EP1423113A1 - Composes de liaison au recepteur nucleaire nr1h4 - Google Patents

Composes de liaison au recepteur nucleaire nr1h4

Info

Publication number
EP1423113A1
EP1423113A1 EP02750474A EP02750474A EP1423113A1 EP 1423113 A1 EP1423113 A1 EP 1423113A1 EP 02750474 A EP02750474 A EP 02750474A EP 02750474 A EP02750474 A EP 02750474A EP 1423113 A1 EP1423113 A1 EP 1423113A1
Authority
EP
European Patent Office
Prior art keywords
substituted
compound
alkyl
alkylphenyl
phenyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP02750474A
Other languages
German (de)
English (en)
Other versions
EP1423113A4 (fr
Inventor
Ulrike Bauer
Zach Cheruvallath
Ulrich Deuschle
Elena Dneprovskaia
Tim Gahman
Kristina Giegrich
Ronnie Hanecak
Normand Hebert
John Kiely
Ingo Kober
Manfred Kogl
Harald Kranz
Claus Kremoser
Matthew Lee
Kerstin Otte
Carlton Sage
Manish Sud
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Phenex Pharmaceuticals AG
Original Assignee
Lion Bioscience AG
Phenex Pharmaceuticals AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP01119473A external-priority patent/EP1285914B1/fr
Application filed by Lion Bioscience AG, Phenex Pharmaceuticals AG filed Critical Lion Bioscience AG
Priority to EP02750474A priority Critical patent/EP1423113A4/fr
Publication of EP1423113A1 publication Critical patent/EP1423113A1/fr
Publication of EP1423113A4 publication Critical patent/EP1423113A4/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • the present invention relates to compounds that bind to the NR1 H4 nuclear receptor and methods of treating diseases or pathological conditions influenced by NR1 H4.
  • the present invention provides, inter alia, novel NR1 H4 nuclear receptor protein binding compounds according to the general formula (I) shown below. These compounds are also binders of mammalian homologues of the receptor. Further the object of the invention is solved by providing for, amongst the NR1 H4 nuclear receptor protein binding, compounds according to the general formula (I) which act as agonists and compounds which act as antagonists of the human FXR receptor or a mammalian homologue thereof.
  • the invention provides for FXR agonists which may be used for the treatment of cholesterol associated conditions or diseases.
  • cholesterol lowering or cholestatic compounds are disclosed.
  • the compounds according to the invention may be used for manufacture of antitumor medicaments and/or for the treatment of diseases such as cancer.
  • the carrier is generally a finely divided solid, which is in a mixture with the finely divided active component.
  • the active compound or combination of active compounds is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • C 7 to C ⁇ 2 substituted phenylalkyl denotes a C 7 to C ⁇ 2 phenylalkyl group substituted on the Ci to C 6 alkyl portion with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, monosubstituted amino, protected monosubstituted amino, disubstituted amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, d to C 8 alkyl, d to C 8 substituted alkyl, Ci to C 8 alkoxy, Ci to C 8 substituted alkoxy, C 1 to C 8 acyl, Ci to C 8 substituted acyl, Ci to C 8 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(C ⁇ to C 6 alkyl)carboxamide,
  • C 7 to C ⁇ 2 substituted phenylalkyl examples include groups such as 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 2- methoxyphenylmethyl, 3-methoxyphenylmethyl, 2,6-difluorophenylmethyl, 2,3- difluorophenylmethyl, 2,6-dichlorophenylmethyl, 2,3-dichlorophenylmethyl, 3,5- dichlorophenylmethyl, 2-hydroxyphenylethyl, 3-hydroxyphenylethyl, 2- methoxyphenylethyl, 3-methoxyphenylethyl, 2,6-difluorophenylethyl, 2,3- difluorophenylethyl, 2,6-dichlorophenylethyl, 2,3-dichlorophenylethyl, 3,5- dichlorophenylmethyl 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl
  • Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, 2-amino-imidazoyl, tetrahydrofurano, pyrrolo, tetrahydrothiophen-yl, hexamethyleneimino and heptamethyleneimino.
  • substituted heterocycle or "substituted heterocyclic ring” means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 8 alkyl, Ci to C 8 alkoxy, Ci to C 8 substituted alkoxy, Ci to C 8 acyl, d to C 8 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino carboxamide, protected carboxamide, N-(d to C 12 alkyl)carboxamide, protected N-(C ⁇ to C 6 alkyl)carboxamide, N, N-di(C ⁇ to
  • substituted naphthyl represents disubstituted naphthyl groups wherein the substituents are different, for example, 3- methyl-4-hydroxynaphth-1 -yl, 3-chloro-4-hydroxynaphth-2-yl, 2-methoxy-4- bromonaphth-1-yl, 4-ethyl-2-hydroxynaphth-1-yl, 3-hydroxy-4-nitronaphth-2-yl, 2- hydroxy-4-chloronaphth-1-yl, 2-methoxy-7-bromonaphth-1-yl, 4-ethyl-5- hydroxynaphth-2-yl, 3-hydroxy-8-nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-1-yl and the like.
  • R 3 and R 4 may be taken together with nitrogen to form a heterocycle or substituted heterocycle of the following kind aziridine, azetidine, pyrrolidine, 3-methylpyrrolidine, 3-aminopyrrolidine, 3-hydroxypyrrolidine, pyrazolidine, imidazolidine, piperidine, 2-methylpiperidine, 4-carboxypiperidine, 4- (carboxymethyl)piperidine, piperazine, morpholine, azepine, and tetrahydroisoquinoline.
  • C to C 8 acyl encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like. Preferred acyl groups are acetyl and benzoyl.
  • Ci to C 8 alkoxy denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred alkoxy is methoxy.
  • Ci to C 8 substituted alkoxy means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to Ci to C 8 substituted alkyl.
  • Ci to C 8 substituted aminoacyl denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, monosubstituted amino, protected monosubstituted amino, disubstituted amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Ci to C 8 alkoxy, Ci to C 8 acyl, Ci to C 8 acyloxy, nitro, Ci to C 8 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(C ⁇ to C 6 alkyl)carboxamide, protected N-(C ⁇ to C 6 alkyl)carboxamide, N,N-di(C ⁇ to C 6 alkyl)
  • compositions comprising an effective amount of a compound according to the invention.
  • Such compositions can be administered by various routes, for example oral, rectal, subcutaneous, intramuscular, intravenous or intracerebral.
  • the preferred route of administration would be oral at daily doses of the compound for adult human treatment of about 0.01-5000 mg, preferably 1-1500 mg per day.
  • the appropriate dose may be administered in a single dose or as divided doses presented at appropriate intervals for example as two, three four or more subdoses per day.
  • inert, pharmaceutically acceptable carriers are used.
  • the pharmaceutical carrier can be either solid or liquid. Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • compositions generally are administered in an amount effective for treatment or prophylaxis of a specific condition or conditions. Initial dosing in a human is accompanied by clinical monitoring of symptoms, such symptoms being determined for the selected condition.
  • the compositions are administered in an amount of active agent of at least about 100 ⁇ g/kg body weight. In most cases they will be administered in one or more doses in an amount not in excess of about 20 mg/kg body weight per day. Preferably, in most cases, the dose is from about 100 ⁇ g/kg to about 5 mg/kg body weight, daily.
  • the daily dosage level of active agent will be 0.1 mg/kg to 10 mg/kg and typically around 1 mg/kg.
  • terapéuticaally effective amount is meant a symptom- alleviating or symptom -reducing amount, a cholesterol-reducing amount, a fatty acid absorption blocking amount, a protein and/or carbohydrate digestion-blocking amount and/or a de novo cholesterol biosynthesis-blocking amount of a compound according to the invention.
  • blocking means either total blockage or partial blockage.
  • FXR is proposed to be a bile acid sensor. As a result, it modulates both the synthetic output of bile acids in the liver and their recycling in the intestine, by regulating bile acid binding proteins.
  • the invention concerns a method for regulating bile transport in a mammal, in a preferred embodiment a human, which comprises activating the NR1 H4 receptor with a therapeutically effective amount of a compound according to the invention.
  • the invention further concerns a method of blocking fatty acid absorption in the intestine of a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to the invention.
  • the invention may also be used to treat obesity in a mammal, particularly in humans.
  • Genes found to be regulated by GW 4064 are genes down-regulated in the liver, genes up-regulated in the liver and genes having altered expression in the intestine.
  • Genes that up-regulate in the liver include small heterodimer partner homolog (d86580); bile salt export pump, bsep (RefSeq NM 003742, XM 003644, and XM 033122); phospholipid transfer protein, PLTP (RefSeq NM 006227, XM 009490, XM 029929, and XM 029930); amithine palmitoyltransferase II, CPTII (RefSeq NM 000098, XM 001758, XM 038866, and XM 038867); phenylethanolamine-N-methyltransferase, PNMT (RefSeq NM 002686, XM 008597, andXM 049837); insulin-induced growth-response protein CL-6 (113619); elongation factor 2, EF-2 (y07504); mouse cornichon;
  • the TIF2 fragment was subsequently biotinylated by addition of 40-120 ⁇ l of a biotinamidocaproate N-hydroxysuccinimide-ester (Sigma) solution (20 mg/ml in DMSO). Overhead rotating samples were incubated for 2 hours at room temperature. Unincorporated label was then separated using G25 Gel filtration chromatography (Pharmacia Biotech, Sweden). Protein containing fractions from the column were pooled and tested for activity in the assay as described below.
  • a biotinamidocaproate N-hydroxysuccinimide-ester Sigma
  • the LANCE signal was detected by a Perkin Elmer VICTOR2VTM
  • Step 5 Preparation of a resin-bound thiourea (compound 7) [0099] A 0.2 M solution of Fmoc-NCS (5 eq) in anhydrous CH 2 CI 2 was added to a bottle containing the aminated Argogel-MB-HCO resin (resin compound 5). The bottle was placed on a shaker for one hour to form resin compound 6. The resin was washed with CH 2 CI 2 (3x) and DMF (3x) and subsequently reacted with 20 % piperidine in DMF (5 eq) for one hour to produce a resin-bound thiourea (resin compound 7). The resin was then washed with DMF (3x) and MeOH (3x) and used directly in the next step.
  • Step 1 Immobilization of a carboxylic acid (compound 11 ) on Bromo-Wang resin
  • Step 4 Cleavage of 2-aminothiazole to form products 10 from resin.
  • Luciferase reporter activity was measured in triplicates from extracts of cells after incubating cells in culture medium (DMEM [Gibco-BRL] + 10% FCS [PAA laboratories]) for 16 hours (5% C0 2 , 37°C) containing 0.5% DMSO (control) or 0.5% DMSO with increasing concentrations of compounds.
  • Examples of such dose response assays in the HEK293-FXR cell line are shown in Fig. 5A for LN6348, in Fig 5B for LN6316, in Fig.5C for LN6365 and in Fig. 5D for LN6322.

Landscapes

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

Abstract

L'invention concerne des composés de formule générale (I) qui se lient au récepteur NR1H4 et agissent comme agonistes dudit récepteur. L'invention concerne également le traitement de maladies et/ou d'états pathologiques par le biais de la liaison de ces composés au récepteur nucléaire, ainsi que la production de médicaments faisant appel à ces composés.
EP02750474A 2001-08-13 2002-08-13 Composes de liaison au recepteur nucleaire nr1h4 Ceased EP1423113A4 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP02750474A EP1423113A4 (fr) 2001-08-13 2002-08-13 Composes de liaison au recepteur nucleaire nr1h4

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP01119473 2001-08-13
EP01119473A EP1285914B1 (fr) 2001-08-13 2001-08-13 Ligands du récepteur nucéaire nr1h4
US185731 2002-07-01
US10/185,731 US6974830B2 (en) 2001-08-13 2002-07-01 NR1H4 nuclear receptor binding compounds
EP02750474A EP1423113A4 (fr) 2001-08-13 2002-08-13 Composes de liaison au recepteur nucleaire nr1h4
PCT/US2002/025438 WO2003015777A1 (fr) 2001-08-13 2002-08-13 Composes de liaison au recepteur nucleaire nr1h4

Publications (2)

Publication Number Publication Date
EP1423113A1 true EP1423113A1 (fr) 2004-06-02
EP1423113A4 EP1423113A4 (fr) 2007-04-18

Family

ID=26076685

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02750474A Ceased EP1423113A4 (fr) 2001-08-13 2002-08-13 Composes de liaison au recepteur nucleaire nr1h4

Country Status (2)

Country Link
EP (1) EP1423113A4 (fr)
WO (1) WO2003015777A1 (fr)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002308295B2 (en) 2001-03-12 2007-08-23 Intercept Pharmaceuticals, Inc. Steroids as agonists for FXR
US6987121B2 (en) 2002-04-25 2006-01-17 Smithkline Beecham Corporation Compositions and methods for hepatoprotection and treatment of cholestasis
GB0315111D0 (en) 2003-06-27 2003-07-30 Cancer Rec Tech Ltd Substituted 5-membered ring compounds and their use
SI3002283T1 (en) 2003-12-26 2018-06-29 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
CA2559476C (fr) 2004-03-12 2012-12-11 Intercept Pharmaceuticals, Inc. Traitement de la fibrose au moyen de ligands de fxr
US10987362B2 (en) 2004-03-12 2021-04-27 Intercept Pharmaceuticals, Inc. Treatment of fibrosis using FXR ligands
PL1773768T3 (pl) * 2004-07-30 2019-03-29 Exelixis, Inc. Pochodne pirolu jako środki farmaceutyczne
WO2006029719A2 (fr) * 2004-09-14 2006-03-23 Bayer Healthcare Ag Diagnostics et traitements de maladies associees a la sous-famille 1, du groupe h, membre 4 de recepteur nucleaire (nr1h4)
ITMI20050912A1 (it) 2005-05-19 2006-11-20 Erregierre Spa Processo di preparazione di acidi 3-a-ya(b)-diidrossi-6-a(b)-alchil-5b-colanici
CN101679476B (zh) 2007-01-19 2014-05-07 英特塞普特医药品公司 23取代的胆汁酸作为tgr5调节剂及其使用方法
AU2009276507B2 (en) 2008-07-30 2015-11-19 Intercept Pharmaceuticals, Inc. TGR5 modulators and methods of use thereof
HUE039171T2 (hu) 2008-11-19 2018-12-28 Intercept Pharmaceuticals Inc TGR5 modulátorok és azok alkalmazási eljárása
WO2010069604A1 (fr) 2008-12-19 2010-06-24 Royal College Of Surgeons In Ireland Traitement de la diarrhée
EP2545964A1 (fr) 2011-07-13 2013-01-16 Phenex Pharmaceuticals AG Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité
CA3028207A1 (fr) 2012-06-19 2013-12-27 Intercept Pharmaceuticals, Inc. Preparation, utilisations et formes solides d'acide obeticholique
US9982008B2 (en) 2012-06-19 2018-05-29 Intercept Pharmaceuticals, Inc. Preparation and uses of obeticholic acid
NZ748641A (en) 2016-06-13 2020-04-24 Gilead Sciences Inc Fxr (nr1h4) modulating compounds
CA2968836A1 (fr) 2016-06-13 2017-12-13 Gilead Sciences, Inc. Composes modulant fxr (nr1h4)
PT4122464T (pt) 2017-03-28 2024-06-27 Gilead Sciences Inc Combinações terapêuticas para o tratamento de doenças do fígado
PE20211907A1 (es) 2019-01-15 2021-09-28 Gilead Sciences Inc Compuestos moduladores de fxr (nr1h4)
CA3129949C (fr) 2019-02-19 2024-04-30 Gilead Sciences, Inc. Formes solides d'agonistes de fxr
CN114008040A (zh) * 2019-06-14 2022-02-01 南京瑞捷医药科技有限公司 用于调节fxr的化合物
CN114173784B (zh) 2019-07-18 2023-12-01 埃尼奥制药公司 降低干扰素的副作用的方法
JP2023510274A (ja) 2020-01-15 2023-03-13 アンセルム（アンスティチュート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル） Ｄ型肝炎ウイルスによる感染を処置するためのｆｘｒアゴニストの使用
US11478533B2 (en) 2020-04-27 2022-10-25 Novo Nordisk A/S Semaglutide for use in medicine
EP4277622A1 (fr) 2021-01-14 2023-11-22 ENYO Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
EP4329761A1 (fr) 2021-04-28 2024-03-06 ENYO Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné

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GB2022085A (en) * 1978-06-02 1979-12-12 Pfizer Novel Aminothiazoles
JPH04173782A (ja) * 1990-11-08 1992-06-22 Taisho Pharmaceut Co Ltd ２―スルホンアミド―４，５―ジフェニルチアゾール誘導体
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JPH07149745A (ja) * 1993-11-30 1995-06-13 Hisamitsu Pharmaceut Co Inc 新規な２−アミノチアゾール誘導体
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GB2022085A (en) * 1978-06-02 1979-12-12 Pfizer Novel Aminothiazoles
JPH04173782A (ja) * 1990-11-08 1992-06-22 Taisho Pharmaceut Co Ltd ２―スルホンアミド―４，５―ジフェニルチアゾール誘導体
EP0592664A1 (fr) * 1991-03-07 1994-04-20 Hisamitsu Pharmaceutical Co., Inc. Nouveau derive de diphenylthiazole
JPH07149745A (ja) * 1993-11-30 1995-06-13 Hisamitsu Pharmaceut Co Inc 新規な２−アミノチアゾール誘導体
FR2735777A1 (fr) * 1995-06-21 1996-12-27 Sanofi Sa Derives de 4-phenylaminothiazole, leur procede de preparation et les compositions pharmaceutiques les contenant
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Also Published As

Publication number Publication date
WO2003015777A1 (fr) 2003-02-27
EP1423113A4 (fr) 2007-04-18

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Inventor name: KOGL, MANFRED

Inventor name: KOBER, INGO

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Inventor name: HANECAK, RONNIE

Inventor name: GIEGRICH, KRISTINA

Inventor name: GAHMAN, TIM

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