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WO2016086134A1 - Dérivés d'acide biliaire utilisés comme agonistes de fxr/tgr5 et leurs procédés d'utilisation - Google Patents

Dérivés d'acide biliaire utilisés comme agonistes de fxr/tgr5 et leurs procédés d'utilisation Download PDF

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Publication number
WO2016086134A1
WO2016086134A1 PCT/US2015/062679 US2015062679W WO2016086134A1 WO 2016086134 A1 WO2016086134 A1 WO 2016086134A1 US 2015062679 W US2015062679 W US 2015062679W WO 2016086134 A1 WO2016086134 A1 WO 2016086134A1
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WO
WIPO (PCT)
Prior art keywords
compound
substituted
unsubstituted
disease
formula
Prior art date
Application number
PCT/US2015/062679
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English (en)
Inventor
Guoqiang Wang
Yat Sun Or
Ruichao Shen
Jiang Long
Peng Dai
Xuechao Xing
Jing He
Original Assignee
Enanta Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Enanta Pharmaceuticals, Inc. filed Critical Enanta Pharmaceuticals, Inc.
Publication of WO2016086134A1 publication Critical patent/WO2016086134A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • R a , Rb, R 2 , R 3 , R 7 and m are as previously defined in Formula I or I'.
  • R 1 and m are as previously defined in Formula I or I'.
  • Representative compounds of the invention include, but are not limited to, the following compounds (compounds 601 to 675 in Table 9) according to Formula VII- A, wherein, R 1 and m are delineated for each compound in Table 9.
  • the present invention provides a method for the prevention or treatment of an FXR mediated disease or condition.
  • the method comprises administering a therapeutically effective amount of a compound of the invention.
  • the present invention also provides the use of a compound of the invention for the preparation of a medicament for the prevention or treatment of an FXR mediated disease or condition.
  • the cardiovascular disease is atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, or hypertriglyceridemia.
  • the compound is a selective FXR agonist over TGR 5 activator.
  • Yet a further aspect of the present invention is a process of making any of the compounds delineated herein employing any of the synthetic means delineated herein.
  • cycloalkenyl denote a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • Preferred cycloalkenyl groups include C 3 -C 8 cycloalkenyl and C 3 -C 12 cycloalkenyl groups.
  • aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxy group so that it will depart during synthetic procedures such as in a substitution or elimination reactions.
  • hydroxy activating group include, but not limited to, mesylate, tosylate, triflate, />nitrobenzoate, phosphonate and the like.
  • activated hydroxy refers to a hydroxy group activated with a hydroxy activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al, (ed). "Design and
  • tetrahydrofuran and N-methylpyrrolidinone and ethers such as diethyl ether, bis- methoxymethyl ether.
  • solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et ah, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
  • protogenic organic solvent or “protic solvent” as used herein, refer to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et ah, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
  • excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • DIPEA for diisopropyl ethylamine
  • TrCl for trityl chloride
  • DMTrCl for 4,4'-dimethoxytrityl chloride
  • sulfonamide compound of formula (4-3) is illustrated in scheme 4, wherein R 1 , m and R 7 are defined as previously, Pi and P2 are hydroxyl protecting groups.
  • the compound of formula (1-2) is coupled with sulfonamide using suitable coupling condition to give the compound of formula (4-1).
  • the coupling reagent can be selected from, but not limited to, DCC, EDC, CDI, di- isopropyl carbodiimide, BOP-C1, PyBOP, PyAOP, TFFH and HATU.
  • Suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, DBU, N- methylmorpholine and DMAP.
  • FXR Reporter Assay kit purchased from Indigo Bioscience (Catalogue number: ⁇ 00601 ) to determine the potency and efficacy of compound developed by Enanta that can induce FXR activation.
  • the principle application of this reporter assay system is to quantify functional activity of human FXR.
  • the assay utilizes non-human mammalian ceils, CHO (Chinese hamster ovary) cells engineered to express human NR1H4 protein (referred to as FXR). Reporter cells also incorporate the cDNA encoding beetle luciferase which catalyzes the substrates and yields photon emission.
  • Luminescence intensity of the reaction is quantified using a plate-reading luminometer, Envision.
  • Reporter Cells include the luciferase reporter gene functionally linked to an FXR responsive promoter. Thus, quantifying changes in luciferase expression in the treated reporter cells provides a sensitive surrogate measure of the changes in FXR activity.
  • EC5 0 and efficacy (normalize to CDCA set as 100%) is determined by XLFit.
  • the assay is according to the manufacturer's instructions. In brief, the assay was performed in white, 96 well plates using final volume of lOOul containing cells with different doses of compounds. Retrieve Reporter Cells from -80°C storage.
  • TGR 5 receptor The potency and efficacy of the compounds of the invention on TGR 5 receptor was evaluated using in vitro assays which carried out using the express kit from DiscoverX (cAMP HunterTM eXpress GPBAR1 CHO-K1 GPCR Assay; Cataloguer number: 95-0049E2CP2S)GPBARl (G protein-coupled bile acid receptor 1) encodes a member of the G protein-coupled receptor (GPCR) superfamily.
  • DiscoverX cAMP HunterTM eXpress GPBAR1 CHO-K1 GPCR Assay; Cataloguer number: 95-0049E2CP2S)GPBARl (G protein-coupled bile acid receptor 1) encodes a member of the G protein-coupled receptor (GPCR) superfamily.
  • GPBAR1 activation following ligand binding initiates a series of second messenger cascades that result in a cellular response.
  • Treatment of CHO cells expressing GPBAR1 with bile acids induces the production of intracellular cAMP and internalization of the receptor.
  • the potency and efficacy of compound for GPBAR1 activation by measuring cyclic adenosine monophosphate (cyclic AMP or cAMP) levels in live cells using a competitive immunoassay based on Enzyme Fragment Complementation (EFC).
  • EFC Enzyme Fragment Complementation

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de dérivés d'acide biliaire amino-substitués, des compositions pharmaceutiques comprenant ces composés et des procédés d'utilisation de ces composés pour prévenir ou traiter des maladies ou états pathologiques médiés par FXR ou par TGR5. Dans un autre mode de réalisation, la présente invention concerne une composition pharmaceutique contenant une quantité thérapeutiquement efficace d'un composé ou d'une combinaison de composés de la présente invention, ou d'un sel, stéréoisomère, solvate, hydrate pharmaceutiquement acceptable de ce composé ou d'une combinaison de ceux-ci, en association avec un véhicule ou un excipient pharmaceutiquement acceptable.
PCT/US2015/062679 2014-11-26 2015-11-25 Dérivés d'acide biliaire utilisés comme agonistes de fxr/tgr5 et leurs procédés d'utilisation WO2016086134A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462084769P 2014-11-26 2014-11-26
US62/084,769 2014-11-26
US201562103374P 2015-01-14 2015-01-14
US62/103,374 2015-01-14

Publications (1)

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017129125A1 (fr) * 2016-01-28 2017-08-03 正大天晴药业集团股份有限公司 Agoniste stéroïdien du récepteur fxr (récepteur farnesoïde x)
EP3223822A4 (fr) * 2014-11-26 2018-07-11 Enanta Pharmaceuticals, Inc. Dérivés d'acide biliaire utilisés comme agonistes de fxr/tgr5 et leurs procédés d'utilisation
WO2018153933A1 (fr) 2017-02-21 2018-08-30 Genfit Combinaison d'un agoniste ppar avec un agoniste fxr
US10131688B2 (en) 2014-11-19 2018-11-20 NZP UK Limited 5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal FXR modulators
US10220027B2 (en) 2011-07-13 2019-03-05 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10266560B2 (en) 2014-11-06 2019-04-23 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10301350B2 (en) 2014-11-19 2019-05-28 NZP UK Limited 6-alkyl-7-hydroxy-4-en-3-one steroids as intermediates for the production of steroidal FXR modulators
US10329286B2 (en) 2016-06-13 2019-06-25 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10421730B2 (en) 2016-06-13 2019-09-24 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
KR20190114960A (ko) * 2016-11-29 2019-10-10 이난타 파마슈티칼스, 인코포레이티드 술포닐우레아 담즙산 유도체의 제조 방법
US10538550B2 (en) 2014-11-19 2020-01-21 NZP UK Limited 6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal FXR modulators
WO2020025942A1 (fr) 2018-07-30 2020-02-06 NZP UK Limited Dérivés fluorés d'acide biliaire
US10597423B2 (en) 2014-11-19 2020-03-24 NZP UK Limited 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal FXR modulators
US10968250B2 (en) 2016-05-18 2021-04-06 NZP UK Limited Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid
EA038580B1 (ru) * 2016-05-18 2021-09-17 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Агонист fxr, представляющий собой производное стероидов
US11225473B2 (en) 2019-01-15 2022-01-18 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11524005B2 (en) 2019-02-19 2022-12-13 Gilead Sciences, Inc. Solid forms of FXR agonists
WO2023083343A1 (fr) * 2021-11-15 2023-05-19 Hepaitech (Beijing) Biopharma Technology Co., Ltd. Composés polycycliques et leurs procédés
US11833150B2 (en) 2017-03-28 2023-12-05 Gilead Sciences, Inc. Methods of treating liver disease
US12358903B2 (en) 2022-01-11 2025-07-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds

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US20130116218A1 (en) * 2011-09-29 2013-05-09 Ethicon Endo-Surgery, Inc. Methods and compositions of bile acids

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10220027B2 (en) 2011-07-13 2019-03-05 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10485795B2 (en) 2011-07-13 2019-11-26 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10266560B2 (en) 2014-11-06 2019-04-23 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10597423B2 (en) 2014-11-19 2020-03-24 NZP UK Limited 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal FXR modulators
US10131688B2 (en) 2014-11-19 2018-11-20 NZP UK Limited 5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal FXR modulators
US10301350B2 (en) 2014-11-19 2019-05-28 NZP UK Limited 6-alkyl-7-hydroxy-4-en-3-one steroids as intermediates for the production of steroidal FXR modulators
US10538550B2 (en) 2014-11-19 2020-01-21 NZP UK Limited 6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal FXR modulators
AU2015353372B2 (en) * 2014-11-26 2020-07-23 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
EP3223822A4 (fr) * 2014-11-26 2018-07-11 Enanta Pharmaceuticals, Inc. Dérivés d'acide biliaire utilisés comme agonistes de fxr/tgr5 et leurs procédés d'utilisation
WO2017129125A1 (fr) * 2016-01-28 2017-08-03 正大天晴药业集团股份有限公司 Agoniste stéroïdien du récepteur fxr (récepteur farnesoïde x)
JP2019503392A (ja) * 2016-01-28 2019-02-07 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドＣｈｉａ Ｔａｉ Ｔｉａｎｑｉｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｇｒｏｕｐ Ｃｏ．， Ｌｔｄ． ステロイド誘導体ｆｘｒ作動薬
US10875888B2 (en) 2016-01-28 2020-12-29 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Steroid derivative FXR agonist
CN109071593A (zh) * 2016-01-28 2018-12-21 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂
US11479577B2 (en) 2016-05-18 2022-10-25 NZP UK Limited Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid
EA038580B1 (ru) * 2016-05-18 2021-09-17 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Агонист fxr, представляющий собой производное стероидов
US10968250B2 (en) 2016-05-18 2021-04-06 NZP UK Limited Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid
US10774054B2 (en) 2016-06-13 2020-09-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11247986B2 (en) 2016-06-13 2022-02-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11739065B2 (en) 2016-06-13 2023-08-29 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10329286B2 (en) 2016-06-13 2019-06-25 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10981881B2 (en) 2016-06-13 2021-04-20 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10421730B2 (en) 2016-06-13 2019-09-24 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
KR102499441B1 (ko) 2016-11-29 2023-02-13 이난타 파마슈티칼스, 인코포레이티드 술포닐우레아 담즙산 유도체의 제조 방법
KR20190114960A (ko) * 2016-11-29 2019-10-10 이난타 파마슈티칼스, 인코포레이티드 술포닐우레아 담즙산 유도체의 제조 방법
EP3548038A4 (fr) * 2016-11-29 2020-07-01 Enanta Pharmaceuticals, Inc. Procédé de préparation de dérivés de type acide biliaire de la famille des sulfonylurées
JP7057783B2 (ja) 2016-11-29 2022-04-20 エナンタ ファーマシューティカルズ インコーポレイテッド スルホニル尿素胆汁酸誘導体の調製方法
JP2019535777A (ja) * 2016-11-29 2019-12-12 エナンタ ファーマシューティカルズ インコーポレイテッド スルホニル尿素胆汁酸誘導体の調製方法
WO2018153933A1 (fr) 2017-02-21 2018-08-30 Genfit Combinaison d'un agoniste ppar avec un agoniste fxr
US11833150B2 (en) 2017-03-28 2023-12-05 Gilead Sciences, Inc. Methods of treating liver disease
WO2020025942A1 (fr) 2018-07-30 2020-02-06 NZP UK Limited Dérivés fluorés d'acide biliaire
US11225473B2 (en) 2019-01-15 2022-01-18 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11524005B2 (en) 2019-02-19 2022-12-13 Gilead Sciences, Inc. Solid forms of FXR agonists
US12102625B2 (en) 2019-02-19 2024-10-01 Gilead Sciences, Inc. Solid forms of FXR agonists
WO2023083343A1 (fr) * 2021-11-15 2023-05-19 Hepaitech (Beijing) Biopharma Technology Co., Ltd. Composés polycycliques et leurs procédés
US12358903B2 (en) 2022-01-11 2025-07-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds

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