JP7438148B2 - 心臓サルコメア阻害剤 - Google Patents
心臓サルコメア阻害剤 Download PDFInfo
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- JP7438148B2 JP7438148B2 JP2020572525A JP2020572525A JP7438148B2 JP 7438148 B2 JP7438148 B2 JP 7438148B2 JP 2020572525 A JP2020572525 A JP 2020572525A JP 2020572525 A JP2020572525 A JP 2020572525A JP 7438148 B2 JP7438148 B2 JP 7438148B2
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- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- RXVMYNJUHKBFOS-UHFFFAOYSA-N methyl 5-cyano-2,3-dihydro-1H-indene-1-carboxylate Chemical compound C(#N)C=1C=C2CCC(C2=CC=1)C(=O)OC RXVMYNJUHKBFOS-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229960003574 milrinone Drugs 0.000 description 1
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000010016 myocardial function Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002644 neurohormonal effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical group C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- LBWZSUHDRDWJEC-UHFFFAOYSA-N oxadiazolo[4,5-c]pyridine Chemical compound C1=NC=CC2=C1N=NO2 LBWZSUHDRDWJEC-UHFFFAOYSA-N 0.000 description 1
- RWXCVESEMJNNMF-UHFFFAOYSA-N oxadiazolo[5,4-b]pyridine Chemical compound C1=CN=C2ON=NC2=C1 RWXCVESEMJNNMF-UHFFFAOYSA-N 0.000 description 1
- SVMOLIXMHXABPH-UHFFFAOYSA-N oxadiazolo[5,4-c]pyridine Chemical compound C1=NC=CC2=C1ON=N2 SVMOLIXMHXABPH-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- QNNHQVPFZIFNFK-UHFFFAOYSA-N oxazolo[4,5-b]pyridine Chemical compound C1=CC=C2OC=NC2=N1 QNNHQVPFZIFNFK-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- CNDQSXOVEQXJOE-UHFFFAOYSA-N oxyphenbutazone hydrate Chemical compound O.O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 CNDQSXOVEQXJOE-UHFFFAOYSA-N 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000034272 protein filaments Human genes 0.000 description 1
- 108091005974 protein filaments Proteins 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical compound C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 210000002807 slow-twitch muscle fiber Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- GNXPUXGOQIHJLJ-UHFFFAOYSA-N thiadiazolo[4,5-b]pyridine Chemical compound C1=CN=C2N=NSC2=C1 GNXPUXGOQIHJLJ-UHFFFAOYSA-N 0.000 description 1
- HKMXLNRHGNWKJG-UHFFFAOYSA-N thiadiazolo[4,5-c]pyridine Chemical compound C1=NC=CC2=C1N=NS2 HKMXLNRHGNWKJG-UHFFFAOYSA-N 0.000 description 1
- QKTRRACPJVYJNU-UHFFFAOYSA-N thiadiazolo[5,4-b]pyridine Chemical compound C1=CN=C2SN=NC2=C1 QKTRRACPJVYJNU-UHFFFAOYSA-N 0.000 description 1
- DNWLQCBSEZHTMF-UHFFFAOYSA-N thiadiazolo[5,4-c]pyridine Chemical compound C1=NC=CC2=C1SN=N2 DNWLQCBSEZHTMF-UHFFFAOYSA-N 0.000 description 1
- SMZMHUCIDGHERP-UHFFFAOYSA-N thieno[2,3-b]pyridine Chemical compound C1=CN=C2SC=CC2=C1 SMZMHUCIDGHERP-UHFFFAOYSA-N 0.000 description 1
- GDQBPBMIAFIRIU-UHFFFAOYSA-N thieno[2,3-c]pyridine Chemical compound C1=NC=C2SC=CC2=C1 GDQBPBMIAFIRIU-UHFFFAOYSA-N 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical compound N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- UPCXAARSWVHVLY-UHFFFAOYSA-N tris(2-hydroxyethyl)azanium;acetate Chemical compound CC(O)=O.OCCN(CCO)CCO UPCXAARSWVHVLY-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本願は、2018年6月26日出願の発明の名称「CARDIAC SARCOMERE INHIBITORS」の米国仮出願第62/690,248号に対する優先権を主張し、その内容は、あらゆる目的でその全体が参照により本明細書に組み込まれる。
分野
本明細書では、複素環式化合物、このような化合物を含む医薬組成物、ならびにこのような化合物を用いて様々な心臓疾患および状態を処置する方法が提供される。
Xは、-O-または-CH2-であり、
R1は、Hであり、R2は、-C(O)NHRaであるか、またはR1およびR2は、一緒になって、-CH2OC(O)NH-であり、
R3は、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換シクロアルキル、置換または非置換シクロアルケニル、置換または非置換シクロアルキニル、置換または非置換ヘテロシクリル、置換または非置換アリール、および置換または非置換ヘテロアリールからなる群から選択され、
Raは、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換シクロアルキル、置換または非置換シクロアルケニル、置換または非置換シクロアルキニル、置換または非置換ヘテロシクリル、置換または非置換アリール、および置換または非置換ヘテロアリールからなる群から選択される]。
本明細書で使用される場合、以下の用語および句は、一般に、それらが使用される文脈によってそうでないと指示される場合を除き、下記の通りの意味を有することを企図される。
化合物
Xは、-O-または-CH2-であり、
R1は、Hであり、R2は、-C(O)NHRaであるか、またはR1およびR2は、一緒になって、-CH2OC(O)NH-であり、
R3は、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換シクロアルキル、置換または非置換シクロアルケニル、置換または非置換シクロアルキニル、置換または非置換ヘテロシクリル、置換または非置換アリール、および置換または非置換ヘテロアリールからなる群から選択され、
Raは、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換シクロアルキル、置換または非置換シクロアルケニル、置換または非置換シクロアルキニル、置換または非置換ヘテロシクリル、置換または非置換アリール、および置換または非置換ヘテロアリールからなる群から選択される]。
組成物
使用方法
投薬量
キット
組合せ物
一般合成法
(実施例1)
化合物2の合成
1.中間体1-2の合成
2.中間体1-3の合成
3.中間体1-4の合成
4.中間体1-5の合成
5.中間体1-6の合成
6.中間体1-7の合成
7.化合物2の合成
化合物41の合成
中間体3-2の合成
2.中間体3-3の合成
3.中間体3-4の合成
4.中間体3-5の合成
5.中間体3-6の合成
6.中間体3-7の合成
7.中間体3-8の合成
8.中間体3-9の合成
9.中間体3-10の合成
10.化合物41の合成
(実施例4)
エナンチオマー41Aおよび41Bの合成
(実施例5)
化合物26の合成
1.中間体5-2の合成
2.中間体5-3の合成
3.中間体5-4の合成
4.中間体5-5の合成
5.中間体5-6の合成
7.化合物26の合成
筋細胞アッセイ
(i)成体ラット心臓の心室筋細胞の調製。
(ii)成体の心室筋細胞収縮性実験。
(iii)収縮性の分析。
生物学的実施例B-3
生物学的実施例B-4
生物学的実施例B-5
本発明は、例えば、以下の項目を提供する。
(項目1)
式(I)の化合物
またはその薬学的に許容される塩[式中、
Xは、-O-または-CH 2 -であり、
R 1 は、Hであり、R 2 は、-C(O)NHR a であるか、またはR 1 およびR 2 は、一緒になって、-CH 2 OC(O)NH-であり、
R 3 は、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換シクロアルキル、置換または非置換シクロアルケニル、置換または非置換シクロアルキニル、置換または非置換ヘテロシクリル、置換または非置換アリール、および置換または非置換ヘテロアリールからなる群から選択され、
R a は、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換シクロアルキル、置換または非置換シクロアルケニル、置換または非置換シクロアルキニル、置換または非置換ヘテロシクリル、置換または非置換アリール、および置換または非置換ヘテロアリールからなる群から選択される]。
(項目2)
Xが、-CH 2 -である、項目1に記載の化合物、またはその薬学的に許容される塩。
(項目3)
Xが、-O-である、項目1に記載の化合物、またはその薬学的に許容される塩。
(項目4)
R 1 が、Hであり、R 2 が、-C(O)NHR a である、項目1~3のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目5)
R a が、置換もしくは非置換アルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールである、項目1~4のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目6)
R a が、置換もしくは非置換フェニル、置換もしくは非置換ピラゾリル、または置換もしくは非置換ピリジニルである、項目1~5のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目7)
R a が、
からなる群から選択され、nは、1~3であり、各R 4 が、独立に、アルコキシ、アシル、アシルオキシ、カルボニルアルコキシ、アシルアミノ、アミノ、アミノアシル、アミノカルボニルアミノ、アミノカルボニルオキシ、シクロアルキル、シクロアルケニル、アリール、ヘテロアリール、アリールオキシ、シアノ、アジド、ハロ、ヒドロキシル、ニトロ、カルボキシル、チオール、チオアルキル、シクロアルキル、シクロアルケニル、アルキル、アルケニル、アルキニル、ヘテロシクリル、アラルキル、アミノスルホニル、スルホニルアミノ、スルホニル、およびオキソからなる群から選択される、項目1~6のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目8)
R a が、
からなる群から選択される、項目1~7のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目9)
R a が、メチル、エチル、プロピル、またはブチルである、項目1~5のいずれかに記載の化合物、またはその薬学的に許容される塩。
(項目10)
R a が、エチルである、項目1~5もしくは9のいずれかに記載の化合物、またはその薬学的に許容される塩。
(項目11)
R 1 およびR 2 が、一緒になって、-CH 2 OC(O)NH-である、項目1~3のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目12)
R 3 が、置換もしくは非置換アルキル、または置換もしくは非置換シクロアルキルである、項目1~11のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目13)
R 3 が、メチル、エチル、プロピル、イソプロピル、またはブチルである、項目1~12のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目14)
R 3 が、ハロアルキルである、項目1~12のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目15)
R 3 が、-CHF 2 である、項目1~12もしくは14のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目16)
R 3 が、シクロプロピルである、項目1~12のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
(項目17)
表1の化合物からなる群から選択される化合物、またはその薬学的に許容される塩。
(項目18)
項目1~17のいずれか一項に記載の化合物、またはその薬学的に許容される塩、および薬学的に許容される賦形剤を含む、医薬組成物。
(項目19)
心臓疾患を処置することを必要とする対象における心臓疾患を処置する方法であって、項目1~17のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目18に記載の医薬組成物を前記対象に投与するステップを含む、方法。
(項目20)
前記心臓疾患が、肥大型心筋症である、項目19に記載の方法。
(項目21)
前記肥大型心筋症が、閉塞性もしくは非閉塞性であるか、またはサルコメアおよび/もしくは非サルコメア突然変異によって引き起こされる、項目20に記載の方法。
(項目22)
前記心臓疾患が、駆出分画が保たれた心不全である、項目19に記載の方法。
(項目23)
前記心臓疾患が、拡張機能障害、原発性または続発性拘束型心筋症、心筋梗塞および狭心症、左心室流出路閉塞、高血圧性心臓疾患、先天性心臓疾患、心虚血、冠状動脈性心臓疾患、糖尿病性心臓疾患、うっ血性心不全、右心不全、心腎症候群、ならびに浸潤性心筋症からなる群から選択される、項目19に記載の方法。
(項目24)
前記心臓疾患が、心臓老化、加齢に起因する拡張機能障害、左心室肥大および求心性左心室リモデリングからなる群から選択される1つまたは複数の状態であるか、またはそれに関係する、項目19に記載の方法。
(項目25)
肥大型心筋症と関連する疾患または状態を処置することを必要とする対象における肥大型心筋症と関連する疾患または状態を処置する方法であって、項目1~17のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目18に記載の医薬組成物を前記対象に投与するステップを含む、方法。
(項目26)
前記疾患または状態が、ファブリー病、ダノン病、ミトコンドリア心筋症、およびヌーナン症候群からなる群から選択される、項目25に記載の方法。
(項目27)
続発性左心室壁肥厚と関連する疾患または状態を処置することを必要とする対象における続発性左心室壁肥厚と関連する疾患または状態を処置する方法であって、項目1~17のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目18に記載の医薬組成物を前記対象に投与するステップを含む、方法。
(項目28)
前記疾患または状態が、高血圧、心臓弁膜症、大動脈弁狭窄、僧帽弁逆流、メタボリック症候群、糖尿病、肥満、末期腎疾患、強皮症、睡眠時無呼吸、アミロイドーシス、ファブリー病、フリードライヒ運動失調、ダノン病、ヌーナン症候群、およびポンペ病からなる群から選択される、項目27に記載の方法。
(項目29)
小左心室内腔および内腔閉塞、運動過多性左心室収縮、心筋虚血、または心臓線維症と関連する疾患または状態を処置することを必要とする対象における、小左心室内腔および内腔閉塞、運動過多性左心室収縮、心筋虚血、または心臓線維症と関連する疾患または状態を処置する方法であって、項目1~17のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目18に記載の医薬組成物を前記対象に投与するステップを含む、方法。
(項目30)
筋ジストロフィーおよび糖原病から選択される疾患または状態を処置することを必要とする対象における、筋ジストロフィーおよび糖原病から選択される疾患または状態を処置する方法であって、項目1~17のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目18に記載の医薬組成物を前記対象に投与するステップを含む、方法。
(項目31)
心臓サルコメアを阻害する方法であって、前記心臓サルコメアを、項目1~17のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目18に記載の医薬組成物と接触させるステップを含む、方法。
Claims (18)
- Xが、-CH2-である、請求項1に記載の化合物、またはその薬学的に許容される塩。
- Xが、-O-である、請求項1に記載の化合物、またはその薬学的に許容される塩。
- R3が、置換もしくは非置換アルキル、または置換もしくは非置換シクロアルキルである、請求項1~3のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- R3が、メチル、エチル、プロピル、イソプロピル、またはブチルである、請求項1~4のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- R3が、ハロアルキルである、請求項1~4のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- R3が、-CHF2である、請求項1~4もしくは6のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- R3が、シクロプロピルである、請求項1~4のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- 請求項1~9のいずれか一項に記載の化合物、またはその薬学的に許容される塩、および薬学的に許容される賦形剤を含む、医薬組成物。
- 心臓疾患を処置するための、請求項1~9のいずれか一項に記載の化合物もしくはその薬学的に許容される塩を含む、組成物、または請求項10に記載の医薬組成物。
- 前記心臓疾患が、肥大型心筋症である、請求項11に記載の組成物。
- 前記肥大型心筋症が、閉塞性もしくは非閉塞性であるか、またはサルコメアおよび/もしくは非サルコメア突然変異によって引き起こされる、請求項12に記載の組成物。
- 前記心臓疾患が、駆出分画が保たれた心不全である、請求項11に記載の組成物。
- 前記心臓疾患が、拡張機能障害、原発性または続発性拘束型心筋症、心筋梗塞および狭心症、左心室流出路閉塞、高血圧性心臓疾患、先天性心臓疾患、心虚血、冠状動脈性心臓疾患、糖尿病性心臓疾患、うっ血性心不全、右心不全、心腎症候群、ならびに浸潤性心筋症からなる群から選択される、請求項11に記載の組成物。
- 前記心臓疾患が、心臓老化、加齢に起因する拡張機能障害、左心室肥大および求心性左心室リモデリングからなる群から選択される、請求項11に記載の組成物。
- 小左心室内腔、内腔閉塞、運動過多性左心室収縮、心筋虚血、または心臓線維症を処置するための、請求項1~9のいずれか一項に記載の化合物もしくはその薬学的に許容される塩を含む、組成物、または請求項10に記載の医薬組成物。
- 心臓サルコメアを阻害するための、請求項1~9のいずれか一項に記載の化合物もしくはその薬学的に許容される塩を含む、組成物、または請求項10に記載の医薬組成物であって、前記化合物もしくはその薬学的に許容される塩、または前記組成物が前記心臓サルコメアと接触することを特徴とする、組成物または医薬組成物。
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