R 9 , R 12 and R 13 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (II) wherein R 14 is a suitable ester-forming group, e.g. C 1 -C 6 alkyl or an alternative biolabile ester-forming group as previously defined (i.e. a compound of the formula (I) wherein R 10 is COOR 11 ), or p-nitrophenyl, and X, Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I), with an amine of the formula R 12 R 13 NH wherein R 12 and R 13 are as previously defined for this method.
  • the reaction may be carried out in a suitable solvent, e.g. a C 1 -C 4 alkanol, at from room
  • the reaction is usually carried using an excess of the amine and in a sealed reaction vessel.
  • R 18 and R 19 are either each C 1 -C 4 alkyl or when taken together represent C 2 -C 3 alkylene, said alkylene group being optionally substituted by C 1 -C 4 alkyl, and R 20 is OH, OR 21 wherein R 21 is a suitable ester-forming group that may be removed by hydrolysis, e.g. C 1 -C 6 alkyl or an
  • hydrolysis may be carried out using a suitable acid, e.g. hydrochloric acid or p-toluenesulphoni ⁇ acid, in the presence of water.
  • a suitable acid e.g. hydrochloric acid or p-toluenesulphoni ⁇ acid
  • a compound of the formula (VII) may be prepared by first forming the corresponding ketal of a compound of the formula (VIII) wherein X, R and R 1 to R 9 are as previously defined for this method by reacting with the corresponding alcohol under acidic
  • compound of the formula (I) may be prepared by alkylation of a base salt (i.e. the N-deprotonated form) of a compound of the formula:-
  • X, R and R 1 to R 9 are as previously defined for a compound of the formula (I), with a compound of the formula Z 3 -Y-COOR 22 , Z 3 -Y-CONR 12 R 13 or a base salt of a compound of the formula Z 3 -Y-COOH, as appropriate, wherein Y, R 12 and R 13 are as previously defined for a compound of the formula (I), Z 3 is a leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or p- toluenesulphonyloxy, and R 22 is a biolabile ester- forming group as previously defined for R 11 .
  • Z 3 is a leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or p- toluenesulphonyloxy
  • R 22 is a biolabile ester- forming
  • the preferred base salts of the compounds of the formula Z 3 -Y-COOH are the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts.
  • the preferred base salts of the compounds of the formula (VIII) are the alkali metal salts, e.g. the sodium and potassium salts.
  • the reaction may be performed by initial
  • reaction may also be carried out using potassium carbonate as the base and in 2- butanone as the solvent at about the reflux
  • reaction may be carried out under phase transfer conditions where a suitable base is sodium or potassium hydroxide.
  • R 23 is either OR 24 wherein R 24 is a biolabile ester-forming group as previously defined for R 11 , or is NR 12 R 13 wherein R 12 and R 13 are as previously defined for a compound of the formula (I), with a compound of the formula:-
  • X and R 5 to R 9 are as previously defined for this method and Z 4 is a leaving group, e.g. halo, preferably chloro, and in the presence of a Lewis acid where R is not OH and optionally in the presence of a Lewis acid where R is OH.
  • Suitable Lewis acids include aluminium chloride and
  • the reaction may be carried out in a suitable solvent, e.g. toluene, at from room temperature to the reflux temperature.
  • a suitable solvent e.g. toluene
  • the preferred base salts of the indoles of the formula (X) are the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts.
  • an indole of the formula (IX) where R is OH or a base salt of an indole of the formula (X) where R is OH should first be treated with one equivalent of a suitable base, e.g. calcium
  • the reaction may be carried out by ozonolysis or by treatment with aqueous potassium permanganate
  • Z 6 is a leaving group, e.g. chloro or bromo, with a phenol of the formula (XIV) wherein R 5 to R 9 are as
  • the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0°C to room temperature.
  • an acid acceptor e.g. pyridine
  • a suitable solvent e.g. dichloromethane
  • R 24 is H or C 1 -C 4 alkyl and R 5 to R 9 are as previously defined for this method.
  • the reaction may be carried out in the presence of a suitable dehydrating agent, e.g.
  • reaction may be carried out by first forming an activated ester or
  • the compounds of the formula (I) wherein X, Y, R and R 1 to R 10 are as defined for a compound of the formula (I) in method (19) may be prepared by reaction of a compound of the formula (XV) wherein Y, R, R 1 to R 4 , R 11 , R 12 and R 13 are as previously defined for this method and Z 6 is as previously defined for a compound of the formula (XV), with an amine of the formula (XVI) wherein R 5 to R 9 and R 24 are as previously defined for an amine of the formula (XVI).
  • the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0°C to room temperature.
  • R 25 is a suitable ester- forming group, e.g. C 1 -C 4 alkyl or p-nitrophenyl, with an amine of the formula (XVI) wherein R 5 to R 9 are as previously defined for this method and R 24 is as previously defined for a compound of the formula (XVI).
  • the reaction may be carried out in a suitable solvent, e.g. a C 1 -C 4 alkanol, at from room
  • the compounds of the formula (I) wherein X is C 2 -C 4 alkylene optionally substituted by C 1 -C 4 alkyl or aryl, and Y, R and R 1 to R 10 are as previously defined for a compound of the formula (I), may be prepared by reduction of a compound of the formula (I) wherein X is C 2 -C 4 alkenylene or C 2 -C 4 alkynylene, said alkenylene or alkynylene group being optionally substituted by C 1 -C 4 alkyl or aryl, and Y, R and R 1 to R 10 are as previously defined for a compound of the formula (I).
  • the reduction may be carried out using hydrogen in the presence of a suitable catalyst, e.g. palladium- on-charcoal, and in a suitable solvent, e.g. ethanol or ethyl acetate, at from room temperature to the reflux temperature and at a pressure of from one to five atmospheres (1.01 x 10 5 to 5.07 x 10 5 Pa).
  • a suitable catalyst e.g. palladium- on-charcoal
  • a suitable solvent e.g. ethanol or ethyl acetate
  • R 6 , R 7 and R 8 is a group of the formula -Z(C 1 -C 15 alkyl) or -Z(C 3 -C 7 cycloalkyl), the alkyl of
  • said -Z(C 1 -C 15 alkyl) group being optionally
  • Z is O, S, NH or N(C 1 -C 6 alkyl) and the
  • R 6 , R 7 and R 8 , R 5 , R 9 , X, Y, R, R 1 to R 4 , R 10 and "aryl" are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula:-
  • R 27 , R 28 and R 29 is a group of the formula -Z 7 -H wherein Z 7 is O, S, NH or N(C 1 -C 6 alkyl) and the remainder of R 27 , R 28 and R 29 are as previously defined for this method for the remainder of R 6 , R 7 and R 8 , R 26 and R 30 are as previously defined for this method for R 5 and R 9 and X, Y, R, R 1 to R 4 and R 10 are as previously defined for this method, with a compound of the formula R 31 Z 8 wherein R 31 is C 1 -C 15 alkyl or C 3 -C 7 cycloalkyl, as appropriate, said alkyl group being optionally substituted by C 1 -C 10 alkoxy, aryl, C 3 -C 7 cycloalkyl or a group of the formula -Z(aryl), wherein "aryl" and Z are as
  • Z 8 is a suitable leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or p-toluenesulphonyloxy.
  • halo preferably chloro, bromo or iodo, methanesulphonyloxy or p-toluenesulphonyloxy.
  • the preferred base salts of the compounds of the formula (XIX) are the sodium and potassium salts.
  • thiophenoxide base salt of a compound of the formula (XIX) which may be generated in situ from the corresponding phenol or thiophenol of the formula (XIX) using a suitable base, e.g. sodium or potassium hydroxide or sodium hydride, and in a suitable solvent, e.g. ethanol or N,N- dimethylformamide, at from 0°C to the reflux
  • a suitable base e.g. sodium or potassium hydroxide or sodium hydride
  • a suitable solvent e.g. ethanol or N,N- dimethylformamide
  • a compound of the formula (XIX) may be reacted with a compound of the formula R 31 Z 8 in the presence of an additional acid acceptor, e.g. pyridine, and in a suitable organic solvent, e.g. dichloromethane.
  • an additional acid acceptor e.g. pyridine
  • a suitable organic solvent e.g. dichloromethane.
  • cycloalkyl the alkyl of said -O(C 1 -C 15 alkyl) group being optionally substituted by C 1 -C 10 alkoxy, aryl, C 3 -C 7 cycloalkyl or a group of the formula -Z(aryl), and the remainder of R 6 , R 7 and R 8 , R 5 , R 9 , X, Y, z, R, R 1 to R 4 , R 11 , R 12 , R 13 and "aryl" are as previously defined for a compound of the formula (I), may be prepared by reaction of a compound of the formula (XIX) wherein one of R 27 , R 28 and R 29 is OH and the remainder of R 27 , R 28 and R 29 and R 26 and R 30 are as previously defined for a compound of the formula (XIX) in method (24) and X, Y, R, R 1 to R 4 and R 10 are as previously defined for this method, with a
  • R 32 OH
  • R 32 is C 1 -C 15 alkyl, aryl or C 3 -C 7 cycloalkyl, as appropriate.
  • said alkyl group being optionally substituted by C 1 - C 10 alkoxy, aryl, C 3 -C 7 cycloalkyl or a group of the formula -Z(aryl), wherein "aryl" and Z are as previously defined for this method, in the presence of a suitable dehydrating agent, e.g.
  • the reaction may be carried out in a suitable solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature.
  • a suitable solvent e.g. tetrahydrofuran
  • the compounds of the formula (I) wherein X is CH(C 1 - C 4 alkyl), R 10 is COOR 11 or CONR 12 R 13 and Y, R, R 1 to R 9 , R 11 , R 12 and R 13 are as previously defined for a compound of the formula (I), may be prepared by alkylation of a base salt of a compound of the formula (I) wherein X is CH 2 and Y, R and R 1 to R 13 are as previously defined for this method, with a compound of the formula (C 1 -C 4 alkyl) Z 9 wherein Z 9 is a suitable leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or
  • the preferred base salts of the compounds of the formula (I) for use in this method are the sodium and potassium salts.
  • the reaction may be carried out by first reacting a compound of the formula (I) wherein X is CH 2 with a suitable base, e.g. sodium hydride, and in a
  • a pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or is recovered by evaporation of the solvent.
  • the compounds of the formula (I) are steroid 5 ⁇ - reductase inhibitors and they are therefore 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.
  • Certain compounds of the formula (I) are also useful in the treatment of human prostate
  • the compounds of the formula (I) may be tested in vitro for steroid 5 ⁇ -reductase inhibitory activity using prostate tissue from rats or humans.
  • the compounds of the formula (I) may be tested for potency in inhibiting rat steroid 5 ⁇ -reductase using ventral prostate tissue from male rats.
  • 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
  • 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 human steroid 5 ⁇ -reductase using tissue from hyperplastic human prostates. In determining inhibitory potency against human prostatic 5 ⁇ -reductase 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, ImM dithiothreitol and 50 ⁇ M NADPH) with an Ultra-Turrax (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 (1ml per g of prostate tissue originally used) with the Ultra- Turrax homogeniser. This particulate preparation was then filtered through 2 layers of cheesecloth and the filtrate was stored as 1ml samples at -70°C.
  • NADPH 50mM glucose 6-phosphate, 5 units/ml glucose 6-phosphate dehydrogenase), a compound of the formula (I) dissolved in 5 ⁇ l of dimethyl sulphoxide, and Buffer B to give a final reaction volume of 1ml.
  • the mixture was warmed to 37°C and the reaction started by addition of an aliquot of prostate particulate suspension.
  • the 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
  • 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:-
  • DMEM Dulbecco's Modified Eagles medium
  • the radiochemical content in the bands of the substrate (testosterone) and the product (5 ⁇ - dihydrotestosterone) was determined with a RITA
  • the compounds of the formula (I) can be administered alone but will generally be
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they can be administered orally in the form of tablets containing 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,
  • 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 formula (I) will 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
  • tablets or capsules of the compounds will contain from lmg 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 above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • 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.
  • 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
  • a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be
  • the compounds of the formula (I) may also be any organic compound.
  • the compounds of the formula (I) may also be any organic compound.
  • ce-antagonist e.g.
  • an antiandrogen e.g.
  • composition comprising a
  • composition thereof for the manufacture of a medicament for inhibiting a steroid 5 ⁇ - reductase
  • composition thereof for the manufacture of a medicament for the curative or prophylactic treatment of acne vulgaris, alopecia,
  • Example 35 (1g) in ethyl acetate (25ml) was hydrogenated in the presence of 10% palladium-on-charcoal (250mg) at 4.15 x 10 5 Pa for 4.5 hours. The reaction was filtered through a cellulose-based filter aid and the filtrate concentrated in vacuo. The residual oil was
  • dichloromethane 200ml was added pyridine (7.5ml) followed by a solution of the acid chloride prepared above in dichloromethane (200ml). After stirring
  • the title compound was prepared using a similar method to that described in illustrative Method 5 except using 4-benzyloxyphenylacetic acid as the starting material. The material obtained was used immediately.
  • the title compound was prepared using a similar method to that described in illustrative Method 5 except using (E)-3-(4-benzyloxyphenyl)propenoic acid as the starting material. The material obtained was used immediately.
  • Example 36 was tested in vitro for steroid 5 ⁇ -reductase inhibitory activity using tissue from hyperplastic human prostates by the procedure outlined on pages 35 to 37 of the specification. An IC 50 value of 89.7nM was obtained for this compound.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Composés répondant à la formule (I), et leurs sels pharmaceutiquement acceptables, dans laquelle X représente O, NH, N(alkyle C1-4), alkylène C1-4, alcénylène C2-4, ou alcynylène C2-4, lesdits groupes alkylène, alcénylène et alcynylène étant éventuellement substitués par alkyle C1-4 ou par aryle; Y représente alkylène C1-6 éventuellement substitué par aryle C1-6; R représente H, OH, halo, alkyle C1-4 ou alcoxy C1-4; R?1, R2, R3 et R4¿, indépendamment les uns des autres, sont sélectionnés parmi H, alkyle C¿1-4?, alcoxy C1-4, OH, halo et CF3; l'un de R?6, R7 et R8¿ représente alkyle C¿1-15? ou un groupe répondant à la formule -Z(alkyle C1-15), -Z(aryle) ou -Z(cycloalkyle C3-7), ledit groupe alkyle étant éventuellement interrompu par O, S(O)q, NH ou N(alkyle C1-6), et ledit groupe alkyle ainsi que le groupe alkyle dudit groupe -Z(alkyle C1-15) étant éventuellement substitués par alcoxy C1-10, aryle, cycloalkyle C3-7, ou un groupe répondant à la formule -Z(aryle), les autres parmi R?6, R7 et R8¿, ainsi que R5 et R9, indépendamment les uns des autres, étant sélectionnés parmi H, alkyle C¿1-4?, alcoxy C1-4, halo et halo(alkyle C1-4); R?10¿ représente COOH, COOR11 ou CONR?12R13; R11¿ représente un groupe biolabile à formation d'esters; R?12 et R13¿ indépendamment l'un de l'autre, sont sélectionnés parmi H et alkyle C¿1-4?; Z représente O, S(O)q, NH ou N(alkyle C1-6); q vaut 0, 1 ou 2; et le terme ''aryle'', tel qu'il est employé dans les définitions de X, R?6, R7 et R8¿, signifie phényle éventuellement substitué par alkyle C¿1-6?, alcoxy C1-6, alcényle C2-6, OH, halo, CF3, halo(alkyle C1-6), nitro, amino, alcanamido C2-6, alcanoyle C2-6 ou phényle; compositions pharmaceutiques les contenant; leurs procédés de préparation; et leurs utilisations.
PCT/EP1992/001626 1991-07-24 1992-07-20 Indoles WO1993002051A1 (fr)

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JP5502592A JPH06511483A (ja) 1991-07-24 1992-07-20 インドール類
EP92915891A EP0598754A1 (fr) 1991-07-24 1992-07-20 Indoles
FI940311A FI940311A7 (fi) 1991-07-24 1994-01-21 Indoleja
NO940237A NO940237L (no) 1991-07-24 1994-01-24 Indoler

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GB9115951.7 1991-07-24

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CA (2) CA2112678A1 (fr)
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FI (2) FI940311A7 (fr)
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IE (2) IE922386A1 (fr)
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PT (2) PT100718A (fr)
SK (1) SK8494A3 (fr)
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994018168A1 (fr) * 1993-02-10 1994-08-18 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole utilises comme inhibiteurs de 5-alpha-reductase
WO1994022821A1 (fr) * 1993-04-05 1994-10-13 Fujisawa Pharmaceutical Co., Ltd. Derives de l'indole utilises en tant qu'inhibiteurs de la 5-alpha-reductase de testosterone
WO1994026710A1 (fr) * 1993-05-17 1994-11-24 Fujisawa Pharmaceutical Co., Ltd. DERIVES D'INDOLE UTILES COMME INHIBITEURS DE LA TESTOSTERONE 5α-REDUCTASE
WO1995005375A1 (fr) * 1993-08-17 1995-02-23 Pfizer Limited Derives d'indole en tant qu'inhibiteurs de 5-alpha-reductase-1
WO1995026955A1 (fr) * 1994-03-30 1995-10-12 Zeria Pharmaceutical Co., Ltd. Derive d'indole et medicament le contenant
WO1995031453A1 (fr) * 1994-05-13 1995-11-23 Pfizer Limited Derives d'indole a titre d'inhibiteurs de la 5-alpha-reductase 1
US6602914B2 (en) 1997-05-14 2003-08-05 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6670398B2 (en) 1997-05-14 2003-12-30 Atherogenics, Inc. Compounds and methods for treating transplant rejection
US8252840B2 (en) 2007-03-26 2012-08-28 Salutria Pharmaceuticals Llc Methods of derivatives of probucol for the treatment of type II diabetes
US11016096B2 (en) * 2016-09-27 2021-05-25 Kaohsiung Medical University Detection kit for quaternary ammonium compound having γ-carboxyl group

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9204024D0 (en) * 1992-02-25 1992-04-08 Fujisawa Pharmaceutical Co Indole derivatives
US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
US7417063B2 (en) 2004-04-13 2008-08-26 Bristol-Myers Squibb Company Bicyclic heterocycles useful as serine protease inhibitors
FR2893615B1 (fr) * 2005-11-18 2008-03-07 Sanofi Aventis Sa Derives de 3-acylindole, leur preparation et leur application en therapeutique
PE20090159A1 (es) 2007-03-08 2009-02-21 Plexxikon Inc COMPUESTOS DERIVADOS DE ACIDO INDOL-PROPIONICO COMO MODULADORES PPARs

Citations (1)

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Publication number Priority date Publication date Assignee Title
EP0458207A2 (fr) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'indole

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993005020A1 (fr) * 1991-09-06 1993-03-18 Merck & Co., Inc. Indoles utilises comme inhibiteurs de la transcriptase inverse du vih

Patent Citations (1)

* 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
European Journal of Medicinal Chemistry, vol. 10, no. 2, March-April 1975, (Paris, FR), A. ALLAIS et al.: "Recherche d'analgésiques non narcotiques et d'anti-inflammatoires dans la série des carboxyalcoyl-1 acyl-3 indoles", pages 187-199, see page 194, table X, compounds with Ar=-CH=CH- *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994018168A1 (fr) * 1993-02-10 1994-08-18 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole utilises comme inhibiteurs de 5-alpha-reductase
WO1994022821A1 (fr) * 1993-04-05 1994-10-13 Fujisawa Pharmaceutical Co., Ltd. Derives de l'indole utilises en tant qu'inhibiteurs de la 5-alpha-reductase de testosterone
US5530019A (en) * 1993-04-05 1996-06-25 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives useful as testosterone 5α-reductase inhibitors
WO1994026710A1 (fr) * 1993-05-17 1994-11-24 Fujisawa Pharmaceutical Co., Ltd. DERIVES D'INDOLE UTILES COMME INHIBITEURS DE LA TESTOSTERONE 5α-REDUCTASE
WO1995005375A1 (fr) * 1993-08-17 1995-02-23 Pfizer Limited Derives d'indole en tant qu'inhibiteurs de 5-alpha-reductase-1
US5912357A (en) * 1993-08-17 1999-06-15 Pfizer Inc Indole derivatives as 5-α-reductase-1-inhibitors
WO1995026955A1 (fr) * 1994-03-30 1995-10-12 Zeria Pharmaceutical Co., Ltd. Derive d'indole et medicament le contenant
WO1995031453A1 (fr) * 1994-05-13 1995-11-23 Pfizer Limited Derives d'indole a titre d'inhibiteurs de la 5-alpha-reductase 1
US6602914B2 (en) 1997-05-14 2003-08-05 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6617352B2 (en) 1997-05-14 2003-09-09 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6670398B2 (en) 1997-05-14 2003-12-30 Atherogenics, Inc. Compounds and methods for treating transplant rejection
US6828447B2 (en) 1997-05-14 2004-12-07 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US7087645B2 (en) 1997-05-14 2006-08-08 Atherogenics, Inc. Compounds and methods for treating transplant rejection
US7189870B2 (en) 1997-05-14 2007-03-13 Atherogenic, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US7375252B2 (en) 1997-05-14 2008-05-20 Atherogenics, Inc. Compounds and method for the inhibition of the expression of VCAM-1
US8252840B2 (en) 2007-03-26 2012-08-28 Salutria Pharmaceuticals Llc Methods of derivatives of probucol for the treatment of type II diabetes
US11016096B2 (en) * 2016-09-27 2021-05-25 Kaohsiung Medical University Detection kit for quaternary ammonium compound having γ-carboxyl group

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NO940237D0 (no) 1994-01-24
JPH06509336A (ja) 1994-10-20
HU9400199D0 (en) 1994-05-30
FI940311A0 (fi) 1994-01-21
NZ243687A (en) 1994-12-22
AU2327192A (en) 1993-02-23
WO1993002050A1 (fr) 1993-02-04
CN1068816A (zh) 1993-02-10
BR9206306A (pt) 1994-11-08
EP0598750A1 (fr) 1994-06-01
ZA925547B (en) 1994-01-24
SK8494A3 (en) 1994-11-09
IL102544A0 (en) 1993-01-14
IE922386A1 (en) 1993-01-27
CA2112678A1 (fr) 1993-02-04
PT100717A (pt) 1993-08-31
NO940237L (no) 1994-01-24
ZA925546B (en) 1994-01-24
IL102545A0 (en) 1993-01-14
IE922387A1 (en) 1993-01-27
JPH06511483A (ja) 1994-12-22
PT100718A (pt) 1993-08-31
FI940310A7 (fi) 1994-01-21
CA2112689A1 (fr) 1993-02-04
GB9115951D0 (en) 1991-09-11
FI940310A0 (fi) 1994-01-21
FI940311A7 (fi) 1994-01-21
EP0598754A1 (fr) 1994-06-01
MX9204342A (es) 1994-03-31
CN1068817A (zh) 1993-02-10
CZ13694A3 (en) 1994-07-13
TW223060B (fr) 1994-05-01
AU655662B2 (en) 1995-01-05
AU2327092A (en) 1993-02-23

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