WO2016084790A1 - Dérivé hydronaphthoquinoléine - Google Patents

Dérivé hydronaphthoquinoléine Download PDF

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Publication number
WO2016084790A1
WO2016084790A1 PCT/JP2015/082909 JP2015082909W WO2016084790A1 WO 2016084790 A1 WO2016084790 A1 WO 2016084790A1 JP 2015082909 W JP2015082909 W JP 2015082909W WO 2016084790 A1 WO2016084790 A1 WO 2016084790A1
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Prior art keywords
group
compound
methanone
general formula
quinolin
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PCT/JP2015/082909
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English (en)
Japanese (ja)
Inventor
雅己 大塚
藤井　邦彦
敏史 津田
史尚 土居
智 宮内
崇 磯部
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第一三共株式会社
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Publication of WO2016084790A1 publication Critical patent/WO2016084790A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0016—Oximes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • the “(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group” means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 alkyl group”. It is a group bonded to For example, a methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-ethoxyethyl, 2-butoxyethyl or 3-isopropoxypropyl group, preferably A group ((C 1 -C 4 alkoxy)-(C 1 -C 3 alkyl) group) in which one “C 1 -C 4 alkoxy group” is bonded to the “C 1 -C 3 alkyl group” And more preferably, a group ((C 1 -C 2 alkoxy)-(C 1 -C 2 ) in which one “C 1 -C 2 alkoxy group” is bonded
  • R 5 is preferably a hydrogen atom; a C 2 -C 7 alkylcarbonyl group; C 1 which may be independently substituted with a group selected from a hydroxyl group, a methoxy group and an aminocarbonyl group.
  • These pharmaceutically acceptable salts refer to salts that have no significant toxicity and can be used as pharmaceuticals.
  • the compound represented by the general formula (I) of the present invention can be converted into a salt by reacting with an acid when it has a basic group, or by reacting with a base when it has an acidic group. can do.
  • prevention means to suppress or delay the onset of a disease that is diagnosed as having a high risk of developing the disease targeted by the present invention due to genetic background or chronic inflammation.
  • a disease whose onset risk can be diagnosed by single nucleotide polymorphisms (SNPs) or gene mutations is known.
  • SNPs single nucleotide polymorphisms
  • colorectal cancer it is known that the risk of colorectal cancer is clearly increased due to chronic persistence of colitis.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. Prophylactic administration to patients diagnosed with a high risk of onset is expected to have an effect of suppressing or delaying onset.
  • a base triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc.
  • the base is used in a catalytic amount to an excess mol, preferably 0.2 to 2 mol, relative to 1 mol of the compound represented by the general formula (XVI).
  • the reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.
  • Step D-III This step is represented by the general formula (XXVI) by subjecting the compound represented by the general formula (XXV) to a nucleophilic addition reaction of an organometallic reagent using a known organic chemical method. This is a process for producing a compound. This is carried out in the same manner as in the C-II step of Method C.
  • Step D-IV the compound represented by the general formula (XXVII) is reacted with the compound represented by the general formula (XXVII) by a deprotection reaction using a known organic chemical method. It is a manufacturing process. This is carried out in the same manner as the BX process of Method B.
  • Step G-III This step is represented by the general formula (XXXV) by subjecting the compound represented by the general formula (VI) to an alkylation reaction or a glycosylation reaction using a known organic chemical method. This is a process for producing a compound. This is carried out in the same manner as the A-VIII step of Method A.
  • Step HV the compound represented by the general formula (XXXIX) is subjected to an amidation reaction, carbamation reaction, or ureaation reaction using a known organic chemical method to obtain a compound represented by the general formula (I- This is a process for producing a compound represented by X).
  • R 5 is a hydrogen atom, the reaction is performed in the same manner as in Step A-IV of Method A.
  • Step JI the compound represented by the general formula (XLIV) is produced by subjecting the compound represented by the general formula (XXXVIII) to an oxidation reaction using a known organic chemical technique. It is. This is carried out in the same manner as the CI process in the C method.
  • m is 1 to 3 and / or a saturated ring containing a nitrogen atom is obtained.
  • a compound that is condensed with a cyclopropane ring to form a condensed ring can be produced.
  • Step KI the compound represented by the general formula (II) is once converted to trimethylsilyl enol ether using a known organic chemical method and then alkylated using a known organic chemical method.
  • the compound represented by the general formula (XLVII) is produced by a reaction or a halogenation reaction.
  • Trimethylsilyl enol ether obtained from the compound represented by the general formula (II) in a solvent (dichloromethane, acetonitrile, N, N-dimethylformamide or the like or a mixed solvent thereof) from ⁇ 78 ° C. to 120 ° C., preferably ⁇ At 20 ° C.
  • a solvent diichloromethane, acetonitrile, N, N-dimethylformamide or the like or a mixed solvent thereof
  • an alkyl halide such as methyl iodide
  • a halogenating reagent N-fluorobenzenesulfonimide, N-fluoropyridinium trifluoromethanesulfonate, chloromethyl-4-fluoro-1,4-diazoniabicyclo [ 2,2,2] octane bis (tetrafluoroborate), xenon fluoride, etc.
  • a reaction accelerator titanium tetrachloride, tetra-n-butylammonium fluoride, etc.
  • the reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.
  • Step M-III the compound represented by the general formula (LVII) is subjected to a deprotection group reaction using a known organic chemical method, followed by a hydrolysis reaction of silyl enol ether.
  • This is a process for producing a compound represented by the formula (LVIII). Both reactions can be carried out simultaneously according to the case where PRO 2 in the D-VI step of Method D is a tert-butyldimethylsilyl group.
  • solutions, emulsions or suspensions When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
  • the solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.
  • reaction solution was poured into two layers of ethyl acetate and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane], and then purified again by preparative TLC [ethyl acetate / hexane] to give the title compound (19 mg) as a white solid. Obtained.
  • Step 2 (2-Fluorocyclohex-1-en-1-yl) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone
  • the compound obtained in the above Step 1 (59 mg) is dissolved in a mixed solvent of tetrahydrofuran (2 ml) and methanol (1 ml), and 1N is obtained at room temperature. Hydrochloric acid (0.5 ml) was added and stirred at the same temperature for 3 hours.
  • (diethylamino) difluorosulfonium tetrafluoroborate (25.0 g) was added with stirring at ⁇ 78 ° C., and the mixture was allowed to stand overnight, and the temperature was slowly raised to room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, and the filtrate is concentrated. The resulting residue is separated and purified by silica gel column chromatography [ethyl acetate-hexane] and [ethyl acetate / dichloromethane] to give the title compound (fluorine).
  • the reaction solution was poured into two layers of dichloromethane and 1N hydrochloric acid, and extracted three times with dichloromethane.
  • the organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] and crystallized from [diethyl ether / hexane] to give the title compound ( 63 mg) was obtained as a white solid.
  • reaction solution After adding a saturated aqueous ammonium chloride solution to the reaction solution, the reaction solution was poured into two layers of ethyl acetate and a saturated aqueous ammonium chloride solution, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (58 mg) as a white solid.
  • Diastereomer B; (Rf lower: high polarity):

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Abstract

La présente invention concerne un composé représenté par la formule générale (I) qui présente une excellente activité inhibitrice du récepteur orphelin γt apparenté aux récepteurs de l'acide rétinoïque et une activité inhibitrice de la production d'IL-17, ou un sel pharmaceutiquement acceptable de ce dernier. (Dans la formule, U représente un groupe phényle, un groupe pyridyle, un groupe tétrahydrofuryle, un groupe tétrahydropyranyle ou un groupe benzyle qui peut être indépendamment mono à tétra-substitué par des groupes choisis parmi les atomes d'halogènes, des groupes alkyle en C1-C6 et des groupes alcoxy en C1-C6, un groupe alkyle en C1-C6, un groupe alkyle halogéné en C1-C6 ou analogue ; R1 représente un atome d'hydrogène, un atome d'halogène, un groupe hydroxyle ou analogue ; R2 représente un atome d'hydrogène ou un groupe alkyle en C1-C6 ; R3 représente un atome d'hydrogène, un atome d'halogène, un groupe hydroxyle ou analogue ; R4 représente un atome d'hydrogène ou analogue ; R5 représente un groupe alkyle en C1-C6 qui peut être indépendamment mono à tétra-substitué par des groupes choisis parmi un groupe hydroxyle et des groupes alcoxy en C1-C6, un atome d'hydrogène ou analogue ; R6 représente un groupe alkyle en C1-C6 qui peut être indépendamment mono ou di-substitué par des groupes choisis parmi des groupes alkylsulfonyle en C1-C6 et un groupe hydroxyle, un atome d'hydrogène, un groupe hydroxyle ou analogue ; R7 représente un atome d'hydrogène ou un atome de fluor ; R8 représente un atome d'hydrogène, un atome de fluor ou analogue ; R9 représente un atome d'hydrogène ; T représente une liaison simple, un atome d'oxygène ou un groupe représenté par la formule -NH- ; Y peuvent être identiques ou différents et chacun représente un atome d'halogène ou un groupe alkyle en C1-C6 ; m représente un nombre entier de 0 à 3 ; un cycle saturé contenant un atome d'azote peut être condensé avec un cycle cyclopropane pour former un cycle condensé ; et n représente un nombre entier de 1 à 3.)
PCT/JP2015/082909 2014-11-25 2015-11-24 Dérivé hydronaphthoquinoléine WO2016084790A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108727453A (zh) * 2017-04-20 2018-11-02 华东理工大学 新型pd-1抑制剂及其应用
CN110709409A (zh) * 2018-02-11 2020-01-17 江苏豪森药业集团有限公司 一种甾族类衍生物调节剂及其制备方法和应用
JP2020512289A (ja) * 2016-12-16 2020-04-23 リアタ ファーマシューティカルズ インコーポレイテッド ＲＯＲγの阻害および他の使用のためのピリミジン三環式エノン誘導体
CN111205264A (zh) * 2020-02-25 2020-05-29 成都睿智化学研究有限公司 一种合成同位羟基和甲磺酰甲基化合物的新方法
WO2021023213A1 (fr) * 2019-08-07 2021-02-11 上海翰森生物医药科技有限公司 Sel et forme cristalline d'un régulateur de dérivé de stéroïde
JP2021512909A (ja) * 2018-02-11 2021-05-20 江▲蘇▼豪森▲薬▼▲業▼集▲団▼有限公司 ステロイド系誘導体モジュレーター、その製造方法及び応用
WO2023241717A1 (fr) * 2022-06-16 2023-12-21 中国科学院动物研究所 Substance favorisant la régénération et la réparation d'organes de mammifères et son utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107746396B (zh) * 2017-10-16 2020-02-11 河南交通职业技术学院 一种新型化合物6,6-二甲基四氢吡喃-2-甲醇及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5076063A (fr) * 1973-09-26 1975-06-21
JPS5448799A (en) * 1977-08-18 1979-04-17 Richter Gedeon Vegyeszet 33aminoo17aaazaaddhomooandrostane derivative*its manufacture and medicine containing it
JPH04230695A (ja) * 1990-10-01 1992-08-19 Anaquest Inc ３−置換−アミノメチル−３−置換−オキシ−１７Ａ−メチル−１７Ａ−低級アルキル−１７Ａ−アザ−Ｄ−ホモ−５−α−アンドロスタン
JP2001524524A (ja) * 1997-12-04 2001-12-04 ステリックス リミテッド エストロンスルファターゼのインヒビターとしてのステロイド３−ｏ−スルファメート誘導体
JP2012506998A (ja) * 2008-10-28 2012-03-22 フェネックス ファーマシューティカルス アーゲー オーファン核内受容体ｒａｒ関連オーファン受容体ガンマ（ｎｒ１ｆ３）活性を調節するための新規リガンドの同定方法
WO2012145254A2 (fr) * 2011-04-16 2012-10-26 Board Of Regents, The University Of Texas System Procédés d'utilisation d'inhibiteurs de rorϒt pour traiter une maladie

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5076063A (fr) * 1973-09-26 1975-06-21
JPS5448799A (en) * 1977-08-18 1979-04-17 Richter Gedeon Vegyeszet 33aminoo17aaazaaddhomooandrostane derivative*its manufacture and medicine containing it
JPH04230695A (ja) * 1990-10-01 1992-08-19 Anaquest Inc ３−置換−アミノメチル−３−置換−オキシ−１７Ａ−メチル−１７Ａ−低級アルキル−１７Ａ−アザ−Ｄ−ホモ−５−α−アンドロスタン
JP2001524524A (ja) * 1997-12-04 2001-12-04 ステリックス リミテッド エストロンスルファターゼのインヒビターとしてのステロイド３−ｏ−スルファメート誘導体
JP2012506998A (ja) * 2008-10-28 2012-03-22 フェネックス ファーマシューティカルス アーゲー オーファン核内受容体ｒａｒ関連オーファン受容体ガンマ（ｎｒ１ｆ３）活性を調節するための新規リガンドの同定方法
WO2012145254A2 (fr) * 2011-04-16 2012-10-26 Board Of Regents, The University Of Texas System Procédés d'utilisation d'inhibiteurs de rorϒt pour traiter une maladie

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020512289A (ja) * 2016-12-16 2020-04-23 リアタ ファーマシューティカルズ インコーポレイテッド ＲＯＲγの阻害および他の使用のためのピリミジン三環式エノン誘導体
JP7177059B2 (ja) 2016-12-16 2022-11-22 リアタ ファーマシューティカルズ インコーポレイテッド ＲＯＲγの阻害および他の使用のためのピリミジン三環式エノン誘導体
CN108727453A (zh) * 2017-04-20 2018-11-02 华东理工大学 新型pd-1抑制剂及其应用
CN110709409A (zh) * 2018-02-11 2020-01-17 江苏豪森药业集团有限公司 一种甾族类衍生物调节剂及其制备方法和应用
JP2021512909A (ja) * 2018-02-11 2021-05-20 江▲蘇▼豪森▲薬▼▲業▼集▲団▼有限公司 ステロイド系誘導体モジュレーター、その製造方法及び応用
CN114805462A (zh) * 2018-02-11 2022-07-29 江苏豪森药业集团有限公司 一种甾族类衍生物调节剂及其制备方法和应用
WO2021023213A1 (fr) * 2019-08-07 2021-02-11 上海翰森生物医药科技有限公司 Sel et forme cristalline d'un régulateur de dérivé de stéroïde
CN112638928A (zh) * 2019-08-07 2021-04-09 上海翰森生物医药科技有限公司 一种甾族类衍生物调节剂的盐及其晶型
CN112638928B (zh) * 2019-08-07 2023-12-22 上海翰森生物医药科技有限公司 一种甾族类衍生物调节剂的盐及其晶型
CN111205264A (zh) * 2020-02-25 2020-05-29 成都睿智化学研究有限公司 一种合成同位羟基和甲磺酰甲基化合物的新方法
WO2023241717A1 (fr) * 2022-06-16 2023-12-21 中国科学院动物研究所 Substance favorisant la régénération et la réparation d'organes de mammifères et son utilisation

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