WO1993002050A1 - Indoles - Google Patents

Indoles Download PDF

Info

Publication number
WO1993002050A1
WO1993002050A1 PCT/EP1992/001625 EP9201625W WO9302050A1 WO 1993002050 A1 WO1993002050 A1 WO 1993002050A1 EP 9201625 W EP9201625 W EP 9201625W WO 9302050 A1 WO9302050 A1 WO 9302050A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
alkyl
aryl
phenyl
Prior art date
Application number
PCT/EP1992/001625
Other languages
English (en)
French (fr)
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 BR9206306A priority Critical patent/BR9206306A/pt
Priority to JP5502591A priority patent/JPH06509336A/ja
Priority to CS94136A priority patent/CZ13694A3/cs
Priority to EP92915417A priority patent/EP0598750A1/en
Priority to SK84-94A priority patent/SK8494A3/sk
Priority to AU23270/92A priority patent/AU655662B2/en
Publication of WO1993002050A1 publication Critical patent/WO1993002050A1/en
Priority to FI940310A priority patent/FI940310A7/fi

Links

Classifications

    • 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 Sce-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:-
  • Y is C 1 -C 6 alkylene optionally substituted by
  • 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 ; one of R 6 , R 7 and R 8 is a group of the formula:-
  • 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 ;
  • R 14 is H, C 1 -C 6 alkyl , C 3 -C 7 cycloalkyl or aryl ; and "aryl" , used in the definitions of R 6 , R 7 , R 8 and R 14 , 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 .
  • 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 ; one of R 6 , R 7 and R 8 is a group of the formula : -
  • CH-Aryl or -CHO-Aryl are each independently selected from H, 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
  • R 14 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or aryl; and "aryl" , used in the definitions of R 6 , R 7 , R 8 and R 14 , 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 3 alkanoyl or phenyl: with the provisos
  • R 7 is 1-(4-(2-methylpropyl)- phenyl)propoxy or 2,2-dimethyl-1-(4-(2- methylpropyl)phenyl)propoxy
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are all H and Y is -(CH 2 ) 3 -, that R 10 is not COOH or COOC 2 H 5 when the compound of the formula (I) is in the racemic form;
  • R 7 is bis(4-(2-methylpropyl)phenyl)- methoxy
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are all H and Y is -(CH 2 ) 3 -, that R 10 is not COOH;
  • R 6 is bis(4-(2-methylpropyl)phenyl)- methoxy
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are all H and Y is -(CH 2 ) 3 -, that R 10 is not COOH;
  • R 6 is 4-(2-methylpropyl)phenoxymethyl or 3- (2-methylpropyl)phenoxymethyl
  • R, R 1 , R z , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are all H and Y is -(CH 2 ) 3 -, that R 10 is not COOH or
  • 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 8 alkyl) are steroid 5 ⁇ -reductase inhibitors per se but, in general, where R 10 is COOR 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
  • Y is C 1 -C 6 alkylene.
  • Y is methylene, propylene, butylene or pentylene.
  • Y is propylene
  • R is H or C 1 -C 4 alkyl.
  • R is H or methyl
  • R is H.
  • R 1 , R 2 , R 3 and R 4 are each H.
  • R 6 , R 7 and R 8 is a group of the formula:-
  • R 7 is a group of the formula:-
  • R 5 , R 6 , R 8 and R 9 are each independently selected from H and C 1 -C 4 alkyl.
  • R 7 is a group of the formula:- -O
  • 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
  • R 14 is H, C 1 -C 4 alkyl, C 4 -C 6 cycloalkyl or phenyl substituted by C 1 -C 4 alkyl.
  • R 14 is H, methyl, n-propyl
  • R 14 is methyl
  • 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 or halo, more preferably means phenyl optionally
  • 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
  • a preferred group of compounds of the formula (I) is where one of R 6 , R 7 and R 8 is a group of the formula:-
  • R 15 is a suitable ester-forming group and Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I).
  • suitable 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 15 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.
  • the hydrolysis is typically carried out at from room temperature to the reflux temperature and preferably is carried out 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 15 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 compounds of the formula (I) wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) may be prepared by hydrolysis of a compound of the formula (I) wherein
  • R 10 is CONR 12 R 13 and Y, R, R 1 to R 9 , R 12 and R 13 are as previously defined for a compound of the formula (I).
  • 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
  • Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) and R 16 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
  • a suitable acid e.g. hydrochloric or sulphuric acid
  • a suitable inorganic base e.g. sodium or potassium hydroxide
  • hydrogen peroxide may optionally be present and also the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
  • Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) and R 17 and R 18 taken together represent ethylene, said ethylene group being optionally substituted by phenyl or C 1 -C 4 alkyl (preferably methyl).
  • R 17 and R 18 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 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 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 compounds of the formula (I) wherein R 10 is COOR 11 and 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 esterification of a compound of the formula (I) wherein R 10 is COOH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I) 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 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.
  • 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 dehydrating agent, e.g.
  • 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. 1-(3- N,N-dimethylaminopropyl)-3-ethylcarbodiimide, and in a suitable solvent, e.g. dichloromethane, at room temperature.
  • a suitable dehydrating agent e.g. 1-(3- N,N-dimethylaminopropyl)-3-ethylcarbodiimide
  • a suitable solvent e.g. dichloromethane
  • 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
  • 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 potassium salts.
  • the reaction may be carried out in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran, at from room temperature to the reflux temperature.
  • a compound of the formula (I) may be prepared by reaction of a compound of the formula (I) wherein R 10 is COOH and 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).
  • a compound of the formula (I) may be prepared by reaction of a compound of the formula (VI) wherein 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 12 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.
  • a compound of the formula (I) may be prepared by reaction of a compound of the formula (II) wherein R 15 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 Y, R and R 1 to R 9 are as
  • reaction may be carried out in a suitable solvent, e.g. a C 1 -C 4 alkanol, at from room temperature to the reflux temperature.
  • a suitable solvent e.g. a C 1 -C 4 alkanol
  • reaction vessel e.g. a bomb
  • R 19 and R 20 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
  • R 21 is -OH, -OR 22 wherein R 22 is a suitable ester-forming group that may be removed by hydrolysis, e.g. C 1 -C 6 alkyl or an alternative biolabile ester-forming group as
  • a compound of the formula (VII) may be prepared by first forming the corresponding ketal of a compound of the formula (VIII) wherein R and R 1 to R 9 are as previously defined for this method by reacting with the corresponding alcohol under acidic conditions, e.g. see T.W. Greene and P.G. Wuts, "Protective Groups in Organic Synthesis", Wiley-Interscience (2nd edition, 1991), followed by N-alkylation of the ketal by a similar procedure to that described in method (14) for alkylation of a compound of the formula (VIII).
  • a suitable acid e.g. hydrochloric acid or p-toluenesulphonic acid
  • 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:-
  • 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 n or Z 3 -Y-CONR 12 R 13 or with a base salt of a compound of the formula Z 3 -Y-COOH, as appropriate, wherein Y, R 11 , R 12 and R 13 are as previously defined for a compound of the formula (I) and Z 3 is a leaving group, e.g. halo, preferably chloro, bromo or iodo, methanesulphonyloxy or p- toluenesulphonyloxy.
  • 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 or acetone as the solvent at about the reflux temperature of the solvent.
  • reaction may be carried out under phase transfer conditions where a suitable base is sodium or potassium hydroxide.
  • a suitable base is 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.
  • 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. Where a compound of the formula (I) wherein R 10 is COOH is required the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
  • 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 solution.
  • Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I).
  • a suitable oxidising agent for this purpose is chromium
  • R 24 is H or OH and Y, R and R 1 to R 9 are as previously defined for a compound of the formula (I).
  • a suitable oxidising agent for this purpose is chromium trioxide-pyridine complex.
  • the oxidation may alternatively be carried out on a compound of the formula (XV) wherein R 24 is H using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidising agent.
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • the oxidation may alternatively be carried out on a compound of the formula (XV) wherein R 24 is OH using manganese dioxide as the oxidising agent or under the conditions of the Swern oxidation reaction.
  • the starting materials of the formula (XIV) or (XV) wherein R 24 is H may be prepared by reacting the corresponding 1H-indole-1-magnesium halide
  • R 5 to R 9 are as previously defined for this method and Z 6 is halo, preferably chloro or bromo, followed by N-alkylation of the indole by a similar procedure to that described in method (14).
  • a starting material of the formula (XIV) or (XV) wherein R 24 is OH may be prepared by reacting the corresponding 1H-indole-1-magnesium halide
  • R 5 to R 9 are as previously defined for this method.
  • R 7 and R 8 is a group of the formula:-
  • R 10 R 14 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 25 , R 26 and R 27 is OH and the remainder of R 25 ,26 and R 27 are as previously defined in this method for the remainder of R 6 , R 7 and R 8 , and Y, R, R 1 to R 5 , R 9 and R 10 are as previously defined for this method, with a compound of the formula:-
  • Z 7 -CH-Aryl .... (XIX) wherein R 14 and "aryl" are as previously defined for this method and Z 7 is a suitable leaving group, e.g. halo, preferably chloro, bromo or iodo,
  • the preferred base salts of the compounds of the formula (XVIII) are the sodium and potassium salts.
  • the reaction is preferably carried out using a base salt of a compound of the formula (XVIII) (i.e. a phenoxide) which may be generated in situ from the corresponding phenol of the formula (XVIII) using a suitable base, e.g. sodium or potassium hydroxide or sodium hydride, and in a suitable solvent, e.g.
  • reaction may also be carried out using potassium carbonate as the base and in 2-butanone or acetone as the solvent at about the reflux temperature of the solvent.
  • R 11 , R 12 , R 13 and Y, R, R 1 to R 5 and R 9 are as previously defined for this method and
  • R 25 to R 27 are as previously defined for a compound of the formula (XVIII) in method (19), with a compound of the formula:-
  • dehydrating agent e.g. diethylazodicarboxylate/ triphenylphosphine.
  • the reaction may be carried out in a suitable solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature.
  • R 7 and R 8 is a group of the formula:-
  • R 28 , R 29 and R 30 is a group of the formula:-
  • a base salt of a compound of the formula (XXII) (i.e. a phenoxide) may be generated in situ from the corresponding phenol of the formula (XXII) using a suitable base, e.g. sodium or potassium hydroxide or sodium hydride, and in a suitable solvent, e.g.
  • reaction may also be
  • a phenol of the formula (XXII) with a compound of the formula (XXI) in the presence of potassium carbonate and in a suitable solvent, e.g. 2-butanone, at up to, and preferably at, the reflux temperature of the solvent.
  • a suitable solvent e.g. 2-butanone
  • R 31 , R 32 and R 33 is a group of the formula:-
  • triphenylphosphine 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
  • 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 adenocarcinomas.
  • 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.
  • 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 (1000rpm) Potter Elvehjem (teflon-to- glass) homogeniser.
  • 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.,
  • 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 5ot-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, lmM dithiothreitol and 50 ⁇ M NADPH) with an Ultra-Turrax (Janke and Kunkel GmBH & Co. , Staufen i . BR. , Germany) . The homogenate was
  • 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 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.,
  • 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.
  • inhibitory potency against 5 ce-reductase the following procedure was employed:- Human prostate adenocarcinoma cell lines were grown in Dulbecco's Modified Eagles medium (DMEM)
  • the cells were recovered from the medium by centrifugation, washed in serum free DMEM and suspended at 5-10 x 10 6 cells/ml. in serum free medium.
  • test tube 10 ⁇ l of [ 3 H]-testosterone (1 ⁇ Ci, 20 pmol) dissolved in ethanol (Du Pont, NEN Research Products,
  • 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 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,
  • 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 aay be
  • the compounds of the formula (I) may also be administered together with an ot-antagonist (e.g. prazosin or doxazosin), 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,
  • a method of treatment of a human to inhibit a steroid 5 ⁇ -reductase which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof;
  • DMF dry dimethylformamide
  • the title compound may also be prepared by
  • Example 38 were prepared by similar methods to that used in Example 38 using the corresponding indoles (see Preparations 5 to 8) and the corresponding ethyl bromoalkanoates as the starting materials.
  • alkyl bromides were prepared by dissolving the corresponding alcohol (see Preparations 12 to 16 and 19) in dichloromethane and cooling the solution in an ice-bath whilst saturating with dry hydrogen bromide. After stirring the mixture for a short period the reaction was evaporated in vacuo to provide the desired alkyl bromide which was used directly without characterisation.
  • part (a) (13.5g) was dissolved in 95% aqueous ethanol (108ml), treated with 2N aqueous sodium hydroxide (32ml) and heated at 60-70°C for 90 minutes. The solvent was evaporated and water
  • the compound of Example 1 was administered orally to mice up to dose of 1000mg/kg and the animal showed normal appearance and behaviour throughout the duration of the study.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)
PCT/EP1992/001625 1991-07-24 1992-07-20 Indoles WO1993002050A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
BR9206306A BR9206306A (pt) 1991-07-24 1992-07-20 Indóis
JP5502591A JPH06509336A (ja) 1991-07-24 1992-07-20 インドール類
CS94136A CZ13694A3 (en) 1991-07-24 1992-07-20 Indoles, process of their preparation and pharmaceutical preparations based thereon
EP92915417A EP0598750A1 (en) 1991-07-24 1992-07-20 Indoles
SK84-94A SK8494A3 (en) 1991-07-24 1992-07-20 Endoles, method of their manufacturing and pharmaceutical preparations on their base
AU23270/92A AU655662B2 (en) 1991-07-24 1992-07-20 pndoles
FI940310A FI940310A7 (fi) 1991-07-24 1994-01-21 Indoleja

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919115951A GB9115951D0 (en) 1991-07-24 1991-07-24 Indoles
GB9115951.7 1991-07-24

Publications (1)

Publication Number Publication Date
WO1993002050A1 true WO1993002050A1 (en) 1993-02-04

Family

ID=10698873

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP1992/001625 WO1993002050A1 (en) 1991-07-24 1992-07-20 Indoles
PCT/EP1992/001626 WO1993002051A1 (en) 1991-07-24 1992-07-20 Indoles

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/001626 WO1993002051A1 (en) 1991-07-24 1992-07-20 Indoles

Country Status (20)

Country Link
EP (2) EP0598754A1 (enrdf_load_stackoverflow)
JP (2) JPH06509336A (enrdf_load_stackoverflow)
CN (2) CN1068816A (enrdf_load_stackoverflow)
AU (2) AU655662B2 (enrdf_load_stackoverflow)
BR (1) BR9206306A (enrdf_load_stackoverflow)
CA (2) CA2112678A1 (enrdf_load_stackoverflow)
CZ (1) CZ13694A3 (enrdf_load_stackoverflow)
FI (2) FI940311A7 (enrdf_load_stackoverflow)
GB (1) GB9115951D0 (enrdf_load_stackoverflow)
HU (1) HU9400199D0 (enrdf_load_stackoverflow)
IE (2) IE922387A1 (enrdf_load_stackoverflow)
IL (2) IL102544A0 (enrdf_load_stackoverflow)
MX (1) MX9204342A (enrdf_load_stackoverflow)
NO (1) NO940237L (enrdf_load_stackoverflow)
NZ (1) NZ243687A (enrdf_load_stackoverflow)
PT (2) PT100717A (enrdf_load_stackoverflow)
SK (1) SK8494A3 (enrdf_load_stackoverflow)
TW (1) TW223060B (enrdf_load_stackoverflow)
WO (2) WO1993002050A1 (enrdf_load_stackoverflow)
ZA (2) ZA925546B (enrdf_load_stackoverflow)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993016996A1 (en) * 1992-02-25 1993-09-02 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives as testosterone-5-alpha-reductase inhibitors
WO1994018168A1 (en) * 1993-02-10 1994-08-18 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives as 5-alpha-reductase inhibitors
WO1994026710A1 (en) * 1993-05-17 1994-11-24 Fujisawa Pharmaceutical Co., Ltd. INDOLE DERIVATIVES AS TESTOSTERONE 5α-REDUCTASE INHIBITORS
WO1995005375A1 (en) * 1993-08-17 1995-02-23 Pfizer Limited Indole derivatives as 5-alpha-reductase-1-inhibitors
WO1995026955A1 (fr) 1994-03-30 1995-10-12 Zeria Pharmaceutical Co., Ltd. Derive d'indole et medicament le contenant
WO1995031453A1 (en) * 1994-05-13 1995-11-23 Pfizer Limited Indole derivatives as 5 alpha-reductase 1 inhibitors
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
US8053463B2 (en) 2007-03-08 2011-11-08 Plexxikon Inc. PPAR active compounds

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5530019A (en) * 1993-04-05 1996-06-25 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives useful as testosterone 5α-reductase inhibitors
KR100953990B1 (ko) 1997-05-14 2010-04-21 아테로제닉스, 인코포레이티드 Ｖｃａｍ-1의 발현을 억제하기 위한 화합물 및 억제방법
US6670398B2 (en) 1997-05-14 2003-12-30 Atherogenics, Inc. Compounds and methods for treating transplant rejection
FR2893615B1 (fr) * 2005-11-18 2008-03-07 Sanofi Aventis Sa Derives de 3-acylindole, leur preparation et leur application en therapeutique
US8252840B2 (en) 2007-03-26 2012-08-28 Salutria Pharmaceuticals Llc Methods of derivatives of probucol for the treatment of type II diabetes
US10703969B2 (en) * 2016-09-27 2020-07-07 Kaohsiung Medical University Detection method for quaternary ammonium compound having γ-carboxyl group

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0458207A2 (en) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993005020A1 (en) * 1991-09-06 1993-03-18 Merck & Co., Inc. Indoles as inhibitors of hiv reverse transcriptase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0458207A2 (en) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
European Journal of Medicinal Chemistry - Chimica Therapeutica, 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 188, compound 15602 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993016996A1 (en) * 1992-02-25 1993-09-02 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives as testosterone-5-alpha-reductase inhibitors
WO1994018168A1 (en) * 1993-02-10 1994-08-18 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives as 5-alpha-reductase inhibitors
WO1994026710A1 (en) * 1993-05-17 1994-11-24 Fujisawa Pharmaceutical Co., Ltd. INDOLE DERIVATIVES AS TESTOSTERONE 5α-REDUCTASE INHIBITORS
WO1995005375A1 (en) * 1993-08-17 1995-02-23 Pfizer Limited Indole derivatives as 5-alpha-reductase-1-inhibitors
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 (en) * 1994-05-13 1995-11-23 Pfizer Limited Indole derivatives as 5 alpha-reductase 1 inhibitors
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
US8053463B2 (en) 2007-03-08 2011-11-08 Plexxikon Inc. PPAR active compounds

Also Published As

Publication number Publication date
NZ243687A (en) 1994-12-22
IL102545A0 (en) 1993-01-14
FI940310A0 (fi) 1994-01-21
CA2112689A1 (en) 1993-02-04
CN1068816A (zh) 1993-02-10
WO1993002051A1 (en) 1993-02-04
AU2327192A (en) 1993-02-23
HU9400199D0 (en) 1994-05-30
EP0598750A1 (en) 1994-06-01
FI940311A0 (fi) 1994-01-21
FI940311A7 (fi) 1994-01-21
AU655662B2 (en) 1995-01-05
AU2327092A (en) 1993-02-23
ZA925546B (en) 1994-01-24
CZ13694A3 (en) 1994-07-13
SK8494A3 (en) 1994-11-09
TW223060B (enrdf_load_stackoverflow) 1994-05-01
ZA925547B (en) 1994-01-24
PT100717A (pt) 1993-08-31
BR9206306A (pt) 1994-11-08
NO940237D0 (no) 1994-01-24
EP0598754A1 (en) 1994-06-01
CA2112678A1 (en) 1993-02-04
PT100718A (pt) 1993-08-31
IE922387A1 (en) 1993-01-27
JPH06511483A (ja) 1994-12-22
NO940237L (no) 1994-01-24
IE922386A1 (en) 1993-01-27
IL102544A0 (en) 1993-01-14
JPH06509336A (ja) 1994-10-20
CN1068817A (zh) 1993-02-10
MX9204342A (es) 1994-03-31
FI940310A7 (fi) 1994-01-21
GB9115951D0 (en) 1991-09-11

Similar Documents

Publication Publication Date Title
US6306852B1 (en) Indole derivatives useful as endothelin receptor antagonists
WO1993002050A1 (en) Indoles
EP0628040B1 (en) Indole derivatives as steroid 5 alpha-reductase inhibitors
KR100349634B1 (ko) 인돌유도체및이를함유하는제제
US5912357A (en) Indole derivatives as 5-α-reductase-1-inhibitors
US5922747A (en) Indole derivatives as steroid 5α-reductase inhibitors
WO1995031453A1 (en) Indole derivatives as 5 alpha-reductase 1 inhibitors
WO1995023143A1 (en) Indole derivatives as testosterone-5-alpha-reductase inhibitors
JP2987643B2 (ja) インドール誘導体及びこれを含有する医薬

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR CA CH CS DE DK ES FI GB HU JP KP KR LK LU MG MN MW NL NO PL RO RU SD SE US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2112689

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1992915417

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: PV1994-136

Country of ref document: CZ

Ref document number: 940310

Country of ref document: FI

ENP Entry into the national phase

Ref document number: 1994 190017

Country of ref document: US

Date of ref document: 19940124

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 8494

Country of ref document: SK

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1992915417

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1994-136

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: PV1994-136

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1992915417

Country of ref document: EP