WO2004111012A1 - イミダゾリジン誘導体 - Google Patents
イミダゾリジン誘導体 Download PDFInfo
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- WO2004111012A1 WO2004111012A1 PCT/JP2004/008211 JP2004008211W WO2004111012A1 WO 2004111012 A1 WO2004111012 A1 WO 2004111012A1 JP 2004008211 W JP2004008211 W JP 2004008211W WO 2004111012 A1 WO2004111012 A1 WO 2004111012A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- 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
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P17/10—Anti-acne agents
-
- 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
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
Definitions
- the present invention relates to an imidazolidine derivative having a substituted alkyl group at the 3-position, and a medicament containing the imidazolidine derivative as an active ingredient.
- prostate cancer benign prostatic hyperplasia
- androgenetic alopecia precocious puberty
- acne vulgaris seborrhea and hirsutism
- androgen a male hormone
- an anti-androgen IJ ie, an androgen receptor antagonist
- an androgen receptor antagonist for example, cyproterone acetate, chlormadinone acetate, funoletamide, bicalutamide and the like have been used.
- These antiandrogens have been successful in many cases, including drug treatment in prostate cancer, and have become one of the main therapeutic agents.
- Cyproterone acetate is also known to suppress the progression of acne and baldness in teenagers.
- cyproterone acetate has been used in women to treat virilization and alopecia. Flutamide and bicalutamide are used as prostate cancer therapeutics.
- hydroxyflutamide which is the active form of flutamide, increases the transcription activity of the androgen receptor at a concentration of 10 ⁇ mol ZL.
- the blood concentration of hydroxyflutamide in prostate cancer patients treated with flutamide is a few ⁇ ⁇ L, and according to the above report, this concentration was reported to be a concentration showing agonist action. (See Non-Patent Document 1).
- Patent Document 1 JP-A-4-1308579
- Patent Document 2 JP-A-4-1308579
- Patent Document 3 JP-A-4-494819
- Patent Document 3 Japanese Patent Application Laid-Open No. H10-510845 (Patent Document 3) and the corresponding WO97 / 00071 Patent Document 4 (Patent Document 4) describe the following. Compounds represented by the formula are known.
- Patent Document 1 JP-A-4-308579
- Patent Document 2 European Patent Application Publication No. 494819
- Patent Document 3 Japanese Patent Publication No. Hei 10-510845
- Patent Document 4 WO 97/00071 pamphlet
- Non-Patent Document 1 J. Biol. Chem., Vol. 270, pp. 19998-20003, 1995
- Non-Patent Document 2 Journal of Endocrine Society, Vol. 66, pp. 597-606, 1990 Disclosure of the Invention Problems to be Solved by the Invention
- An object of the present invention is to provide an imidazolidine derivative having a substituted alkyl group at the 3-position, a salt, a prodrug or a solvate thereof, which has a pharmaceutically useful activity, particularly an antiandrogenic activity. To provide.
- Another object of the present invention is to provide a medicine containing the above imidazolidine derivative.
- an imidazolidine derivative having a sulfonamide group represented by (I) exhibits antiandrogenic activity and shows no or almost no agonist activity, thereby completing the present invention.
- the present invention provides a compound represented by the formula (I)
- n is an integer selected from 1 to 20, and R 1 and R 2 are the same or different and are each a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. Indicate And a salt, prodrug and solvate thereof.
- the present invention also provides a compound represented by the formula (I), wherein n is an integer selected from 1 to 10, a salt thereof, a prodrug and a solvate thereof.
- the present invention also provides a compound represented by the formula (I), wherein R 1 and R 2 are hydrogen atoms, a salt, a prodrug and a solvate thereof.
- the present invention also provides a compound represented by the formula (I), and a compound, wherein at least one of R 2 is an S-methyl group, a salt, a prodrug or a solvate thereof. Further, the present invention provides
- a medicament comprising a compound represented by the formula (I), a salt, a prodrug or a solvate thereof as an active ingredient.
- a pharmaceutical composition comprising a compound represented by the formula (I), a salt, a prodrug or a solvate thereof as an active ingredient.
- the present invention also provides an antiandrogen containing a compound represented by the formula (I), a salt, a prodrug or a solvate thereof as an active ingredient.
- the present invention provides a compound represented by the formula (I), a salt thereof, a prodrug or a solvate thereof as an active ingredient, prostate cancer, prostatic hypertrophy, androgenetic alopecia, sexual precociousness, vulgaris
- an agent for preventing or treating a disease selected from acne, seborrhea and hirsutism are also provided.
- n is an integer selected from 1 to 20;
- Ra and Rb are the same or different number of 1 one 6 carbon atoms substituted by Yogu 1 or more W 1 optionally linear or branched alkyl group, substitution by one or more W 1 carbon atoms which may have 1 one 6 straight or branched alkyl group of one or more W 2 by optionally substituted ⁇ reel carbonyl group, 1 or its being by W 1 above substituted carbon atoms and optionally 1 single 6 straight or branched chain alkoxides aryloxycarbonyl group, one or more W 2 by optionally substituted Ariruo alkoxycarbonyl group, one or more linear or branched alkylaminocarbonyl group W 1 C 1 one 6 may be substituted by one or more W carbon atoms which may be substituted by 1 1 one 6 linear Or branched dialkyla Nokarubo group, one or more linear or branched alkylsulfonyl group W C 1 one 6 may be substituted by 1, optionally substituted by one or more W 2 Selected from the group consisting of
- W 1 is a linear or branched alkoxy group having 16 carbon atoms, a linear or branched alkylthio group having 16 carbon atoms, a linear or branched alkyl thio group having 16 carbon atoms.
- W 2 represents a linear or branched alkyl group having 1 one 6 carbon atoms, straight-chain or branched alkoxy group having 1 one 6 carbon atoms, straight-chain or branched 1 one 6 carbon atoms A chain haloalkyl group, a halogen atom, a cyano group, or a nitro group;
- W 3 is a straight-chain or branched alkyl group having 16 carbon atoms, a straight-chain or branched alkoxy group having 16 carbon atoms, a straight-chain or branched chain having 16 carbon atoms.
- a chain alkylamino group which is a linear or branched dialkylamino group having 1 to 6 carbon atoms;
- R 1 and R 2 are as previously defined;
- Rc is a linear or branched alkyl group having 1 to 6 carbon atoms.
- n, Ra, and Rb are as defined above.
- n, Ra, and Rb are as previously defined in this specification. Or a salt, prodrug or solvate thereof.
- a method for preventing or treating a disease comprising administering a compound represented by the formula (I), a salt, a prodrug or a solvate thereof. .
- the invention's effect comprising administering a compound represented by the formula (I), a salt, a prodrug or a solvate thereof.
- the present invention provides an imidazolidine derivative that can be an antiandrogen agent that does not exhibit side effects such as expression of androgen resistance and / or hepatotoxicity due to long-term administration.
- Examples of the linear or branched alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, and an i- Examples thereof include a butyl group, a t-butyl group, an n-pentyl group, a 3-methylbutyl group, a 2-methylbutyl group, a 1-methylbutyl group, a 1-ethylpropyl group, and an n-hexyl group.
- a methyl group is more preferred, preferably a straight or branched alkyl group having 13 carbon atoms.
- the linear or branched alkoxy group having 1 to 6 carbon atoms has an alkyl group as defined above as an alkyl moiety, and includes a methoxy group, an ethoxy group, an n-propoxy group, and an i- Poxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3_methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpyrp And a mouth oxy group and an n-hexynoleoxy group.
- a linear or branched alkylcarbonyl group having 1 to 6 carbon atoms is the same as defined above. It has a alkyl group as an alkyl moiety, and includes an acetyl group, a propionyl group, a 2-methylpropionyl group, a 2,2-dimethylpropionyl group, and the like.
- the aryl group means a monocyclic or condensed ring aromatic hydrocarbon group having 6 to 14 carbon atoms, and includes a phenyl group, a 1_naphthyl group, a 2_naphthyl group, an anthracenyl group and the like. The same applies to the case where the aryl group is included as a part of another substituent.
- the aryloxy group has an aryl group as defined above as an aryl moiety, and includes a phenoxy group, a 1_naphthyloxy group, a 2_naphthyloxy group, and the like.
- the arylcarbonyl group includes a benzoyl group, a 1_naphthoyl group, a 2_naphthoyl group and the like.
- the linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms has an alkyl group as defined above as an alkyl moiety, and includes a methoxycarbonyl group, an ethoxycarbonyl group, and a t-butoxy group. And a carbonyl group.
- the aryloxycarbonyl group includes a phenoxycarbonyl group, a 1-naphthyloxycarbonyl group, a 2-naphthyloxycarbonyl group, and the like.
- the straight-chain or branched-chain alkylaminocarbonyl group having 1 to 6 carbon atoms has an alkyl group as defined above as an alkyl moiety, and includes a methinoleaminocarbinole group, an ethylamino group. Includes carbonyl group, t-butylaminocarbonyl group and the like.
- the linear or branched dialkylaminocarbonyl group having 1 to 6 carbon atoms has an alkyl group as defined above as an alkyl moiety, and is a dimethylaminocarbonyl group.
- Tert-butylaminocarbonyl group diisopropylaminocarbonyl group, diisopropylaminocarbonyl group, methyl-t-butynoleaminocarbonyl group and the like.
- the straight-chain or branched-chain alkylthio group having 1 to 6 carbon atoms has the already defined alkyl group as the alkyl portion, and includes a methylthio group, an ethylthio group and the like.
- the straight-chain or branched-chain alkylsulfinyl group having 1 to 6 carbon atoms has an alkyl group as defined above as an alkyl moiety, and includes a methylsulfiel group, an ethylsulfiel group and the like.
- a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms is the same as defined above. It has a kill group as an alkyl moiety, and includes a methanesulfonyl group, an ethanesulfonyl group and the like.
- the arylsulfonyl group includes a benzenesulfonyl group, a 1-naphthalenesulfonyl group, a 2_naphthalenesulfonyl group, and the like.
- a straight-chain or branched aralkyl group having 13 carbon atoms has an alkyl group as defined above as a straight-chain or branched alkyl moiety having 13 carbon atoms, and is a benzyl group.
- the straight-chain or branched aralkyloxy group having 13 carbon atoms has the aralkyl group defined above as a straight-chain or branched aralkyl moiety having 13 carbon atoms.
- the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like.
- a straight or branched haloalkyl group having 13 carbon atoms is an alkyl group substituted with one or more halogen atoms as defined above.
- the haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, chlorodifluoromethyl, 1,1,1-trifluoroethyl, 1 , 1, 1 trichloroethyl group, perfluoroethyl group, perfluorophenol group and the like.
- Ra and Rb include, in addition to the above substituents, a C alkoxy C alkyl group such as a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group;
- n 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 are preferable, and 2 to 9 are preferable, In addition, 2-6 strengths are preferred.
- n is 3 or 4 a significant difference between agonist activity and antagonist activity is observed.
- the deprotection step is not particularly limited, but examples thereof include a hydrolysis reaction in the presence of an acid or a base, a reduction reaction including hydrogenation using PdZC, and dichlorodisianquinone. And the like.
- R 1 and R 2 are preferably a hydrogen atom which may be the same or different, or a straight or branched alkyl group having 13 to 13 carbon atoms.
- the salt of the compound represented by the formula (I) is a pharmaceutically acceptable salt produced by bringing the compound into contact with an acid or a base that can be used for producing a pharmaceutical.
- Such salts include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, sulfonate, phosphate, phosphonate; acetate, citrate, malate, Carbonates such as salicylates, or alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium salts and potassium salts; ammonium salts, alkyl ammonium salts, and dialkyl ammonium salts Salts, ammonium salts such as trialkylammonium salts and tetraalkylammonium salts.
- a prodrug of a compound represented by the formula (I) is a chemical reaction in a living body that produces a compound represented by the formula (I) in a living body after being administered as a pharmaceutical. This includes compounds that have been subjected to chemical modification intended for.
- Such prodrugs include, for example, C
- prodrug examples include a compound represented by the formula (III).
- the solvate of the compound represented by the formula (I) includes a compound in which a molecule of a solvent usable for the production of a pharmaceutical is coordinated with the compound.
- the solvate includes, for example, hydrate.
- the compound represented by the general formula (I) of the present invention is expected to be an antiandrogen agent that does not exhibit androgen resistance due to long-term administration and / or does not show side effects such as hepatotoxicity. It is expected to be useful as a pharmaceutical composition, for example, a therapeutic agent for diseases such as prostate cancer, benign prostatic hyperplasia, androgenetic alopecia, sexual precociousness, acne vulgaris, seborrhea, and hirsutism. Is done.
- the compound represented by the general formula (I) of the present invention is administered in advance, prostate cancer, prostatic hypertrophy, male pattern baldness, sexual precociousness, acne vulgaris, seborrhea, and Since it can be expected to prevent or delay the onset of diseases such as hirsutism, it can also be expected to be a preventive agent for these diseases.
- the pharmaceutical composition of the present invention contains a therapeutically effective amount of the compound represented by the formula (I), a salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier. If so, other chemotherapeutic agents may be included. Chemotherapeutic agents include, for example, cytostatics, alkylating agents, metabolic inhibitors, interactivating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, enzyme inhibitors, aromatase inhibitors, topoisomerases It may be one or more selected from the group consisting of inhibitors, biological response modifiers, antihormones, antiestrogens and antiandrogens.
- the compound represented by the general formula (I) of the present invention is expected to be an anti-androgen agent which does not exhibit androgen resistance by long-term administration and / or does not show side effects such as hepatotoxicity. It is expected to be useful as a pharmaceutical composition, for example, as a therapeutic agent for diseases such as prostate cancer, benign prostatic hyperplasia, androgenetic alopecia, sexual precociousness, acne vulgaris, seborrhea, and hirsutism. .
- the compound represented by the general formula (I) of the present invention is administered in advance, prostate cancer, benign prostatic hyperplasia, male pattern baldness, sexual precociousness, acne vulgaris, seborrhea, and Since it can be expected to prevent or delay the onset of diseases such as hirsutism, it can also be expected to be a preventive agent for these diseases.
- the compound of the present invention represented by the formula (I), a salt, a prodrug and a solvate thereof may be a pharmaceutically acceptable carrier, excipient, binder, diluent, stabilizer, Lubricants, flavoring agents, disintegrants, coating agents, coloring agents, antioxidants, buffers, aqueous solvents, oil solvents, isotonic agents, dispersants, preservatives, dissolution aids, fluidizers, soothing agents It can be orally or parenterally administered as a pharmaceutical composition containing an additive, a pH adjuster, a preservative, a base and the like together with additional components.
- oral preparations include, for example, granules, powders, tablets, hard capsules Preparations, soft capsules, syrups, emulsions, suspensions, and the like.
- parenteral preparations include injections such as subcutaneous injections, intravenous injections, intramuscular injections, and intraperitoneal injections.
- Transdermal preparations such as ointments, creams and lotions; suppositories such as rectal suppositories and vaginal suppositories; and intranasal preparations. These preparations can be manufactured by a known method usually used in a preparation process.
- excipient used in the pharmaceutical composition of the present invention examples include sugars such as lactose, sucrose, glucose, D-mannitol, and sorbitol; crystalline cellulose, hydroxypropyl cellulose, and hydroxypropinolemethi.
- Senololose and derivatives thereof such as noresenorelose and methinoresenorelose; starch and derivatives thereof such as corn starch, potato starch, sunflower starch, dextrin, / 3-cyclodextrin, sodium carboxymethyl starch, hydroxypropyl starch; Silicates such as aluminum silicate, magnesium aluminate, calcium silicate and magnesium silicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate; tartaric acid; Potassium stone oxyhydrogen, magnesium hydroxide.
- binder for example, agar, stearyl alcohol, gelatin, tragacanth, polyvinyl alcohol, polyvinylpyrrolidone; crystalline cellulose, hydroxypropylcellulose, hydroxypropinolemethinoresenorelose, methinoresenorelose Corn starch, potato starch, ⁇ -starch, dextrin, _ cyclodextrin, sodium carboxymethyl starch, hydroxypropyl starch, and derivatives thereof; lactose, sucrose, glucose, D-mannitol, sorbie And sugars such as nuts.
- Examples of the stabilizer include hardened oil, sesame oil, chondroitin sulfate, dibutylhydroxytoluene, adipic acid, ascorbic acid, L-ascorbate stearate, sodium L-ascorbate, L-aspartic acid, L-aspartate sodium, acetyltryptophan sodium, acetoanilide, aprotune solution, aminoethylsolephonic acid, aminoacetic acid, DL-alanine, L-alanine; paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, Alcohols such as phenylethyl alcohol; benzalkonium chloride; phenol, sauce Phenols such as sol; sorbic acid; sulfites such as sodium bisulfite and sodium sulfite; and edetates such as sodium edetate and tetras
- Lubricants include, for example, gum arabic powder, cacao butter, potash noremelose calcium, carmellose sodium, carpoxide, hydrated silicon dioxide, hydrated amorphous silicon oxide, and dried aluminum hydroxide gel Glycerin, light liquid paraffin, crystalline cellulose, hardened oil, synthetic aluminum silicate, sesame oil, wheat starch, tanolek, macrogol, phosphoric acid; stearic acids such as stearic acid, calcium stearate, magnesium stearate; salami beeswax, carnauba wax And the like. Sulfates such as sodium sulfate; magnesium acids and light acids such as light anhydrous silicic acid; and sodium sulfate lauryl sulfate and the like.
- flavoring agent examples include ascorbic acid, L-aspartic acid, sodium L-aspartate, magnesium L-aspartate, aspartame, Amatilla, Amatilla extract, Amatilla powder, aminoethylsulfonic acid, aminoaminoacetic acid, DL- Alanine, saccharin sodium, dl-menthol, 1-menthol; lactose, sucrose, glucose, D-mannitol and other sugars.
- Disintegrators include, for example, agar, gelatin, tragacanth, adipic acid, alginic acid, sodium alginate; cellulose such as crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose and derivatives thereof; calcium carbonate, sodium hydrogen carbonate And starches such as corn starch, potato starch, ⁇ -starch, dextrin, —cyclodextrin, sodium carboxymethyl starch, hydroxypropyl starch and derivatives thereof.
- Examples of the coating agent include shellac, polyvinylpyrrolidone, polyethylene dalicol, macrogol, methacrylic acid copolymer, liquid paraffin, and Eudragit; And cellulose derivatives such as hydroxypropylmethylcellulose.
- Examples of the coloring agent include indigo carmine, caramel, riboflavin and the like.
- Examples of the buffer include, for example, aminoacetic acid, L-arginine, benzoic acid, sodium benzoate, ammonium chloride, potassium chloride, sodium chloride, dried sodium sulfite, dried sodium carbonate, dilute hydrochloric acid, citrate, Calcium citrate, sodium citrate, disodium citrate, calcium dalconate, L-glutamic acid, sodium L-glutamate, creatine, chlorobutanol, crystalline sodium dihydrogen phosphate, disodium succinate, acetic acid, potassium acetate, acetic acid Sodium, tartaric acid, sodium bicarbonate, sodium carbonate, trietanolamine, lactic acid, sodium lactate solution, glacial acetic acid, boric acid, maleic acid, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium acetate, anhydrous sodium carbonate, anhydrous
- aqueous solvent examples include distilled water, physiological saline, Ringer's solution and the like.
- oily solvent examples include propylene glycol; vegetable oils such as olive oil, sesame oil, cottonseed oil, and corn oil.
- Examples of the tonicity agent include potassium chloride, sodium chloride, glycerin, sodium bromide, D-sorbitol, nicotinamide, glucose, and boric acid.
- dispersant examples include gum arabic, propylene glycol alginate, sorbitan sesquioleate, D-sorbitol, tragacanth, methylcellulose, aluminum monostearate, aminoalkyl methacrylate copolymer RS, lactose, concentrated glycerin, propylene glycol, macro Galls, sodium lauryl sulfate; stearic acid such as zinc stearate and magnesium stearate, and salts thereof.
- preservative examples include, for example, benzanolone chloride, sodium salt, dried sodium sulfite, dried sodium sulfate, cresol, closol cresol, dibutylhydroxytonolene, potassium sorbate, and sodium dehydroacetate.
- solubilizer examples include sodium benzoate, ethylenediamine, citric acid, sodium citrate, glycerin, sodium acetate, sodium salicylate, sorbitan sesquioleate, nicotinamide, glucose, benzyl alcohol, and polybutylpyrrolidone And acetone, ethanol, isopropanol, D-sonolebitone, sodium bicarbonate, sodium carbonate, lactose, urea, sucrose and the like.
- Examples of the fluidizing agent include hydrous silicon dioxide, talc, anhydrous ethanol, crystalline cellulose, synthetic aluminum silicate, calcium hydrogen phosphate; stearic acid such as calcium stearate and magnesium stearate, and salts thereof. can give.
- Examples of the soothing agent include benzanolecone chloride, proforce hydrochloride, mepril hydrochloride, lidocaine hydrochloride, lidocaine and the like.
- Examples of the pH adjuster include hydrochloric acid, citric acid, succinic acid, acetic acid, boric acid, maleic acid, sodium hydroxide and the like.
- preservatives include benzoic acid, sodium benzoate, cetylpyridinium chloride, salicinoleic acid, sodium salicylate, sorbic acid, potassium sorbate, thymol, methyl paraoxybenzoate, butyloxybenzoate. And so on.
- Examples of the base include glycerin, stearyl alcohol, polyethylene glycols, propylene glycol, cetanol, lard, white petrolatum, paraffin, bentonite, isopropyl lanolin fatty acid, petrolatum, polysorbates, macrogol, lauryl alcohol. Coal, sodium lauryl sulfate, ethyl linoleate, sodium hydrogen phosphate, rosin; and vegetable oils such as olive oil, sesame oil, and wheat germ oil.
- the amount of the compound represented by the general formula (I) contained in the pharmaceutical composition of the present invention varies depending on the dosage form, but is preferably about 0.1 100% by weight based on the total amount of the pharmaceutical composition. is there.
- the dosage of the pharmaceutical composition of the present invention may vary widely depending on the type of administration control (human or other warm-blooded animals, etc.), severity of symptoms, age, sex, administration method, diagnosis by a doctor, and the like.
- the dose of the compound represented by formula (I) to adults for oral or parenteral administration is about 0.1 to 500 mg / kg per day, although it can be varied.
- the above dose is a value per unit weight of the administration subject.
- the above dosage may be administered once or twice a day or divided into several times depending on the severity of symptoms, judgment of a doctor, etc. May be.
- the compound represented by the general formula (I) of the present invention can be produced, for example, according to the following Method A-D or a method wherein Method A-D is partially modified depending on the target compound.
- R represents a linear or branched alkyl group having 16 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group Group, i-butyl group, t-butyl group, n-pentyl group, 3-methylbutyl group, 2-methylbutyl group, 1-methylbutyl group, 1-ethylpropyl group, n-hexynole group, and the like.
- Preferred are straight-chain or branched-chain alkyl groups of the number 1 to 3, and more preferred are methyl and ethyl groups.
- X represents a leaving group, for example, a chlorine atom, a bromine atom, a halogen atom such as an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and the like.
- a halogen atom such as an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and the like.
- An atom and a halogen atom such as an iodine atom are preferred.
- Step A1 is a step of producing compound 2, which is achieved by reacting compound 1 with compound 15 in an inert solvent.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- Ether solvents aromatic solvents such as benzene, toluene, xylene, quinoline, and benzene, cyclohexane, dimethyl sulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylphos Noremamide, N-methylpyrrolidone, acetonitrile and the like, preferably dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylformamide, N-methylvinylidone and acetonitrile, and more preferably dimethylformamide and the like It is.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually -30 ° C to 100 ° C, and preferably 0 ° C to 50 ° C.
- the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
- Step A2 is a step of producing compound 3, which is achieved by reacting compound 2 with compound 16 in an inert solvent, in the presence of a base, in the presence or absence of an additive.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- Ether solvents aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide, N-methylpyrrolidone, Acetonitrile and the like, preferably dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylformamide, N-methylvinylidone, acetonitrile and the like.
- These inert solvents may be used alone or as a mixture.
- the base used is a carbonate such as potassium carbonate or sodium carbonate, a metal hydride such as sodium hydride, potassium hydride, calcium hydride, methyllithium, ethyllithium, n-butyllithium, t-butyl.
- Alkyl lithium such as lithium, lithium hydroxide, metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, cesium hydroxide, sodium amide, potassium bistrimethyl Amines such as metal amides, triethynoleamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7_ndecene, pyridine, dimethylaminopyridine, pyrazine, sodium tetraphosphate , Sodium iodide, lithium hexamethyldisilazane, sodium hexamethyl Silazanes, Yogu preferably potassium carbonate be hexamethyldisilazane or the like to potassium Pum, carbonates such as sodium carbonate.
- metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, cesium hydroxide, sodium amide, potassium bistrimethyl Amines such
- spiked kashimi material used as long as it promotes the progress of the reaction.
- potassium iodide, sodium iodide, tetra-n-butylammonium iodide and the like are used. You.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually 0 ° C 150 ° C, preferably 30 ° C to 100 ° C.
- the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
- Step A3 is a step of producing compound 4, which is achieved by reacting compound 3 with compound 17 in an inert solvent in the presence or absence of a base.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- Ether solvents aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethyl sulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide, N-methylpyrrolidone , Acetonitrile, and the like, preferably a halogen-based solvent such as dichloromethane, chlorophonolem, or carbon tetrachloride, or an ether-based solvent such as getyl ether, tetrahydrofuran, dioxane, or dimethoxyethane, and more preferably dichloromethane. Down, tetrahydrofuran and the like.
- aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethyl sulfoxide, dimethylacetamide, dimethylimidazolidinone
- the base used is, for example, amines such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] _7_indene, pyridine, dimethylaminopyridine and pyrazine. Yes, preferably, triethylamine, dimethylaminopyridine and the like.
- the base may or may not be used, but is preferably used.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually from -30 ° C to 100 ° C, and preferably from 0 ° C to 50 ° C.
- the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and is preferably
- Step A4 is a step of producing compound 5, in which compound 4 is acid-hydrolyzed in an inert solvent. It is achieved by doing.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction.
- methanol-free ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t- Butanol, Pentanol, Hexanol, Cyclopropanol, Cyclobutanol, Cyclopentanol, Cyclohexanol, Ethylene guanore, 1, 3_propanediol, 1,4_butanediol, 1,5_pentane Alcohol-based solvents such as diols, halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride; ether-based solvents such as tetraethylfuran, dioxane, and dimethoxyethane; benzene, toluene, xylene, quinoline,
- the acid used is not particularly limited, but may be, for example, hydrochloric acid, sulfuric acid or the like, preferably hydrochloric acid or the like.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C.
- reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and is preferably
- B method is a compound represented by formula (I), R 1 and R 2 are the same or different, straight-chain or branched alkyl having a hydrogen atom or a C 1 one 6 This is a method for producing compound 8, which is a group.
- Step B1 is a step of producing compound 7, which is achieved by reacting compound 6 with compound 16 in an inert solvent in the presence of a base, in the presence or absence of an additive, and the method A This is performed in the same manner as in step A2.
- Step B2 is a step of producing compound 8, which is achieved by reacting compound 7 with compound 17 in an inert solvent in the presence or absence of a base, and is similar to Step A3 of Method A. Done in
- Step C1 is a step of producing compound 10, which is carried out in an inert solvent in the presence of a base.
- the alcohol used in this step may be a linear or branched alkyl alcohol having 16 to 16 carbon atoms, a linear or branched aralkyl alcohol or aryl alcohol having 13 to 13 carbon atoms.
- the alcohol used in this step may be methanolic ethanol, n-propanol, isopropanol, t-butanol, neopentyl alcohol (distilled compound 18), or benzyl alcohol.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- Ether solvents aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide, N-methylpyrrolidone , Acetonitrile, and the like, preferably a halogen-based solvent such as dichloromethane, chlorophonolem, or carbon tetrachloride, or an ether-based solvent such as getyl ether, tetrahydrofuran, dioxane, or dimethoxyethane, and more preferably dichloromethane. It is down or the like.
- aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide
- the base used is, for example, amines such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] _7_indene, pyridine, dimethylaminopyridine and pyrazine. Yes, preferably, triethylamine, dimethylaminopyridine and the like.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually -30 ° C to 100 ° C, and preferably -10 ° C to 30 ° C.
- the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and is preferably 30 minutes to 24 hours.
- Step C2 is a step of producing compound 11, which is achieved by reacting compound 10 with compound 16 in an inert solvent in the presence of a base, in the presence or absence of an additive. Is performed in the same manner as in Step A2 of Method A.
- Step C3 is a step of producing compound 12, which is achieved by reacting compound 11 with compound 17 in an inert solvent in the presence or absence of a base. Performed in the same manner as in step A3.
- Step C4 is a step of producing compound 13, which is achieved by reacting compound 12 with tetramethylammonium chloride or the like in an inert solvent.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- Ether solvents aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide, N-methylpyrrolidone And acetonitrile, preferably dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylformamide, N-methylvinylidone, acetonitrile, and more preferably dimethylformamide.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually 30 ° C to 250 ° C, and preferably 80. C-1 230. C.
- reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and is preferably
- Step C5 is a step of producing compound 14, in which a salt formed between compound 13 and a base such as triethylamine in an inert solvent is reacted with a reagent such as triphenylphosphine thionyl monochloride. This is achieved by:
- the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- Ether solvents aromatic solvents such as benzene, toluene, xylene, quinoline, and benzene Dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide, N-methylpyrrolidone, acetonitrile, etc .; Ether solvents such as tetrahydrofuran, dioxane and dimethoxyethane, and more preferably dichloromethane and the like.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually -30 ° C to 50 ° C, and preferably 0 ° C to 30 ° C.
- reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and is preferably
- Step C6 is a step of producing compound 8, which is achieved by reacting compound 14 with compound 19 in an inert solvent.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- Ether solvents aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide, N-methylpyrrolidone , Acetonitrile and the like, preferably a halogenated solvent such as dichloromethane, chlorophonolem, carbon tetrachloride, getyl ether, tetrahydrofuran.
- aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide, N-methylpyrrolidone , Acetonitrile and the like
- a halogenated solvent such as dichloromethane, chlorophonolem, carbon
- ether solvents such as dioxane and dimethoxyethane, and more preferably dichloromethane.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually -30 ° C to 50 ° C, and preferably 0 ° C to 30 ° C.
- reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and is preferably
- Method D is a method for preparing a compound represented by the general formula (I) wherein R 1 and R 2 are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 16 carbon atoms. Another method for producing certain compounds 8.
- Step D1 is a step of producing compound 56, in which compound 55 is compound 5 in an inert solvent. Achieved by reacting with 8.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction.
- ethenol-based solvents such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, methanol, ethanol, n_propanol, i_propanol, n-butanol, s-butano, t-butano, pentano, hexanol, cyclopropanol, cyclobutano, cyclopentano, cyclohexanol, ethylenegnore, Alcohol solvents such as 1,3-propanediol, 1,4-butanediol and 1,5-pentanediol, dimethyl sulfoxide, dimethylacetamide, etc., and preferably methanol, ethanol, getyl ether, etc. And more preferably methanol.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually 0 ° C to 200 ° C, preferably 10 ° C to 100 ° C.
- the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
- Step D2 is a step of producing compound 57, which is achieved by reacting compound 56 with compound 17 in an inert solvent in the presence or absence of a base.
- the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride, gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane.
- Ether solvents aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylhonolemamide, N-methylpyrrolidone , Acetonitrile, and the like, preferably a halogen-based solvent such as dichloromethane, chlorophonolem, or carbon tetrachloride, or an ether-based solvent such as getyl ether, tetrahydrofuran, dioxane, or dimethoxyethane, and more preferably dichloromethane. Down, tetrahydrofuran and the like.
- aromatic solvents such as benzene, toluene, xylene, quinoline and benzene, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, di
- the base used is, for example, amines such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] _7_indene, pyridine, dimethylaminopyridine and pyrazine. Yes, preferably, triethylamine, dimethylaminopyridine and the like.
- the base may or may not be used, but is preferably used.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually from -30 ° C to 100 ° C, and preferably from 0 ° C to 50 ° C.
- reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and is preferably
- the step D3 is a step of producing the compound (8), which is achieved by hydrolyzing the compound (57) with an acidic solvent in an inert solvent.
- the inert solvent used is not specifically limited unless it is involved in the reaction, for example, main Tano one Honoré, ethanol, n _ propanol, i_ propanol, n- butanol, s- butanol Honoré, t- Butanol, Pentanol, Hexanol, Cyclopropanol, Cyclobutanol, Cyclopentanol, Cyclohexanol, Ethylene Gunoconole, 1,3_propanediol, 1,4_butanediol, 1,5_pentane Alcohol-based solvents such as diols, halogen-based solvents such as dichloromethane, chlorophonolem, and carbon tetrachloride; ether-based solvents such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; benzene, toluene, xylene
- the acid used is not particularly limited, but may be, for example, hydrochloric acid, sulfuric acid or the like, and is preferably hydrochloric acid or the like.
- the reaction temperature varies depending on the type of the solvent and the like, but is usually 0 ° C 200 ° C, preferably 20 ° C to 150 ° C.
- reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and is preferably
- each step of Method A to Method D when there is a group requiring protection and deprotection, protection and deprotection of each group can be performed by a method well known to those skilled in the art. .
- protection and deprotection for example, reference can be made to "Protective Groups in Organic Synthesis 2nd edition", Theodora W. Green, John Wiley & Sons, Inc., 1991.
- the starting materials Compound 9, Compound 15, Compound 16, Compound 18 and Compound 19 are easily produced according to the power of readily available commercial products, known methods, or known methods or methods similar thereto.
- the compound 16 used in the present invention is preferably a hydrochloride, which may be a salt such as a hydrochloride.
- Compound 17 as a raw material is known, and is easily produced according to a known method or a method similar thereto.
- a known method or a method similar thereto For example, The 'Journal of steroids' Biochemistry I and 'Morekiura I' Biology, Vol. 48, No. 1, pp. 111-119, 1994: The Journal of steroid Biochemistry and Molecular Biology 48 (1),
- NMR measurement was performed using a nuclear magnetic resonance apparatus ARX300 (manufactured by Bruker).
- the mass spectrometry was measured using a mass spectrometer Q-micro, Triple Quadrupole Mass Spectrometer (manufactured by MICRO MASS).
- the Rf value in thin-layer chromatography Measured using a silica gel plate Silica gel 60 F (Merck)
- Rf value (silica gel plate, developing solvent; ethyl acetate): 0.556.
- Triethylamine (2.4 ml) was added to compound 33 (80 mg), the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain a triethylammonium salt of compound 33 (86 mg).
- a separate vessel dissolve triphenylphosphine (93 mg) in dichloromethane and at 0 ° C thionyl chloride (0.0205 ml) was added.
- a dichloromethane solution of the triethylammonium salt of compound 33 54 mg was added at 0 ° C, and the mixture was stirred at room temperature for 4 hours.
- a mixed solvent of pentane-diethyl ether (1: 1 5 ml) was added to the reaction solution, and the supernatant was separated and concentrated under reduced pressure.
- the obtained residue was dissolved in dichloromethane, aqueous ammonia (0.5 ml) was added at 0 ° C, and the mixture was stirred at 0 ° C for 1 hour.
- 2-Aminoisobutyric acid ethyl ester hydrochloride (592 mg) and potassium carbonate (1.02 g) were dissolved in a mixed solvent of acetonitrile (5 ml) and dimethylformamide (1 ml), and the mixture was stirred at room temperature for 1 hour.
- Compound 44 800 mg
- sodium iodide (441 mg) were added, and the mixture was stirred at 80 to 90 ° C for 22 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate.
- HeLa cells purchased from Dainippon Pharmaceutical Co., Ltd. were treated with charcoal-treated fetal bovine serum (FBS) (hereinafter referred to as DCC-FBS) containing 3% phenol red, Dulbecco's Modified Eagle Medium (hereinafter phenol red).
- FBS charcoal-treated fetal bovine serum
- DCC-FBS charcoal-treated fetal bovine serum
- phenol red Dulbecco's Modified Eagle Medium
- the cells were cultured in free DMEM).
- MMTV-Luc-Hyg vector (a reporter fufumid from Nuefu IT, which has a mouse tumor long terminal repeat containing an androgen response element and a hygromycin resistance gene):
- a GM-CAT vector ATCC No. 67282
- the chloramphenicol acetyltransferase gene was replaced with the firefly luciferase gene and the hygromycin resistance gene was inserted into the vector, and pSG5-hAR-neo (a human androgen receptor expression vector under the control of the SV40 promoter).
- HeLa cells were obtained using FuGENE TM 6 Transfection Reagent (obtained from Roche), which further inserted a neomycin resistance gene as a drug resistance gene having an androgen receptor gene. Transfection.
- the transfected cells are transcribed in a dose-dependent manner by dihydrotestosterone (DHT) by culturing them in DMEM containing 500 ⁇ g / mL neomycin, 300 ⁇ g / mL hygromycin and 10% FBS. A clone with increased activity was obtained.
- the resulting clone (11A11B2 cells) was maintained in DMEM containing 400 ⁇ g / mL neomycin, 200 ⁇ g / mL hygromycin and 10% FBS, and subcultured 34 days before the androgen receptor reporter gene assay. Passage was performed with phenol red-free DMEM containing 10% DCC-FBS.
- 11A11B2 Cells 3% DCC-FBS off including enol red-free DMEM (hereinafter Atsusi medium) were seeded 1.0xl0 to 4 / well become as white 'clear bottom 96 well microplates (COSTAR) at, and cultured overnight.
- the compounds were added at a final concentration of 1, 10, 100, 1000, 10,000, and 100,000 nmol / L), and after culturing for 48 hours, the transcription activity value was measured. Transcription activity was measured using the Bright-Glo TM Luciferase Assay System (Promega).
- the transcriptional activity ratio of the example compound was calculated, assuming that the transcriptional activity value using 0.1 nmol / L DHT was 100% and the transcriptional activity value of Atsushi medium alone was 0%.
- the concentration of the compound exhibiting 5% transcription activity was calculated from two linear equations sandwiching 5%.
- 11A11B2 Cells 3% DCC-FBS off including enol red-free DMEM (hereinafter Atsusi medium) were seeded 1.0xl0 to 4 / well become as white 'clear bottom 96 well microplates (COSTAR) at and over ⁇ culture.
- the ATSEY medium containing the example compound or the comparative example compound was added to the ATSEY medium containing the example compound or the comparative example compound so that the final concentration of the DHT was 0.1 nmol / L.
- the cells were added at 1000 and 10000 nmol / L, respectively, and after culturing for 48 hours, the transcription activity value was measured. Transcription activity is Bright-Glo TM Luciferase It was measured by Assay System (Promega).
- the transcriptional activity ratio of the example compound was calculated by assuming that the transcriptional activity value using 0.1 nmol / L DHT was 100% and the transcriptional activity value of Atsushi medium alone was 0%.
- the IC 50 value was calculated from a linear equation of two points sandwiching 50%.
- Table 1 shows the results of Test Examples 1 and 2.
- Comparative Examples 3 and 4 are known compounds and can be produced by a known method.
- the effect as an antiandrogen with reduced agonist activity can be reduced by half IJ by comparing EC5 / IC50 values. That is, a compound having a high EC5 / IC50 value is a compound having a more favorable effect, and specifically, the EC5 / IC50 value is desirably 5 or more, preferably 10 or more, and more preferably 20 or more. It is.
- the compound of the present invention represented by the formula (I) is expected to be an anti-androgen agent which does not exhibit androgen resistance by long-term administration and / or does not show side effects such as hepatotoxicity.
- it is expected to be useful as a therapeutic agent for diseases such as prostate cancer, prostatic hypertrophy, male pattern baldness, sexual precociousness, acne vulgaris, seborrhea, and hirsutism.
- prostate cancer prostatic hypertrophy, male pattern baldness, sexual precociousness, acne vulgaris, seborrhea
- prostatic hypertrophy male pattern baldness, sexual precociousness, acne vulgaris, seborrhea
- acne vulgaris seborrhea
- prostatic hypertrophy male pattern baldness
- sexual precociousness acne vulgaris
- seborrhea can be expected to prevent or delay the onset of diseases such as dystrophy and hirsutism, and thus can be expected to be a preventive agent for these diseases.
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US10/560,281 US7271188B2 (en) | 2003-06-12 | 2004-06-11 | Imidazolidine derivatives |
JP2005506937A JP4664814B2 (ja) | 2003-06-12 | 2004-06-11 | イミダゾリジン誘導体 |
EP04745805A EP1634874A4 (en) | 2003-06-12 | 2004-06-11 | imidazolidine |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58194891A (ja) * | 1982-04-27 | 1983-11-12 | チバ−ガイギ−・アクチエンゲゼルシヤフト | 7β−アシルアミド−3−セフエム−4−カルボン酸化合物、その製造方法及び該化合物を含む医薬製剤 |
JPH04308579A (ja) * | 1991-01-09 | 1992-10-30 | Roussel Uclaf | 新規なフェニルイミダゾリジン類、それらの製造法、薬剤としての使用及びそれらを含有する製薬組成物 |
JPH0673017A (ja) * | 1992-07-08 | 1994-03-15 | Roussel Uclaf | 新規な置換フェニルイミダゾリジン、それらの製造法、それらの薬剤としての使用及びそれらを含有する製薬組成物 |
JPH10510845A (ja) * | 1995-06-16 | 1998-10-20 | バイオフィジカ ファウンデーション | アンドロゲン関連組成物 |
JP2002528434A (ja) * | 1998-10-23 | 2002-09-03 | ドムペ・ソチエタ・ペル・アツィオーニ | N−(2−アリール−プロピオニル)−スルホンアミド類及びそれらを含む医薬製剤 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI831381L (fi) | 1982-04-27 | 1983-10-28 | Ciba Geigy Ag | 7 -acylamido-3-cefem-4-karboxylsyrafoereningar, foerfarande foer deras framstaellning, farmaceutiskpreparat, vilka innehaoller dessa foereningar, och anvaendning av de sistnaemnda |
US5411981A (en) | 1991-01-09 | 1995-05-02 | Roussel Uclaf | Phenylimidazolidines having antiandrogenic activity |
USRE35956E (en) | 1991-01-09 | 1998-11-10 | Roussel Uclaf | Phenylimidazolidines having antiandrogenic activity |
DE10218963A1 (de) | 2002-04-27 | 2003-11-20 | Aventis Pharma Gmbh | Zubereitungen zur topischen Applikation von antiandrogen wirksamen Substanzen |
DE10318020A1 (de) | 2003-04-19 | 2004-11-11 | Repower Systems Ag | Gitterturm für eine Windkraftanlage |
DE10322108B4 (de) * | 2003-05-09 | 2008-12-11 | Bayer Schering Pharma Aktiengesellschaft | Antiandrogene Pyrrolidine mit tumorhemmender Wirksamkeit |
-
2004
- 2004-06-11 WO PCT/JP2004/008211 patent/WO2004111012A1/ja active Application Filing
- 2004-06-11 EP EP04745805A patent/EP1634874A4/en not_active Withdrawn
- 2004-06-11 US US10/560,281 patent/US7271188B2/en not_active Expired - Fee Related
- 2004-06-11 JP JP2005506937A patent/JP4664814B2/ja not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58194891A (ja) * | 1982-04-27 | 1983-11-12 | チバ−ガイギ−・アクチエンゲゼルシヤフト | 7β−アシルアミド−3−セフエム−4−カルボン酸化合物、その製造方法及び該化合物を含む医薬製剤 |
JPH04308579A (ja) * | 1991-01-09 | 1992-10-30 | Roussel Uclaf | 新規なフェニルイミダゾリジン類、それらの製造法、薬剤としての使用及びそれらを含有する製薬組成物 |
JPH0673017A (ja) * | 1992-07-08 | 1994-03-15 | Roussel Uclaf | 新規な置換フェニルイミダゾリジン、それらの製造法、それらの薬剤としての使用及びそれらを含有する製薬組成物 |
JPH10510845A (ja) * | 1995-06-16 | 1998-10-20 | バイオフィジカ ファウンデーション | アンドロゲン関連組成物 |
JP2002528434A (ja) * | 1998-10-23 | 2002-09-03 | ドムペ・ソチエタ・ペル・アツィオーニ | N−(2−アリール−プロピオニル)−スルホンアミド類及びそれらを含む医薬製剤 |
Non-Patent Citations (1)
Title |
---|
See also references of EP1634874A4 * |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1775289A1 (en) * | 2004-08-03 | 2007-04-18 | Chugai Seiyaku Kabushiki Kaisha | Novel imidazolidine derivatives |
WO2006013887A1 (ja) * | 2004-08-03 | 2006-02-09 | Chugai Seiyaku Kabushiki Kaisha | 新規イミダゾリジン誘導体 |
EP1775289A4 (en) * | 2004-08-03 | 2009-09-02 | Chugai Pharmaceutical Co Ltd | NEW IMIDAZOLIDINE DERIVATIVES |
US7803826B2 (en) | 2004-08-03 | 2010-09-28 | Chugai Seiyaku Kabushiki Kaisha | Imidazolidine derivatives |
JP2013049691A (ja) * | 2005-03-29 | 2013-03-14 | Trustees Of The Univ Of Pennsylvania | 新しい毛包の形成、はげ頭症の治療、及び除毛をするための方法 |
WO2006133567A1 (en) | 2005-06-17 | 2006-12-21 | Endorecherche, Inc. | Helix 12 directed non-steroidal antiandrogens |
US7709516B2 (en) | 2005-06-17 | 2010-05-04 | Endorecherche, Inc. | Helix 12 directed non-steroidal antiandrogens |
US8168627B2 (en) | 2005-06-17 | 2012-05-01 | Endorecherche, Inc. | Helix 12 directed non-steroidal antiandrogens |
WO2008124922A1 (en) | 2007-04-12 | 2008-10-23 | Endorecherche, Inc. | 17alpha-substituted steroids as systemic antiandrogens and selective androgen receptor modulators |
US9284345B2 (en) | 2007-04-12 | 2016-03-15 | Endorecherche, Inc. | 17alpha-substituted steroids as systemic antiandrogens and selective androgen receptor modulators |
US11207511B2 (en) | 2010-12-06 | 2021-12-28 | Follica, Inc. | Methods for treating baldness and promoting hair growth |
JP2014510074A (ja) * | 2011-03-10 | 2014-04-24 | スジョウ キンター ファーマシューティカルズ インコーポレイテッド | アンドロゲン受容体アンタゴニストおよびその使用 |
US9216957B2 (en) | 2011-03-10 | 2015-12-22 | Suzhou Kintor Pharmaceuticals, Inc. | Androgen receptor antagonists and uses thereof |
WO2015089634A1 (en) | 2013-12-19 | 2015-06-25 | Endorecherche, Inc. | Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety |
US9682960B2 (en) | 2013-12-19 | 2017-06-20 | Endorecherche, Inc. | Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety |
Also Published As
Publication number | Publication date |
---|---|
EP1634874A4 (en) | 2008-04-02 |
EP1634874A1 (en) | 2006-03-15 |
US7271188B2 (en) | 2007-09-18 |
JPWO2004111012A1 (ja) | 2006-08-03 |
US20060135583A1 (en) | 2006-06-22 |
JP4664814B2 (ja) | 2011-04-06 |
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