WO1992018132A1 - Association pharmaceutique destinee au traitement de l'hyperplasie prostatique benigne et contenant un inhibiteur de 5 alpha-reductase - Google Patents

Association pharmaceutique destinee au traitement de l'hyperplasie prostatique benigne et contenant un inhibiteur de 5 alpha-reductase Download PDF

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WO1992018132A1
WO1992018132A1 PCT/US1992/002749 US9202749W WO9218132A1 WO 1992018132 A1 WO1992018132 A1 WO 1992018132A1 US 9202749 W US9202749 W US 9202749W WO 9218132 A1 WO9218132 A1 WO 9218132A1
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alkyl
methyl
acid
amino
group
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PCT/US1992/002749
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English (en)
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Glen J. Gormley
Elizabeth Stoner
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Merck & Co., Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • This invention relates to a new method of treatment for patients, i.e. men having benign
  • BPH prostatic hyperplasia
  • Benign prostatic hyperplasia affects a substantial number of males over the age of 50 and usually requires surgery in advanced stages for relief.
  • testosterone (T) is secreted by the testes and adrenal glands but can undergo a 5 ⁇ -reductase mediated conversion to
  • DHT dihydrotestosterone
  • DHT is preferentially bound by the nucleus of prostatic cells thus indicating that DHT, rather than T, is the primary androgen required by the prostate for its growth and function. This led to the hypothesis that, by inhibiting 5 ⁇ -reductase, the formation of DHT could be curtailed and hopefully prostate regression obtained.
  • Finasteride, 17B(N-t-butyl)carbamoyl-4-aza- 5 ⁇ -androst-1-en-3-one was developed as a compound which was found to inhibit 5 ⁇ -reductase and exhibit positive effects against benign prostatic hyperplasia. Finasteride is a 4-azasteroid and a competitive inhibitor of the enzyme.
  • Typical 4-aza steroid 5 ⁇ -reductase inhibitors known in the art include those developed by Merck. (See U.S. Pat. 4,377,584 to Rasmusson, et al.; U.S. Pat. 4,220,735 to Rasmusson, et al.; U.S. Pat. 4,845,104 to Carlin, et al.; U.S. Pat. 4,760,071 to
  • Rasmusson, et al. which discloses finasteride, being 17ß-(N-t-butyl)carbamoyl-4-aza-5 ⁇ -androst-1-en-3-one, known by its trademark as PROSCAR®; U.S. Pat. 4,732,897 to Cainelli, et al.; U.S. Pat. 4,859,681 to Rasmusson, et al.; EPO Publn. 0 155 076; EPO Publn. 0 004 949; and EPO Publn. 0 314 189.
  • estrogens i.g. estradiol
  • estradiol may be formed in the testes and prostate by the action of the enzyme, aromatase.
  • estrogens participate biochemically, but they are implicated and associated with prostate enlargement, i.e. benign prostatic hyperplasia.
  • a method of treating patients with benign prostatic hyperplasia who are in need of such treatment comprising the step of administering in combination to such patients therapeutically effective amounts of a 5 ⁇ -reductase inhibitor, e.g. a 17ß-substituted non-azasteroid, 17ß-acyl-3-carboxyandrost-3,5-diene, benzoylaminophenoxybutanoic acid derivative, fused benz(thio)- amide or cinnamoylamide derivative, aromatic 1,2- diethers or thioethers, aromatic ortho acylaminophenoxy alkanoic acids, ortho thioalkylacylaminophenoxy alkanoic acids, pharmaceutically acceptable salts and esters thereof, and an aromatase inhibitor.
  • a 5 ⁇ -reductase inhibitor e.g. a 17ß-substituted non-azasteroid, 17ß-acyl-3-carboxyandrost-3,5-diene, benzoylaminoph
  • the present invention provides an effective method of treating BPH in patients in need of symptomatic relief by administering therapeutically effective amounts
  • the aromatase inhibitor in association with a 5 ⁇ -reductase inhibitor or pharmaceutical composition thereof.
  • the active compounds may be administered together or in any order, as discussed hereinafter.
  • patients in need of such treating is meant male patients with functioning gonads who are being treated with a 5 ⁇ -reductase inhibitor in a therapeutic program designed to combat benign prostatic hyperplasia (BPH) and are discovered to be in need of symptomatic relief.
  • BPH benign prostatic hyperplasia
  • Aromatase is an enzyme complex incorporating a NADPH-cytochrome c-reductase and a cytochrome P450 component which mediates the conversion of androgens to estrogens, Bellino, J. Steroid Biochem. 17:261-270 (1982).
  • the reaction is believed to involve three hydroxylation steps, two at the C-19 position (Meyer, Biochem. Biophys. Acta 17: 441-442 [1955]; Marato et al., Biochem. Biophys. Res. Comm. 6: 334-338 [1961]) and one at C-2 (Hahn and Fishman, J. Biol. Chem. 259: 1689-1694 [1984]; Brodie et al., J. Am.
  • aromatase inhibitor as defined herein is any steroidal or non-steroidal compound which prevents the conversion of androgens to estrogens.
  • the compounds include substrate analogues of
  • Non-steroidal compounds that block aromatase activity are also included within the scope of the invention. These non-steroidal compounds include compounds or analogues that can bind to the enzymatic active site of aromatase and inhibit enzymatic activity. Nonsteroidal or steroidal compounds will also include compounds or analogues that bind to the enzyme at a site away from the enzymatic site and cause a structural change in the enzyme which results in a loss of enzymatic activity.
  • Aromatase inhibitors further include non-steroidal compounds that interfere with cytochrome P450 mediated hydroxylations such as those described by Brodie, et al., J. Steroid Biochem. 27: 899-903 (1987). The following compounds are known
  • non-steroidal aromatase inhibitors as disclosed by the associated reference.
  • the reference will also directly contain a method for making the compound or will direct one who wishes to use the compound to a method for producing the compound.
  • the aromatase inhibitors of the instant invention known in the art include, but are not limited to, the following compounds:
  • the invention is also intended to include any biologically active equivalents of an aromatase inhibitor as described above.
  • Preferred is where the 4-aza steroid has the formula:
  • R 1 and R 3 are independently hydrogen, methyl or ethyl
  • R 2 is a hydrocarbon radical selected from straight or branched chain substituted or unsubstituted alkyl, cycloalkyl, or aralkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or more halogen substituents,
  • R' is hydrogen or methyl
  • R' hydrogen or ß-methyl
  • R''' is hydrogen, ⁇ -methyl or ß-methyl
  • R 1 is hydrogen, methyl or ethyl
  • R 2 is branched chain alkyl cycloalkyl, aralkyl of from 4-12 carbons, phenyl, optionally substituted by methyl, chloro or fluoro, substituted or unsubstituted 1-, 2-adamantyl, 1-,
  • Representative compounds of the present invention include the following:
  • N-substituent, and wherein a double bond can be optionally present as indicated by the dotted line in position 1.
  • alkyl, cycloalkyl, aralkyl, monocyclic aryl, 1-, 2-adamantyl or 1-, 2-norbornanyl moieties can be substituted with one or more substi- tuents of the following: C 1 -C 4 linear/branched alkyl, including methyl, ethyl, isopropyl, n-butyl; nitro; oxo; C 7 -C 9 aralkyl, including benzyl; (CH 2 ) n COOR where n is 0-2 and R is H or C 1 -C 4 linear/branched alkyl including methyl, ethyl; CH 2 OH; OH; OR where R is C 1 -C 4 linear/branched alkyl including methyl, ethyl; halo, including fluoro, bromo, iodo; COOH;
  • amino group of the adamantyl or norbornanyl moiety can also be substituted as R 1 with methyl and ethyl, as well as hydrogen.
  • compositions or esters where a basic or acidic group is present on the substituted alkyl, cycloalkyl, aralkyl, adamantyl or norbornanyl moiety.
  • an acidic substituent i.e. -COOH, there can be formed the
  • a basic group i.e. amino
  • acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
  • a basic group i.e. amino
  • acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
  • esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl , and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • 1-aminocarboxyl-1-AD 2-cyano-2-AD; 3,5-dimethyl- 7-ethyl-1-AD; 4-hydroxy-1-AD; 1-hydroxy-2-AD;
  • R 2 as substituted norbornanyl moieties are (where NB is norbornanyl):
  • novel compounds of formula I of the present invention can be prepared by a method
  • 17ß-(carbomethoxy)-4-aza-5- ⁇ -androstan-3-ones which includes the stages of optionally 1) dehydrogenating said starting material to produce the corresponding compound containing a double-bond in the 1,2-position of the A-ring, 2) converting the 17-carbomethoxy substituent into an N-substituted alkyl, cycloalkyl, aralkyl, monocylic acyl, or adamantylcarbamoyl substituent and, if desired, 3) alkylating the A-ring nitrogen to introduce a N-methyl or N-ethyl
  • the products of our invention are formed by optionally: (1) heating a 17ß-alkoxycarbonyl-4-aza-5 ⁇ -androstan-3-ones, com pound III, (prepared in the literature as described in the reference US Patent 4,377,584) with a dehydrogenating agent such as benzeneseleninic anhydride in a refluxing inert solvent, e.g. chlorobenzene, to form a 17ß-alkoxycarbonyl-4-aza-5 ⁇ -androst-1-ene-3-one IV (alternately, the dichlorodicyanobenzoquinone process of Dolling, et al., JACS 1988, Vol. 110, pp.
  • a dehydrogenating agent such as benzeneseleninic anhydride
  • a refluxing inert solvent e.g. chlorobenzene
  • the formed 5 ⁇ -androst- 1-en-3-one compound from Step 1 can be reacted with, e.g. sodium hydride under anhydrous conditions in a neutral solvent such as dimethylformamide; (3) contacting the resulting reaction mixture with an alkyl (methyl or ethyl) iodide to form the corresponding 17-ß-alkoxy-adamantyl-carbamoyl-4-alkyl-4-aza-5 ⁇ - androst-1-en-3-one V; (4) subsequently hydrolyzing said 17ß-alkoxycarbonyl-4-alkyl-4-aza-5 ⁇ -androst- 1-en-3-one with a strong base, such as aqueous
  • 17ß-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5 ⁇ -androst-1-en-3-one VII can be isolated by chromatography on e.g. silica gel; and (6) said pyridylthio ester can be thenreacted with 1-adamantyl-, 2-adamantylamine or norbornanylamine in an inert solvent e.g. tetrahydrofuran, to form the desired product 17ß-N-adamantyl- carbamoyl-4-alkyl-4-aza-5 ⁇ -androst-1-en-3-one VIII which can be isolated by chromatography e.g. on silica gel.
  • the previous reaction is carried out in the absence of first forming the double bond at position 1, the corresponding 17B-(N-adamantyl-carbamoyl)-4-alkyl-4-aza-5 ⁇ -androstan-3-one (or
  • N-norbornanyl carbamoyl compound is prepared.
  • the corresponding N-unsubstituted-17ß(N-adamantyl-carbamoyl)-4-aza-5 ⁇ -androst-1-en-3-one XIV is readily prepared from the 17ß (alkoxycarbonyl)-4-aza-5 ⁇ -androstone-3-one IV by repeating the above series of reaction steps but omitting the alkylation Step 2 herein above, i.e. treatment of the 4-aza-5- ⁇ -androst-1-en-3-one with e.g. sodium amide followed by methyl or ethyl iodide via intermediates XII and XIII.
  • the 16-methyl derivative wherein R''' is methyl are prepared from known 16-methyl-17-acyl-4-methyl-4-aza-5 ⁇ -androstan-3-ones, e.g.
  • X is 2-pyridylthio or 1-benzotriazoloxy.
  • R 2 is 1- or 2-adamantyl or norbornanyl.
  • a preferred 4-azasteroid is a 17ß-acyl-4-aza- 5 ⁇ -androst-1-ene-3-one compound of the formula:
  • R is selected from hydrogen, methyl and ethyl;
  • R 2 is (a) a monovalent radical selected from
  • oxygen-containing radicals is present; (2) -SH, -SC 1 -C 4 alkyl, -SOC 1 -C 4 alkyl,
  • N(R3) 2 which can be protected, where R 3 is independently H or C 1 -C 4 alkyl, where the monoaryl ring can also be further substituted with C 1 -C 4 alkyl;
  • heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl;
  • R', R'' and R'' are each selected from hydrogen and methyl, and pharmaceutically acceptable salts thereof.
  • a preferred embodiment of the compounds of our invention process is: the compound of above Structure IA,
  • R is hydrogen or methyl
  • R 2 is branched chain alkyl, or cycloalkyl of from 4-10 carbons, and R'' and R''' are hydrogen.
  • Another embodiment of the invention is the compounds of above Structure I where R 2 is phenyl, or phenyl substituted by substituents described above, including where
  • R 2 is phenyl, 2-, 3-, or 4-tolyl, xylyl,
  • Representative compounds of the invention are:
  • the compounds of formula IA of the present invention are prepared by a method starting with the known steroid ester of the formula:
  • 17ß-(carbomethoxy)-4-aza-5 ⁇ -androstan-3-one which includes the stages of (1) dehydrogenating said starting material to produce the corresponding compound containing a double bond in the 1,2-position of the A-ring, (2) converting the 17-carbomethoxy substituent into a 17ß-acyl substituent and, if desired (3) alkylating the A-ring nitrogen to introduce 4-methyl or 4-ethyl substituents into the A-ring.
  • the 4-aza nitrogen be unsubstituted.
  • the dehydrogenation step can be carried out, e.g. according to the procedure of Dolling, et al. involving dichlorodicyanobenzoquinone, JACS (1988) Vol. 110, pp. 3318-3319.
  • Stage (2) may consist of one or more chemical steps and if desired may take place before stage (1) or following stage (1) or stage (3).
  • the products of our invention are formed by (1) heating a 17ß-alkoxycarbonyl-4-aza-5 ⁇ - androstan-3-one compound III with a dehydrogenating agent such as benzeneseleninic anhydride in refluxing chlorobenzene to form a 17ß-alkoxycarbonyl-4-aza-5 ⁇ -androst-1-en-3-one (IV), (2) the formed 5 ⁇ -androst- 1-en-3-one compound from step (1) is reacted with sodium hydride and under anhydrous conditions in a neutral solvent such as dimethylformamide, (2) contacting the resulting reaction mixture with an alkyl (methyl or ethyl) iodide to form the corresponding 17ß-alkoxycarbonyl-4-alkyl-4-aza-5 ⁇ -androst-1-en-3-one (V), (3) subsequently hydrolyzing said 17ß-alkoxycarbonyl-4-alkyl-4-aza-5 ⁇ -androst-1-en-3-one with a
  • the corresponding 17ß-acyl-4-aza-5 ⁇ -androst-1-en-3-one XV is readily prepared from the 17ß(alkoxycarbonyl)-4-aza-5 ⁇ -androsten-3-one (IV) by repeating the above series of reaction steps but omitting step 2 hereinabove, i.e., treatment of the 4-aza-5 ⁇ -androst-1-en-3-one with sodium amide followed by methyl or ethyl iodide.
  • reaction with a Grignard reagent R 2 MgX gives the ketone, 17ß-R 2 CO-, corresponding to the R 2 moiety associated with the Grignard reagent.
  • the 16-methyl derivative wherein R''' is methyl are prepared from known 16-methyl-17-acyl-4-methyl-4-aza-5 ⁇ -androstan-3-ones, e.g.
  • R 2 is p-hydroxybiphenyl
  • this can be derived by starting with an appropriate bromobiphenylylphenol, e.g. p-bromobiphenylphenol, protecting the phenolic -OH with a conventional blocking group, e.g.
  • trioganosilyl i.e. t-butyldimethylsilyl
  • silyl group by the use of, e.g. refluxing aqueous tetrabutylammonium fluoride.
  • protected hydroxy is meant the alcoholic or carboxylic -OH groups which can be protected by conventional means
  • C 1 -C 4 alkyl is meant linear or branched alkyl, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.
  • thiophenyl substituted R 2 e.g. p-methylthiophenyl magnesium chloride
  • the corresponding 17ß- (substituted thio-benzoyl)-4-alkyl-4-aza-5 ⁇ -androst- 1-en-3-one is prepared wherein phenyl is R 2 .
  • R 2 MgX for all the species included within the scope of this invention, are available or can readily be made by one skilled in the art.
  • R 2 is C 1 -C 4 alkyl thiophenyl
  • R 2 can be formed from the appropriate C 1 -C 4 alkyl thiobromobenzene, e.g. p-methylthiobromobenzene
  • the formed C 1 -C 4 alkyl thiobenzene can be used to further prepare C 1 -C 4 alkyl sulfoxides by oxidation with e.g. m-chloroperbenzoic acid.
  • the resulting sulfoxide can be further oxidized by the use of the m-chloroperbenzoic acid reaction to proceed for a longer period of time to form the C 1 -C 4 alkyl sulfone.
  • the sulfoxide can be used in the Pummerer rearrangement to form the corresponding thiol.
  • R 2 is formed from the appropriate bromobenzene, e.g. p-N,N-dimethylaminosulfobromobenzene which is used directly in the Grignard reaction to form the final product.
  • the thioalkyl groups on the phenyl ring i.e. -(CH 2 ) m SH, where m is 1-4, are readily formed via a four step procedure from an alkoxy alkyl phenyl bromide, Br-C 6 H 4 -(CH 2 ) m OCH 3 .
  • Direct addition of the Grignard reagent prepared from above-bromoalkyl phenyl derivative to the thiopyridyl ester results in the keto derivative, i.e. 17ß(4-methoxyalkyl- benzoyl)-4-aza-5 ⁇ -androst-1-ene-3-one.
  • VTII 17ß-(p-dimethylaminophenyl-carbonyl)-4- alkyl-4-aza-5a-androst-1-en-3-one
  • R 2 is hydroxyphenyl
  • this can be derived by starting with an appropriate bromophenol, e.g. p-bromophenol, protecting the phenolic -OH with a conventional blocking group, e.g. trioganosilyl, i.e. t-butyldimethylsilyl, carrying out the Grignard reaction and then deblocking the silyl group by the use of, e.g. refluxing aqueous tetrabutylammonium fluoride.
  • a conventional blocking group e.g. trioganosilyl, i.e. t-butyldimethylsilyl
  • R 2 being hydroxyethylphenyl
  • the same blocking procedure can be analogously conducted starting with the appropriate hydroxyalkyl
  • bromophenol e.g. p-hydroxymethylbromobenzene, or p-hydroxyethylbromobenzene.
  • R 2 is carboxyphenyl
  • R 2 is -O-C 1 -C 4 alkyl
  • the appropriate bromo-O-C 1 -C 4 alkyl benzene e.g. p-methoxybromo-benzene, is utilized for the Grignard reaction.
  • protected hydroxy is meant the alcoholic or carboxylic -OH groups which can be protected by conventional means
  • ketone reduction products of IA in combination with an aromatase inhibitor for treatment of BPH being secondary alcohols of the formula:
  • R is selected from hydrogen, methyl and
  • R 2 is (a) a monovalent radical selected from
  • a polycyclic aromatic radical which can be substituted with one or more of: -OH, protected -OH, -OC 1 -C 4 alkyl, C 1 -C 4 alkyl, halo or nitro;
  • oxygen-containing radicals is present
  • R 3 is independently H or C 1 -C 4 alkyl, where the monoaryl ring can also be further substituted with C 1 -C 4 alkyl; and (4) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl;
  • R', R'' and R''' are hydrogen or methyl, wherein the dotted line represents a double bond which can be present, and pharmaceutically
  • R 2 phenyl contains a carbonyl function, it can be selectively blocked and then regenerated after the borohydride reduction by conventional methods.
  • the borohydride reduction can be carried out in, e.g. water or aqueous methanol, at a temperature of room temperature to 50oC and the product then isolated and purified by conventional means.
  • the compounds are also active as 5-alpha reductase inhibitors in the treatment of patterned alopecia.
  • the compounds of the present invention prepared in accordance with the method described above, are, as already described, potent agents in combination with an aromatase inhibitor for the treatment of BPH.
  • the aromatase inhibitor, and the 5 ⁇ -reductase inhibitor are administered in combination separately or as one single combined pharmaceutical composition via parenteral or oral means.
  • the aromatase inhibitor and the 5 ⁇ -reductase inhibitor are administered orally as separate compositions.
  • the amount of each component administered is determined by the attending clinicians taking into consideration the etiology and severity of the disease, the patient's condition and age, the potency of each component and other factors.
  • the aromatase inhibitor compositions are generally administered in a dosage range of about ⁇ o to 400 mg/kg (body weight) per day with 50 to 250 mg per day in a single dose being preferred.
  • 17 ⁇ -substituted steroidal 5a-reductase inhibitors which are non-4-aza steroids are known in the art and include those developed by SmithKline Beckmann as disclosed in U.S. Pat. 4,882,319 to Holt, et al.; U.S. Pat. 4,910,226 to Holt, et al; EPO
  • the A ring has up to 2 double bonds
  • the B, C, and D rings have optimal double bonds where indicated by the broken lines, provided that the A, B, and C rings do not have adjacent double bonds and the D ring does not have a C 16 -C 17 double bond when R3 represents two substituents or a divalent substituent;
  • Z is (CH 2 )n and n is 0 or 2, provided that Z is (CH)n when adjacent to a double bond;
  • X is H, Cl, F, Br, I, CF 3 , or C 1-6 alkyl
  • Y is H, CF 3 , F, Cl, or CH 3 , provided that Y is H when there is no C 5 -C 6 double bond;
  • R 1 is H or C 1-8 alkyl
  • R 2 is absent or present as H or CH 3 , provided R 2 is absent when the carbon to which it is attached is unsaturated; and R 3 is
  • NR 5 R 6 where R 5 and R 6 are each independently selected from hydrogen, C 1-8 alkyl,
  • OR 7 where R 7 is hydrogen, alkali metal, C 1-8 alkyl, benzyl, or (b) -Alk-OR 8 , where Alk is C 1-12 alkylidene, and R 8 is
  • the B ring has a C 5 -C 6 double bond, R 1 is CH 3 , and R 3 is keto,
  • the A-nor ring has a C 3 -C 4 double bond and R 3 is acetoxy or acetyl;
  • R 1 is CH 3 and R 3 is acetoxy or acetyl
  • the A-nor ring has a C 3 -C 4 double bond and R 1 is methyl; or (v) the B ring has a C 3 -C 4 double bond and R 3 is ß-hydroxy.
  • N-t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid N,N-diisopropyl-androst-3,5-diene-17 ⁇ -carboxamide-3- carboxylic acid,
  • R 1 is (a) C 1 -C 6 linear or branched alkyl
  • C 3 -C 12 cycloalkyl which can be substituted with C 1 -C 4 alkoxy or C 1 -C 4 linear/branched alkyl;
  • C 6 -C 12 aryl, or C 7 -C 13 aralkyl which can be substituted with one or more of: -OH, -OC 1 -C 4 alkyl, C 1 -C 4 alkyl, -(CH 2 ) m OH, -(CH 2 ) n COOH, including protected -OH, where m is 1-4, n is 1-3;
  • C 3 -C 12 cycloalkyl which can be substituted with C 1 -C 4 alkoxy or C 1 -C 4 linear/branched alkyl; C 5 -C 12 aryl, or C 7 -C 13 aralkyl which can be substituted with one or more of: -OH, -OC 1 -C 4 alkyl, C 1 -C 4 alkyl, -(CH 2 ) m OH, -(CH 2 ) n COOH, including protected -OH, where m is 1-4, n is 1-3, and R 2 is selected from COOH, SO3H, PO(OH) 2 , PH(O)OH.
  • R 1 is t-butyl, cyclokalkyl, phenyl, p-hydroxyphenyl, 1-adamantyl, 2-adamantyl, NH-t-butyl, NH-isobutyl, NH-cyclohexyl, NH-phenyl, NH-p-hydroxy-phenyl, NH-1-adaxmantyl, NH-2-adamantyl, and R 2 is COOH,
  • Representative compounds include:
  • non-steroidal 5a-reductase inhibitors as developed by ONO Pharmaceutical Co., LTD., Osaka, Japan and as described in US patents 4,780,469; 4,847,275;
  • the benzoylaminophenoxy butanoic acid derivatives are of the formula:
  • R' is hydrogen or alkyl of from 1 to 4 carbon atom(s);
  • A is oxygen atom, sulfur atom or sulfinyl (SO) group; both R 1 's are methyl or chlorine, or the two R 1 's and the carbon atoms of the benzene ring to which the two R 1 's are linked together are
  • R 2 represents a group of formula
  • B is oxygen, sulfur or a group of formula: NR 11 wherein R 11 is hydrogen or alkyl of from 1 to 4 carbon atom(s),
  • R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are, independently, hydrogen, alkyl of from 1 to 4 carbon atom(s), halogen, trifluoromethyl or cyclobutylmethyl,
  • n 0 or 1
  • n is an integer of from 1 to 5
  • R 9 is a hydrogen, alkyl of from 1 to 5 carbon atom(s) or a group of formula:
  • R 12 , R 13 , R 14 , and R 15 are, independently, hydrogen, alkyl of from 1 to 4 carbon atom(s), halogen, trif luoromethyl or cyclobutylmethyl, and 1 is an integer of from 1 to 4, and
  • R 10 is a group of formula:
  • a 5 ⁇ -reductase inhibitor in this invention is a cinnamoylamide of the
  • R 2 and R 3 each independently represents a hydrogen or methyl group with the proviso that
  • R 1 represents hydrogen and (R 1 )n represents a member selected from the group consisting of 3-group, 4-pentyl group, 4-neopentyl group, 4-(2-ethylbutyl) group and
  • Representative compounds include:
  • A represents a single bond or a group of methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group optionally being substituted by one, two or three of straight or branched alkyl group(s) of from 1 to 10 carbon atom(s) and/or phenyl group(s);
  • B represents a heterocyclic ring of from 4 to 8 members containing one, two or three hetero atom(s) selected from the group consisting of oxygen, nitrogen and sulphur atom(s), wherein the said ring may
  • T represents an oxygen atom or a sulphur atom
  • R 1 represents a group of general formula:
  • R 3 represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a group of general formula: ⁇ COOR 7 , wherein R 7 represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s), or a straight or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon atom(s);
  • R 4 represents a group of general formula:
  • U represents an oxygen atom or a sulphur atom
  • R 8 represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s)
  • n and m represent an integer of from 1 to 10, respectively
  • p and q represent zero or an integer of from 1 to 10, respectively, or non-toxic salts thereof.
  • Representative compounds include:
  • aromatic 1,2-di(thio)ethers of the formula:
  • A is an 1,2-disubstituted aromatic ring; preferably a benzene ring; wherein
  • X is independently O, S, SO, or SO 2 ;
  • R is H
  • R' and R" are independently
  • the compounds of the instant invention are inhibitors of the human testosterone-5 ⁇ -reductase enzyme.
  • X in the general formula above is O or S, preferably where one X is 0, and particularly where both Xs are 0, e.g., resulting in the catechol
  • C 1 -C 4 alkyl includes linear or branched species, e.g. methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl.
  • C 1 -C 4 alkoxy includes linear or branched
  • Halo includes fluoro, chloro, bromo or iodo.
  • Substituted phenyl includes phenyl substituted by one or more of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halo, and the like, as defined above, representative examples include o, m-, p-methoxy phenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxyphenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl, o-fluorophenyl, and the like.
  • Haloalkyl includes C 1 -C 4 alkyl, defined above, substitued with one or more "halo" as
  • C 1 -C 4 alkylthio includes C 1 -C 4 alkyl, defined above, substituted with at least one
  • divalent thio (-S-) grouping including; methylthio, ethylthio, isopropylthio, n-butylthio, and the like.
  • C 1 -C 4 alkylsulfinyl includes C 1 -C 4 alkyl, defined above, substituted with at least one -SO-grouping including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, and the like.
  • C 1 -C 4 alkylsulfonyl includes C 1 -C 4 alkyl, defined above, substituted with at least one sulfonyl group, -SO 2 -, including; methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and the like.
  • C 1 -C 4 mono or dialkyl amino includes amino, substituted with one or more C 1 -C 4 alkyl groups as defined hereinabove, including: methylamino,
  • the R group or groups on the benzene ring can be present initially in the process, such as in starting material I in Flow Chart A, e.g. phenyl, methyl, methoxy, cyano, trifluoromethyl,
  • reaction e.g. chloro, as by chlorination, nitro by nitration, or created from a starting or added
  • salts and esters thereof are meant, salts and esters of the acid groups in the final molecule which can be used as part of the human drug delivery system and include the salts: sodium, potassium, calcium, ammonium, substituted ammonium, quaternary ammonium, and esters: ethyl ester, aceturate, besylate, edetate, phenpropionate, acetate, pamoate, and esters which serve as "prodrug” formulations which will hydrolyze in the body at physiological pH's to regenerate the acid, including pivaloylates, e.g. pivoxetil and pivoxil, and Kanebo esters, and the like.
  • pivaloylates e.g. pivoxetil and pivoxil
  • Kanebo esters and the like.
  • y where y is 1-6, preferably 3, can contain at least one R' substituent as defined above, and can be, e.g., -CH 2 -; -CH 2 -CH 2 -; -CH 2 -CH 2 -CH 2 -, ; -; -; -; ; ;
  • -CH 2 -CH CH-(CH 2 ) 2 -; and the like.
  • z is 6-20, preferably 10-16, can contain at least one R" substituent as defined above, and can be; e.g., -(CH 2 ) 6 -, -(CH 2 ) 20 -, ;
  • R' and R" can also be -NHCOCH 3 , which can be hydrolyzed to amino by conventional acid or base hydrolysis in the final molecule; R' and R" can also be oxo, obtained by, for example, HBr addition to an alkene followed by conversion to an alcohol and subsequent oxidation to the ketone.
  • R' or R" is H and particularly preferred is where both and
  • one X is O and R, R' , R" , y and z are defined above ; and particularly preferred are the compounds ,
  • X is O or S and n is 10-16.
  • the compounds of the instant invention can be made by the procedure outlined in the following Flowchart A-1.
  • Compound I is the starting substrate in the invention process and is a 1,2-substit ⁇ ted benzene ring.
  • X can be independently 0 or S and "PG" represents a hydroxy or thio protecting group which is inactive during Step (A) but can be subsequently removed by, e.g. palladium on carbon catalyst in ethanol under a pressurized H 2 atmosphere.
  • PG Representative examples of “PG” include:
  • Step (A) benzyl, p-methoxybenzyl, p-halobenzyl; including p-chlorobenzyl, p-fluorobenzyl, and the like.
  • Other protective groups which are known will be obvious to one skilled in the art to carry out the function of Step (A).
  • L is a leaving group, e.g., halogen, including bromo, chloro, or sulfonate, and the like
  • R a is a C 1 -C 4 linear or branched alkyl portion of the ester, including methyl, ethyl, isopropyl, t-butyl, sec-butyl, and the like
  • R 1 and Y are or defined above, include, but are not limited to:
  • Step (A) the condensation of I and II to produce III takes place in an non-hydroxylated polar organic solvent, e.g., acetone, ethyl acetate, methylethylketone, dioxan, THF, diethyIketone, and the like,
  • a proton acceptor is also present, e.g. potassium carbonate, sodium bicarbonate, pyridine, triethylamine, and the like.
  • the reaction is carried out under an inert atomosphere, e.g. dry nitrogen, and heated at reflux or allowed to sit for an extended period of time at room temperature. Workup is conventional.
  • Step (B) the protecting group, "PG", is catalytically removed at ambient temperature under a pressurized, hydrogen atmosphere in an organic solvent to produce IV, being a phenol or thiophenol.
  • Operable catalysts include 5% Pd/C, and the like.
  • the organic solvent should be inert under the reaction conditions and includes ethyl acetate, ethanol, methanol, dioxane, and the like.
  • Step (C) involves reacting IV with V to produce VI, the diester.
  • the reaction conditions are similar to those described in Step (A) utilizing an inert organic solvent for the reactants and a proton acceptor.
  • V useful in the invention are:
  • Step (D) the diester can be deesterified by aqueous basic hydrolysis, e.g. NaOH in MeOH/H 2 O to yield the diacid VII upon acidification.
  • Flow Sheet B-1 illustrates the specific synthesis of 7.
  • a solution of 3 in e.g., ethyl acetate is catalytically hydrogenated at room temperature under e.g. 40 psig of H 2 in the presence of a 5% Pd/C catalyst to yield ethyl 4-(2-hydroxyphenoxy) butyrate 4 in Step (B).

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Abstract

On décrit un nouveau traitement destiné aux hommes souffrant d'hyperplasie prostatique bénigne (HPB), et qui comprend une thérapie d'association composée d'un inhibiteur de 5α-réductase, par exemple un dérivé d'acide benzoylaminophénoxybutanoïque, 17β-substitué non azastéroïde, 17β-acyl-3-carboxy-androst-3,5-diène, un dérivé de cinnamoylamide ou de benz(thio)amide fusionné, des thioéthers ou 1,2-diéthers aromatiques, des acides alcanoïques aromatiques d'ortho acylaminophénoxy, des acides alcanoïques d'ortho thioalkylacylamino-phénoxy, des sels et des esters pharmaceutiquement acceptables de ces éléments, par exemple de la finastéride, en association avec un inhibiteur d'aromatase, c'est-à-dire du fadrazole, étant composé de 4-(5,6,7,8-tétrahydro-imidazo-[1,5-α]pyridin-5-yle) benzonitrile. L'association constitue une thérapie au niveau moléculaire dirigée contre la cause sous-jacente de la maladie tout en produisant un soulagement symptomatique. Des compositions pharmaceutiques utilisées pour ce traitement sont aussi décrites.
PCT/US1992/002749 1991-04-17 1992-04-06 Association pharmaceutique destinee au traitement de l'hyperplasie prostatique benigne et contenant un inhibiteur de 5 alpha-reductase WO1992018132A1 (fr)

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US68672091A 1991-04-17 1991-04-17
US686,720 1991-04-17
US74638891A 1991-08-16 1991-08-16
US746,388 1991-08-16
US84615592A 1992-03-11 1992-03-11
US846,155 1992-03-11

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Cited By (24)

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US5536714A (en) * 1992-04-20 1996-07-16 Sankyo Company, Limited Steroid derivatives for the treatment of prostatic hypertrophy their preparation and uses
US5541322A (en) * 1994-10-14 1996-07-30 Glaxo Wellcome Inc. Synthesis of 6-azaandrostenones
US5565467A (en) * 1993-09-17 1996-10-15 Glaxo Wellcome Inc. Androstenone derivative
US5698720A (en) * 1992-04-20 1997-12-16 Sankyo Company, Limited Steroid derivatives
WO1998027986A1 (fr) * 1996-12-24 1998-07-02 Zymogenetics, Inc. Agents therapeutiques et procedes de traitement du diabete de type ii et symptomes du diabete de type ii
US5817818A (en) * 1994-09-16 1998-10-06 Glaxo Wellcome Inc. Androstenones
WO1999007357A1 (fr) * 1997-08-08 1999-02-18 Ono Pharmaceutical Co., Ltd. REGULATEURS DE TYPE η DE RECEPTEUR ACTIVE D'AGENT DE PROLIFERATION DE PEROXYSOME
US5977126A (en) * 1993-09-17 1999-11-02 Glaxo Wellcome Inc. Androstenones
US5998427A (en) * 1998-05-14 1999-12-07 Glaxo Wellcome Inc. Androstenones
WO2001012206A2 (fr) * 1999-08-13 2001-02-22 Heinrich Wieland Substances et moyens permettant d'influencer positivement le collagene
EP1099438A2 (fr) * 1999-11-10 2001-05-16 Pfizer Products Inc. Utilisation d'inibiteurs de la MTP ou de la sécrétion de l'ApoB
WO2002036129A2 (fr) * 2000-11-02 2002-05-10 Alfred Schmidt Traitement topique de la mastalgie
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
US6689799B1 (en) 1999-08-23 2004-02-10 Rephartox 1,4-dihydropyridine-5-carboxylic acid ester derivatives and method for the preparation thereof
EP1610778A2 (fr) * 2003-01-17 2006-01-04 Threshold Pharmaceuticals, Inc. Traitement de l'hypertrophie prostatique benigne
US7329750B2 (en) 2003-06-30 2008-02-12 Merck & Co., Inc. 17-Acetamido-4-azasteroid derivatives as androgen receptor modulators
US7482357B2 (en) 2003-06-30 2009-01-27 Merck & Co., Inc. 17-acetamido-4-azasteroid derivatives as androgen receptor modulators
US7696217B2 (en) 2003-06-30 2010-04-13 Merck Sharp & Dohme Corp. 17-acetamido-4-azasteroid derivatives as androgen receptor modulators
US7727978B2 (en) 2006-08-24 2010-06-01 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
WO2012035553A1 (fr) * 2010-09-15 2012-03-22 Ind-Swift Laboratories Limited Procédé de préparation de dérivés d'androsténone
US8314097B2 (en) 2005-08-25 2012-11-20 Novartis Ag Organic compounds
US20150322001A1 (en) * 2012-11-21 2015-11-12 The University Of Sydney Omega-3 analogues
US10869855B2 (en) 2012-07-26 2020-12-22 The William M. Yarbrough Foundation Method for treating benign prostatic hyperplasia (BPH), prostatitis, and prostate cancer

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WO1987005216A1 (fr) * 1986-03-06 1987-09-11 Schering Aktiengesellschaft Berlin Und Bergkamen COMBINAISON D'INHIBITEURS D'AROMATASE ET D'INHIBITEURS DE 5alpha-REDUCTASE
WO1991000731A1 (fr) * 1989-07-07 1991-01-24 Endorecherche Inc. Therapie combinee pour la prophylaxie et/ou le traitement de l'hyperplasie prostatique benigne

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WO1987005216A1 (fr) * 1986-03-06 1987-09-11 Schering Aktiengesellschaft Berlin Und Bergkamen COMBINAISON D'INHIBITEURS D'AROMATASE ET D'INHIBITEURS DE 5alpha-REDUCTASE
WO1991000731A1 (fr) * 1989-07-07 1991-01-24 Endorecherche Inc. Therapie combinee pour la prophylaxie et/ou le traitement de l'hyperplasie prostatique benigne

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5698720A (en) * 1992-04-20 1997-12-16 Sankyo Company, Limited Steroid derivatives
US5717088A (en) * 1992-04-20 1998-02-10 Sankyo Company, Limited Method of making steroid derivatives for the treatment of prostatic hypertrophy
US5760025A (en) * 1992-04-20 1998-06-02 Sankyo Company, Limited Steroid derivatives for the treatment of prostatic hypertrophy, their preparation and uses
US5536714A (en) * 1992-04-20 1996-07-16 Sankyo Company, Limited Steroid derivatives for the treatment of prostatic hypertrophy their preparation and uses
US5977126A (en) * 1993-09-17 1999-11-02 Glaxo Wellcome Inc. Androstenones
US5565467A (en) * 1993-09-17 1996-10-15 Glaxo Wellcome Inc. Androstenone derivative
US5846976A (en) * 1993-09-17 1998-12-08 Glaxo Wellcome Inc. Androstenone derivative
US5817818A (en) * 1994-09-16 1998-10-06 Glaxo Wellcome Inc. Androstenones
US5541322A (en) * 1994-10-14 1996-07-30 Glaxo Wellcome Inc. Synthesis of 6-azaandrostenones
US5929058A (en) * 1996-12-24 1999-07-27 Zymogenetics, Inc. Treatment agents and methods for treating type II diabetes and symptoms of type II diabetes
WO1998027986A1 (fr) * 1996-12-24 1998-07-02 Zymogenetics, Inc. Agents therapeutiques et procedes de traitement du diabete de type ii et symptomes du diabete de type ii
WO1999007357A1 (fr) * 1997-08-08 1999-02-18 Ono Pharmaceutical Co., Ltd. REGULATEURS DE TYPE η DE RECEPTEUR ACTIVE D'AGENT DE PROLIFERATION DE PEROXYSOME
US5998427A (en) * 1998-05-14 1999-12-07 Glaxo Wellcome Inc. Androstenones
US8278291B1 (en) 1999-08-13 2012-10-02 Curadis Gmbh Treatment of wrinkles and strias with 4-hydroxyandrostenedione or a derivative thereof
WO2001012206A2 (fr) * 1999-08-13 2001-02-22 Heinrich Wieland Substances et moyens permettant d'influencer positivement le collagene
WO2001012206A3 (fr) * 1999-08-13 2002-08-01 Heinrich Wieland Substances et moyens permettant d'influencer positivement le collagene
US6689799B1 (en) 1999-08-23 2004-02-10 Rephartox 1,4-dihydropyridine-5-carboxylic acid ester derivatives and method for the preparation thereof
EP1099438A2 (fr) * 1999-11-10 2001-05-16 Pfizer Products Inc. Utilisation d'inibiteurs de la MTP ou de la sécrétion de l'ApoB
EP1099438A3 (fr) * 1999-11-10 2003-03-19 Pfizer Products Inc. Utilisation d'inibiteurs de la MTP ou de la sécrétion de l'ApoB
WO2002036129A2 (fr) * 2000-11-02 2002-05-10 Alfred Schmidt Traitement topique de la mastalgie
WO2002036129A3 (fr) * 2000-11-02 2004-02-26 Alfred Schmidt Traitement topique de la mastalgie
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
EP1610778A4 (fr) * 2003-01-17 2006-05-31 Threshold Pharmaceuticals Inc Traitement de l'hypertrophie prostatique benigne
JP2006516571A (ja) * 2003-01-17 2006-07-06 スレッシュオールド ファーマシューティカルズ， インコーポレイテッド 良性前立腺増殖症の処置
EP1610778A2 (fr) * 2003-01-17 2006-01-04 Threshold Pharmaceuticals, Inc. Traitement de l'hypertrophie prostatique benigne
US7696217B2 (en) 2003-06-30 2010-04-13 Merck Sharp & Dohme Corp. 17-acetamido-4-azasteroid derivatives as androgen receptor modulators
US7482357B2 (en) 2003-06-30 2009-01-27 Merck & Co., Inc. 17-acetamido-4-azasteroid derivatives as androgen receptor modulators
US7329750B2 (en) 2003-06-30 2008-02-12 Merck & Co., Inc. 17-Acetamido-4-azasteroid derivatives as androgen receptor modulators
US8314097B2 (en) 2005-08-25 2012-11-20 Novartis Ag Organic compounds
US8835646B2 (en) 2005-08-25 2014-09-16 Novartis Ag Organic compounds
US9278969B2 (en) 2005-08-25 2016-03-08 Novartis Ag Organic compounds
US7727978B2 (en) 2006-08-24 2010-06-01 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors
US8299054B2 (en) 2006-08-24 2012-10-30 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type 1 inhibitors
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
US8541444B2 (en) 2007-10-01 2013-09-24 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
WO2012035553A1 (fr) * 2010-09-15 2012-03-22 Ind-Swift Laboratories Limited Procédé de préparation de dérivés d'androsténone
US10869855B2 (en) 2012-07-26 2020-12-22 The William M. Yarbrough Foundation Method for treating benign prostatic hyperplasia (BPH), prostatitis, and prostate cancer
US20150322001A1 (en) * 2012-11-21 2015-11-12 The University Of Sydney Omega-3 analogues

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IL101574A0 (en) 1992-12-30
AU1893492A (en) 1992-11-17
PT100388A (pt) 1993-07-30

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