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WO2018038668A1 - Inhibiteurs du virus respiratoire syncytial - Google Patents

Inhibiteurs du virus respiratoire syncytial Download PDF

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Publication number
WO2018038668A1
WO2018038668A1 PCT/SE2017/050847 SE2017050847W WO2018038668A1 WO 2018038668 A1 WO2018038668 A1 WO 2018038668A1 SE 2017050847 W SE2017050847 W SE 2017050847W WO 2018038668 A1 WO2018038668 A1 WO 2018038668A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
pyridazin
isoquinolin
pyrrolo
mmol
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
PCT/SE2017/050847
Other languages
English (en)
Inventor
Susana Ayesa
Johan Bylund
Karolina Ersmark
Lourdes Salvador Oden
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.)
Medivir AB
Original Assignee
Medivir AB
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 Medivir AB filed Critical Medivir AB
Publication of WO2018038668A1 publication Critical patent/WO2018038668A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • 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
    • C07D487/10—Spiro-condensed systems

Definitions

  • the invention relates to a compound having Formula (I) or racemate, enantiomer, diastereoisomer or tautomer thereof:
  • W is NR 1A or CR 1 B R 1 B ;
  • Still another aspect of this invention relates to a method of inhibiting the replication of RSV comprising exposing the virus to an effective amount of the compound of Formula (I), or a salt thereof, under conditions where replication of RSV is inhibited.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Typical values for R 3 according to this embodiment is fluoro, chloro or methyl.
  • R 1C is CrC 3 alkyl, C 3 -C 5 cycloalkyl or a 4-, 5- or 6-membered heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from methyl, amino, fluoro and trifluoromethyl
  • R 1C is Ci-C 3 alkyl
  • R 1C is methyl, cyclopropyl or cyclopropyl which is substituted with trifluoromethyl
  • R 3 is chloro or methyl
  • palladium catalysts for this purpose include but is not limited to bis(tri-tert-butylphosphine)palladium(0) or similar.
  • the pyridazinyl group may be introduced by a Suzuki reaction or any other convenient diaryl coupling method known to the skilled person.
  • An alternative approach to compounds of the invention is illustrated by Method B wherein the two steps are performed in the reverse order, i.e. the synthesis starts with the diaryl coupling, i.e.
  • the substituents to the core structure are introduced on the isoquinoline and R 1 building blocks prior to coupling or they can be introduced after the coupling step.
  • precursors to the final substituents may be present on the building blocks and transformed to the desired substituents at a later stage of synthesis of final compounds.
  • the benzylic hydroxy group can then be transformed to a suitable leaving group such as chloro or bromo.
  • a suitable leaving group such as chloro or bromo.
  • the chloro derivative (3C) is achieved by treatment of the alcohol with phosgene
  • the bromo derivative (3D) is typically achieved by treatment of the alcohol with carbontetra chloride in the presence of triphenylphosphine.
  • the iodo derivative (3B) may be further reacted to introduce a desired R 2 substituent or suitable precursor thereof.
  • a useful intermediate for R 1 building blocks wherein W is CR 1 B R 1 B and the two R 1 B together with the carbon atom to which they are attached form an azetidine moiety can be prepared, for example, as illustrated in Scheme 4.
  • R 1 building block useful for the preparation of compounds of formula I wherein Z 1 is NR 1A and R 1A is optionally substituted C 3 -C 4 cycloalkyl in Scheme 9.
  • Suitable inhalatives may be obtained, for example, by administering one or more compounds of the invention in the form of a solution, dry powder or suspension.
  • the compounds of the invention may be administered via inhalation of a solution in nebulized or aerosolized doses.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the production and/or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the production and/or replication of a virus in a human being.
  • Such agents can be selected from: RSV Fusion inhibitors, such as MDT-637 (MicroDose), BTA-9881 (Biota); RSV Polymerase inhibitors, such as ALS-81 12 (Alios), ALS-8176 (Alios) and Virazole (ribavirin); others, such as GS-5806 (Gilead Sciences) and RSV-604 (Novartis); antibodies, such as Synagis® (palimizumab), RespiGam® (RSV-IG), MEDI-557 (Medlmmune/AstraZeneca), ALX- 0171 (Ablynx), motavizumab (Medlmmune/AstraZeneca); other biological, such as ALN-RSV-01 (Alnylam) and Vaccines, such as MEDI-559 (Medlmmune/AstraZeneca), RSV F (Novavax), MEDI-534 (Medlmm u ne/AstraZen
  • Step b) tert-butyl 3-((2-bromophenvn(4-methoxybenzvncarbamovnazetidine-1 -carboxylate (l-3b)
  • acetonitrile 80 mL
  • K 2 C0 3 7.24 g, 50.72 mmol, 3 eq
  • the reaction mixture was stirred under reflux for 12 h.
  • the reaction mixture was filtered and the solid residue was washed with acetonitrile.
  • the filtrate was concentrated in vacuo and the crude product was triturated with hexane/ethyl acetate (30:1 ), which gave the title compound (6.5g, 81 .25%) as an off white solid.
  • N-(3-fluorobenzyl)-1 ,1 -dimethoxypropan-2-amine (32 g, 141 mmol) was added dropwise at ⁇ 5 °C to chlorosulfonic acid (96.5 ml_, 1 .41 mmol).
  • the mixture was heated to 100 °C for 10 min, then cooled and poured into ice (700 g).
  • the mixture was washed with MTBE (700 ml_), the aqueous layer was cooled to 5 °C and basified pH14 with 50% aq NaOH solution (400 ml_).
  • the aqueous layer was extracted with DCM (2 x 100 ml_).
  • the combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to obtain crude title
  • N-iodo succinimide (8.38 g) was added to a stirred solution of l-9b (5 g) in acetic acid (50 ml_). The reaction mixture was heated at 80 °C for 3 days, then cooled to rt. Sodium hydroxide solution (150 mL) was added and the mixture was extracted with ethyl acetate (2 x 200 ml_). The combined organic phases were washed with saturated sodium thiosulfate solution (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude compound was purified by column chromatography on silica gel eluted with 10% EtOAc in p. ether. Pure fractions were pooled and concentrated under reduced pressure which gave the title compound (2, 3 g, 33%). MS (ES+) 288.01 [M+H] + .
  • Step a) tert-butyl 3-((4-bromopyridin-3-yl)carbamoyl)azetidine-1 -carboxylate (1-10a)
  • 3-amino-4-bromopyridine 5.05 g, 29.2 mmol
  • N -boc-azetidine-3- carboxylic acid 6.17 g, 30.6 mmol
  • DMAP 4.64 g, 38.0 mmol
  • EDAC'HCI 7.27 g, 38.0 mmol
  • Step b) Tert-butyl 1 '-((4-bromo-7-(trifluoromethyl)isoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate(l-12b)
  • Step a) tert-butyl 1 -bromo ⁇ -chloroisoquinolin-S-vOmethvO ⁇ '-oxo-l ' ⁇ '- dihvdrospirofazetidine-S.S'-pyrrolo ⁇ .S-clpyridinel-l -cafo ⁇ (l-22a)
  • Step b) Tert-butyl 1 '-((7-chloro-4-(pyridazin-4-yl)isoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (l-22b)
  • Step c) 1 '-((7-Chloro-4-(pyridazin-4-yl)isoauinolin-3-yl)methyl)spiro[azetidine-3,3'-pyrrolo[2,3- clpyridinl-2'(1 'H)-one (l-22c)
  • CPE assay For the CPE assay, cells are infected at a Multiplicity of Infection (MOI) of 0.015 using 20 ⁇ _ of RSV Long (ATCC) diluted in assay media. The DMSO concentration is constant throughout the assay plate, including the negative and positive controls. The assay plate is incubated for 3 days at 37 °C in an incubator containing 5% C0 2 . Cell viability is evaluated with the addition of 10 ⁇ of CellTiter-Glo (ProMega). Luminescence is measured using an EnVision plate reader (Perkin Elmer). EC 50 values are calculated using the raw data from the CPE assays.
  • MOI Multiplicity of Infection
  • ATCC RSV Long

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I): où W est NR1A ou CR1BR1B; Z est N ou CH, R1A est un alkyle C1-C3, un haloalkyl C1-C3, un cycloalkyle C3-C4 ou un phényle où le cycloalkyle ou le phényle est facultativement mono-, bi-, ou tri-substitué avec des substituants sélectionnés indépendamment parmi un alkyle C1-C3, un halo, un amino et un alcoxy C1-C3 ; les deux R1B ensemble avec l'atome de carbone lesquelles sont attachées se combinent et forment un cycloalkyle C3-C6 ou un hétérocyclyl, où le cycloalkyle est substitué avec C(=O)OR1C, NHC(=O)OR1C ou NHS(=O)2 R1C, et l'hétérocyclyl est substitué avec C(=O)R1C, C(=O)OR1C, S(=O)2 R1C, C(=O)NH2 ou C(=O)NR1CR1C'; q, n, R1C, R2 et R3 sont tels que défini ici, leur utilisation comme des inhibiteurs de RSV et des aspects apparentés.
PCT/SE2017/050847 2016-08-25 2017-08-23 Inhibiteurs du virus respiratoire syncytial Ceased WO2018038668A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE1651151-1 2016-08-25
SE1651151 2016-08-25

Publications (1)

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WO2018038668A1 true WO2018038668A1 (fr) 2018-03-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025076632A1 (fr) * 2023-10-13 2025-04-17 Fibrocor Therapeutics Inc. Composés et leurs utilisations

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506738B1 (en) * 2000-09-27 2003-01-14 Bristol-Myers Squibb Company Benzimidazolone antiviral agents
WO2013186335A1 (fr) * 2012-06-15 2013-12-19 Janssen R&D Ireland Dérivés 1,3-dihydro-2h-benzimidazol-2-one substitués par des hétérocycles comme agents antiviraux anti-virus respiratoire syncytial
WO2014060411A1 (fr) * 2012-10-16 2014-04-24 Janssen R&D Ireland Composés antiviraux contre le vrs
WO2015065338A1 (fr) * 2013-10-29 2015-05-07 Medivir Ab Inhibiteurs du virus syncytial respiratoire à base de quinazoline
WO2015085844A1 (fr) * 2013-12-10 2015-06-18 南京明德新药研发股份有限公司 Dérivé d'imidazole utilisé en tant qu'agent antiviral et son utilisation pour la préparation d'un médicament
WO2017018924A1 (fr) * 2015-07-30 2017-02-02 Medivir Ab Inhibiteurs du virus respiratoire syncytial

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506738B1 (en) * 2000-09-27 2003-01-14 Bristol-Myers Squibb Company Benzimidazolone antiviral agents
WO2013186335A1 (fr) * 2012-06-15 2013-12-19 Janssen R&D Ireland Dérivés 1,3-dihydro-2h-benzimidazol-2-one substitués par des hétérocycles comme agents antiviraux anti-virus respiratoire syncytial
WO2014060411A1 (fr) * 2012-10-16 2014-04-24 Janssen R&D Ireland Composés antiviraux contre le vrs
WO2015065338A1 (fr) * 2013-10-29 2015-05-07 Medivir Ab Inhibiteurs du virus syncytial respiratoire à base de quinazoline
WO2015085844A1 (fr) * 2013-12-10 2015-06-18 南京明德新药研发股份有限公司 Dérivé d'imidazole utilisé en tant qu'agent antiviral et son utilisation pour la préparation d'un médicament
WO2017018924A1 (fr) * 2015-07-30 2017-02-02 Medivir Ab Inhibiteurs du virus respiratoire syncytial

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COMBRINK, K. D. ET AL.: "Respiratory syncytial virus fusion inhibitors. Part 6: An examination of the effect of structural variation of the benzimidazol-2-one heterocycle moiety", BIOORG. MED. CHEM. LETT., vol. 17, no. 17, September 2007 (2007-09-01), pages 4784 - 4790, XP022184908 *
PRYDE, D. C. ET AL.: "Non-benzimidazole containing inhibitors of respiratory syncytial virus", BIOORG. MED. CHEM. LETT., vol. 23, no. 3, February 2013 (2013-02-01), pages 827 - 833, XP028962613 *
WANG, X. A. ET AL.: "Respiratory syncytial virus fusion inhibitors. Part 5: Optimization of benzimidazole substitution patterns towards derivatives with improved activity", BIOORG. MED. CHEM. LETT., vol. 17, no. 16, August 2007 (2007-08-01), pages 4592 - 4598, XP029094765 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025076632A1 (fr) * 2023-10-13 2025-04-17 Fibrocor Therapeutics Inc. Composés et leurs utilisations

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