CN100358515C - 神经退行性及心血管疾病之治疗药物 - Google Patents
神经退行性及心血管疾病之治疗药物 Download PDFInfo
- Publication number
- CN100358515C CN100358515C CNB02823183XA CN02823183A CN100358515C CN 100358515 C CN100358515 C CN 100358515C CN B02823183X A CNB02823183X A CN B02823183XA CN 02823183 A CN02823183 A CN 02823183A CN 100358515 C CN100358515 C CN 100358515C
- Authority
- CN
- China
- Prior art keywords
- purposes
- carbon number
- disease
- aryl
- cape
- 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
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 14
- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 5
- 230000000626 neurodegenerative effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- WWVKQTNONPWVEL-UHFFFAOYSA-N caffeic acid phenethyl ester Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCC1=CC=CC=C1 WWVKQTNONPWVEL-UHFFFAOYSA-N 0.000 claims description 22
- SWUARLUWKZWEBQ-UHFFFAOYSA-N phenylethyl ester of caffeic acid Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-UHFFFAOYSA-N 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 208000006011 Stroke Diseases 0.000 claims description 7
- 125000001118 alkylidene group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- -1 phenyl (3,4-dihydroxyphenyl) Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 238000012217 deletion Methods 0.000 claims description 2
- 230000037430 deletion Effects 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 208000031225 myocardial ischemia Diseases 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 20
- SWUARLUWKZWEBQ-VQHVLOKHSA-N phenethyl caffeate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-VQHVLOKHSA-N 0.000 description 20
- 241000699670 Mus sp. Species 0.000 description 16
- 210000002569 neuron Anatomy 0.000 description 14
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- 239000011593 sulfur Substances 0.000 description 9
- CFFZDZCDUFSOFZ-UHFFFAOYSA-N 3,4-Dihydroxy-phenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C(O)=C1 CFFZDZCDUFSOFZ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 101710180319 Protease 1 Proteins 0.000 description 6
- 101710137710 Thioesterase 1/protease 1/lysophospholipase L1 Proteins 0.000 description 6
- 229960003638 dopamine Drugs 0.000 description 6
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 108091000117 Tyrosine 3-Monooxygenase Proteins 0.000 description 5
- 102000048218 Tyrosine 3-monooxygenases Human genes 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 229960003067 cystine Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- QRMZSPFSDQBLIX-UHFFFAOYSA-N homovanillic acid Chemical compound COC1=CC(CC(O)=O)=CC=C1O QRMZSPFSDQBLIX-UHFFFAOYSA-N 0.000 description 5
- 208000028867 ischemia Diseases 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000004224 protection Effects 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 208000031229 Cardiomyopathies Diseases 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 208000009525 Myocarditis Diseases 0.000 description 3
- 208000020339 Spinal injury Diseases 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 210000001577 neostriatum Anatomy 0.000 description 3
- 230000000324 neuroprotective effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 125000004853 tetrahydropyridinyl group Chemical class N1(CCCC=C1)* 0.000 description 3
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 2
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000006727 cell loss Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000002064 heart cell Anatomy 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000002101 lytic effect Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 210000003200 peritoneal cavity Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 2
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 240000005020 Acaciella glauca Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 240000003291 Armoracia rusticana Species 0.000 description 1
- 235000011330 Armoracia rusticana Nutrition 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 102100035904 Caspase-1 Human genes 0.000 description 1
- 241001573498 Compacta Species 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- QWVMSYBGKWZIIE-RDFNRINOSA-N Flavochrome Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C1OC2(C)CCCC(C)(C)C2=C1)C=CC=C(/C)C=CC3C(=CCCC3(C)C)C QWVMSYBGKWZIIE-RDFNRINOSA-N 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- OWYWGLHRNBIFJP-UHFFFAOYSA-N Ipazine Chemical compound CCN(CC)C1=NC(Cl)=NC(NC(C)C)=N1 OWYWGLHRNBIFJP-UHFFFAOYSA-N 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 1
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 1
- 206010030312 On and off phenomenon Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- WBTSIYXTUSVTJU-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound NNC1=CC=C(C2=CC=C(NN)C=C2)C=C1.NNC1=CC=C(C=C1)C1=CC=C(NN)C=C1 WBTSIYXTUSVTJU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940074360 caffeic acid Drugs 0.000 description 1
- 235000004883 caffeic acid Nutrition 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000008148 cardioplegic solution Substances 0.000 description 1
- 230000005961 cardioprotection Effects 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- QWVMSYBGKWZIIE-FZKBJVJCSA-N flavochrome Chemical compound O1C2(C)CCCC(C)(C)C2=CC1C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1C(C)=CCCC1(C)C QWVMSYBGKWZIIE-FZKBJVJCSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 230000010247 heart contraction Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- NHDHVHZZCFYRSB-UHFFFAOYSA-N pyriproxyfen Chemical compound C=1C=CC=NC=1OC(C)COC(C=C1)=CC=C1OC1=CC=CC=C1 NHDHVHZZCFYRSB-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000003499 redwood Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound 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
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000010572 single replacement reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- XDFGPVSVSMWVQE-UHFFFAOYSA-M sodium;dodecanoic acid;hydrogen sulfate Chemical compound [Na+].OS([O-])(=O)=O.CCCCCCCCCCCC(O)=O XDFGPVSVSMWVQE-UHFFFAOYSA-M 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- 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
Abstract
一种以如下列化学式(I)所示的化合物在制备治疗神经退行性或心血管疾病的药物中的用途：其中，该化合物中的X、Y、A1、A2、R1和R2都在说明书中定义。
Description
发明背景
由一氧化氮所引发(Nitric Oxide(NO)-induced)以及与硫胱氨酸蛋白酶1有关(caspase 1-related)的神经元丧失(neuronal loss)会导致神经退行性疾病，如：新生儿与成人的中风(neonatal and adult stroke)、帕金森氏症(Parkinson’s disease)、亨丁顿氏舞蹈症(Huntington’sdisease)、阿滋海默氏症(Alzheimer’s disease)、肌萎缩侧索硬化症(amyothrophic lateral sclerosis)、中风(stroke)、脊柱损伤(spinal injury)、移植(transplantation)、多发性硬化症(multiple sclerosis)和听力丧失(hearing loss)。目前尚无任何神经保护药物(neuroprotective drug)能有效治疗这些疾病。有一些药物藉由增加剩余神经元的功能而治疗这些疾病。然而，没有一种药物能非常成功地减缓这些疾病的恶化，有些药物甚至会产生不好的副作用，例如，帕金森氏症病人会产生运动症状波动(motor fluctuations)和乱动症(dyskinesias)(参考Quinn，et al.，Neurology，1998，51，S25-29)。此外，由一氧化氮引发及与硫胱氨酸蛋白酶1有关的心脏细胞丧失(heart cell loss)会导致心脏血管疾病，包括：心脏衰竭(heart failure)、动脉硬化(arteriosclerosis)、心肌炎(myocarditis)和心肌病(cardiomyopathy)。
发明内容
本发明是有关于一种治疗神经退行性和心血管疾病，以及其他由一氧化氮引发或与硫胱氨酸蛋白酶1有关的细胞死亡所造成的疾病的方法。上述方法包括为一个需要治疗的个体投予一个或更多的如下式所代表的化合物(I)：
其中，R1和R2分别是碳数1～8的次烷基(alkylene)，碳数2～8的次烯烃基(alkenylene)，或将其删除；A1和A2分别是芳基(aryl)或异芳基(heteroaryl)，可以卤素(halogen)，-CN、-NO2、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4、-C(O)R3、-S(O)R3、-S(O)2R3、-NR4R5、-C(O)OR3、-C(O)NR4R5、-O(O)CR4、或-NR4(O)CR5任意地单一取代或多取代(例如：双取代或三取代)，而X和Y分别是氧(O)、硫(S)或NR6，其中R3是碳数1～4的烷基(C1-4alkyl)，R4、R5和R6则分别是氢(H)或碳数1～4的烷基。
“烷基”是单价的烃基(hydrocarbon radical)，该烃基为直链或分支链(例如：-CH2CH2CH3或-CH(CH3)2)。“次烷基”是双价的烃基，该烃基为直链或分支链(例如：-CH2CH2-或-CH2CH(CH3)-CH3)。“次烯烃基”是双价的烃基，该烃基为直链或分支链，并且包含一个或多个双键(例如：-CH2CH＝CH-CH2-或-CH2CH(CH3)CH＝CH-CH2-)。“芳基”是碳数6～12的单环(monocyclic)或多环(multicyclic)(稠合的或分离的)芳香系统(aromatic system)，其中每个环上有高达4个原子会被取代。芳基族的例子包括苯基(phenyl)和萘基(naphthyl)。“异芳基(heteroaryl)”是5-8元单环，8-12元双环，或11-14元三环的芳环系统。若该系统为单环系统，则包含1-3个异原子；若为双环系统，则包含1-6个异原子；若为三环系统，则包含1-9个异原子(这些异原子包括氧、氮或硫)。异芳基族的例子包括吡啶基(pyridyl)、呋喃基(furyl)、咪唑基(imidazolyl)、苯并咪唑基(benzimidazolyl)、嘧啶基(pyrimidinyl)、喹啉基(quinolinyl)、吲哚(indolyl)或噻唑(thiazolyl)。
接着讨论(I)式化合物。能够用以实行本发明方法的化合物当中，其中一子集的X与Y各自为氧。另一子集中，R1是碳数2～8的次烯烃基，而R2是碳数1～8的次烷基。另一子集中，A1和A2各自为芳基(例如：苯基)，并可以卤素，-CN、-OH、-SH，、OR3、-SR3、-R3、-R3-OR4、或-NR4R5任意地取代。再另一子集中，R1是碳数2～3的次烯烃基(例如：-CH＝CH-)，而R2是碳数1～3的次烷基(例如：-CH2-CH2-)。该等化合物的其中一例为咖啡酸苯乙酯(caffeic acid phenethyl ester)：
可用本发明方法治疗神经退行性及心血管疾病的起因是由一氧化氮引发或与硫胱氨酸蛋白酶1有关的细胞丧失(cell loss)，以及多巴胺(dopamine)或多巴胺能神经细胞(dopaminergic neurons)的数量减少。此类疾病与一些疾病有关联，例如：新生儿与成人的中风、帕金森氏症、亨丁顿氏舞蹈症、阿滋海默氏症、肌萎缩侧索硬化症、中风、脊柱损伤、移植、多发性硬化症、听力丧失、心脏衰竭、动脉硬化、心肌炎、心肌病和糖尿病。因此，在本发明的范围内，可利用一个或更多上述化合物作为治疗这些疾病的药物。
在为一个需要治疗神经退行性或心血管疾病的病人投予一个或更多上述化合物之前，需先将该化合物配制成药学组合物(pharmaceuticalcomposition)。因此，本发明也有关于一药学组合物，该药学组合物包含药学上可接受的载体以及一有效量的上述一个或更多用以治疗神经退行性或心血管疾病的化合物。另一方面，进一步讲，本发明是有关于一种制品，该制品包括：I)容器；II)药学组合物，该药学组合物包含了药学上可接受的载体以及一有效量的一个或更多上述化合物；III)标签，该标签配置于容器上，并且标示用以治疗神经退行性或心血管疾病的药学组合物的用法说明。该用法说明可以提供病人药学组合物的使用指示，例如：硬膜(epidural)注射、鞘内(intrathecal)注射、非口服给药(parenteral)，或局部用药。
同时，在本发明范畴之内，也包括使用一个或以上的上述化合物的药剂制品，用于治疗上述神经退行性及心血管疾病。
在适当情况下，上述化合物也包括其盐类及前驱药物(prodrug)。举例来说，该盐类可经由上述化合物中的正价取代基(例如：胺基(amino))与阴离子(anion)结合而成。适当的阴离子包括：氯化物(chloride)、溴化物(bromide)、碘化物(iodide)、硫酸盐(sulfate)、硝酸盐(nitrate)、磷酸盐(phosphate)、柠檬酸盐(citrate)、甲磺酸(methanesulfonate)、三氟乙酯(trifluoroacetate)、和乙酯(acetate)，但不只限于此。同样地，上述化合物中的负价取代基(例如：羧酸盐(carboxylate))可以和阳离子(cation)形成盐类。适当的阳离子包括：钠离子、钾离子、镁离子、钙离子和阳离子铵(ammonium cation)(例如：四甲基铵离子(tetramethylammonium ion))。前驱药物的例子包括：酯类(esters)和其他药学上可接受的衍生物。在为病人投予药物的过程中，该前驱药物能供给上述化合物。
本发明的详细实施例会在下列实施方式中提及。本发明的其他特色、目的和优点将列于实施方式与申请专利范围之中。
发明详述
本发明是有关于一种治疗神经退行性和心血管疾病，以及其他由一氧化氮引发或与硫胱氨酸蛋白酶1有关的细胞死亡所造成的疾病的方法。该方法是使用一个或以上的下式化合物：
其中，A1、A2、R1、R2、X和Y已于先前定义。
通过已知技术可合成这些化合物。例如：将分子式A1-R1-C(＝X)-OH的前驱物(precursor)与分子式A2-R2-YH(Y是O、S或NH)的前驱物反应可得到X是氧或硫的化合物。参考：Loudon，OrganicChemistry，3rd Ed.，1995，Benjamin/Cummings Publishing Company，Inc.，Redwood，City，CA.。由此得到的化合物与氨(ammonia)或胺(amine)反应后可任意地转变成亚胺(imine)(即X为NH或氮(烷基)(N(alkyl)))。参考：Verardo et al.，Synth Commun，1998，18，1501；andFarrar，Rec.Chem.Prog.1968，29，85-101.。
举例来说，将咖啡酸与过量的苯乙醇(phenethyl alcohol)以及酸催化剂(acid catalyst)(例如：甲苯磺酸(p-toluene sulfonic acid)在适当溶剂(例如：苯(benzene))中，经回流(reflux)反应一段长时间(例如：3或4天)后，可合成咖啡酸苯乙酯。利用蒸馏法除去过多的苯乙醇即可获得纯咖啡酸苯乙酯(熔点126-128℃，针晶)。见Grunberger etal.，Experientia，1988，44，23-232.。
一适当、有效量的(I)式化合物或其盐类需要先以药学上可接受的载体将其配制成药学组合物，才能将该化合物或其盐类投与需治疗神经退行性和心血管疾病、以及其他由一氧化氮引发或与硫胱氨酸蛋白酶1有关的细胞死亡(cell death)所造成疾病的病人。“有效量(an effectiveamount)”是指能给予被治疗个体治疗效果的化合物量，该有效量则是根据动物和临床研究而确立的。动物与人类之间剂量的相互关系(以每平方米体表面积的毫克数为根据)可参考Freireich et al.，CancerChemother Rep，1966，50，219的叙述。由病人的身高与体重可大致确定体表面积(body surface)(参考：Scientific Tables，Geigy Pharmaceuticals，Ardley，New York，1970，537.)。根据已知技术，有效剂量会随着给药途径、赋形剂用法(excipient usage)和选择性地并用其他疗法而改变。药学上可接受的载体包括胶态二氧化矽(colloidal silicon dioxide)、硬脂酸镁(magnesium stearate)、纤维素(cellulose)、硫酸月桂酸钠(sodium laurylsulfate)和D&C10号黄色素(D&C Yellow#10)等。
药学组合物可以通过非口服途径(parenteral route)给予，例如：腹膜腔内(intraperitoneally)给药和静脉内(intravenously)给药。非口服剂量形式的例子包括：将活性化合物溶于磷酸盐缓冲液生理食盐水(phosphate buffer saline，PBS)中，或利用其他药学上可接受的载体混合。已知技术中常用的溶解剂(solubilizing agents)(例如：环糊精(cyclodextrins)或其他溶解剂)也可以包含在药学组合物中。
利用已知技术中的体外和体内分析(in vitro and in vivo assays)，可评估(I)式化合物治疗神经退行性或心血管疾病的效能。见以下提供的三个实例。
即使没有更进一步的详细说明，一般相信熟悉此技术的人士能以此处的说明为基础，将本发明使用至极致。所有在此引用的出版品全部并入参考文献。因此，下列特定的范例描述一种(I)式化合物——咖啡酸苯乙酯——的生物检定(biological testing)，而该范例只以图式说明，并且不以任何方式局限于揭露的其余部分。
实施例1
根据Du，et al.，Proc Natl Acad Sci，2001，98，14669-14674.一文中所描述的方法，欲评估咖啡酸苯乙酯对于治疗神经退行性疾病和其他由一氧化氮引发细胞死亡所造成疾病的效能，可在培养的神经元上测试咖啡酸苯乙酯阻碍由一氧化氮引发的细胞死亡的能力。
从小脑颗粒状神经元(cerebellar granule neurons，CGN)培养物中发现，由一氧化氮所引发的显著的神经元细胞死亡现象会被咖啡酸苯乙酯以浓度依赖(concentration-dependent)方式(半数抑制浓度(IC50)～1微摩尔(μM))阻断。当使用6-羟基多巴胺(6-hydroxydopamine)诱导神经毒性(neurotoxicity)时，也会观察到咖啡酸苯乙酯的神经保护作用。
实施例2
利用小鼠来评估咖啡酸苯乙酯治疗神经元退化性疾病的效能。使用三组8周大的C57B1/6雄性小鼠(Taconic Farms Inc.，Germantown，NY)，每组5-7只。一组小鼠给予咖啡酸苯乙酯(将咖啡酸苯乙酯溶于10％乙醇，再以胃管经口灌食5或20毫克/公斤/天(mg/kg/day)，或者经由腹膜腔内给药40毫克/公斤/天)9天。第二组小鼠为对照组，只给予10％乙醇，而不给予咖啡酸苯乙酯。然后，这两组小鼠在一天之内每隔两小时一次，经由腹膜腔内给予4次以生理食盐水溶解的1-甲基-4-苯基-1，2，3，6-四氢吡啶盐酸盐(1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine(“MPTP”)-HCl)(20毫克/公斤，不含碱(base))(见Liberatore，et al.，Nat Med，1999，5，1403-1409的描述)。
在最后一次给予1-甲基-4-苯基-1，2，3，6-四氢吡啶7天之后，以哈药仙吸入剂(halothane inhalation)麻醉小鼠，然后取出小鼠的脑，以含有4％三聚甲醛(paraformaldehyde)的0.1摩尔磷酸盐缓冲液(pH7.4)灌注固定。经过固定以及随后以30％蔗糖/磷酸盐缓冲液低温保护(cryoprotection)之后，将脑置于液态氮中冷冻，并且将其中脑连续切片成40微米。该组织切片以含有0.1％非离子性界面活性剂Triton X-100的0.1摩尔磷酸盐缓冲液生理食盐水冲洗三次，每次5分钟。然后将该切片置于多株兔抗酪氨酸羟化酶抗体(rabbit polyclonal anti-tyrosinehydroxylase(anti-TH)antibody)(1:2，500，CALBIOCHEM，La Jolla，CA)、生物素化结合的多株羊抗兔抗体(goat biotinylated-conjugatedpolyclonal anti-rabbit antibody)(1:250；Vector Laboratories，Burlingame，CA)与马萝卜过氧化物酶结合的卵白素/生物素复合体(horseradish-peroxidase conjugated avidin/biotin complex)(VECTASTAIN ABC Reagent，Vector Laboratories)中，接着将其曝于二氨基联苯胺(diaminobenzidine)以进行酪酸胺羟化酶免疫组织化学(TH-immunohistochemistry)分析和酪氨酸羟化酶阳性神经元(TH-positive neurons)的体视学定量(stereological quantification)。用以计算酪氨酸羟化酶阳性神经元数量的体视学方法可参考Triarhou，etal.，J Neurocytol，1988，17，221-232.的叙述。
第三组小鼠为另一组对照组，只给予生理食盐水，而不给予咖啡酸苯乙酯和1-甲基-4-苯基-1，2，3，6-四氢吡啶。
第二组小鼠的黑质致密区(substantia nigra pars compacta，SNpc)中的酪氨酸羟化酶阳性神经元数量大约为第三组小鼠的49％。第一组小鼠的酪氨酸羟化酶阳性神经元数量(达100％)比第二组小鼠高。只给予咖啡酸苯乙酯9天的小鼠的酪氨酸羟化酶阳性神经元数量无显著改变。
通过高效液相层析仪(HPLC)结合电化学侦测器(electrochemicaldetector)，可确定纹状体(striatal)内的多巴胺及其代谢物二羟苯乙酸(dihydroxyphenylacetic acid，DOPAC)与高香草酸(homovanillic acid，HVA)的含量(参考Du，et al.，Proc Natl Acad Sci，2001，98，14669-14674)。比较第二组小鼠与第三组小鼠的数据，其结果显示，在给予1-甲基-4-苯基-1，2，3，6四氢吡啶而未以予咖啡酸苯乙酯48小时以后，第二组小鼠纹状体的多巴胺、二羟苯乙酸和高香草酸含量分别减少了62％、46％和35％。在第一组小鼠当中，咖啡酸苯乙酯(腹膜腔内给药40毫克/公斤)明显地阻断在纹状体中由1-甲基-4-苯基-1，2，3，6四氢吡啶所引发的多巴胺及其代谢物的减少。更具体地说，给予咖啡酸苯乙酯的结果是使得纹状体中由1-甲基-4-苯基-1，2，3，6四氢吡啶所引发的多巴胺、二羟苯乙酸和高香草酸的减少分别只有3％、-2％和16％。
这些结果意外地显示咖啡酸苯乙酯能有效保护神经元不至于因1-甲基-4-苯基-1，2，3，6四氢吡啶而造成死亡。
实施例3
根据Choong，et al.，J Cardiovasc Surg(Torino)，1993 Oct.，34(5)：423-433.文章中所描述的方法，采用兔离体工作心脏模型(isolatedworking rabbit heart model)说明局部缺血(ischaemia)时咖啡酸苯乙酯的心脏保护作用(cardioprotective effects)(功能、新陈代谢和超微结构(ultrastructure))。更具体地来说，在局部缺血期间，使心脏(每组7个样本)停搏并回输(45分钟)冰的(4℃)心脏冷冻液(cardioplegicsolution)。咖啡酸苯乙酯(腹膜腔内给药30毫克/公斤)在一个小时之内显著地(p＜0.05)提升局部缺血后心输出量(cardiac output)的恢复百分比，从71.48+/-9.66％增加至90.83+/-3.2％。在40分钟的局部缺血停搏(ischaemic arrest)期间(对照组与处理组分别以55.14+/-8.65与19.33+/-7.4免疫单位/升(IU/L)灌注，p＞0.05)，乳酸去氢酶(lactatedehydrogenase)的释出量减少。见Ersahin et al.，J Cardiovasc Pharmacol，1999 Oct；34(4)：604-611.。其结果显示咖啡酸苯乙酯保护心肌(myocardium)免于局部缺血的伤害，因此能用以治疗心跳停止(cardiacarrest)。
虽然本发明比较有效的实施案例已如上文所述，但是本发明并非仅限于这些案例。任何熟习此技术的人士，在不脱离本发明的精神和范围内，可以进行各种变更和润饰，因此本发明的保护范围应按后附权利要求书所界定的内容为准。
Claims (14)
1.下式化合物(I)在制备治疗神经退行性或心血管疾病的药物中的用途：
其中
R1和R2分别是碳数1～8的次烷基，碳数2～8的次烯烃基，或将其删除；
A1和A2分别是芳基或异芳基，并且可以卤素，-CN、-NO2、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4、-C(O)R3、-S(O)R3、-S(O)2R3、-NR4R5、-C(O)OR3、-C(O)NR4R5、-O(O)CR4、或-NR4(O)CR5任意地取代；以及
X和Y分别是氧，其中R3是碳数1～4的烷基，以及R4和R5分别是氢或碳数1～4的烷基。
2.如权利要求1所述的用途，其中R1是碳数2～8的次烯烃基，以及R2是碳数1～8的次烷基。
3.如权利要求2所述的用途，其中R1是碳数2～3的次烯烃基，以及R2是碳数1～3的次烷基。
4.如权利要求3所述的用途，其中A1是和A2各自为芳基，并且可以卤素，-CN、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4、或-NR4R5任意地取代。
5.如权利要求3所述的用途，其中R1是-CH＝CH-，以及R2是-CH2-CH2-。
6.如权利要求5所述的用途，其中A1是和A2各自为芳基，并且可以卤素，-CN、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4或-NR4R5任意地取代。
7.如权利要求6所述的用途，其中A1是和A2各自为苯基，并可以任意地以-OH或-SH取代。
8.如权利要求1所述的用途，其中A1是和A2各自为芳基，并且可以卤素，-CN、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4或-NR4R5任意地取代。
9.如权利要求8所述的用途，其中A1是和A2各自为苯基，并可以任意地以-OH或-SH取代。
10.如权利要求4所述的用途，其中A1是3，4-二羟基苯基(3，4-dihydroxyphenyl)，A2是苯基。
11.如权利要求10所述的用途，其中R1是-CH＝CH-，R2是-CH2-CH2-。
12.如权利要求1-11任一项所述的用途，其中神经退行性疾病选自帕金森病、阿滋海默病、肌萎缩侧索硬化症、中风、亨丁顿氏舞蹈症。
13.咖啡酸苯乙酯在制备治疗或预防帕金森病的药物中的用途。
14.咖啡酸苯乙酯在制备治疗或预防心肌局部缺血损伤的药物中的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33921501P | 2001-12-10 | 2001-12-10 | |
| US60/339,215 | 2001-12-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1589137A CN1589137A (zh) | 2005-03-02 |
| CN100358515C true CN100358515C (zh) | 2008-01-02 |
Family
ID=23328006
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB02823183XA Expired - Fee Related CN100358515C (zh) | 2001-12-10 | 2002-12-10 | 神经退行性及心血管疾病之治疗药物 |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US20030139458A1 (zh) |
| EP (1) | EP1461025B1 (zh) |
| JP (1) | JP4511183B2 (zh) |
| CN (1) | CN100358515C (zh) |
| AT (1) | ATE517617T1 (zh) |
| AU (1) | AU2002351341A1 (zh) |
| CA (1) | CA2466928A1 (zh) |
| TW (1) | TWI335220B (zh) |
| WO (1) | WO2003053425A1 (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070208087A1 (en) | 2001-11-02 | 2007-09-06 | Sanders Virginia J | Compounds, compositions and methods for the treatment of inflammatory diseases |
| JP4568603B2 (ja) | 2002-05-31 | 2010-10-27 | プロテオテック・インコーポレイテッド | アミロイド疾患およびシヌクレイノパチー（例えばアルツハイマー病、タイプ２型糖尿病、およびパーキンソン病）を処置するための化合物、組成物、および方法 |
| US20040167217A1 (en) * | 2003-02-26 | 2004-08-26 | Giovanni Scapagnini | Neuroprotective effects of polyphenolic compounds |
| WO2007084383A2 (en) * | 2006-01-13 | 2007-07-26 | University Of South Carolina | Method and composition for the treatment of parkinson's disease |
| EP2125712B1 (en) * | 2006-12-04 | 2014-07-23 | Novotyr Therapeutics Ltd. | Novel protein kinase modulators and therapeutic uses thereof |
| CA2758016A1 (en) | 2008-06-05 | 2009-12-10 | Novotyr Therapeutics Ltd. | Novel modulators of protein kinase signaling |
| CN101941907B (zh) * | 2010-05-28 | 2015-04-01 | 毛腾淑 | 4-叔丁基苄基-3,4-二羟基肉桂酸酯及其用途和制备方法 |
| WO2012054446A2 (en) * | 2010-10-18 | 2012-04-26 | Chemigen | Combination therapy |
| WO2012068038A2 (en) * | 2010-11-15 | 2012-05-24 | Chemigen | Caffeic acid derivatives and their use in improving neuronal cell viability |
| EP3021944B1 (en) | 2013-07-14 | 2018-12-19 | Yissum Research Development Company of the Hebrew University of Jerusalem, Ltd. | Igf-1r signaling pathway inhibitors useful in the treatment of neurodegenerative diseases |
| EP3750530A1 (en) | 2015-02-05 | 2020-12-16 | TyrNovo Ltd. | Combinations of irs/stat3 dual modulators and anti-cancer agents for treating cancer |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4246198A (en) * | 1976-05-19 | 1981-01-20 | Ciba-Geigy Corporation | Hindered phenolic amides |
| EP0404039A1 (de) * | 1989-06-23 | 1990-12-27 | Roche Diagnostics GmbH | Arzneimittel, enthaltend Di-tert.-Butylhydroxyphenyl-Derivate sowie neue Derivate |
| EP0527458A1 (de) * | 1991-08-13 | 1993-02-17 | Roche Diagnostics GmbH | Neue 3,5-Di-tert.butyl-4-hydroxyphenyl-Derivate, Verfahren zu ihrer Herstellung und Arzneimittel |
| WO1997023202A1 (en) * | 1995-12-22 | 1997-07-03 | STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITYA ND THE UNIVERSITY OF OREGON, EUGENE OREGON | Subtype-selective nmda receptor ligands and the use thereof |
| CN1233171A (zh) * | 1996-09-05 | 1999-10-27 | 研究发展基金会 | 用咖啡酸苯乙酯(CAPE)、CAPE的衍生物、辣椒素(8－甲基－N－香兰基－6－壬烯酰胺)和树脂毒素来抑制核转录因子NF－κB |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4959503A (en) * | 1986-04-11 | 1990-09-25 | Warner-Lambert Company | Diarylalkanoids having activity as lipoxygenase inhibitors |
| JPS62294634A (ja) * | 1986-04-11 | 1987-12-22 | ワ−ナ−−ランバ−ト・コンパニ− | ジアリ−ルアルカノイドおよびその製法 |
| JPH0678286B2 (ja) * | 1988-03-18 | 1994-10-05 | 三井東圧化学株式会社 | ジヒドロカフェイン酸誘導体およびそれを有効成分として含有する治療剤 |
| TW466115B (en) * | 1996-12-10 | 2001-12-01 | American Home Prod | Pharmaceutical composition of antioxidant from equilenin |
| NZ337364A (en) * | 1997-02-15 | 2001-06-29 | Millennium Pharm Inc | Treatment of infarcts, ischemia and reperfusion through inhibition of NFkappaB |
| GB9801398D0 (en) * | 1998-01-22 | 1998-03-18 | Anggard Erik E | Chemical compounds |
| CA2350992C (en) * | 1999-09-17 | 2009-06-23 | Suntory Limited | Preventive or therapeutic agents for myocarditis, dilated cardiomyopathy and heart failure comprising nf-kb inhibitors as active ingredients |
-
2002
- 2002-12-10 CN CNB02823183XA patent/CN100358515C/zh not_active Expired - Fee Related
- 2002-12-10 US US10/316,145 patent/US20030139458A1/en not_active Abandoned
- 2002-12-10 AT AT02786994T patent/ATE517617T1/de not_active IP Right Cessation
- 2002-12-10 JP JP2003554183A patent/JP4511183B2/ja not_active Expired - Fee Related
- 2002-12-10 EP EP02786994A patent/EP1461025B1/en not_active Expired - Lifetime
- 2002-12-10 TW TW091135703A patent/TWI335220B/zh not_active IP Right Cessation
- 2002-12-10 WO PCT/US2002/039458 patent/WO2003053425A1/en active Application Filing
- 2002-12-10 CA CA002466928A patent/CA2466928A1/en not_active Abandoned
- 2002-12-10 AU AU2002351341A patent/AU2002351341A1/en not_active Abandoned
-
2010
- 2010-02-18 US US12/708,401 patent/US8575215B2/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4246198A (en) * | 1976-05-19 | 1981-01-20 | Ciba-Geigy Corporation | Hindered phenolic amides |
| EP0404039A1 (de) * | 1989-06-23 | 1990-12-27 | Roche Diagnostics GmbH | Arzneimittel, enthaltend Di-tert.-Butylhydroxyphenyl-Derivate sowie neue Derivate |
| EP0527458A1 (de) * | 1991-08-13 | 1993-02-17 | Roche Diagnostics GmbH | Neue 3,5-Di-tert.butyl-4-hydroxyphenyl-Derivate, Verfahren zu ihrer Herstellung und Arzneimittel |
| WO1997023202A1 (en) * | 1995-12-22 | 1997-07-03 | STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITYA ND THE UNIVERSITY OF OREGON, EUGENE OREGON | Subtype-selective nmda receptor ligands and the use thereof |
| CN1233171A (zh) * | 1996-09-05 | 1999-10-27 | 研究发展基金会 | 用咖啡酸苯乙酯(CAPE)、CAPE的衍生物、辣椒素(8－甲基－N－香兰基－6－壬烯酰胺)和树脂毒素来抑制核转录因子NF－κB |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2466928A1 (en) | 2003-07-03 |
| ATE517617T1 (de) | 2011-08-15 |
| US20100160433A1 (en) | 2010-06-24 |
| WO2003053425A1 (en) | 2003-07-03 |
| TW200301100A (en) | 2003-07-01 |
| EP1461025B1 (en) | 2011-07-27 |
| JP4511183B2 (ja) | 2010-07-28 |
| TWI335220B (en) | 2011-01-01 |
| CN1589137A (zh) | 2005-03-02 |
| AU2002351341A1 (en) | 2003-07-09 |
| EP1461025A4 (en) | 2009-07-29 |
| JP2005513100A (ja) | 2005-05-12 |
| EP1461025A1 (en) | 2004-09-29 |
| US8575215B2 (en) | 2013-11-05 |
| US20030139458A1 (en) | 2003-07-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1305056C (en) | Method and compositions for reducing neurotoxic injury | |
| US8575215B2 (en) | Treatment of neurodegenerative and cardiovascular disorders | |
| US20080300253A1 (en) | Treatment of inflammatory disorders with praziquantel | |
| JPH01254623A (ja) | スフインゴ糖脂質代謝の阻害剤を有効成分として含有する癌治療薬 | |
| JPS62158210A (ja) | Ｌ−ド−パの直腸吸収形態 | |
| CN107074839A (zh) | 用于治疗代谢和体重相关的病症的组合物和方法 | |
| US5089517A (en) | Neuroprotection by indolactam v and derivatives thereof | |
| KR20090102782A (ko) | 의약 조성물 | |
| CA1228818A (en) | Treatment of seizure disorders and pharmaceutical compositions useful therein | |
| US20200215068A1 (en) | Treatment of type i and type ii diabetes | |
| JPS60500288A (ja) | ３−（３−置換アミノ−２−ヒドロキシプロポキシ）−４−置換−１・２・５−チアゾ−ル誘導体のエステル | |
| US5556862A (en) | Pharmaceutical compositions containing isoquinoline derivatives | |
| NZ518554A (en) | 6-methoxy-2-naphthylacetic acid prodrugs | |
| US4391809A (en) | Methods for treating psoriasis | |
| JP2002520300A (ja) | Ｇａｂａ類縁体及び抗ウイルス剤を含んでなる帯状ヘルペスを治療するための医薬組成物 | |
| EP0694303A1 (fr) | Utilisation de l'eliprodil et de ses énantiomères pour la préparation de médicaments utiles dans la prévention des neuropathies induites par des agents anticancéreux, e.g. le paclitaxel | |
| US11458144B1 (en) | Methods for using 5-HMF analogs with increased solubility to inhibit or reverse RBC sickling | |
| PT95698B (pt) | Processo para a preparacao de composicoes farmaceuticas contendo aril-alquilamidas utilizadas no tratamento de doencas neurodegenarativas | |
| CN107556209A (zh) | 一种新型褪黑激素类化合物及其制备方法和在医学上的应用 | |
| JPS58174322A (ja) | 線溶促進剤 | |
| NZ626495B2 (en) | Treatment of type i and type ii diabetes | |
| WO2007087215A2 (en) | N-acetyl-cysteine and its derivatives as an antitussive | |
| JPH02286617A (ja) | 血管新生阻害剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: YANGZIJIANG PHARMACEUTICAL GROUP CO., LTD. Effective date: 20050708 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20050708 Address after: City of Camo, Indiana, USA Applicant after: Du Yansheng Co-applicant after: YANGTZE RIVER PHARMACEUTICAL GROUP Co.,Ltd. Address before: City of Camo, Indiana, USA Applicant before: Du Yansheng |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20070727 Address after: City of Camo, Indiana, USA Applicant after: Du Yansheng Co-applicant after: Du Ruyu Address before: City of Camo, Indiana, USA Applicant before: Du Yansheng Co-applicant before: YANGTZE RIVER PHARMACEUTICAL GROUP Co.,Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: NANJING AIPIKA BIOTECHNOLOGY CO., LTD. Free format text: FORMER OWNER: DU YANSHENG Effective date: 20121206 Free format text: FORMER OWNER: DU RUYU Effective date: 20121206 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; TO: 210009 NANJING, JIANGSU PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20121206 Address after: 01, building 5, Metro 69, 210009 Olympic Sports Avenue, Jianye District, Jiangsu, Nanjing Patentee after: Nanjing Epica Biotechnology Co.,Ltd. Address before: Compact city Indiana Patentee before: Du Yansheng Patentee before: Du Ruyu |
|
| ASS | Succession or assignment of patent right |
Owner name: MAO TENGSHU Free format text: FORMER OWNER: NANJING AIPIKA BIOTECHNOLOGY CO., LTD. Effective date: 20131209 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 210009 NANJING, JIANGSU PROVINCE TO: 100096 HAIDIAN, BEIJING |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20131209 Address after: 100096 Beijing Haidian District City Garden 68 Building No. 305, producing up new Patentee after: Mao Tengshu Address before: 01, building 5, Metro 69, 210009 Olympic Sports Avenue, Jianye District, Jiangsu, Nanjing Patentee before: Nanjing Epica Biotechnology Co.,Ltd. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160725 Address after: 100102 Beijing city Chaoyang District Dongyuan Wangjing No. 523 building 13 layer 11610 Patentee after: Beijing Maidi Pharma Pharmaceutical Technology Co.,Ltd. Address before: 100096 Beijing Haidian District City Garden 68 Building No. 305, producing up new Patentee before: Mao Tengshu |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20180327 Address after: 100096 Beijing Haidian District City Garden 68 Building No. 305, producing up new Patentee after: Mao Tengshu Address before: 100102 Beijing city Chaoyang District Dongyuan Wangjing No. 523 building 13 layer 11610 Patentee before: Beijing Maidi Pharma Pharmaceutical Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180619 Address after: 100102 13 floor 11610, Wangjing East Garden 523, Chaoyang District, Beijing. Patentee after: Beijing Maidi Pharma Pharmaceutical Technology Co.,Ltd. Address before: 100096 305, 68 / F, new West Garden, Haidian District, Beijing. Patentee before: Mao Tengshu |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080102 Termination date: 20211210 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |