WO2023092175A1 - Nouveaux antagonistes du récepteur p2x7 - Google Patents

Nouveaux antagonistes du récepteur p2x7 Download PDF

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WO2023092175A1
WO2023092175A1 PCT/AU2022/051400 AU2022051400W WO2023092175A1 WO 2023092175 A1 WO2023092175 A1 WO 2023092175A1 AU 2022051400 W AU2022051400 W AU 2022051400W WO 2023092175 A1 WO2023092175 A1 WO 2023092175A1
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methyl
mmol
compound
indazolyl
nmr
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PCT/AU2022/051400
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Michael Kassiou
James O'BRIEN-BROWN
Jayson GILCHRIST
Gemma Figtree
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The University Of Sydney
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a series of novel heterocyclic adamantyl and F3- adamantyl cyanoguanidine P2X7 receptor antagonists of Formula (I), wherein Ri is preferably a bicyclic aromatic heterocyclic moiety such as indazolyl, benzimidazolyl, benzotriazolyl, indolyl, benzoxazolyl, benzoxadiazolyl and benzothiazolyl; and wherein R2 is H or F: (i).
  • Ri is preferably a bicyclic aromatic heterocyclic moiety such as indazolyl, benzimidazolyl, benzotriazolyl, indolyl, benzoxazolyl, benzoxadiazolyl and benzothiazolyl; and wherein R2 is H or F: (i).
  • P2X7R The P2X7 receptor
  • CNS central nervous system
  • Activation of the P2X7R releases pro-inflammatory cytokines such as interleukin 1 ⁇ , which have been shown to underlie the pathogenesis of many neurodegenerative disorders.
  • P2X7R antagonist compounds may have utility in the treatment of neurodegenerative conditions associated with several progressive CNS disorders, including stroke, ALS, MS and Alzheimer's disease.
  • P2X7 signalling has also been heavily implicated in atherosclerosis and atherothrombosis through in vitro and in vivo experiments, with blockage of receptor- mediated signalling mitigating atherosclerosis, hypertension and diabetic retinopathy, as well as dilated cardiomyopathy and arrhythmia post myocardial infarction.
  • the compounds are non-competitive receptor antagonists for the NMDA receptor and may have a favourable use either for treating CNS diseases, for instance Alzheimer's disease, senile dementia, cerebral ischaemia and depression, or for treating neuropathic peripheral forms, these pathologies possibly being correlated at least partially with dysfunction of the glutamatergic system.
  • the present invention comprises a series of 5,6-fused heterocyclic adamantyl and F 3 -adamantyl cyanoguanidines, developed with the aim of refining the pharmacophore for P2X7R antagonism.
  • the inventive series of compounds represents a potentially-significant advancement in the development of a drug-like P2X7R antagonist.
  • the phrase “consisting of” excludes any element, step, or ingredient not specified in the claim.
  • the phrase “consists of' (or variations thereof) appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
  • the phrase “consisting essentially of'” limits the scope of a claim to the specified elements or method steps, plus those that do not materially affect the basis and novel characteristic(s) of the claimed subject matter.
  • heteroaryl means an aromatic monocyclic ring or an aromatic bicyclic ring.
  • the aromatic monocyclic rings are five or six membered rings containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S.
  • the nitrogen heteroatoms can be optionally quatemised or oxidized to the N- oxide.
  • the nitrogen containing rings can be optionally N-protected.
  • the five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds.
  • the aromatic bicyclic rings are composed of an aromatic monocyclic ring fused to a phenyl group.
  • aromatic bicyclic rings are composed of an aromatic monocyclic ring fused to another aromatic monocyclic ring.
  • the aromatic monocyclic rings and the aromatic bicyclic rings are connected to the parent molecular moiety through a carbon or nitrogen atom.
  • Representative examples of heteroaryl include, but are not limited to, benzothienyl, benzoxadiazolyl, cinnolinyl, dibenzofuranyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridinium N-oxide, pyrrolyl, quinolinyl, tetrazolyl, thiadiazolyl,
  • heteroaryl groups of the present invention are substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, -OR a , alkylOR a , -C(O)OR a , alkyl, - C(O)R a , -OC(O)R a , -SR a , alkynyl, -C(O)O- cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NR c R c , and (NR c R d )carbonyl, wherein R c and R d are independently selected from hydrogen, alkyl, -C(O)R a , formyl, aryl and arylalkyl.
  • Representative examples include, but are not limited to, 3-cyanopyridin-2-yl, 5- hydroxypyridin-2-yl, and 3-methylpyr
  • heterocycle refers to a monocyclic or bicyclic, nonaromatic, saturated or partially unsaturated ring system.
  • Monocyclic ring systems are exemplified by any 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6-, 7-, or 8-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur.
  • the 5 -membered ring has 0 or 1 double bond.
  • the 6-memebered ring has 0, 1 or 2 double bonds.
  • the 7- or 8-membered ring has 0, 1, 2 or 3 double bonds.
  • monocyclic ring systems include, but are not limited to azetidinyl, azepanyl, azepinyl, diazepinyl, dioxolanyl, dioxanyl, dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 3- oxo-morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, 2-oxo-oxazolinyl, oxazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl,
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocycle group, as defined herein.
  • bicyclic ring systems include but are not limited to, benzodioxinyl, benzopyranyl, benzothiopyranyl, 2,3-dihydroindolyl, indolizinyl, pyranopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiopyranopyridinyl, 2-oxo- 1,3-benzoxazolyl, 3-oxo-benzoxazinyl, 3-azabicyclo[3.2.0]heptyl, 3,6- diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, hexahydro-lH-furo[3,4- c]pyrrolyl, and octahydropyrrolo[3,4-c]pyrrolyl.
  • the monocyclic or bicyclic ring systems as defined herein may have two of the
  • Representative examples of monocyclic or bicyclic ring systems that contain such connection between two non-adjacent carbon atoms include, but not limited to, 2- azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2- azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 3 -azabicyclo [3. l.
  • heterocycle groups of this invention can be optionally substituted with 1, 2, or 3 substituents independently selected from alkenyl, -OR a , -C(O)OR a , -alkylC(O)OR a , alkyl, -COR a , -OC(O)R a , alkylOC(O)R a , - S(O)R a , -S(O)2R a , -S(O) 2 NR a R b , alkynyl, -C(O)NR a R b >, cyano, halo, haloalkyl, haloalkoxy, nitro, -NR a R b , and (NR a R b )alkyl, wherein R a and R b are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl and arylalkyl, wherein R a and R b
  • the heterocycle groups of this invention are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom in the groups.
  • the nitrogen heteroatom may or may not be quatemised and may or may not be oxidized to the N-oxide.
  • the nitrogen containing heterocyclic rings may or may not be N-protected.
  • a compound of Formula (I) wherein Ri is a bicyclic fused heterocyclic moiety; and wherein R2 is H or F.
  • the Ri moiety is a 5,6-fused heterocyclic moiety.
  • the Ri moiety is selected from the group consisting of: benzothienyl, benzoxadiazolyl, cinnolinyl, dibenzofuranyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridinium N-oxide, pyrrolyl, quinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, triazinyl and benzothiazolyl.
  • the Ri moiety is selected from the group consisting of: indazolyl, benzimidazolyl, benzotriazolyl, indolyl, benzoxazolyl, benzoxadiazolyl and benzothiazolyl.
  • the Ri moiety is selected from the group consisting of: 4-NH-l- Me-indazolyl; 4-NH-l-Me-benzimidazolyl; 4-NH-2-Me-indazolyl; 7-NH-2-Me-indazolyl; 7-NH-l -Me -indazolyl; 7 -NH-1 -Me -benzimidazolyl; 7-NH-l -Me -benzotriazolyl; 7-NH-l - Me-indolyl; 6-NH-l-Me-indazolyl; 6-NH-l-Me-benzimidazolyl; 6-NH-2-Me-indazolyl; 5- NH-2-Me-indazolyl; 5-NH-l-Me-indazolyl; 5-NH-l-Me-benzimidazolyl; 4-NH- benzoxazolyl; 5-NH-benzoxazolyl; 6-NH-benzoxazolyl; 6-NH-
  • the Ri moiety is selected from the group consisting of: 7-NH- benzoxazolyl; 4-NH-l-Me-indazolyl; 6-NH-l-Me-indazolyl; 7-NH-l-Me-indazolyl; 5-NH- 2-Me-indazolyl; 6-NH-l-Me-benzimidazolyl; and 7-NH-benzothiazolyl.
  • the compound is selected from the group consisting of:
  • Ri is selected from the group consisting of: 7-NH-benzoxazolyl
  • the compound is selected from the group consisting of:
  • Ri is 7-NH-benzoxazolyl and the compound is:
  • Ri is 7-NH-l-Me-indazolyl and the compound is:
  • Ri is 4-NH-2-Me-indazolyl and the compound is:
  • a compound being 1 -(adamantan- 1 -ylmethyl)-2-cyano-3 -( 1 -methyl- lH-indazol-7 -yl)guanidine :
  • a compound being (E)-l-(benzo[d]thiazol-7-yl)-2-cyano-3-(((3s,5s,7s)-3,5,7-trifluoroadamantan-l- yl)methyl)guanidine : [057]
  • the compound is a P2X7 receptor antagonist.
  • a seventh aspect of the present invention there is provided use of a compound as defined according to the first, second, third or fourth aspects of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: stroke; amyotrophic lateral sclerosis; multiple sclerosis; Alzheimer's disease; Huntington's disease, atherosclerosis, diabetic retinopathy; dilated cardiomyopathy; ischemic injury and left ventricular hypertrophy post myocardial infarction.
  • a disease or condition selected from the group consisting of: stroke; amyotrophic lateral sclerosis; multiple sclerosis; Alzheimer's disease; Huntington's disease, atherosclerosis, diabetic retinopathy; dilated cardiomyopathy; ischemic injury and left ventricular hypertrophy post myocardial infarction.
  • a disease or condition selected from the group consisting of: stroke; amyotrophic lateral sclerosis; multiple sclerosis; Alzheimer's disease; Huntington's disease, atherosclerosis, diabetic retinopathy; dilated cardiomyopathy; ischemic injury and left ventricular hypertrophy post myocardial infarction.
  • a ninth aspect of the present invention there is provided a method for the synthesis of a compound according to the first, second, third, fourth or fifth aspects of the invention, the method comprising the steps of:
  • a ninth aspect of the present invention there is provided a method for the synthesis of l-(adamantan-l-ylmethyl)-2-cyano-3-(1-methyl-lH-indazol-7-yl)guanidine the method comprising the steps of:
  • Tamm -Horsfall protein 1 (THP-1) cells are a human monocytic leukaemia cell line derived from a 1 year old male infant, and used extensively as a model of monocyte and macrophage function. Cells were cultured in suspension in T 175 flasks (Coming), using RPMI 1640 media (with ATCC modification; Gibco) supplemented with 10% heat- inactivated foetal bovine serum (FBS; Gibco). THP-1 cells were separated from old media by centrifugation (125 g, 5 min) and a proportion of cell pellet resuspended back into a T175 flask with fresh media.
  • THP-1 cells were separated from old media by centrifugation (125 g, 5 min) and a proportion of cell pellet resuspended back into a T175 flask with fresh media.
  • THP-1 cells were harvested from culture by centrifugation (125 g, 5 min) and resuspended in RPMI 1640 media (Gibco) supplemented with 5% FBS (Gibco), 100 ng ml- 1 lipopolysaccharide (LPS; from E. coli strain 0111:B4, Sigma-Aldrich), and 10 ng mL -1 recombinant human interferon gamma (IFN- ⁇ ; R&D Systems).
  • Cells were immediately seeded onto 96-well black-walled, CellBIND plates (Coming) at a density of 1.5 x 10 5 cells per well and incubated for 24 h (37 °C, 5% CO2) to allow differentiation into macrophages. Supernatant was removed from each well, and cells were washed once with 150 ⁇ L of warm modified Hanks' Balanced Salt Solution containing low Ca 2+ (HBSS; KC1 5.37 mM, KH2PO4 0.44 mM, NaCl 136.89 mM, Na 2 HPO 4 0.34 mM, glucose 5.55 mM, NaHCO 3 4.17 mM, CaCl 2 0. 1 mM, pH 7.4, 37 °C).
  • HBSS Hanks' Balanced Salt Solution containing low Ca 2+
  • test compound 0.1 - 10 ⁇ M or vehicle control (0.1% DMSO) (v/v) diluted in RPMI 1640 media for 30 min at 37 °C. Pre-treatments were aspirated, and cells were washed once with 150 pL dPBS buffer (pH 7.4, 37 °C). Cells were treated with (i) 1 mM BzATP (Sigma- Aldrich) or vehicle control (0.4% ultra-pure water) (v/v), and (ii) test compound (0.1 - 10 ⁇ M) or vehicle control (0.1% DMSO) (v/v) for 1 h (37 °C, 5% CO2).
  • Leads will be assessed on their ability to reduce secreted levels of interleukin- 1 ⁇ in a human monocytic cell line, and in ex vivo peripheral blood mononuclear cells from ST elevation myocardial infarction patients.
  • Mouse models for different cardiovascular disease states are planned and a combination of echocardiography, histology and ELISA will be used to measure endpoints and establish effectiveness of each therapy.
  • Inhibitors that progress through the first cellular screen will be assessed for cytotoxicity, AMES fluctuations, CYP profiles, and possible liabilities such as hERG, followed by in vivo pharmacokinetic profiling. After demonstration of the efficacy of any lead compound in these models, the Inventors aim to select a candidate to take forward to clinical trials.
  • PKT 100 A close structural analogue of the inventive compounds, "PKT 100", has recently shown efficacy in pre-clinical models of CVD. Early stage testing of the inventive series shows superior potency to PKT 100, and the breadth of potent assay results increases the chance of identifying a lead with a promising pharmacokinetic profde. Heteroaromatic adamantyl cyanoguanidines have previously been shown to bind non-competitively to P2X7Rs, meaning these ligands do not compete with endogenous ATP. Non-competitive inhibitors are superior drugs as they avoid increased concentrations of endogenous ligand in the extracellular space, which can lead to off-site binding, side-effects, etc.
  • Methyl iodide (0.88 mL, 14 mmol, 1.15 eq) was then added dropwise with rapid stirring, and allowed to stir until the reaction had reached completion. Excess volatiles were removed under nitrogen gas flow, and the crude residue was dissolved in ethyl acetate (300 mL). This was washed with aqueous sodium hydroxide (1 M, 4 x 100 mL), brine (150 mL), dried over MgSCri, and then reduced in vacuo. The crude residue was purified by flash chromatography with hexane/ethyl acetate eluent, to yield a mixture of 1 -methyl- and 2-methyl-nitroindazoles.
  • the 1 -methyl regioisomer was less polar and eluted before the 2-methyl regioisomer for all of the nitroindazoles synthesised.
  • the regioselectivity of the methylation reactions were confirmed by full assignment with HSQC and HMBC for all methylated nitroindazoles.
  • reaction mixture was filtered through a silica plug, and the eluate was reduced in vacuo to yield the aminoindazole. Due to stability issues with aminoindazoles, the crudely purified products were immediately coupled with diphenyl N- cyanocarbonimidate according to the general procedure C or general procedure O.
  • N.B. the 2-methylated aminoindazoles are less thermally stable than the 1- methylated indazoles, and general procedure O forms complex product mixtures when used for these derivatives and as such general procedure C is suggested for these methylated regioisomers.
  • 7 -amino- 1 -methylindazole is not sufficiently nucleophilic to undergo coupling with diphenyl N-cyanocarbonimidate at reflux under neutral conditions, and general procedure C (using sodium hydride) is required to form this derivative.
  • the product mixture was filtered through a Celite® plug, washing with dichloromethane, and the filtrate was reduced in vacuo to yield the amine.
  • the amine was dissolved in diethyl ether (1 mL/mmol), and then washed with aqueous sodium hydroxide (1 M, 1 mL/mmol), water (1 mL/mmol), brine (1 mL/mmol), dried over MgSO 4 and filtered.
  • the filtrate was cooled in an ice bath, and then HC1 in dioxane (4 M, 0.4 mL/mmol) was added dropwise with stirring to form a white precipitate.
  • Method B Trimethyloxonium tetrafluoroborate (638 mg, 4.31 mmol, 1.39 eq) was added to a partially dissolved suspension of 4-nitroindazole 315 (507 mg, 3.11 mmol, 1.00 eq) in ethyl acetate (10 mL). The reagent was weighed in a vial in the fumehood, and all materials in contact with the methylating agent were placed in a beaker filled with methanol saturated with ammonia. This was stirred at room temperature, quickly becoming a lighter shade of orange and forming a viscous syrup-like mixture.
  • reaction mixture After stirring for an hour, the reaction mixture was more mobile and after stirring at room temperature for 20 h, had become a light pink colour. When stirring was stopped a white precipitate with a yellow supernatant was evident.
  • the reaction mixture was diluted with ethyl acetate (60 mL) and aqueous sodium bicarbonate (50 mL). The phases were separated, and the aqueous fraction was extracted with ethyl acetate (2 x 50 mL). The combined organic fractions were washed with brine (50 mL), dried over MgSO 4 , and reduced in vacuo to yield a yellow-orange solid.
  • Method B To a stirred pale orange suspension of 5-nitro- 1 H -indazole 316 (1.04 g, 6.36 mmol, 1.00 eq) in dichloromethane (35 mL) was added a solution of trifluoromethanesulfonic acid (1.06 g, 7.01 mmol, 1.11 eq) in dichloromethane (15 mL). This mixture was stirred at room temperature for 15 min and then treated with methyl 2,2,2- trichloroacetimidate (2.0 mL, 16 mmol, 2.5 eq). After stirring for ⁇ 10 min, the reaction mixture had formed a clear orange-red solution.
  • reaction mixture was stirred at room temperature for 18 h, and then slowly quenched with saturated aqueous sodium bicarbonate (40 mL). The phases were separated, and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic fractions were then washed with water (2 x 40 mL), aqueous lithium chloride (5% w/v, 2 x 40 mL; to remove 2,2,2- trichloroacetamide byproduct), brine (80 mL), dried over MgSO 4 and reduced in vacuo to yield an orange solid.
  • 326 was prepared from 7-nitroindazole 318 (2.43 g, 14.9 mmol) according to the general procedure M to provide the title compound as a yellow solid (2. 10 g, 80%).
  • the 1- methyl-7-nitro- 1 H-indazole 322 was only formed in trace amounts and its alternative synthesis is described below.
  • S10 was prepared from 319 (1.05 g, 5.92 mmol) according to the general procedure N to yield the product as a white crystalline solid (0.829 g, 95%) which rapidly discolours in air and was used immediately in the subsequent coupling step without characterisation.
  • 333 was prepared from S10 (150 mg, 1.02 mmol) and diphenyl N- cyanocarbonimidate (255 mg, 1.07 mmol, 1.05 eq) according to the general procedure O to yield the title compound as a white solid (254 mg, 86%).
  • the title compound was prepared from 334 (151 mg, 0.520 mmol, 1.00 eq), 64 HC1 (111 mg, 0.550 mmol, 1.05 eq), and triethylamine (0.22 mL, 1.6 mmol, 3.0 eq) according to the general procedure D, and purified by flash chromatography (0.5-1.0% v/v MeOH in CH 2 CI 2 ) to yield 300 (88 mg, 47%) as a white solid.
  • the title compound S12 was prepared from 321 (156 mg, 0.881 mmol) according to the general procedure N to give a white solid which was used immediately in the subsequent coupling step without further characterisation.
  • the title compound was prepared from 335 (96 mg, 0.330 mmol, 1.00 eq), 64 HC1 (70 mg, 0.35 mmol, 1.1 eq), and triethylamine (0.14 mL, 1.0 mmol, 3.0 eq) according to the general procedure D, and purified by flash chromatography (0.5-1.0% v/v MeOH in CH 2 CI 2 ) to yield 301 (73 mg, 61%) as a white solid.
  • S13 was prepared from 322 (200 mg, 1.13 mmol, 1.00 eq) according to the general procedure N to provide the title compound (170 mg, >quant.) as a white crystalline solid with black impurities which was taken through to the next step immediately below.
  • 336 was prepared from S13 (170 mg, 1.16 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil, 144 mg, 3.6 mmol, 3.1 eq), and diphenyl N- cyanocarbonimidate (858 mg, 3.60 mmol, 3.12 eq) in anhydrous tetrahydrofuran (10 mL) according to general procedure C, and then purified by flash chromatography (5% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ) to yield a white solid.
  • S14 was prepared according to general procedure N using 323 (245 mg, 1.38 mmol, 1.00 eq) and palladium on carbon (Pd/C, 10% w/w, 70 mg, 5 mol% Pd) in EtOAc (25 mL).
  • the reaction mixture was fdtered through a basic alumina plug, eluting with an additional 100 mL of ethyl acetate to yield a colourless filtrate.
  • the filtrate was reduced in vacuo to give a white solid which quickly discoloured in the presence of air, and this was further purified by flash chromatography (0.5% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ), eluting rapidly. This was reduced in vacuo to yield the title compound as a white solid (178 mg, 87%) which was used immediately in the subsequent coupling reaction.
  • 337 was prepared according to the general procedure C using S14 (178 mg, 1.20 mmol, 1.00 e), sodium hydride (60% w/w dispersion in mineral oil, 146 mg, 3.7 mmol, 3.0 eq), and diphenyl N-cyanocarbonimidate (582 mg, 2.44 mmol, 2.03 eq; ⁇ 0.5 eq every 20 min, effervescence) in tetrahydrofuran (10 mL) at room temperature for 17 h. Volatiles were removed under a stream of nitrogen gas, and the crude residue was eluted through a silica plug with 10% MeOH sat. w/ NH 3 in CH 2 CI 2 .
  • 303 was prepared according to general procedure D using 64 (77 mg, 0.47 mmol, 1.4 eq) and 337 (94.5 mg, 0.324 mmol, 1.00 eq) in 2-propanol (3 mL) at reflux for 20 h.
  • the reaction mixture was cooled to room temperature, and the precipitate was collected by vacuum filtration, washing with 2-propanol ( 1 mL) and then diethyl ether (3 x 2 mL) to yield a white solid (85 mg, 72%).
  • mp 226-227 °C; R ⁇ 0.21 (2.5% v/v MeOH sat.
  • S15 was prepared using 324 (222 mg, 1.25 mmol, 1.00 eq) according to the general procedure N. This was purified by flash chromatography (0.5% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ) to elute the compound as a colourless fraction just before a deep blue-coloured band, which was reduced in vacuo to yield a white solid (116 mg, 63%) which rapidly discolours to yellow in air. This was used in the next step immediately without further characterisation.
  • 338 was prepared according to the general procedure C using S15 (116 mg, 0.788 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil, 98 mg, 2.5 mmol, 3. 1 eq), and diphenyl N-cyanocarbonimidate (379 mg, 1.59 mmol, 2.02 eq). Volatiles were removed under a stream of nitrogen gas, and the crude residue was eluted through a silica plug with 10% MeOH sat. w/ NH 3 in CH 2 CI 2 . The filtrate was reduced in vacuo and then purified by flash chromatography (1% v/v MeOH sat. w/ NH 3 ) to give the title compound (210 mg, 91%) as a fluffy white solid.
  • [0136] 304 was prepared according to general procedure D using 64 (63 mg, 0.38 mmol, 1.1 eq) and 338 (99 mg, 0.34 mmol, 1.0 eq) in 2-propanol (3 mL) at reflux for 20 h. The reaction mixture was cooled to room temperature, and the precipitate was collected by vacuum filtration, washing with 2-propanol (1 mL) and then diethyl ether (3 x 2 mL) to yield a white solid (94 mg, 76%).
  • S16 was prepared according to general procedure N using 325 (508 mg, 2.87 mmol, 1.00 eq) and palladium on carbon (Pd/C, 10% w/w, 125 mg, 4mol% Pd) in EtOAc (40 mL).
  • the reaction mixture was filtered through a basic alumina plug, eluting with an additional 100 mL of ethyl acetate to yield a golden coloured filtrate. This was reduced in vacuo to yield an orange oil, which under a flow of nitrogen overnight formed an orange solid.
  • EtOAc ⁇ 8 mL
  • 339 was prepared according to the general procedure C using S16 (187 mg, 1.27 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil, 153 mg, 3.8 mmol, 3.0 eq), and diphenyl /V-cyanocarbonimidate (673 mg, 2.82 mmol, 2.22 eq; ⁇ 0.5 eq every 20 min, effervescence) in tetrahydrofuran (10 mL) at room temperature for 17 h. Volatiles were removed under a stream of nitrogen gas, and the crude residue was eluted through a silica plug with 10% MeOH sat. w/ NH 3 in CH 2 CI 2 .
  • [0139] 305 was prepared according to general procedure D using 64 (63 mg, 0.381 mmol, 1.1 eq) and 339 (104 mg, 0.357 mmol, 1.00 eq) in 2-propanol (3 mL) at reflux for 20 h.
  • S17 was prepared from 326 (442 mg, 2.49 mmol, 1.00 eq) according to general procedure N, yielding the title compound (367 mg, quant.) as a pale pink oil which was used immediately in the following step without further characterisation.
  • 340 was prepared according to the general procedure C using S17 (367 mg, 2.49 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil, 300 mg, 7.5 mmol, 3.0 eq), and diphenyl N-cyanocarbonimidate (1.19 g, 4.99 mmol, 2.00 eq) in tetrahydrofuran (20 mL). This was purified by flash chromatography (1% v/v MeOH sat. w/ NH 3 , eluting as a pale salmon -pink band on silica after a yellow band had eluted). 340 was collected as a pale pink to off-white solid (651 mg, 90%).
  • Aqueous hydrochloric acid (32% w/w, 1.0 mL, 11 mmol, 6.7 eq) was added to a solution of 3-nitro-l,2-phenylenediamine 348 (253 mg, 1.65 mmol, 1.00 eq) in ethanol (3 mL).
  • aqueous formaldehyde (37% w/w, 0.30 mL, 4.0 mmol, 2.4 eq)
  • the reaction mixture was heated at reflux for 3 h after which the reaction had gone to completion.
  • 353 was prepared from 352 (292 mg, 1.48 mmol, 1.00 eq) according to the general procedure N, obtained the title compound (203 mg, quant.) as a brown oil which was used immediately in the subsequent cyclisation reaction without further characterisation.
  • 358 was prepared from 350 (101 mg, 0.686 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil, 300 mg, 7.5 mmol, 3.0 eq), and diphenyl N- cyanocarbonimidate (327 mg, 1.37 mmol, 2.00 eq) according to the general procedure C.
  • the resulting oily brown residue was crudely purified by flash chromatography (10% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ), and then re-purified by flash chromatography (1-2% v/v MeOH sat.
  • the title compound was prepared from 356 (203 mg, 1.38 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil, 118 mg, 3.0 mmol, 2.1 eq), and diphenyl /V- cyanocarbonimidate (657 mg, 2.76 mmol, 2.00 eq) according to the general procedure C.
  • the resulting brown oily residue was crudely purified by flash chromatography (5% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ), and then re-purified by flash chromatography (0.5% v/v MeOH sat.
  • 360 was prepared from 1-methyl-6-aminobenzimidazole 357 (203 mg, 1.38 mmol, I.00 eq), sodium hydride (60% w/w dispersion in mineral oil, 113 mg, 2.8 mmol, 2.1 eq), and diphenyl /V-cyanocarbonimidate (657 mg, 2.76 mmol, 2.00 eq) according to the general procedure C.
  • the resulting brown oily residue was purified crudely by flash chromatography (5% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ) and then re-purified by flash chromatography (1% v/v MeOH sat.
  • 361 was prepared from 355 (87 mg, 0.59 mmol, 1.0 eq), sodium hydride (60% w/w dispersion in mineral oil; 78 mg, 2.0 mmol, 3.3 eq), and diphenyl /V-cyanocarbonimidate (282 mg, 1.18 mmol, 2.00 eq) according to the general procedure C.
  • the crude brown-grey residue was purified by flash chromatography (5% v/v MeOH sat. w/NH 3 in CH 2 CI 2 ), eluting before a blue by-product on the column, isolating the title compound as a grey -white solid (166 mg, 97%).
  • 310 was prepared from 361 (47 mg, 0.16 mmol, 1.0 eq) and 64 (57 mg, 0.34 mmol, 2. 1 eq) according to the general procedure D, collecting the title compound as a white solid (14 mg, 22%) with the remainder eluting through the filter.
  • the neutral compound is virtually insoluble in all organic solvents, including DMSO, diglyme, and N- methylpyrrolidine when heated to their respective boiling points.
  • the retentate was dissolved in concentrated aqueous hydrochloric acid (32% w/v, 1 mL), and the acid was evaporated under a stream of nitrogen gas to afford the title compound as the hydrochloride salt.
  • S18 was prepared from 363 (206 mg, 1.17 mmol, 1.00 eq) according to the general procedure N to afford the title compound (170 mg, quant.) as a brown oil which was used immediately in the subsequent coupling step without further characterisation.
  • 364 was prepared from S18 (170 mg, 1.16 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil; 154 mg, 3.9 mmol, 3.3 eq), and diphenyl N- cyanocarbonimidate (609 mg, 2.56 mmol, 2.20 eq) according to the general procedure C.
  • 365 was prepared from 364 (126 mg, 0.434 mmol, 1.00 eq) and 64 (110 mg, 0.666 mmol, 1.53 eq) according to the general procedure D to afford the title compound.
  • the title compound was prepared from 367 (144 mg, 0.808 mmol, 1.00 eq) according to the general procedure N, purifying the crude product by flash chromatography (1% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ) to isolate the title compound 368 (102 mg, 85%) as a white solid which was used immediately in the subsequent coupling step below.
  • Rf 0.25 (2.5% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ; ninhydrin stain).
  • the title compound was prepared from 368 (100 mg, 0.675 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil; 81 mg, 2.0 mmol, 3.0 eq), and diphenyl N- cyanocarbonimidate (330 mg, 1.39 mmol, 2.05 eq) according to the general procedure C.
  • the crude brown-grey residue was crudely purified by flash chromatography (5% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 until phenol eluted, and then increased to 10% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ).
  • 370 was prepared from 369 (59 mg, 0.20 mmol, 1.0 eq) and 1- adamantylmethylamine (55 mg, 0.33 mmol, 1.7 eq) according to the general procedure D. The precipitate was collected to afford the title compound 370 (14 mg, 13%) as a white solid, which as for the benzimidazole analogue 310 was insoluble in organic solvents.
  • 45 - Benzo [c] [1 ,2,5]oxadiazol-4-amine [0180] 45 was prepared from 44 (500 mg, 3.03 mmol) according to general procedure N. TLC analysis of the crude product indicated multiple UV active compounds, so flash chromatography (EtOAc/Hex, 1:4, 1% NEti) was performed to yield the title compound as yellow and orange crystals (311 mg, 76%) which did not degrade upon exposure to air, permitting characterisation.
  • This procedure used lithium bis(trimethylsilyl)amide (LiHMDS) instead of sodium hydride as a base in an analogous procedure as outlined by general procedure C.
  • 46 was prepared from benzoxadiazol-4-amine 45 (288 mg, 2.13 mmol), diphenyl cyanocarbonimidate (1.07 g, 4.48 mmol, 2.1 eq) and LiHMDS in THF (2.34 mL, I M, 1.1 eq) according to general procedure C. Purification by flash chromatography (2.5% v/v MeOH sat. NH 3 in CH 2 CI 2 ) afforded the title compound as a white, crystalline solid (354 mg, 60%).
  • JSG_B24 was prepared from laa (283 mg, 1.88 mmol, 1.00 eq), sodium hydride (60% w/w dispersion in mineral oil, 264 mg, 6.6 mmol, 3.5 eq), and diphenyl N- cyanocarbonimidate (943 mg, 3.96 mmol, 2.1 eq) in anhydrous tetrahydrofuran (6 ) mL according to general procedure C, and then purified by flash chromatography (1% v/v MeOH sat.
  • JSG_B25 was prepared from JSG_B24 (160 mg, 0.544 mmol) and 1- adamantylmethylamine (98.8 mg, 0.598 mmol, 1.10 eq) according to general procedure D to provide the title compound (86 mg, 43%) as a white solid.
  • the crude product was dissolved in dichloromethane, washed with aqueous sodium hydroxide (1 M, 3 x 100 mL), aqueous hydrochloric acid (1 M, 2 x 150 mL), and water (2 x 150 mL).
  • JSG_B37 (1.42 g, 6.08 mmol) in anhydrous THF (0.25 mmol/mL) was treated with lithium aluminium hydride (924 mg, 24.34 mmol) at 0 °C with stirring, warmed to room temperature over 30 min, and then heated at reflux for 20 h.
  • the reaction mixture was allowed to cool to room temperature, and then chilled water (0. 17 mL/mmol) was added dropwise, followed by aqueous sodium hydroxide (4 M, 0.17 mL/mmol), and additional water (0.5 mL/mmol).
  • THF was added to mobilise the viscous slurry, and after stirring for 30 min, MgSO 4 was added directly to the reaction mixture.
  • the product mixture was filtered through a Celite® plug, washing with dichloromethane, and the filtrate was reduced in vacuo to yield the amine.
  • the amine was dissolved in diethyl ether (1 mL/mmol), and then washed with aqueous sodium hydroxide (1 M, 1 mL/mmol), water (1 mL/mmol), brine (1 mL/mmol), dried over MgSO 4 and filtered.
  • the filtrate was cooled in an ice bath, and then HC1 in dioxane (4 M, 0.4 mL/mmol) was added dropwise with stirring to form a white precipitate.
  • JSG_B29 was prepared from JSG_B24 (98 mg, 0.333 mmol) and JSG_B38 (120 mg, 0.549 mmol, 1.65 eq) according to general procedure D, and then purified by flash chromatography (1-2.5% v/v MeOH sat. w/ NH 3 in CH 2 CI 2 ) to provide the title compound (49 mg, 35%) as a white solid.
  • JSG D06 was prepared from 336 (115 mg, 0.395 mmol) and JSG B38 (93.6 mg, 0.427 mmol, 1.08 eq) according to general procedure D, and then purified by flash chromatography (0.75-1.75% v/v MeOH in CH 2 CI 2 ) to provide the title compound (48 mg, 29%) as a white solid.

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Abstract

L'invention concerne de manière générale un composé représenté par la formule (I), dans laquelle R1 représente une fraction hétérocyclique fusionnée bicyclique et R2 représente H ou F. Le composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci a une utilisation médicale potentielle dans le traitement ou la prévention d'états tels qu'un accident vasculaire cérébral ; la sclérose latérale amyotrophique ; la sclérose en plaques ; la maladie d'Alzheimer ; la maladie de Huntington, l'athérosclérose, la rétinopathie diabétique ; la cardiomyopathie dilatée ; la lésion ischémique et l'hypertrophie ventriculaire gauche après un infarctus du myocarde.
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WO2020037350A1 (fr) * 2018-08-24 2020-02-27 The University Of Sydney Composés benzamide substitués par adamantanyle et leur utilisation en tant qu'antagonistes du récepteur p2x7

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020037350A1 (fr) * 2018-08-24 2020-02-27 The University Of Sydney Composés benzamide substitués par adamantanyle et leur utilisation en tant qu'antagonistes du récepteur p2x7

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CALLIS, T. B. ET AL.: "The role of polycyclic frameworks in modulating P2X7 receptor function", TETRAHEDRON, vol. 74, 2018, pages 1207 - 1219, XP085355148, DOI: 10.1016/j.tet.2017.10.075 *
O'BRIEN-BROWN, J. ET AL.: "Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 130, 2017, pages 433 - 439, XP029945166, DOI: 10.1016/j.ejmech.2017.02.060 *
WONG, E. C. N. ET AL.: "Pharmacological evaluation of a novel series of urea, thiourea and guanidine derivatives as P2X7 receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 27, 2017, pages 2439 - 2442, XP085002047, DOI: 10.1016/j.bmcl.2017.04.005 *

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