WO1993003012A1 - Derives d'indole - Google Patents

Derives d'indole Download PDF

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Publication number
WO1993003012A1
WO1993003012A1 PCT/JP1992/000981 JP9200981W WO9303012A1 WO 1993003012 A1 WO1993003012 A1 WO 1993003012A1 JP 9200981 W JP9200981 W JP 9200981W WO 9303012 A1 WO9303012 A1 WO 9303012A1
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WO
WIPO (PCT)
Prior art keywords
salt
compound
formula
alkyl
defined above
Prior art date
Application number
PCT/JP1992/000981
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English (en)
Inventor
Satoshi Okada
Kozo Sawada
Natsuko Kayakiri
Yuki Sawada
Hirokazu Tanaka
Masashi Hashimoto
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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 Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to EP92916519A priority Critical patent/EP0600084A1/fr
Priority to JP5503471A priority patent/JPH06511238A/ja
Publication of WO1993003012A1 publication Critical patent/WO1993003012A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom

Definitions

  • the present invention relates to novel indole
  • novel indole derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as inhibitory activity on testosteron 5 ⁇ -reductase and the like, to process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament.
  • one object of the present invention is to provide novel indole derivatives and a
  • Another object of the present invention is to provide process for preparation of said indole derivatives or a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said indole derivatives or a
  • Still further object of the present invention is to provide a use of said indole derivatives or a
  • testosteron 5 ⁇ -reductase inhibitor useful for treating or preventing testosteron 5 ⁇ -reductase mediated diseases such as alopecia, acnes, prostatism, and the like in human being or animals.
  • testosteron 5 ⁇ -reductase inhibitor useful for treating or preventing testosteron 5 ⁇ -reductase mediated diseases such as alopecia, acnes, prostatism, and the like in human being or animals.
  • the indole derivatives of the present invention are novel and can be represented by the formula (I) :
  • R 1 is carboxy or protected carboxy
  • R 2 is hydrogen, lower alkyl or halogen
  • R 3 is aryl or ar( lower) alkyl, each of which may have suitable substituent(s), or a group of the formula : in which - is heterocyclic group
  • n 0 or 1
  • A is lower alkylene which may be substituted by oxo or lower alkenylene
  • Q is carbonyl, sulfonyl or lower alkylene
  • R 4 is hydrogen or lower alkyl
  • R 5 is hydrogen, lower alkyl or
  • Y is bond or lower alkylene
  • Z is bond, lower alkylene, lower alkenylene, -O-,
  • R 6 is lower alkyl, ar( lower) alkyl which may have suitable
  • X-Y-Z-R is 6H-dibenzo[b,d]pyranyl which may have suitable substituent(s).
  • the object compound (I) and a salt thereof can be prepared by the following processes.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, Q, X, Y and Z are each as defined above,
  • ar(lower)alkyl which may have suitable substituent(s) or a group of the formula :
  • R 7 is aryl which may have suitable substituent(s)
  • R 8 is carboxy protective group
  • R 9 is amino which may have suitable substituent(s)
  • W 1 , W 2 , W 3 and W 4 are each acid residue.
  • Y 1 is lower alkylene
  • Z 1 is -O-, -S- or
  • Z 2 is -O-, -S- or
  • Suitable salts of the compounds (I) are conventional non-toxic, pharmaceutically acceptable salt and may
  • a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g.
  • lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
  • Suitable “lower alkyl” may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
  • halogen means fluoro, chloro, bromo and iodo.
  • Suitable "lower alkylene” means straight or branched bivalent lower alkane such as methylene, ethylene,
  • trimethylene tetramethylene, pentamethylene
  • Suitable "acid residue” may include halogen (e.g.
  • acyloxy e.g. acetoxy, tosyloxy, mesyloxy, etc.
  • aryloxy e.g. phenoxy, etc.
  • Suitable "lower alkenylene” may include one having 2 to 6 carbon atoms such as vinylene, propenylene, and the like.
  • substituent(s) may include a conventional group such as aryl (e.g. phenyl, naphthyl, etc.), substituted aryl, for example, lower alkylaryl (e.g. tolyl, xylyl, mesityl, cumenyl, isobutylphenyl, isopentylphenyl, etc.), haloaryl (e.g. chlorophenyl, bromophenyl, dichlorophenyl, etc.), lower alkoxyaryl (e.g. isopropoxyphenyl, etc.), lower alkylcarbamoylaryl (e.g. t-butylcarbamoylphenyl, etc.), and the like.
  • aryl e.g. phenyl, naphthyl, etc.
  • substituted aryl for example, lower alkylaryl (e.g. tolyl, xylyl, mesityl, cumenyl, iso
  • Suitable "ar(lower)alkyl which may have suitable substituent(s)” may include a conventional group such as ar(lower)alkyl (e.g. trityl, benzhydryl, benzyl,
  • ar(lower) alkyl for example, ar(lower) alkyl substituted by one or more substituents such as lower alkyl as mentioned above, halogen as mentioned above, cyano, carboxy, protected carboxy as mentioned below, aryl which may have suitable substituent(s) as mentioned above, amidated carboxy as mentioned below and oxo.
  • substituents such as lower alkyl as mentioned above, halogen as mentioned above, cyano, carboxy, protected carboxy as mentioned below, aryl which may have suitable substituent(s) as mentioned above, amidated carboxy as mentioned below and oxo.
  • aromatic(lower)alkyl which may have suitable substituents may be methylbenzyl, propylbenzyl,
  • Suitable "amino protective group” may be a
  • conventional protective group which is used in the field of organic chemistry, that is, may include acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
  • acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
  • Suitable "protected carboxy” may include an
  • esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which may have at least one suitable lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which may have at least one suitable
  • substituent(s) for example, lower alkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,
  • lower alkanoyloxy(lower)alkyl ester e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester
  • alkanesulfonyl(lower) alkyl ester e.g. 2-mesylethyl ester, etc.
  • mono( or di or tri)-halo(lower)alkyl ester e.g.
  • alkyl-2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester e.g.
  • lower alkenyl ester e.g. vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g. ethynyl ester, propynyl ester, etc.
  • ar(lower)alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester,
  • substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • phthalidyl ester e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • esterified carboxy as mentioned above may include lower alkoxycarbonyl (e.g.
  • Suitable “carboxy protective group” may be the ester moiety of the above defined “protected carboxy” and may include lower alkyl (e.g. methyl, ethyl, etc.),
  • ar(lower)alkyl e.g. benzyl, etc.
  • ar(lower)alkyl e.g. benzyl, etc.
  • pharmaceutical field may include amino, mono or
  • di(lower)alkylamino e.g. methylamino, dimethylamino, ethylamino, diethylamino, butylamino, t-butylamino, etc.
  • arylamino e.g. phenylamino, etc.
  • lower alkylarylamino e.g. isobutylphenylamino, etc.
  • Suitable "heterocyclic group containing nitrogen atom” may include saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom.
  • Especially preferable heterocyclic group may be 5- or 6- membered aliphatic heteromonocyclic group (e.g. morpholinyl, pyrrolidinyl, imidazolidinyl,
  • piperidyl, piperazinyl, etc. unsaturated condensed heterocyclic group such as dibenzo[6 or 7-membered unsaturated]heteromonocyclic group (e.g. phenoxazinyl, phenothiazinyl, 10,11-dihydro-5H-dibenzoazepinyl, etc.), and the like.
  • unsaturated condensed heterocyclic group such as dibenzo[6 or 7-membered unsaturated]heteromonocyclic group (e.g. phenoxazinyl, phenothiazinyl, 10,11-dihydro-5H-dibenzoazepinyl, etc.), and the like.
  • Suitable "amidated carboxy” may carbamoyl which may have suitable substituent( s) and may include carbamoyl, mono or di( lower)alkylcarbamoyl (e.g. methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl diethylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, etc.), lower alkylaryl- carbamoyl (e.g. isobutylphenylcarbamoyl, etc.), and the like.
  • lower alkylaryl- carbamoyl e.g. isobutylphenylcarbamoyl, etc.
  • Suitable "6H-dibenzo[b,d]pyranyl which may have suitable substituent(s)" may include
  • 6H-dibenzo[b,d]pyranyl substituted by lower alkyl as mentioned above e.g. 8-isobutyl-3,4,6,6-tetramethyl-6H- dibenzo[b,d]pyranyl, etc., and the like.
  • R 1 , R 2 , R 3 , A, Q, X, Y and Z are as follows.
  • R 1 is carboxy;
  • alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, etc.
  • ar(lower)alkoxycarbonyl more preferably mono- or di- or triphenyl(C 1 -C 4 )alkoxycarbonyl (e.g.
  • R 2 is hydrogen
  • lower alkyl more preferably C 1 -C 4 alkyl (e.g.
  • R 3 is aryl which may be substituted by one to three substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and lower
  • alkylcarbamoyl more preferably phenyl which may be substituted by one to three substituent(s) selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and C 1 -C 4 alkylcarbamoyl (e.g.
  • ar(lower) alkyl which may be substituted by one to three substituents selected from the group consisting of lower alkyl, halogen, cyano, carboxy, protected carboxy, amidated carboxy, and oxo, more preferably mono- or di- or triphenyK lower)alkyl which may be substituted by one or two the groups selected from lower alkyl, halogen, cyano, carboxy, phenyl(lower)- alkoxycarbonyl, mono or di(lower)alkylcarbamoyl, phenylcarbamoyl and lower alkylphenylcarbamoyl, most preferably mono- or di- or triphenyl(C 1 -C 6 )alkyl which may be substituted by the group selected from (C 1 -C 4 )alkyl, halogen, cyano, carboxy,
  • (C 1 -C 4 )alkylphenylcarbamoyl and oxo e.g. benzyl, propylbenzyl, isobutylbenzyl, isobutylphenylethyl, isobutylphenylpropyl, isobutylphenylpentyl,
  • A is lower alkylene which may be substituted by oxo, more preferably C 1 -C 4 alkylene which may be substituted by oxo (e.g. ethylene, trimethylene, oxotrimethylene, etc.); or
  • lower alkylene more preferably C 1 -C 4 alkylene (e.g. methylene, etc.),
  • R 4 is hydrogen; or lower alkyl, more
  • C 1 -C 4 alkyl e.g. methyl, etc.
  • R 5 is hydrogen; lower alkyl, more preferably C 1 -C 4 alkyl (e.g. methyl, etc.); or ar(lower)alkylamino which may be
  • alkylbenzylamino e.g.
  • Y is bond
  • lower alkylene more preferably C 1 -C 4 alkylene (e.g. methylene, etc.), and
  • lower alkylene more preferably C 1 -C 4 alkylene (e.g. methylene, etc.);
  • alkenylene more preferably C 2 -C 4 alkenylene (e.g. propenylene, etc.),
  • R 6 is lower alkyl, preferably
  • C 1 -C 4 alkyl e.g. methyl, ethyl, etc.
  • lower alkoxycarbonyl preferably C 1 -C 4 alkoxycarbonyl (e.g. t-butoxycarbonyl, etc.);
  • ar(lower)alkyl which may be substituted by lower alkyl, more preferably mono- or di- or triphenyKlower)alkyl which may be substituted by lower alkyl, most
  • triphenyl(C 1 -C 6 ) alkyl which may be
  • C 1 -C 4 alkyl e.g. benzyl, isobutylbenzyl, etc.
  • X-Y-Z-R 3 is 6H-dibenzo[b,d]pyranyl which may be substituted by lower alkyl, more preferably 6H-dibenzo[b,d]pyranyl
  • the object compound (I-a) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
  • This reaction is usually carried out in a solvent such as alcohol [e.g. methanol, ethanol, etc.],
  • the reaction may be carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide [e.g. sodium hydroxide, potassium hydroxide, etc.], an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), tri(lower)alkylamine [e.g. trimethylamine, triethylamine, diisopropylethylamine, etc.], pyridine or its derivative [e.g. picoline, lutidine,
  • an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate
  • the base to be used is liquid, it can also be used as a solvent.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling, at room
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
  • reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
  • the object compound (I-b) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.
  • reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
  • the object compound (I-c) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof with the compound (III) or a salt thereof.
  • reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
  • the present reaction includes, within its scope, the case that when R is carboxy, it is protected during the reacting or at the post-treating step of the present process.
  • the object compound (I-e) or a salt thereof can be prepared by subjecting the compound (I-d) or a salt thereof to elimination reaction of the carboxy protective group.
  • hydrolysis is preferably carried out in the presence of a base or an acid.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium bicarbonate), sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal acetate e.g. sodium acetate, potassium acetate, etc.
  • alkaline earth metal phosphate e.g. magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline-, N-methylpyrrolidine, N-methylmorpholine,
  • the hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
  • Suitable acid may include an organic acid (e.g.
  • formic acid acetic acid, propionic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.
  • the reaction temperature is not critical, and it may suitable be selected in accordance with the kind of the carboxy protective group and the elimination method.
  • the elimination using Lewis acid is preferable to eliminate substituted or unsubstituted ar(lower)alkyl ester and carried out by reacting the compound (Ig) or a salt thereof with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetrachloride, titanium
  • tetrabromide e.g. tin
  • tetrachloride tin tetrabromide, etc.
  • aluminum halide e.g. aluminum chloride, aluminum bromide, etc.
  • trihaloacetic acid e.g. trichloroacetic acid
  • This elimination reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol, etc.) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane, etc.), alkylene halide (e.g. methylene chloride, ethylene chloride, etc.), diethyl ether, carbon disulfide or any other solvent which does not adversely affect the reaction. These solvents may be used as a mixture thereof.
  • the reduction elimination can be applied preferably for elimination of the protective group such as
  • halo(lower)alkyl e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.
  • ar(lower)alkyl e.g. benzyl, etc.
  • the reduction method applicable for the elimination reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chromium compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or an inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); and conventional catalytic reduction in the
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
  • the object compound (I-g) or a salt thereof can be prepared by subjecting the compound (I-f) or a salt thereof to elimination reaction of the carboxy protective group.
  • reaction can be carried out in substantially the same manner as Process 5, and therefore the reaction mode and reaction conditions [e.g. bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 5.
  • reaction mode and reaction conditions e.g. bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.
  • the object compound (I-h) or a salt thereof can be prepared by reacting a compound (I-g) or its reactive derivative at the carboxy group or a salt thereof with a compound (IX) or its reactive derivative at the amino group or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (IX) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IX) wit a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (IX) with a silyl compound such as bis(trimethylsilyl)acetamide,
  • Suitable reactive derivative at the carboxy group of the compound (I-g) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride within acid such as substituted phosphoric acid [e.g.
  • halogenated phosphoric acid, etc. dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, is ⁇ butyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole,
  • dimethylpyrazole, triazole or tetrazole or an activated ester
  • N-hydroxy compound e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
  • N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
  • These reactive derivatives can optionally be selected from them according to the kind of the
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • triphenylphosphine 2-ethyl-7-hydroxybenzisoxazolium salt
  • reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine,
  • N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the object compound (I-i) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (XI) or a salt thereof.
  • reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
  • the present reaction includes, within its scope, the case that when R 1 is carboxy, it is protected during the reaction or at the post-treating step of the present process.
  • the object compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-e) or a salt thereof to introduction reaction of the carboxy protective group.
  • reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvent,s reaction
  • the starting compounds (II), (IV) and (VI) can be prepared by the details of which are shown in Preparations mentioned below, or a conventional manner.
  • the object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional
  • the object compound (I) of the present invention is useful as a testosteron 5 ⁇ -reductase inhibitor and
  • testosteron 5 ⁇ -reductase mediated diseases such as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism, etc.), androgenic alopecia (or male-pattern baldness), acne (e.g. acne vulgarism, pimple etc.), other hyperandrogenism, and the like.
  • Test Compound (1) 4-[1-[3-(3-Isobutylphenoxymethyl)benzoyl]indol-3-yl]- butyric acid
  • 1,2,6,7- 3 H-Testosterone (85-105 Ci/mmol) is a mixture of 1,2,6,7- 3 H-testosterone and testosterone which includes 85-105 Ci of 1,2,6,7- 3 H-testosterone per mmol of testosterone and is purchased from New
  • the reaction solution contains 1 mM dithiothreitol, 40 mM sodium phosphate pH 6.5, 50 ⁇ M NADPH,
  • the object compound (I) of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external
  • the pharmaceutical preparation may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, lotion and the like.
  • auxiliary substances such as lactose, citric acid, tartaric acid, stearic acid,
  • magnesium stearate magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
  • While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 rag, 100 mg of the object compound (I) of the present invention may be used in treating diseases.
  • dichloromethane 300 ml was added a solution of bromine (8.20 ml) in dichloromethane (20 ml) at -20°C. After stirred for 1.5 hours, the mixture was washed with water. The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was
  • Triphenylphosphine (7.23 g) was added to a mixture of 3-bromo-4,5-dimethylbenzyl alcohol (3.95 g) and carbon tetrabromide (9.14 g) in ether (100 ml) at 0°C, and the mixture was allowed to warm up to 25°C. The reaction mixture was stirred at 25°C for 2 hours, and then the precipitates were filtered off. The filtrate was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was
  • 1,4-cyclohexanedione mono-ethylene acetal (10.0 g) in tetrahydrofuran (100 ml). The mixture was stirred at room temperature for 3 days and partitioned between diethyl ether and water. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel (300 g) using a mixture of n-hexane and 5% ethyl acetate as the eluent. Appropriate fractions were combined and evaporated to give 4-(2-methyl-1-propylidene)cyclohexan ⁇ ne ethylene acetal (12.16 g) as a colorless oil.
  • tetrahydrofuran (30 ml) was added a solution of potassium tert-butoxide (1.67 g) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 1 hour. To the mixture was added a solution of 3-bromobenzaldehyde (1.6 ml) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature for 3 hours, and portioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate and then a solution of 4-isobutylcyclohexanone (2.0 g) in tetrahydrofuran (30 ml) was added at 25°C.
  • reaction mixture was poured into a mixture of ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate.
  • triphenylphosphonium iodide (5.82 g) in tetrahydrofuran (50 ml) at 0°C.
  • the reaction mixture was allowed to warm up to 25°C and stirred at the same temperature for 1 hour .
  • a solution of methyl 3- ( 3-formylphenoxymethyl)benzoate (2.8 g) in tetrahydrofuran (20 ml) was added to the mixture at 0°C.
  • the reaction mixture was stirred at 0°C for 30 minutes and the solvent was evaporated off.
  • the residue was quenched with 1N hydrochloric acid and the mixture was extracted with ether.
  • the extract was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was
  • n-Butyl lithium (1.6 M solution in hexane) (6 ml) was added to a solution of bis(4-isobutylphenyl)methane (2.25 g) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 5 hours and cooled at 0°C. To the mixture was added a solution of 4-bromobenzylbromide (2.0 g) in tetrahydrofuran (10 ml). The mixture was stirred at 0°C for 30 minutes and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate and evaporated.
  • Acetic anhydride (20 ml) was added to a solution of bis (4-isobutylphenyl)methanol (11.07 g) in pyridine (40 ml). The mixture was stirred at room temperature for 5 hours and partitioned between ethyl acetate and water.
  • Acetyl chloride (0.94 ml) was added to a suspension of aluminum chloride (1.76 g) in dichloromethane (15 ml) at 3°C. The mixture was stirred at 3°C for 15 minutes. To the mixture was added a solution of 4-isobutylphenyl phenyl ether (2.67 g) in dichloromethane (15 ml). The mixture was stirred at 0°C for 1 hour and poured into 7% hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated to give 4-(4-isobutylphenoxy)acetophenone (3.30 g) as a colourless oil.
  • Trifluoroacetic acid (10 ml) was added to a solution of methyl 3-[N-t-butoxycarbonyl-N-'(4-isobutylphenyl)- aminomethyl]benzoate (1.5 g) in dichloromethane (10 ml). The mixture was stirred at room temperature for 2 hours and evaporated. The residue was dissolved in
  • 6-chloroindole (3.0 g) in dichloromethane (20 ml) at 25°C.
  • the reaction mixture was stirred at 25°C for.1 hour, and poured into a mixture of ice and 1N hydrochloric acid.
  • reaction mixture was stirred at 25°C for 15 minutes and poured into a mixture of ethyl acetate and 1N hydrochloric acid.
  • the organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (50 g) eluting with
  • Methyl 4-(6-chloroindol-3-yl)butyrate (1.2 g) was hydrolyzed with 1N aqueous solution of sodium hydroxide (12 ml) and the crude product was recrystallized from a mixture of ethyl acetate and hexane to give 4-(6- chloroindol-3-yl)butyric acid (1.09 g) as colorless crystals.
  • N,N-dimethylformamide (20 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 1.05 g) in N,N-dimethylformamide (30 ml) at 25°C over 15 minutes. The mixture was stirred at 25°C for 1.5 hours and cooled to -40°C. A solution of phenyl 3-(methoxymethoxy)benzoate (3.07 g) in tetrahydrofuran (40 ml) was added at -40°C over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes.
  • Benzyl 4-[1-[4-(methoxymethoxy)benzoyl]indol-3-yl]- butyrate was dissolved in trifluoroacetic acid (12 ml) at 25°C and the mixture was stirred at the same temperature for 15 minutes. After evaporation of the solvent, the residue was dissolved with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated.
  • Chloromethyl methyl ether (0.17 ml) was added to a mixture of 4-[1-[4-(4'-benzyloxycarbonyl)biphenylcarbonyl]indol-3-yl]butyric acid (0.55 g) and potassium carbonate (0.21 g) in dimethylformamide (10 ml). The mixture was stirred at room temperature for 5 hours and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (40 g) using a mixture of n-hexane and ethyl acetate (5:1) as an eluent.

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Abstract

Dérivés d'indole de formule (I) ou leur sel, utiles comme inhibiteur de la testostérone 5α-réductase.
PCT/JP1992/000981 1991-08-02 1992-08-03 Derives d'indole WO1993003012A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP92916519A EP0600084A1 (fr) 1991-08-02 1992-08-03 Derives d'indole
JP5503471A JPH06511238A (ja) 1991-08-02 1992-08-03 インドール誘導体

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GB919116732A GB9116732D0 (en) 1991-08-02 1991-08-02 Indole derivatives
GB9116732.0 1991-08-02

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WO1993003012A1 true WO1993003012A1 (fr) 1993-02-18

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Cited By (11)

* Cited by examiner, † Cited by third party
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EP0757982A1 (fr) * 1995-08-08 1997-02-12 Roussel Uclaf Composés biphényles, leur procédé de préparation et les intermédiaires de ce procédé, leur application en tant qu'inhibiteur de la 5-alpha-réductase et les compositions pharmaceutiques les contenant
EP0967195A1 (fr) * 1998-03-30 1999-12-29 Quest International B.V. Cétones aldéhydiques et leur utilisation dans des parfums
US6448220B1 (en) 1998-03-30 2002-09-10 Quest International B.V. Fragrance compound
US7022708B2 (en) 2002-10-18 2006-04-04 Roche Palo Alto Llc 4-piperazinyl benzenesulfonyl indoles and uses thereof
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7855225B2 (en) 2006-03-02 2010-12-21 Astellas Pharma Inc. 17βHSD type 5 inhibitor
US8513422B2 (en) 2007-08-31 2013-08-20 Astellas Pharma Inc. Piperidine derivative
WO2018154118A3 (fr) * 2017-02-24 2018-12-06 Xeniopro GmbH Nouveaux composés aromatiques
JP2019513703A (ja) * 2016-03-17 2019-05-30 ゼニオプロ ゲーエムベーハー ＮｏｔｃｈシグナリングのエンハンサーならびにＮｏｔｃｈのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用
US11591289B2 (en) 2017-02-24 2023-02-28 Xeniopro GmbH Aromatic compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA67754C2 (uk) * 1997-10-10 2004-07-15 Пфайзер, Інк. Агоністи простагландину, фармацевтична композиція на їх основі (варіанти), спосіб нарощення та збереження кісткової маси у хребетних та спосіб лікування (варіанти)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013060A1 (fr) * 1990-02-26 1991-09-05 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013060A1 (fr) * 1990-02-26 1991-09-05 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0757982A1 (fr) * 1995-08-08 1997-02-12 Roussel Uclaf Composés biphényles, leur procédé de préparation et les intermédiaires de ce procédé, leur application en tant qu'inhibiteur de la 5-alpha-réductase et les compositions pharmaceutiques les contenant
FR2737721A1 (fr) * 1995-08-08 1997-02-14 Roussel Uclaf Nouveaux composes biphenyles, leur procede de preparation et les intermediaires de ce procede, leur application a titre de medicament et les compositions pharmaceutiques les contenant
US5827887A (en) * 1995-08-08 1998-10-27 Roussel Uclaf Biphenyl compounds
EP0967195A1 (fr) * 1998-03-30 1999-12-29 Quest International B.V. Cétones aldéhydiques et leur utilisation dans des parfums
US6448220B1 (en) 1998-03-30 2002-09-10 Quest International B.V. Fragrance compound
US7022708B2 (en) 2002-10-18 2006-04-04 Roche Palo Alto Llc 4-piperazinyl benzenesulfonyl indoles and uses thereof
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7507754B2 (en) 2003-01-29 2009-03-24 Asterand Uk Limited EP4 receptor antagonists
US7528157B2 (en) 2003-01-29 2009-05-05 Asterand Uk Limited EP4 receptor antagonists
US7569602B2 (en) 2003-10-16 2009-08-04 Asterand Uk Limited Furan derivatives as EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7855225B2 (en) 2006-03-02 2010-12-21 Astellas Pharma Inc. 17βHSD type 5 inhibitor
US8513422B2 (en) 2007-08-31 2013-08-20 Astellas Pharma Inc. Piperidine derivative
JP2019513703A (ja) * 2016-03-17 2019-05-30 ゼニオプロ ゲーエムベーハー ＮｏｔｃｈシグナリングのエンハンサーならびにＮｏｔｃｈのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用
JP2023002688A (ja) * 2016-03-17 2023-01-10 ゼニオプロ ゲーエムベーハー ＮｏｔｃｈシグナリングのエンハンサーならびにＮｏｔｃｈのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用
JP2023027160A (ja) * 2016-03-17 2023-03-01 ゼニオプロ ゲーエムベーハー ＮｏｔｃｈシグナリングのエンハンサーならびにＮｏｔｃｈのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用
JP7402300B2 (ja) 2016-03-17 2023-12-20 ゼニオプロ ゲーエムベーハー ＮｏｔｃｈシグナリングのエンハンサーならびにＮｏｔｃｈのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用
WO2018154118A3 (fr) * 2017-02-24 2018-12-06 Xeniopro GmbH Nouveaux composés aromatiques
US11591289B2 (en) 2017-02-24 2023-02-28 Xeniopro GmbH Aromatic compounds

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GB9116732D0 (en) 1991-09-18
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