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WO1992013828A1 - Nouveau derive de benzanilide ou son sel - Google Patents

Nouveau derive de benzanilide ou son sel Download PDF

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Publication number
WO1992013828A1
WO1992013828A1 PCT/JP1992/000121 JP9200121W WO9213828A1 WO 1992013828 A1 WO1992013828 A1 WO 1992013828A1 JP 9200121 W JP9200121 W JP 9200121W WO 9213828 A1 WO9213828 A1 WO 9213828A1
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WO
WIPO (PCT)
Prior art keywords
reference example
group
ethyl
magnetic resonance
nuclear magnetic
Prior art date
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Ceased
Application number
PCT/JP1992/000121
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English (en)
Japanese (ja)
Inventor
Toshiyasu Mase
Susumu Igarashi
Ichio Noda
Takenori Kimura
Hiroshi Koutoku
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yamanouchi Pharmaceutical Co Ltd
Original Assignee
Yamanouchi 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
Priority claimed from JP36158491A external-priority patent/JPH05163223A/ja
Application filed by Yamanouchi Pharmaceutical Co Ltd filed Critical Yamanouchi Pharmaceutical Co Ltd
Publication of WO1992013828A1 publication Critical patent/WO1992013828A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention relates to a novel benzanilide derivative having a testosterone 5-reductase inhibitory action, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and a method for producing them.
  • Testosterone (TS) secreted by the testis and adrenal gland is taken up by the target cells of the orchid diyun, and then reduced to dihydrotestosterone (DHT) by the action of intracellular 5-reductase. It is. DHT generated in this way is thought to be closely related to the development of prostatic hyperplasia and prostate cancer. In addition, the onset and exacerbation of androgenetic alopecia and acne seborrhea are also thought to be one of the causes of excess DHT and TS.
  • DHT dihydrotestosterone
  • the present inventors have created various compounds and proceeded with screening, and as a result, the benzanilide derivative represented by the following general formula (I) or a salt thereof has been shown to inhibit testosterone 5-reductase in comparison with the above-mentioned known compounds.
  • the present inventors have found that they have an excellent antiprostatic hypertrophy action based on the action, and have completed the present invention.
  • R 1 is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom
  • R 2 is a hydrogen atom or a lower alkyl group
  • R 3 is a lower alkyl group or a halogen atom
  • (R 3 ) n represents that the benzene ring is substituted with 0 to 4 R 3 groups which may be the same or different
  • X represents a lower alkylene group
  • X 2 represents 10—
  • the purpose of the present invention is to provide a benzanilide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above derivative or a salt thereof and a pharmaceutically acceptable carrier.
  • Still another object of the present invention is to provide a method for producing the above derivative or a salt thereof.
  • the “lower alkyl group” specifically includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl) Group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl Butyl group, 1-ethylbutyl group, 2-ethylbutyl 3 ⁇ 4, 1, 1, 2-trimethylpropyl group, 1, 2, 2-(
  • the “lower alkoxy group” includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy (amyloxy) group, isopentyl group.
  • Examples include a xy group, a tert-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a 1,2-dimethylpropoxy group, an 11-ethylpropoxy group, and a hexyloxyl group.
  • the “lower alkylene group” includes a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, a 1-methylethylene group, a 2-methylmethylene group, a tetramethylene group, a 1-methyltrimethylene group, and a 2-methyltrimethylene group.
  • alkylene group having 1 to 10 carbon atoms include hexyl methylene in addition to the above “lower alkylene group”.
  • the compound (I) of the present invention may form an acid addition salt.
  • a salt with a base may be formed.
  • Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, drunk acid, propionic acid, oxalic acid, malonic acid, and succinic acid.
  • Fumaric acid maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and other organic acids, aspartic acid, glutamic acid, and other acidic amino acids, and acid addition salts, sodium, potassium
  • inorganic bases such as magnesium, calcium, and aluminum
  • organic bases such as methylamine, ethylamine, and ethanolamine
  • salts with basic amino acids such as lysine and ordithine
  • ammonium salts include inorganic bases such as magnesium, calcium, and aluminum; organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ordithine; and ammonium salts.
  • the present invention also includes various solvates and polymorphs of the compound (I) of the present invention.
  • the compound of the present invention can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • the typical production method is shown below.
  • R 1 , R 2 , R 3 , (R 3 ) n, and 3 ⁇ 4 have the above-mentioned meaning, and R 7 represents a carboxylic acid protecting group.
  • the compound (I) of the present invention can be produced by removing an ester residue from the corresponding ester represented by the general formula (II).
  • the compound represented by the following general formula (1 ') which is a starting compound of the compound of the present invention, comprises a substituted aniline represented by the general formula (II) and a carboxylic acid represented by the general formula (III) or a reactive derivative thereof. It is produced by reacting
  • Z 1 is a group represented by the formula X 2 — (Wherein, X 2 and R 4 have the meanings described above.) Or ⁇ ⁇ which can be substituted with a group represented by the formula X 2 —R ⁇ (wherein, X 2 and R have the meanings described above.) the, Z 2 is wherein one; groups (. wherein, R 7 are each as defined above) represented by Xi -COOR 7 or formula
  • R 7 has the meaning described above. ) Means respectively. ]
  • Reactive derivatives of compound (III) include acid halides such as acid chloride and acid bromide; acid azide; N-hydroxybenzotriazole ⁇ ⁇ active ester with N-hydroxysuccinimide; symmetry Acid anhydrides; mixed acid anhydrides with alkyl carbonic acid; mixed acid anhydrides such as P-toluenesulfonic acid mixed acid anhydride; and the like.
  • compound (II) and compound (II) or a reactive derivative thereof are used in an approximately equimolar amount or one of them in an excess amount, and an organic solvent inert to the reaction, for example, pyridine, tetrahydrofuran.dioxane, ether, benzene, Toluene, xylene, methylene chloride, dichloroethane, chloroform, N, N-dimethylformamide, ethyl acetate,
  • a solvent such as acetonitrile.
  • a base such as triethylamine, pyridine, picoline, lutidine, N, N-dimethylaniline, potassium carbonate, or sodium hydroxide during the reaction facilitates the reaction. May be advantageous. Pyridine can also serve as a solvent.
  • the reaction temperature depends on the type of the reactive derivative and is not particularly limited.
  • Z 1 is a group that can be substituted for a group represented by the formula X 2 —, specifically, for example, a group represented by (li b) or (li e) in the following reaction scheme
  • the method further comprises the step of substituting Z 1 with a group represented by the formula X 2 -R 4 .
  • This reaction can be performed by a known 0-alkylation, 0-allylation or N-alkylation reaction.
  • the reaction can be carried out by reacting a substituted phenol, a substituted aniline, or a substituted alkylamine with a halogenated compound.
  • the reaction is carried out in a solvent inert to the reaction, for example, dimethylformamide, dimethylsulfoxide, alcohols, or, in the case of alkylation of a substituted phenol, in addition to the above solvent, methyl ethyl ketone, acetone, etc. Performed in a solvent.
  • a solvent inert for example, dimethylformamide, dimethylsulfoxide, alcohols, or, in the case of alkylation of a substituted phenol, in addition to the above solvent, methyl ethyl ketone, acetone, etc.
  • a base such as sodium hydroxide, potassium carbonate, or sodium hydride during the reaction to make the reaction proceed smoothly.
  • N-alkylation step of R 2 and Z or R 5 in the above formula can be included.
  • This reaction can be carried out using a conventional N-alkylation reaction.
  • These reactions can be performed in any order, and include the steps of introducing a protecting group and removing the protecting group as necessary.
  • a 1 is hydroxyl group, the two Toro group or the formula - Y 2 -.. N0 based (formula represented by 2, Y 2 are each as defined above)
  • Alpha 2 is a hydroxyl group, an amino group, or A group represented by the formula- ⁇ 2 — ⁇ 2 (wherein ⁇ 2 has the above-mentioned meaning),
  • ⁇ 3 is a hydroxyl group having a protecting group, a dinitro group, and a group represented by the formula ⁇ 2 — ⁇ 0 2
  • the groups (wherein ⁇ 2 has the above-mentioned meaning), A and a hydroxyl group having a protecting group, respectively, have the same meanings as above. If necessary, the alkylation reaction of R 2 and R 5 may be included at any stage.
  • reaction products obtained by the above processes are isolated and purified as free compounds, their salts or various solvates.
  • the salt can be produced by subjecting it to a conventional salt-forming reaction.
  • Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • Industrial applicability such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the compounds of the present invention have testosterone 5 ⁇ -reductase inhibitory activity and are useful for various diseases caused by the effects of benign prostatic hyperplasia and other male hormones, such as prostate cancer, seborrhea, acne, and male pattern baldness. Useful for treatment.
  • the inhibitory effect of the compound of the present invention on 5-reductase is evident from the test of 5-reductase inhibitory activity (in vitro) using human vulvar skin fibroblasts (HS27).
  • Human fibroblasts (HS27) collected by subculture were homogenized by adding lOmM Tris-HCl buffer (PH7.0), and then subjected to sonication for 15 seconds X 3 times with a Sonifia. The solution was further centrifuged (3000 rpm for 10 minutes), and the resulting supernatant was used as the enzyme solution.
  • Test results The table below shows the inhibitory activity of the compound of the present invention on 5 ⁇ -reductase measured using human HS27.
  • the compound of the present invention shows high activity in the test for 5-reductase inhibitory activity using human HS27, and high clinical utility is expected.
  • the control compound is a compound described in European Patent Publication No. 294,035 and is a compound that is being developed as a pharmaceutical product in clinical trial ⁇ -3805. Because the effect is several times stronger and the toxicity is very low, it is considered that a drug with high utility as a medicine can be provided.
  • compositions containing one or more of the compounds represented by the general formula (I) or a salt thereof as an active ingredient can be prepared by using a carrier, an excipient, and other additives that are usually used in formulation. It is prepared by
  • Pharmaceutical carriers and excipients include solid or liquid non-toxic pharmaceutical substances. Examples of these include lactose, magnesium sul- arate, starch, talc, gelatin, agar, pentine, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones.
  • Administration may be oral, such as tablets, pills, capsules, granules, or liquids, or parenteral, such as injections, suppositories, or transdermals, such as intravenous or intramuscular injections. .
  • the dose is determined as appropriate for each individual case, taking into account the symptoms, age of the subject, and gender.
  • oral administration it is usually 0.1 to 500 mg, preferably 1 to 200 mg per day for an adult, and is administered once to several times a day.
  • transdermal administration it is usually administered once to several times a day in the range of 0.01 to 500 mg at a time.
  • the dose is not limited to these.
  • the reaction solution was concentrated under reduced pressure, and the residue was dissolved in a mixture of 3 ml of methanol and a 5N aqueous solution of sodium hydroxide, heated to 50 and stirred for 12 hours.
  • the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate.
  • the extract was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, eluted with a mixture of hexane: ethyl acetate (8: 1), and p- (p-isobutylbenzyloxy) -N-methylaniline 13 Omg I got
  • the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate.
  • the extract was washed successively with 1N hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate.
  • the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and eluted with a mixture of hexane: ethyl ethyl ester (7: 1) to give 2-hydroxy-4 '-(p-isobutylbenzyloxy) -one. 11-Omg of 5-methylbenzanilide was obtained.
  • Raw material compound 5-mouth salicylic acid
  • the reaction solution was poured into a mixture of ice-1N hydrochloric acid and extracted with ethyl acetate.
  • the extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was subjected to silica gel column chromatography, and eluted with a mixture of hexane: ethyl acetate (12: 1 to 5: 1). ) 430 mg of phenyl, carbamoyl, phenoxy] butyrate were obtained.
  • Raw material compound 4-isobutyl pendirubide, 2,3-dimethyl-4,2-trophenenole
  • Raw material compound 4,12-trough 3,5-dimethylphenol

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Dérivé de benzanilide représenté par la formule générale (I), lequel possède une activité inhibitrice de la testostérone 5α réductase, son sel pharmaceutiquement acceptable, sa composition pharmaceutique, et procédé pour le produire.
PCT/JP1992/000121 1991-02-08 1992-02-06 Nouveau derive de benzanilide ou son sel Ceased WO1992013828A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP3/104005 1991-02-08
JP10400591 1991-02-08
JP3/361584 1991-12-17
JP36158491A JPH05163223A (ja) 1991-12-17 1991-12-17 新規なベンズアニリド誘導体またはその塩

Publications (1)

Publication Number Publication Date
WO1992013828A1 true WO1992013828A1 (fr) 1992-08-20

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AU (1) AU1238792A (fr)
WO (1) WO1992013828A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2002044127A1 (fr) * 2000-11-29 2002-06-06 Kyorin Pharmaceutical Co., Ltd. Dérivés d'acide carboxylique substitué
WO2004082677A1 (fr) * 2003-03-21 2004-09-30 H. Lundbeck A/S Derives de para-diaminobenzene substitues
US7547804B2 (en) 2002-07-15 2009-06-16 Myriad Genetics, Inc. Compounds, compositions, and methods employing same
US9580653B2 (en) 2012-12-12 2017-02-28 Merck Patent Gmbh Liquid-crystalline medium

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6391354A (ja) * 1986-10-02 1988-04-22 Yamanouchi Pharmaceut Co Ltd 新規なカルボン酸誘導体
JPS63159342A (ja) * 1985-04-03 1988-07-02 Yamanouchi Pharmaceut Co Ltd 新規カルボン酸化合物
JPH01139558A (ja) * 1987-06-04 1989-06-01 Ono Pharmaceut Co Ltd ５α−リダクターゼ阻害活性を有するベンゾイルアミノフェノキシブタン酸誘導体およびそれらを有効成分として含有する薬剤
JPH01156950A (ja) * 1987-05-11 1989-06-20 Ono Pharmaceut Co Ltd ５α―リダクターゼ阻害活性を有するベンゾイルアミノフェノキシブタン酸誘導体、それらの製造方法およびそれらを含有する薬剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63159342A (ja) * 1985-04-03 1988-07-02 Yamanouchi Pharmaceut Co Ltd 新規カルボン酸化合物
JPS6391354A (ja) * 1986-10-02 1988-04-22 Yamanouchi Pharmaceut Co Ltd 新規なカルボン酸誘導体
JPH01156950A (ja) * 1987-05-11 1989-06-20 Ono Pharmaceut Co Ltd ５α―リダクターゼ阻害活性を有するベンゾイルアミノフェノキシブタン酸誘導体、それらの製造方法およびそれらを含有する薬剤
JPH01139558A (ja) * 1987-06-04 1989-06-01 Ono Pharmaceut Co Ltd ５α−リダクターゼ阻害活性を有するベンゾイルアミノフェノキシブタン酸誘導体およびそれらを有効成分として含有する薬剤

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2002044127A1 (fr) * 2000-11-29 2002-06-06 Kyorin Pharmaceutical Co., Ltd. Dérivés d'acide carboxylique substitué
US7547804B2 (en) 2002-07-15 2009-06-16 Myriad Genetics, Inc. Compounds, compositions, and methods employing same
WO2004082677A1 (fr) * 2003-03-21 2004-09-30 H. Lundbeck A/S Derives de para-diaminobenzene substitues
JP2006520759A (ja) * 2003-03-21 2006-09-14 ハー・ルンドベック・アクチエゼルスカベット 置換されたｐ−ジアミノベンゼン誘導体
AU2004222626B2 (en) * 2003-03-21 2010-06-24 H. Lundbeck A/S Substituted p-diaminobenzene derivatives
US7906537B2 (en) 2003-03-21 2011-03-15 H. Lundbeck A/S Substituted p-diaminobenzene derivatives
US9580653B2 (en) 2012-12-12 2017-02-28 Merck Patent Gmbh Liquid-crystalline medium

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Publication number Publication date
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