CN107304192B - 一类puma抑制剂及其制备方法和用途 - Google Patents
一类puma抑制剂及其制备方法和用途 Download PDFInfo
- Publication number
- CN107304192B CN107304192B CN201610242882.1A CN201610242882A CN107304192B CN 107304192 B CN107304192 B CN 107304192B CN 201610242882 A CN201610242882 A CN 201610242882A CN 107304192 B CN107304192 B CN 107304192B
- Authority
- CN
- China
- Prior art keywords
- puma
- compound
- formula
- inhibitor
- pharmaceutically acceptable
- 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.)
- Expired - Fee Related
Links
- 101000971203 Homo sapiens Bcl-2-binding component 3, isoforms 1/2 Proteins 0.000 title claims abstract description 32
- 101000971209 Homo sapiens Bcl-2-binding component 3, isoforms 3/4 Proteins 0.000 title claims abstract description 32
- 239000003112 inhibitor Substances 0.000 title claims abstract description 15
- 102100021572 Bcl-2-binding component 3, isoforms 1/2 Human genes 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 title abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 17
- 230000005855 radiation Effects 0.000 claims abstract description 16
- 230000006378 damage Effects 0.000 claims abstract description 10
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 7
- 208000014674 injury Diseases 0.000 claims abstract description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 208000012947 ischemia reperfusion injury Diseases 0.000 claims description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 230000002424 anti-apoptotic effect Effects 0.000 claims 1
- 230000004223 radioprotective effect Effects 0.000 claims 1
- 230000004224 protection Effects 0.000 abstract description 16
- 230000006907 apoptotic process Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 10
- 230000006909 anti-apoptosis Effects 0.000 abstract description 6
- 210000001185 bone marrow Anatomy 0.000 abstract description 6
- 102000004169 proteins and genes Human genes 0.000 abstract description 5
- 108090000623 proteins and genes Proteins 0.000 abstract description 5
- 230000002860 competitive effect Effects 0.000 abstract description 4
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 abstract description 3
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 230000003471 anti-radiation Effects 0.000 abstract description 2
- 230000004821 effect on bone Effects 0.000 abstract description 2
- 102100021573 Bcl-2-binding component 3, isoforms 3/4 Human genes 0.000 abstract 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 8
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 208000019155 Radiation injury Diseases 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 3
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- KIWUVOGUEXMXSV-UHFFFAOYSA-N rhodanine Chemical compound O=C1CSC(=S)N1 KIWUVOGUEXMXSV-UHFFFAOYSA-N 0.000 description 3
- KZTWONRVIPPDKH-UHFFFAOYSA-N 2-(piperidin-1-yl)ethanol Chemical compound OCCN1CCCCC1 KZTWONRVIPPDKH-UHFFFAOYSA-N 0.000 description 2
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 2
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 102000051485 Bcl-2 family Human genes 0.000 description 2
- 108700038897 Bcl-2 family Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- 230000010287 polarization Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- YDHRPQYMQCOQQT-UHFFFAOYSA-N 6-chloropyridazine-3-carbaldehyde Chemical compound ClC1=CC=C(C=O)N=N1 YDHRPQYMQCOQQT-UHFFFAOYSA-N 0.000 description 1
- -1 Bcl-xl Proteins 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 208000034615 apoptosis-related disease Diseases 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000010248 power generation Methods 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 239000011251 protective drug Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- YRUFRSUZZACWCW-UHFFFAOYSA-N pyridazine-3-carbaldehyde Chemical compound O=CC1=CC=CN=N1 YRUFRSUZZACWCW-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 229940124553 radioprotectant Drugs 0.000 description 1
- 230000001950 radioprotection Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
-
- 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
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/54—Nitrogen and either oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Virology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Psychiatry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及医药技术领域，具体涉及一类PUMA抑制剂及其制备方法和用途。所述PUMA抑制剂为下述式Ⅰ化合物或其药学上可接受的盐。其中，各取代基的定义如说明书中所述。本发明的式Ⅰ化合物或其药学上可接受的盐能够靶向PUMA蛋白，具有良好的理化性质、很好的抗细胞凋亡和辐射防护作用，可以选择性地抑制PUMA蛋白与Bcl‑2类抗凋亡蛋白之间的竞争性结合作用，阻断细胞凋亡，对骨髓型损伤产生有效地防护作用。本发明为PUMA蛋白的小分子抑制剂在辐射防护药物中的应用提供了新颖的思路和有力的证据，有望成为高效低毒稳定的临床辐射防护药物。
Description
技术领域
本发明涉及医药技术领域，具体涉及一类PUMA抑制剂及其制备方法和用途。
背景技术
高速发展的核辐射技术，已被普遍应用于经济、军事的多个领域，如医学诊疗、核能发电、辐射育种、恐怖活动、核战争等。这些核能的广泛应用造成了越来越多的人会暴露于高能量电离辐射中。辐射可对机体造成严重的损害，如造血干细胞损伤、器官病变、辐射诱变和辐射致癌等。
骨髓型损伤是辐射损伤中最基础、最常见的损伤类型。第一时间中断此类损伤是绝大多数急性辐射防护的首要措施。从辐射损伤的机理出发，确定药物靶标、开发靶向特异性防护药物是急性辐射损伤防护研究最有效的策略。
骨髓型辐射损伤是干细胞等发生凋亡而直接引起的。Bcl-2家族，无论在细胞内源性和外源性凋亡途径中，都发挥着重要作用。PUMA作为Bcl-2家族中只有BH3同源结构域的促凋亡蛋白，优先于其他任何一个促凋亡成员，与所有五种抗凋亡蛋白(Bcl-2，Bcl-xl，Mcl，A1，Bcl-x)发生竞争性结合，在p53依赖和非依赖的凋亡中都发挥非常重要的作用，能导致Bak、Bax等多聚化，从而改变线粒体膜通透性，释放半胱天冬酶caspase，全面引发细胞凋亡。而且，PUMA的蛋白晶体结构明确，其关键结合位点的BH3区域包含9个碱基对。PUMA作为一种竞争有力、功能强大、结构清晰的促凋亡蛋白，是辐射防护剂设计的理想靶标。抑制PUMA与抗凋亡蛋白的结合，是辐射防护研究的前沿领域。
以PUMA蛋白为靶点的辐射损伤药物是世界范围内的创新领域，文献鲜有报道。因此本发明涉及新型靶向PUMA蛋白的小分子抑制剂，以期获得高效、低毒、稳定的急性辐射损伤防护药物。
发明内容
鉴于PUMA小分子抑制剂这一国内空白、国际领先的研究领域，本发明提出一类靶向PUMA蛋白的小分子抑制剂，其可用于辐射防护药物。此外，还可能用于治疗与凋亡相关的疾病，如心肌缺血、缺血再灌注损伤、心力衰竭、阿兹海默症等神经退行性疾病、艾滋病等病毒感染。
因此，本发明的一个目的是提供下述式Ⅰ化合物或其药学上可接受的盐。
本发明的另一目的是提供下述式Ⅰ化合物或其药学上可接受的盐的制备方法。
本发明的又一目的是提供下述式Ⅰ化合物或其药学上可接受的盐在制备药物中的用途。
本发明提供的式Ⅰ化合物或其药学上可接受的盐，
其中：
A为C5～C10芳基、或者含有1～3个选自N、O和S中的杂原子的5～10元杂芳基；
具体地，A可以为：
优选地，A为C5～C6芳基、或者含有1～2个选自N、O和S中的杂原子的5～6元杂芳基；
更优选地，A为苯基或哒嗪基。
式Ⅰ化合物在与PUMA蛋白结合时，A与PUMA蛋白关键氨基酸作用时发挥疏水键的作用。
E为含有0～2个选自N、O和S中的杂原子的5～6元饱和或不饱和脂肪环、-C3～C6烷基-、-NH-C1～C3烷基-、-O-C1～C3烷基-、-C1～C3烷基-NH-C1～C3烷基-、-C1～C3烷基-O-C1～C3烷基-、-NH-C1～C3烷基-NH-、-O-C1～C3烷基-O-；
具体地，E可以为：
优选地，E为含有0～2个选自N、O和S中的杂原子的5～6元饱和脂肪环；
更优选地，E为哌嗪基或者哌啶基。
式Ⅰ化合物在与PUMA蛋白结合时，E与PUMA蛋白关键氨基酸作用时为氢键受体。
Y为O、S、NH或CH2；优选地，Y为O。
R1为H、C1～C6烷基、C1～C6烷氧基、卤素(氟、氯、溴、碘)、-OH、-NH2、R3为H、C1～C6烷基、C1～C6烷氧基、卤素(氟、氯、溴、碘)、-OH、-NH2；
具体地，R1可以为：H、C1～C6烷基、C1～C6烷氧基、卤素(氟、氯、溴、碘)、-OH、-NH2、
R2为H、-OH、-NH2、-SH、-COOH、-CONH2、-SO2NH2、-SO3H、-CH(OH)-CH2-OH。
式Ⅰ化合物在与PUMA蛋白结合时，R2与PUMA蛋白关键氨基酸作用时为氢键供体。
n为1～5的整数；具体地，n可以为1、2、3、4或5。
所述“芳基”指的是不含有杂原子的芳香性基团；
所述“杂芳基”指的是含有杂原子的芳香性基团；
所述“杂环基”指的是含有杂原子的非芳香性基团；
所述“烷基”包括直链或支链烷基。
本发明的上述描述中，A、E、Y、R1、R2和n中的任一个的一般、具体、优选、更优选范围可以和其他任一个的一般、具体、优选、更优选范围进行任意的组合。
优选地，式Ⅰ化合物或其药学上可接受的盐为下述式Ⅱ化合物或其药学上可接受的盐：
其中，A、E、R1、R2和n的定义如上。
在一个实施方案中，式Ⅰ化合物或其药学上可接受的盐或者式Ⅱ化合物或其药学上可接受的盐为以下化合物1～12或其药学上可接受的盐：
在一个实施方案中，式Ⅰ化合物或其药学上可接受的盐或者式Ⅱ化合物或其药学上可接受的盐为以下化合物或其药学上可接受的盐：
本发明提供式Ⅰ化合物或其药学上可接受的盐的制备方法，所述制备方法包括以下步骤：
在容器中加入化合物21、醇(例如，甲醇)和酸(例如，冰醋酸)，在N2保护下，加入化合物22和化合物23，油浴回流，反应完成后冰浴析出固体，抽滤，洗涤，硅胶柱层析纯化，即得；
其中，A、E、R1、R2、R3和n的定义如上。
本发明提供式Ⅰ化合物或其药学上可接受的盐在制备PUMA抑制剂的药物中的用途。
本发明提供式Ⅰ化合物或其药学上可接受的盐在制备辐射防护、抗细胞凋亡的药物中的用途。
本发明提供式Ⅰ化合物或其药学上可接受的盐在制备治疗辐射引起骨髓型损伤、心肌缺血、缺血再灌注损伤、心力衰竭、阿兹海默症、艾滋病的药物中的用途。
本发明提供式Ⅰ化合物或其药学上可接受的盐在制备抗细胞凋亡药物中的用途。
此外，本发明提供一种药物组合物，其含有式Ⅰ化合物或其药学上可接受的盐，以及药学上可接受的辅料。
本发明的式Ⅰ化合物或其药学上可接受的盐能够靶向PUMA蛋白，具有良好的理化性质、很好的抗细胞凋亡和辐射防护作用，可以选择性地抑制PUMA蛋白与Bcl-2类抗凋亡蛋白之间的竞争性结合作用，阻断细胞凋亡，对骨髓型损伤产生有效地防护作用。本发明为PUMA蛋白的小分子抑制剂在辐射防护药物中的应用提供了新颖的思路和有力的证据，有望成为高效低毒稳定的临床辐射防护药物。
具体实施方式
下面通过实施例对本发明进行说明，但本发明并不局限于此。下述实施例中所述试验方法，如无特殊说明，均为常规方法，所述试剂和材料，均为市售产品。
制备实施例1
在三颈瓶中加入绕丹宁2.0g(15mmol)，无水甲醇20mL，冰醋酸0.1mL，在N2保护下，加入羟乙基哌嗪2.9g(22.6mmol)和苯甲醛22.6mmol，油浴回流，得淡黄色澄清反应液，及时TLC监测反应，1-2h后反应完成，冰浴析出黄色固体，抽滤，甲醇滤洗，粗品用硅胶柱层析纯化(DCM:MeOH 10:1)，得到纯品化合物1，产率为35-55％。
黄色固体，产率46％。1H NMR(400MHz,CDCl3)δ＝7.83(s,1H),δ＝7.56(d,2H),δ＝7.47(m,2H),δ＝7.41(t,1H),δ＝4.1(t,2H),δ＝3.69(m,4H),δ＝2.72(t,2H)，δ＝2.66(m,4H)。13CNMR(400MHz,CDCl3)180.84,175.22,134.16,131.94,129.78,129.74,129.03,127.88,59.26,58.05,52.53,52.11,48.68,48.34,HRMS(ESI)calcd.for C16H19N3O2S:317.1[M+H]+,found 317.4[M+H]+.
制备实施例2
除了使用对苯基苯甲醛替代苯甲醛之外，采用与制备实施例1中相似的方法制备化合物2。
淡黄色固体，产率＝52.9％，1H NMR(400MHz,CDCl3)δ＝7.87(s,1H),δ＝7.69(d,2H),δ＝7.63(m,4H)，δ＝7.48(t,2H),δ＝7.42(t,1H),δ＝5.32(s,1H),δ＝4.1(t,2H),δ＝3.71(m,4H),δ＝2.73(t,2H)，δ＝2.68(m,4H)HRMS(ESI)calcd.for C22H23N3O2S 394.2[M+H]+,found 394.2[M+H]+.
制备实施例3
除了使用对甲基苯甲醛替代苯甲醛之外，采用与制备实施例1中相似的方法制备化合物3。
淡黄色固体，产率＝49.1％，1H NMR(400MHz,CDCl3)δ＝7.81(s,1H),δ＝7.43(d,2H),δ＝7.27(t,3H)，δ＝4.12(t,2H),δ＝3.70(m,4H),δ＝2.73(t,2H)，δ＝2.68(m,4H)，δ＝2.40(s,3H)HRMS(ESI)calcd.for C17H21N3O2S 331.4[M+H]+,found 331.8[M+H]+.
制备实施例4
除了使用对甲氧基苯甲醛替代苯甲醛之外，采用与制备实施例1中相似的方法制备化合物4。
淡黄色固体，产率＝47.6％，1H NMR(400MHz,CDCl3)δ＝7.78(s,1H),δ＝7.49(d,2H),δ＝6.98(d,2H)，δ＝4.10(t,2H),δ＝3.86(s,3H),δ＝3.69(m,4H)，δ＝2.71(t,2H)，δ＝2.69(m，4H)。HRMS(ESI)calcd.for C17H21N3O3S 347.4[M+H]+,found 347.7[M+H]+.
制备实施例5
除了使用对氯苯甲醛替代苯甲醛之外，采用与制备实施例1中相似的方法制备化合物5。
淡绿色固体，产率＝37.2％，1H NMR(400MHz,CDCl3)δ＝7.75(s,1H),δ＝7.43(dd,4H),δ＝4.11(t，2H)，δ＝3.69(m,4H),δ＝2.72(t,2H),δ＝2.67(m,4H)。HRMS(ESI)calcd.for C16H18ClN3O2S 351.8[M+H]+,found 352.1[M+H]+.
制备实施例6
在三颈瓶中加入绕丹宁2.0g(15mmol)，无水甲醇20mL，冰醋酸0.1mL，在N2保护下，加入羟乙基哌嗪2.9g(22.6mmol)和3-哒嗪甲醛22.6mmol，油浴回流，得灰黄色澄清反应液，及时TLC监测反应，4h后反应完成，冰浴析出固体，抽滤，乙醇滤洗，粗品用硅胶柱层析纯化(DCM:MeOH 10:2)，得到纯品化合物6。
黄色固体，产率37.1％，1H NMR(400MHz,CDCl3)δ＝8.89(d,1H),δ＝7.55(d,1H),δ＝7.44(d,1H),δ＝7.39(s,1H),δ＝4.20(br,1H),δ＝4.04(t,2H),δ＝3.61(m,4H),δ＝3.12(t,2H)，δ＝2.56(m,4H)13CNMR(400MHz,,CDCl3)170.28,169.24,154.79,134.96,132.94,130.27,128.31,129.03,58.94,57.93,54.72,52.48,48.77,48.39,HRMS(ESI)calcd.forC15H18N4O2S:318.1[M+H]+,found 318.8[M+H]+.
制备实施例7
除了使用6-氯-3-哒嗪甲醛替代3-哒嗪甲醛之外，采用与制备实施例6中相似的方法制备化合物7。
黄色固体，产率＝22.9％，1H NMR(400MHz,CDCl3)δ＝7.58(d,1H),δ＝7.35(d,1H),δ＝7.31(s,1H),δ＝4.62(br,1H),δ＝4.31(t,2H),δ＝3.65(m,4H),δ＝3.21(t,2H)，δ＝2.55(m,4H)13C NMR(400MHz,CDCl3):170.61,169.28,155.43,134.96,132.94,129.71,128.79,129.43,59.36,57.95,54.73,52.71,48.49,48.04；HRMS(ESI)calcd.forC15H17ClN4O2S:352.1[M+H]+,found 352.7[M+H]+.
制备实施例8
在三颈瓶中加入绕丹宁2.0g(15mmol)，无水甲醇20mL，冰醋酸0.1mL，在N2保护下，加入羟乙基哌啶2.9g(22.6mmol)，苯甲醛22.6mmol，油浴回流，得灰黄色澄清反应液，及时TLC监测反应，2h后反应完成，冰浴析出土黄色固体，抽滤，乙醇滤洗，粗品用硅胶柱层析纯化(DCM:MeOH 10:1)，得到纯品化合物8。
黄色固体，产率46％，1H NMR(400MHz,CDCl3)δ＝7.79(s,1H),δ＝7.48(d,2H),δ＝7.45(m,2H),δ＝7.36(t,1H),δ＝4.16(t,2H),δ＝3.79(m,4H),δ＝2.95(m,1H)，δ＝2.68(t,2H)，δ＝2.60(m,4H)HRMS(ESI)calcd.for C17H20N2O2S:316.1[M+H]+,found 316.7[M+H]+.
制备实施例9
除了使用对苯基苯甲醛替代苯甲醛之外，采用与制备实施例8中相似的方法制备化合物9。
淡黄色固体，产率＝52.9％，1H NMR(400MHz,CDCl3)δ＝7.90(s,1H),δ＝7.63(d,2H),δ＝7.57(m,4H)，δ＝7.38(t,2H),δ＝7.30(t,1H),δ＝5.54(s,1H),δ＝4.27(t,2H),δ＝3.63(m,4H),δ＝2.88(m,1H)，δ＝2.69(t,2H)，δ＝2.17(m,4H)HRMS(ESI)calcd.forC23H24N2O2S 392.2[M+H]+,found 392.5[M+H]+.
制备实施例10
除了使用对甲基苯甲醛替代苯甲醛之外，采用与制备实施例8中相似的方法制备化合物10。
淡黄色固体，产率＝49.1％，1H NMR(400MHz,CDCl3)δ＝7.54(s,1H),δ＝7.28(d,2H),δ＝7.18(t,3H)，δ＝4.02(t,2H),δ＝3.55(m,4H),δ＝3.07(m,1H)，δ＝2.69(t,2H)，δ＝2.44(m,4H)，δ＝2.15(s,3H)HRMS(ESI)calcd.for C18H22N2O2S 330.1[M+H]+,found 330.5[M+H]+.
制备实施例11
除了使用对甲氧基苯甲醛替代苯甲醛之外，采用与制备实施例8中相似的方法制备化合物11。
淡黄色固体，产率＝47.6％，1H NMR(400MHz,CDCl3)δ＝7.87(s,1H),δ＝7.56(d,2H),δ＝6.91(d,2H)，δ＝4.05(t,2H),δ＝3.66(s,3H),δ＝3.52(m,4H)，δ＝3.01(m,1H)，δ＝2.69(t,2H)，δ＝2.44(m，4H)。HRMS(ESI)calcd.for C18H22N2O3S 347.1[M+H]+,found 347.7[M+H]+.
制备实施例12
除了使用对氯苯甲醛替代苯甲醛之外，采用与制备实施例8中相似的方法制备化合物12。
淡绿色固体，产率＝37.2％，1H NMR(400MHz,CDCl3)δ＝7.55(s,1H),δ＝7.41(dd,4H),δ＝4.87(t，2H)，δ＝3.98(m,4H),δ＝2.65(m,1H)，δ＝2.27(t,2H),δ＝2.05(m,4H)HRMS(ESI)calcd.for C17H19ClN2O2S 351.1[M+H]+,found351.6[M+H]+.
实验实施例1化合物1～12对Mcl-1的活性抑制试验
本实验通过荧光竞争结合实验的方法检测本发明化合物对Mcl-1的亲和力，用本发明化合物竞争荧光多肽FITC-Mcl-1-BH3与Mcl-1蛋白的结合。当Mcl-1与荧光多肽结合会使荧光基团所产生的偏振光增加，而加入的本发明化合物如果能与Mcl-1结合，则会竞争荧光多肽与蛋白结合，从而使得偏振值降低，当偏振值下降到50％时所加的化合物的浓度即为该化合物对Mcl-1的IC50。
将重组Mcl-1溶解到20mM Tris缓冲液(pH7.5，含50mM NaCl，3mM DTT和2％DMSO)中，使其终浓度为250nM，再加入终浓度250nM的FITC-Mcl-1-BH3作为探针，混合均匀后，在测荧光用的Nunc 96孔板中用1mM MPI-L-008的DMSO溶液滴定(浓度从零开始递增)。在450nm的激发光下，用酶标仪记录520nm左右处的发射荧光波峰值。根据荧光强度变化计算出各化合物在不同浓度的抑制率，再根据抑制率与Log[抑制剂]的关系，计算得IC50值，结果如表1所示：
表1化合物1～12对Mcl-1的活性抑制的IC50
| 化合物 | IC<sub>50</sub> | 化合物 | IC<sub>50</sub> |
| 1 | 294.8nM | 7 | 245.8nM |
| 2 | 376.8nM | 8 | 589.4nM |
| 3 | 400.9nM | 9 | 5.68μM |
| 4 | 160.7nM | 10 | 4.77μM |
| 5 | 89.7nM | 11 | 52.14μM |
| 6 | 1.47μM | 12 | 368.9nM |
实验实施例2化合物1～12对pAd-PUMA感染DLD-1细胞的凋亡活性实验
荧光竞争结合实验表明，本发明化合物在体外对Mcl-1有较高的亲和力。本实验进一步验证本发明化合物对pAd-PUMA感染的DLD-1细胞的凋亡活性，使用Caspase-Glo 3/7方法检测。DLD-1细胞在CO2孵箱中以37℃、5％CO2的条件培养，使细胞密度维持在20％左右，培养24h后用pAd-PUMA感染。病毒的MOI为10，用量为0.01μl。感染24h后，将MPI-L-008配制成10mM的DMSO溶液，按预设定浓度添加本发明化合物。继续培养24h后，加入25μl的Caspase-Glo 3/7试剂，300～500rpm下旋转30s以混匀培养板内试剂。同条件下继续培养2h，使用化学发光法进行检测。通过本发明化合物1～12对pAd-PUMA感染的DLD-1细胞的凋亡抑制作用实验，获得IC50值，结果如表2所示。
表2化合物1～12对pAd-PUMA感染DLD-1细胞的凋亡抑制活性IC50
| 化合物 | IC<sub>50</sub> | 化合物 | IC<sub>50</sub> |
| 1 | 57.42μM | 7 | 37.89μM |
| 2 | 38.93μM | 8 | 158.6μM |
| 3 | 25.98μM | 9 | 11.7mM |
| 4 | 43.89μM | 10 | 7.14mM |
| 5 | 12.87μM | 11 | 2.97mM |
| 6 | 1.89mM | 12 | 387.4μM |
以上的PUMA过表达细胞实验及酶水平亲和力活性研究说明，本发明化合物具有强大的靶向PUMA蛋白的抗细胞凋亡作用，揭示可以将其应用于对PUMA蛋白相关的细胞过度凋亡，如高能量射线辐射引起的骨髓损伤，还可能应用于凋亡相关的疾病，如心肌缺血、缺血再灌注损伤、心力衰竭、阿兹海默症等神经退行性疾病、艾滋病等病毒感染。
Claims (5)
1.式Ⅱ化合物或其药学上可接受的盐在制备PUMA抑制剂的药物中的用途：
其中：
A为C5～C6芳基、或者含有1～2个选自N、O和S中的杂原子的5～6元杂芳基；
E为
R1为H、C1～C6烷基、C1～C6烷氧基、卤素、或者1～3个R3取代的C5～C6芳基；R3为H；
R2为-OH或者-SH；
n为1～5的整数；
且所述式Ⅱ化合物不包括下述化合物：
2.根据权利要求1所述的用途，其特征在于，所述式II化合物选自下述化合物1～5、7：
3.根据权利要求1所述的用途，其特征在于，所述式II化合物选自下述化合物：
4.根据权利要求1所述的用途，其特征在于，所述的式Ⅱ化合物或其药学上可接受的盐作为PUMA抑制剂在制备辐射防护、抗细胞凋亡的药物中的用途。
5.根据权利要求1所述的用途，其特征在于，所述的式Ⅱ化合物或其药学上可接受的盐作为PUMA抑制剂在制备治疗辐射引起骨髓型损伤、心肌缺血、缺血再灌注损伤、心力衰竭、阿兹海默症、艾滋病的药物中的用途。
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610242882.1A CN107304192B (zh) | 2016-04-19 | 2016-04-19 | 一类puma抑制剂及其制备方法和用途 |
| PCT/CN2016/099536 WO2017181585A1 (zh) | 2016-04-19 | 2016-09-21 | 一类puma抑制剂及其制备方法和用途 |
| US16/087,413 US20190062322A1 (en) | 2016-04-19 | 2016-09-21 | Puma inhibitor, method for preparation thereof, and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610242882.1A CN107304192B (zh) | 2016-04-19 | 2016-04-19 | 一类puma抑制剂及其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107304192A CN107304192A (zh) | 2017-10-31 |
| CN107304192B true CN107304192B (zh) | 2020-06-30 |
Family
ID=60115710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610242882.1A Expired - Fee Related CN107304192B (zh) | 2016-04-19 | 2016-04-19 | 一类puma抑制剂及其制备方法和用途 |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US20190062322A1 (zh) |
| CN (1) | CN107304192B (zh) |
| WO (1) | WO2017181585A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107638426B (zh) * | 2016-11-28 | 2020-08-11 | 中国人民解放军第四军医大学 | 噻唑类化合物在制备治疗肿瘤的药物中的用途 |
| WO2020163187A1 (en) * | 2019-02-05 | 2020-08-13 | Jian Yu | Method of preventing or treating treatment-induced gastrointestinal injury |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010075372A1 (en) * | 2008-12-22 | 2010-07-01 | The Trustees Of Columbia University In The City Of New York | Inhibitors of mre11, rad50 and/or nbs1 |
-
2016
- 2016-04-19 CN CN201610242882.1A patent/CN107304192B/zh not_active Expired - Fee Related
- 2016-09-21 WO PCT/CN2016/099536 patent/WO2017181585A1/zh active Application Filing
- 2016-09-21 US US16/087,413 patent/US20190062322A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010075372A1 (en) * | 2008-12-22 | 2010-07-01 | The Trustees Of Columbia University In The City Of New York | Inhibitors of mre11, rad50 and/or nbs1 |
Non-Patent Citations (3)
| Title |
|---|
| CLZ-8, a potent small-molecular compound, protects radiation-induced damages both in vitro and in vivo;Tian Feng et al.,;《Environmental Toxicology and Pharmacology》;20180512;第61卷;第44-51页 * |
| 化合物;STN;《STN》;20100527 * |
| 新型芳香砜类含硫衍生物的合成及其辐射防护性能研究;周楠;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20180315(第03期);E079-37 * |
Also Published As
| Publication number | Publication date |
|---|---|
| US20190062322A1 (en) | 2019-02-28 |
| WO2017181585A1 (zh) | 2017-10-26 |
| CN107304192A (zh) | 2017-10-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3433249B1 (en) | Blocking toll-like receptor 9 signaling with small molecule antagonist | |
| CN103930415B (zh) | 泛素特异性蛋白酶7的选择性和可逆性抑制剂 | |
| CN110114075B (zh) | 含有二硫化物的细胞穿透肽及其制备和使用方法 | |
| ES2934810T3 (es) | Moléculas químicas que inhiben el mecanismo de empalme para tratar enfermedades causadas por anomalías de empalme | |
| PT2673266T (pt) | Sais de fenotiazina diamínio e sua utilização | |
| KR20170070140A (ko) | 암을 치료하기 위한 방법 | |
| Chen et al. | A potent multi-functional neuroprotective derivative of tetramethylpyrazine | |
| AU2017258304B2 (en) | 1,5-disubstituted 1,2,3-triazoles are inhibitors of Rac/Cdc42 GTPases | |
| KR20200069380A (ko) | 글루타르이미드 유도체, 이의 용도, 이를 기반으로 한 약학 조성물 및 글루타르이미드 유도체를 생산하는 방법 | |
| ES2815539T3 (es) | Nuevos derivados de piperazina y piperidina, síntesis y uso de los mismos en la inhibición de la oligomerización de VDAC, la apoptosis y la disfunción mitocondrial | |
| BR112020021569A2 (pt) | Inibidor da interação proteína-proteína mll1-wdr5 de fenil triazol | |
| CN107304192B (zh) | 一类puma抑制剂及其制备方法和用途 | |
| CN106536524B (zh) | 用于在增殖性疾病的治疗中使用的[1,2,4]三唑并[4,3-b]哒嗪 | |
| WO2019164996A1 (en) | 2-aminoaryl-5-aryloxazole analogs for the treatment of neurodegenerative diseases | |
| KR20210034058A (ko) | Lsd1억제제의 염 및 이의 결정형 | |
| EP3250550A1 (en) | Compositions and methods for viral sensitization | |
| WO2019222497A1 (en) | 2,5-aryl-thiazole analogs for the treatment of neurodegenerative diseases | |
| CA3190144A1 (en) | Naphthalene monoimide compounds and methods thereof | |
| CN113336697A (zh) | 一种cdk9抑制化合物及其应用 | |
| US10787423B2 (en) | Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction | |
| CA3056810A1 (en) | Therapeutic compounds and methods | |
| Anumala et al. | Fluorescent rhodanine-3-acetic acids visualize neurofibrillary tangles in Alzheimer’s disease brains | |
| ES2907624T3 (es) | Inhibidores de oxadiazol de HIPK2 para el tratamiento de la fibrosis renal | |
| US11124490B2 (en) | Autotaxin inhibitors | |
| WO2019141246A1 (en) | Zinc-binder based ebna1-specific compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200630 Termination date: 20210419 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |