WO2014133414A2 - Agonistes hétérocycliques des récepteurs d'acides biliaires tgr5, composition pharmaceutique, procédé de fabrication et d'utilisation - Google Patents

Agonistes hétérocycliques des récepteurs d'acides biliaires tgr5, composition pharmaceutique, procédé de fabrication et d'utilisation Download PDF

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Publication number
WO2014133414A2
WO2014133414A2 PCT/RU2014/000108 RU2014000108W WO2014133414A2 WO 2014133414 A2 WO2014133414 A2 WO 2014133414A2 RU 2014000108 W RU2014000108 W RU 2014000108W WO 2014133414 A2 WO2014133414 A2 WO 2014133414A2
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Prior art keywords
methyl
tetrahydro
benzoxazepine
benzoxazepin
dihydro
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Ceased
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PCT/RU2014/000108
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English (en)
Russian (ru)
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WO2014133414A3 (fr
Inventor
Андрей Александрович ИВАЩЕНКО
Николай Филиппович САВЧУК
Сергей Евгеньевич ТКАЧЕНКО
Александр Викторович ХВАТ
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Alla Chem LLC
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Alla Chem LLC
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Publication of WO2014133414A2 publication Critical patent/WO2014133414A2/fr
Publication of WO2014133414A3 publication Critical patent/WO2014133414A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to new physiologically active substances, new non-steroidal TGR5 receptor agonists, active ingredients for pharmaceutical compositions, pharmaceutical compositions and drugs containing a heterocyclic bile acid receptor agonist TGR5, which stimulates the secretion of incretin hormones, a method for treating metabolic diseases such as diabetes, obesity, metabolic syndrome, as well as concomitant cardiovascular and neurodegenerative diseases.
  • Azaheterocycle means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring.
  • Alkyl means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl” (C ! -C 6 ) alkyl substituents.
  • Aryl means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.
  • Aryl may contain one or more “cyclic system substituents”, which may be the same or different.
  • Heteroaryl (hetaryl) means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen.
  • the prefix “aza”, “oxa” or “thia” before “heteroaryl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
  • the nitrogen atom in the heteroaryl can be oxidized to the ⁇ -oxide.
  • Heteroaryl may have one or more “ring system substituents”, which may be the same or different.
  • alkyl substituents are aryl, heteroaryl, heterocyclyl, hydroxy, Ci-C 5 alkoxy, C ⁇ - C 5 alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R ⁇ k + i 3 !
  • the R'R''N fragment of the amidine group may be a non-aromatic azaheterocycle, preferably azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperidine, homopiperazine.
  • Signal cascade (signal system, signal transmission cascade) means a set of interconnected sequential and parallel molecular processes of regulation of cellular metabolism by external (primary) signals that carry information into the cell, which fundamentally distinguishes them from other chemical compounds entering the cell that serve as its source matter and energy.
  • the molecular mechanisms of transmission (transduction) of external signals into the cell imply not only the transmission of signals as such, but also the whole complex of events associated with it, including amplification, attenuation and suppression (or switching off) of signals.
  • the pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers.
  • Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • Pharmaceutical compositions are generally prepared using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier.
  • the subject of this invention is a combined drug intended for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases, containing in an effective amount a TGR5 agonist, a derivative of 2,3,4,5-tetrahydrobenzo [L [1,4] oxazepine total Formulas I and one or more antidiabetic drugs for simultaneous use.
  • FIG. 1 Schematic representation of LCD functions in regulation
  • Each concentration point represents an average value for two repetitions.
  • Alcohol R150H (3.67 mol) was dissolved in dichloromethane (50 ml) and triethylamine (1.37 g, 13.6 mmol) and trimethylchlorosilane (1.20 g, 11 mmol) were successively added, after which the solution was stirred for 30 min at room temperature. Then, 50 ml of distilled water was added to the reaction mass, and the separated aqueous layer was extracted with dichloromethane (3x20 ml). The combined organic layer was dried and evaporated. The resulting product was dissolved in anhydrous dichloromethane (50 ml), cooled to -50 ° C.
  • Racemic aldehyde e5 (Scheme 6) was reduced and condensed with R150H alcohol to give d2 esters. Removal of the Boc protection resulted in B2-Gas racemic synthons, the optical cleavage of which led to the chiral R-B2 and S-B2, LC-MS series, the characteristics of the final racemates and chiral compounds are presented in Tables 1-6.
  • Example 11 Determination of EC50 for the most active substances. Data was analyzed using GraphPad Prizm (GraphPad Software, Inc., San Diego, CA). To build the concentration dependence, the equation was chosen
  • Example 14 The study of the pharmacological effect of the compounds of General formula I on glucose metabolism (glucose tolerance test GTT).
  • the invention can be used in medicine, veterinary medicine, biochemistry.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

1. L'invention concerne des composés de formule générale I ou leurs mélanges racémiques, ou isomères optiques individuels, ou sels pharmaceutiquement acceptables et/ou hydrates, la formule (I) égant la suivante: X présente un groupe aminé R'R''N, substitué ou non substitué par des substituants identiques ou différents R' et R'', ou groupe oxy substitué ; le groupe R'R''N- présente un aza-hétérocycle non aromatique, de préférence azétidine, pyrrolidine, pipéridine, morfoline, thiomorfoline, pipérazine, homopipéridine, homopipérazine; R' et R'' - substituant du groupe aminé R' et R'' se présentent comme hydrogène, alkyle, alkyle substitué, cycloalkyle, aryle, hétéroaryle, hétérocyclyle, alcényle, cycloalcényle, alkinyle, acyle, aroyle, hétéroaroyle, alkylsulfonyle, arylsulfonyle, hétéroarylsulfonyle, alcoxycarbonyle, aryloxycarbonyle, aralcoxycarbonyle, alkylaminocarbonyle, arylaminocarbonyle, hétéroarylaminocarbonyle, hétérocyclylaminocarbonyle, alkylaminothiocarbonyle, arylaminothiocarbonyle, hétéroarylaminothiocarbonyle, hétérocyclylaminothiocarbonyle, aminosulfonyle éventuellement substitué, le groupe R'R''N- peut se présenter comme aza-hétérocycle non aromatique, de préférence azétidine, pyrrolidine, pipéridine, morfoline, thiomorfoline, pipérazine, homopipéridine, homopipérazine; le groupe oxy substitué se présente comme un groupe hydroxy dans lequel l'hydrogène est substitué par alkyle, alcényle, cycloalkyle, cycloalcényle, aryle, hétaryle et hétérocyclyle, ou acyle, ou groupe aminocarbonyle ou groupe oxycarbonyle; R1a et R1b représente hydrogène, alkyle, ou R1a et R1b qui forment ensemble une chaîne de polyéthylène -(CH2)n- dans laquelle n=2-5; R1c et R1d représentent hydrogène, et alkyle ou R1c et R1d forment ensemble une chaine polyméthylène -(CH2)n- dans laquelle n=2-5; R2 représente un groupe acyle, thioacyle, un groupe oxycarbonyle substitué, un groupe amidine substitué, un groupe aminocarbonyle substitué, un groupe aminothiocarbonyle ou sulfonyle substitué; R3 représente hydrogène, un alkyle, C1-C6, un groupe alcoxy, halogène, CF3, CN.
PCT/RU2014/000108 2013-02-26 2014-02-19 Agonistes hétérocycliques des récepteurs d'acides biliaires tgr5, composition pharmaceutique, procédé de fabrication et d'utilisation Ceased WO2014133414A2 (fr)

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RU2013108339 2013-02-26
RU2013108339/04A RU2543485C2 (ru) 2013-02-26 2013-02-26 Гетероциклические агонисты рецепторов желчных кислот tgr5, фармацевтическая композиция, способы их получения и применения

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Cited By (16)

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RU2594154C2 (ru) * 2014-11-10 2016-08-10 федеральное государственное автономное образовательное учреждение высшего образования "Московский физико-технический институт (государственный университет)" КРИСТАЛЛИЧЕСКАЯ ФОРМА МЕТИЛОВОГО ЭФИРА 3-(N-П-ТОЛИЛАЦЕТАМИДО)МЕТИЛ)-2,3,4,5-ТЕТРАГИДРОБЕНЗО[f][1,4]ОКСАЗЕПИН-4-КАРБОКСАМИДО)ТИОФЕН-2-КАРБОНОВОЙ КИСЛОТЫ, АКТИВНЫЙ КОМПОНЕНТ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И ЛЕКАРСТВЕННОЕ СРЕДСТВО
WO2017049176A1 (fr) * 2015-09-16 2017-03-23 Metacrine, Inc. Agonistes du récepteur x farnésoïde et leurs utilisations
WO2017049173A1 (fr) * 2015-09-16 2017-03-23 Metacrine, Inc. Agonistes du récepteur x farnésoïde et leurs utilisations
WO2017205536A3 (fr) * 2016-05-24 2018-01-04 Genentech, Inc. Composés thérapeutiques et leurs utilisations
US10377717B2 (en) 2015-09-16 2019-08-13 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10626081B2 (en) 2015-09-16 2020-04-21 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10870648B2 (en) 2018-06-29 2020-12-22 Forma Therapeutics, Inc. Inhibiting CREB binding protein (CBP)
US10927082B2 (en) 2017-03-15 2021-02-23 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11084817B2 (en) 2018-09-18 2021-08-10 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11236071B1 (en) 2017-03-15 2022-02-01 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11292791B2 (en) 2017-09-15 2022-04-05 Forma Therapeutics, Inc. Tetrahydro-imidazo quinoline compositions as CBP/P300 inhibitors
US11795168B2 (en) 2020-09-23 2023-10-24 Forma Therapeutics, Inc. Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP)
US11801243B2 (en) 2020-09-23 2023-10-31 Forma Therapeutics, Inc. Bromodomain inhibitors for androgen receptor-driven cancers
US12351577B2 (en) 2019-03-15 2025-07-08 Forma Therapeutics, Inc. Inhibiting cyclic AMP-responsive element-binding protein (CREB)
US12491160B2 (en) 2020-03-18 2025-12-09 Eli Lilly And Company Formulations of a farnesoid X receptor agonist
US12545660B2 (en) 2020-03-18 2026-02-10 Eli Lilly And Company Crystalline forms of a farnesoid X receptor agonist

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AR054368A1 (es) * 2005-06-01 2007-06-20 Takeda Pharmaceutical Metodo para tratar hiperlipidemia
RU2303597C1 (ru) * 2006-05-12 2007-07-27 Иващенко Андрей Александрович Фармацевтическая композиция, способы ее получения и применения
AU2008330482A1 (en) * 2007-11-30 2009-06-04 Daiichi Sankyo Company, Limited Agent for improving motor complications or psychiatric symptoms in Parkinson's disease
PE20091339A1 (es) * 2007-12-21 2009-09-26 Glaxo Group Ltd Derivados de oxadiazol con actividad sobre receptores s1p1
WO2010118208A1 (fr) * 2009-04-09 2010-10-14 Exelixis, Inc. Dérivés benzoxazepin-4-(5h)-yle et leur utilisation pour traiter le cancer

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RU2594154C2 (ru) * 2014-11-10 2016-08-10 федеральное государственное автономное образовательное учреждение высшего образования "Московский физико-технический институт (государственный университет)" КРИСТАЛЛИЧЕСКАЯ ФОРМА МЕТИЛОВОГО ЭФИРА 3-(N-П-ТОЛИЛАЦЕТАМИДО)МЕТИЛ)-2,3,4,5-ТЕТРАГИДРОБЕНЗО[f][1,4]ОКСАЗЕПИН-4-КАРБОКСАМИДО)ТИОФЕН-2-КАРБОНОВОЙ КИСЛОТЫ, АКТИВНЫЙ КОМПОНЕНТ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И ЛЕКАРСТВЕННОЕ СРЕДСТВО
US10626081B2 (en) 2015-09-16 2020-04-21 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
WO2017049176A1 (fr) * 2015-09-16 2017-03-23 Metacrine, Inc. Agonistes du récepteur x farnésoïde et leurs utilisations
WO2017049173A1 (fr) * 2015-09-16 2017-03-23 Metacrine, Inc. Agonistes du récepteur x farnésoïde et leurs utilisations
US11214538B2 (en) 2015-09-16 2022-01-04 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10703712B2 (en) 2015-09-16 2020-07-07 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10377717B2 (en) 2015-09-16 2019-08-13 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11168070B2 (en) 2016-05-24 2021-11-09 Genentech, Inc. Therapeutic compounds and uses thereof
CN109476641A (zh) * 2016-05-24 2019-03-15 基因泰克公司 Cbp/ep300的杂环抑制剂及其在治疗癌症中的用途
JP2019516757A (ja) * 2016-05-24 2019-06-20 ジェネンテック， インコーポレイテッド Ｃｂｐ／ｅｐ３００の複素環式インヒビターおよびがんの処置におけるそれらの使用
JP7160688B2 (ja) 2016-05-24 2022-10-25 ジェネンテック， インコーポレイテッド Ｃｂｐ／ｅｐ３００の複素環式インヒビターおよびがんの処置におけるそれらの使用
CN109476641B (zh) * 2016-05-24 2022-07-05 基因泰克公司 Cbp/ep300的杂环抑制剂及其在治疗癌症中的用途
WO2017205536A3 (fr) * 2016-05-24 2018-01-04 Genentech, Inc. Composés thérapeutiques et leurs utilisations
US10696655B2 (en) 2016-05-24 2020-06-30 Genentech, Inc. Therapeutic compounds and uses thereof
US10927082B2 (en) 2017-03-15 2021-02-23 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10961198B2 (en) 2017-03-15 2021-03-30 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11236071B1 (en) 2017-03-15 2022-02-01 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11292791B2 (en) 2017-09-15 2022-04-05 Forma Therapeutics, Inc. Tetrahydro-imidazo quinoline compositions as CBP/P300 inhibitors
US11787803B2 (en) 2017-09-15 2023-10-17 Forma Therapeutics, Inc. Tetrahydro-imidazo quinoline compositions as CBP/P300 inhibitors
US11254674B2 (en) 2018-06-29 2022-02-22 Forma Therapeutics, Inc. Inhibiting CREB binding protein (CBP)
US10870648B2 (en) 2018-06-29 2020-12-22 Forma Therapeutics, Inc. Inhibiting CREB binding protein (CBP)
US12378242B2 (en) 2018-06-29 2025-08-05 Forma Therapeutics, Inc. Inhibiting CREB binding protein (CBP)
US11084817B2 (en) 2018-09-18 2021-08-10 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11773094B2 (en) 2018-09-18 2023-10-03 Organovo, Inc. Farnesoid X receptor agonists and uses thereof
US12351577B2 (en) 2019-03-15 2025-07-08 Forma Therapeutics, Inc. Inhibiting cyclic AMP-responsive element-binding protein (CREB)
US12491160B2 (en) 2020-03-18 2025-12-09 Eli Lilly And Company Formulations of a farnesoid X receptor agonist
US12545660B2 (en) 2020-03-18 2026-02-10 Eli Lilly And Company Crystalline forms of a farnesoid X receptor agonist
US11795168B2 (en) 2020-09-23 2023-10-24 Forma Therapeutics, Inc. Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP)
US11801243B2 (en) 2020-09-23 2023-10-31 Forma Therapeutics, Inc. Bromodomain inhibitors for androgen receptor-driven cancers
US12454532B2 (en) 2020-09-23 2025-10-28 Forma Therapeutics, Inc. Inhibiting cyclic AMP-responsive element-binding protein (CREB) binding protein (CBP)

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WO2014133414A3 (fr) 2014-12-18
RU2543485C2 (ru) 2015-03-10
RU2013108339A (ru) 2014-09-10

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