WO2023285583A1 - Dérivés de 5,6,7,8-tétrahydro-2,6- et 2,7-naphtyridine destinés à être utilisés dans le traitement de maladies sensibles à la modulation du transporteur de citrate - Google Patents

Dérivés de 5,6,7,8-tétrahydro-2,6- et 2,7-naphtyridine destinés à être utilisés dans le traitement de maladies sensibles à la modulation du transporteur de citrate Download PDF

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Publication number
WO2023285583A1
WO2023285583A1 PCT/EP2022/069709 EP2022069709W WO2023285583A1 WO 2023285583 A1 WO2023285583 A1 WO 2023285583A1 EP 2022069709 W EP2022069709 W EP 2022069709W WO 2023285583 A1 WO2023285583 A1 WO 2023285583A1
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WO
WIPO (PCT)
Prior art keywords
compound
inhibitors
group
atom
mmol
Prior art date
Application number
PCT/EP2022/069709
Other languages
English (en)
Inventor
Grit Zahn
Robert Edward ARNOLD
Julia Marie Bainbridge
Giacomo Beretta
Steven Mark Bromidge
Adam James Davenport
Emily Catherine DOCTON
Verity Nicole DOWLING
Stuart Robert FLANAGAN
Laura Jane GLEAVE
Mark Anthony KERRY
Colin Haig MACKINNON
Cristina Lecci
Paula Cristina DE AGUIARPENA
Kevin Michael Thewlis
Patrick Ross WALKER
Christopher John Yarnold
Original Assignee
Eternygen Uk Ltd.
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 Eternygen Uk Ltd. filed Critical Eternygen Uk Ltd.
Priority to EP22751057.5A priority Critical patent/EP4370519A1/fr
Publication of WO2023285583A1 publication Critical patent/WO2023285583A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention provides a combination preparation containing at least one compound of the invention and at least one further active pharmaceutical ingredient.
  • the at least one further active pharmaceutical ingredient is selected from the group comprising: a. anti-obesity agents selected from the group consisting of orlistat, lorcaserin, Phentermine, Topiramate, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine, 5-HT2c receptor agonists, Bupropion, Naltrexone, methionine aminopeptidase 2 inhibitors, GLP1 agonists; b.
  • anti-obesity agents selected from the group consisting of orlistat, lorcaserin, Phentermine, Topiramate, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine, 5-HT2c receptor agonists, Bupropion, Naltrexone, methionine aminopeptidase 2 inhibitors, GLP1
  • selectivity of the inhibitory activity within the SLC family of membrane transport proteins could be demonstrated by tests with two different cellular systems of succinate uptake, namely HEK293 cells over-expressing recombinant human SLC 13 A3 and HEK293 cells overexpressing recombinant human SLC13A2, where no inhibitory activity of the compounds of the invention was observed.
  • the relevance of the inhibitory activity for utility in the treatment of diseases and/or conditions associated with or modulated by uptake of extracellular citrate was further demonstrated in a cell assay with HepG2 cells where it could be shown that the compounds of the invention had a considerable inhibitory effect on lipogenesis.
  • a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. It will be apparent that the compound of the invention may, but need not, be present as a hydrate, solvate or non- covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compound of the invention. Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include n C, 13 C, and 14 C.
  • alkoxyalkyl or alkoxyalkyl group refers to an alkyl group singular bonded to one or more alkoxy group(s), e.g. -alkyl-O-alkyl or -alkyl-O-alkyl-O-alkyl.
  • R 11 is, at each occasion independently, a hydrogen atom, deuterium atom, fluorine atom or
  • n is 1 or 2, provided that n is 2 when m is 1 ;
  • R 2 is Cl or CH 3 ;
  • X 2 is selected from -(CH 2 ) 2 -, -C(CH 3 )H-CH 2 -, -CH 2 -C(CH 3 )H-, - C(CH 3 )H-C(CH 3 )H-, -C(CH 3 ) 2 -CH 2 -, -CH 2 -C(CH 3 ) 2 -, -CDH-CH 2 -, -CD 2 -CH 2 -, -CH 2 - CDH-, -CH 2 -CD 2 -, -CFH-CH 2 -, -CF 2 -CH 2 -, -CFH-CFH-, -OH-CFH-, -CH 2 -
  • ring A represents a phenyl group; a 5-membered heteroaryl group containing one sulphur ring atom, or one nitrogen and one oxygen or sulphur ring atom; or a 6-membered heteroaryl group containing 1, 2, 3 or 4 nitrogen ring atom(s); and p, R 5 and R 6 are defined as in general formula (I) above; in one embodiment, ring A represents a phenyl group; a 5- membered heteroaryl group containing one sulphur ring atom, or one nitrogen and one oxygen or sulphur ring atom; or a 6-membered heteroaryl group containing 1, 2, 3 or 4 nitrogen ring atom(s); p, R 5 and R 6 are defined as in general formula (I) above, and the compound or salt may further include any one of [2] to [15];
  • R 5 is, at each occasion independently, a hydrogen atom, fluorine atom, CH 3 , NH 2 or OCH 3 (preferably a hydrogen atom, fluorine atom or CH 3 ); in one embodiment, R 5 is, at each occasion independently, a hydrogen atom, fluorine atom, CH 3 , NH 2 or OCH 3 (preferably a hydrogen atom, fluorine atom or CH 3 ), and the compound or salt may further include any one of [2] to [17];
  • p is 2; in one embodiment, p is 2, and the compound or salt may further include any one of [2] to [18];
  • Potential cancers to be treated with a compound of general formula (I) comprise liver, pancreas cancer, breast cancer, oesophagus cancer, pancreas cancer, colon cancer, gallbladder cancer, colorectal cancer, endometrium cancer, kidney cancer, gallbladder cancer, thyroid cancer, rectal cancer, melanoma, leukaemia, multiple myeloma, non-Hodgkin lymphoma, prostate cancer, uterine cancer, ovarian cancer, endometrial cancer and cervical cancer.
  • CCR2/CCR5 antagonist e.g. cenicriviroc
  • inhibitors of SLC10A2 inhibitors of LOXL2, inhibitors of Galectin-3, inhibitors of caspase, FGF21 (e.g. BI089-100, BMS-986036), FGF19 (e.g. NGM282), inhibitors of CGRP, AOC3: Amine Oxidase, Copper Containing 3, inhibitors of DPP-4 (e.g. linagliptin, sitagliptin), THR-B agonists (e.g. MGL3196, VK2809), anti-CD3 monoclonal antibody (mAbs), A3AR agonists, inhibitors of SGLT2 (e.g.
  • kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from any acceptable material including, e.g., glass or plastic.
  • the container(s) can comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein.
  • the container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
  • Analytical chiral LC (Method Cl) were performed on Waters LC system using a Cellulose-4 column (4.6mm x 250mm, 5pm) at RT and an isocratic eluent of 8.5/1.5 heptane/ethanol over 25mins, with an injection volume of 20pL and a flow rate of 0.5mL/min.
  • UV spectra were recorded at 254nm using a Waters 2996 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.
  • reaction mixture was then cooled to - 78 °C and to the reaction mixture was added 1 M KHMDS (in THF) (22 mL, 21.7 mmol) and the reaction mixture was stirred for 30 min at -78 °C.
  • Mel 1.1 mL, 18.0 mmol
  • reaction mixture was allowed to warm to RT and stirred for a further 30 min.
  • sat. aq. NH4C1 solution was stirred for 10 min at RT.
  • the organics were diluted with EtOAc and washed with water, then brine. The organics were dried over MgS04, fdtered and concentrated in vacuo.
  • SPA scintillation proximity assay
  • a special plate type (Cytostar-T, Perkin Elmer#RPNQ0166) is used, where the scintillation substance is present in the clear bottom of the plate. Only radioactivity which is present inside the cell and which is therefore in close proximity to the plate bottom can generate a signal.
  • 20,000 HepG2 cells per well were seeded on collagen coated 384-well Cytostar-T plates or 5000 HEK293 cells per well were seeded on ploy-D-lysine coated 384-well Cytostar-T plates.
  • HepG2 cells were maintained in cell medium using cell culture grade flasks (T175 sarstedt). The following media were used: MEM (NEAA, no glutamine) + 10% FCS, 1 x P/S, 2 mM Glutamax,

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne : un composé de formule générale (I), qui agit en tant qu'inhibiteur de citrate, par exemple, un transporteur de citrate couplé au sodium tel que le INDY (SLC13A5) ; une composition pharmaceutique contenant un ou plusieurs composés selon l'invention ; une préparation combinée contenant au moins un composé selon l'invention et au moins un autre ingrédient pharmaceutique actif ; et des utilisations dudit ou desdits composés, y compris l'utilisation en tant que médicament, ainsi que l'utilisation dans le traitement et/ou la prévention d'un état associé à l'activité d'un transporteur de citrate comme les maladies métaboliques et les maladies liées à l'âge.
PCT/EP2022/069709 2021-07-14 2022-07-14 Dérivés de 5,6,7,8-tétrahydro-2,6- et 2,7-naphtyridine destinés à être utilisés dans le traitement de maladies sensibles à la modulation du transporteur de citrate WO2023285583A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP22751057.5A EP4370519A1 (fr) 2021-07-14 2022-07-14 Dérivés de 5,6,7,8-tétrahydro-2,6- et 2,7-naphtyridine destinés à être utilisés dans le traitement de maladies sensibles à la modulation du transporteur de citrate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP21185642.2 2021-07-14
EP21185642 2021-07-14

Publications (1)

Publication Number Publication Date
WO2023285583A1 true WO2023285583A1 (fr) 2023-01-19

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004048925A2 (fr) 2002-11-22 2004-06-10 Medical College Of Georgia Research Institute, Inc. Nact utilise comme cible pour le prolongement de la duree de vie et la reduction de poids
US20200087258A1 (en) * 2017-03-20 2020-03-19 Eternygen Gmbh Inhibitor of citrate transporter and their use in therapy

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004048925A2 (fr) 2002-11-22 2004-06-10 Medical College Of Georgia Research Institute, Inc. Nact utilise comme cible pour le prolongement de la duree de vie et la reduction de poids
US20200087258A1 (en) * 2017-03-20 2020-03-19 Eternygen Gmbh Inhibitor of citrate transporter and their use in therapy

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