CN100334106C - 环孢菌素类似物的合成 - Google Patents
环孢菌素类似物的合成 Download PDFInfo
- Publication number
- CN100334106C CN100334106C CNB028207998A CN02820799A CN100334106C CN 100334106 C CN100334106 C CN 100334106C CN B028207998 A CNB028207998 A CN B028207998A CN 02820799 A CN02820799 A CN 02820799A CN 100334106 C CN100334106 C CN 100334106C
- Authority
- CN
- China
- Prior art keywords
- cyclosporin
- isomer
- mixture
- isa
- ethanoyl
- 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 - Lifetime
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical class CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title claims abstract description 215
- 230000015572 biosynthetic process Effects 0.000 title description 19
- 238000003786 synthesis reaction Methods 0.000 title description 15
- 239000000203 mixture Substances 0.000 claims abstract description 272
- 108010036949 Cyclosporine Proteins 0.000 claims abstract description 268
- 229930105110 Cyclosporin A Natural products 0.000 claims abstract description 262
- 238000006243 chemical reaction Methods 0.000 claims abstract description 104
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 45
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 34
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 26
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims abstract description 25
- 230000002829 reductive effect Effects 0.000 claims abstract description 25
- 239000010703 silicon Substances 0.000 claims abstract description 9
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 9
- 229960001265 ciclosporin Drugs 0.000 claims description 269
- -1 ethanoyl- Chemical group 0.000 claims description 219
- 238000000034 method Methods 0.000 claims description 113
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 108
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 91
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 82
- 238000002360 preparation method Methods 0.000 claims description 64
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 55
- 238000003756 stirring Methods 0.000 claims description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 50
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 235000019439 ethyl acetate Nutrition 0.000 claims description 35
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 230000008859 change Effects 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 23
- 229910052698 phosphorus Inorganic materials 0.000 claims description 22
- 239000011574 phosphorus Substances 0.000 claims description 22
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 21
- 238000007254 oxidation reaction Methods 0.000 claims description 21
- 230000003647 oxidation Effects 0.000 claims description 19
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 18
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000011734 sodium Substances 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 14
- 238000000746 purification Methods 0.000 claims description 13
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 11
- 150000001993 dienes Chemical class 0.000 claims description 11
- 229910052700 potassium Inorganic materials 0.000 claims description 11
- 239000011591 potassium Substances 0.000 claims description 11
- 239000000376 reactant Substances 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 235000015320 potassium carbonate Nutrition 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 claims description 8
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical group CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical group OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052785 arsenic Inorganic materials 0.000 claims description 5
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical group CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 4
- 238000005893 bromination reaction Methods 0.000 claims description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 4
- 238000005949 ozonolysis reaction Methods 0.000 claims description 4
- 229910001927 ruthenium tetroxide Inorganic materials 0.000 claims description 4
- 125000005270 trialkylamine group Chemical group 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 3
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- KUSICUWKCBCAHV-ZSINMPTNSA-N [(e,1r,2r)-1-[(2s,5s,11s,14s,17s,20s,23r,26s,29s,32s)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-y Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](OC(C)=O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O KUSICUWKCBCAHV-ZSINMPTNSA-N 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims 3
- 102100029647 Apoptosis-associated speck-like protein containing a CARD Human genes 0.000 claims 2
- 101000728679 Homo sapiens Apoptosis-associated speck-like protein containing a CARD Proteins 0.000 claims 2
- 101000707471 Homo sapiens Serine incorporator 3 Proteins 0.000 claims 2
- 230000026030 halogenation Effects 0.000 claims 1
- 238000005658 halogenation reaction Methods 0.000 claims 1
- 230000003244 pro-oxidative effect Effects 0.000 claims 1
- 235000015424 sodium Nutrition 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 abstract description 13
- 229930182912 cyclosporin Natural products 0.000 abstract description 13
- 239000010936 titanium Substances 0.000 abstract description 12
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract description 11
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 abstract description 11
- 229910052796 boron Inorganic materials 0.000 abstract description 11
- 231100000419 toxicity Toxicity 0.000 abstract description 11
- 230000001988 toxicity Effects 0.000 abstract description 11
- 229910052719 titanium Inorganic materials 0.000 abstract description 10
- 125000002524 organometallic group Chemical group 0.000 abstract description 9
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract description 8
- 230000000707 stereoselective effect Effects 0.000 abstract description 7
- 108010036941 Cyclosporins Proteins 0.000 abstract 2
- 230000037361 pathway Effects 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 79
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- 239000000543 intermediate Substances 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 37
- 239000007787 solid Substances 0.000 description 37
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 37
- 230000000694 effects Effects 0.000 description 33
- 150000001299 aldehydes Chemical class 0.000 description 32
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 31
- 238000011282 treatment Methods 0.000 description 31
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- 239000000463 material Substances 0.000 description 28
- 241001465754 Metazoa Species 0.000 description 21
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- 239000004327 boric acid Substances 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 19
- 230000007704 transition Effects 0.000 description 19
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- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 17
- 102000004631 Calcineurin Human genes 0.000 description 17
- 108010042955 Calcineurin Proteins 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 17
- 229910000085 borane Inorganic materials 0.000 description 17
- 239000003981 vehicle Substances 0.000 description 17
- 230000001506 immunosuppresive effect Effects 0.000 description 16
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- 241000283973 Oryctolagus cuniculus Species 0.000 description 15
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
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- 239000002243 precursor Substances 0.000 description 14
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- 150000001336 alkenes Chemical class 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 12
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- 230000005764 inhibitory process Effects 0.000 description 12
- 230000004083 survival effect Effects 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 210000003734 kidney Anatomy 0.000 description 11
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
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- 238000003379 elimination reaction Methods 0.000 description 10
- 125000000524 functional group Chemical group 0.000 description 10
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- 231100000417 nephrotoxicity Toxicity 0.000 description 10
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 10
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000004567 concrete Substances 0.000 description 9
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
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- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 5
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 5
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
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Abstract
Description
剂量(mg/kg/天) | 载体对照 | 平均存活时间(手术后天数)平均±SEM(扫描电子显微镜) | |
环孢菌素A | ISATX247 | ||
0 | 9±1 | ||
0.5 | 13a±4 | 11a±2 | |
1.75 | 18b±7 | 57b±32 | |
3 | 50c±8 | 55c±12 |
试验化合物 | 平均存活时间(手术后天数) |
载体对照环孢菌素AI5-M1I4-M2I4-D2 | 9202020+30 |
剂量(mg/kg/天) | 处理 | N | 中位数存活(天) | 平均存活(天) |
01.751.75 | 载体CsAISA | 799 | 171718 | 16.817.418.7 |
1010 | CsAISA | 65 | 2118 | 25.319.2 |
02020 | 载体CsAISA | 1299 | 1619>28 | 15.920.2>28 |
02525 | 载体CsAISA | 5108 | 21ND*50 | 21.1ND*46.4 |
治疗组 | 天:1-7i.v剂量(mg/kg) | 天:8-30s.c剂量(mg/kg) | 动物数雄 雌 |
1.载体对照 | 0 | 0 | 4 4 |
2.环孢菌素A对照 | 10 | 10 | 6 6 |
3.低剂量 | 5 | 5 | 0 2 |
4.中剂量 | 10 | 10 | 4 4 |
5.高剂量 | 15 | 15 | 4 4 |
测量的参数 | 环孢菌素A | ISATX247 | ||
第1天 | 第7天 | 第1天 | 第7天 | |
tmax(小时) | 0.5 | 0.5 | 0.5 | 0.5 |
Cmax(μg/L) | 1954±320 | 2l71±612 | 1915±149 | 1959±470 |
T1/2(小时) | 7.4±2.8 | 9.0±4.0 | 7.4±1.7 | 9.2±1.1 |
曲线下面积(μg≌hr/L) | 6697±1717 | 6685±1247 | 5659±1309 | 5697±1373 |
治疗组 | 第15天 | 第30天 |
载体 | +6% | -3% |
环孢菌素A(10mg/kg) | +22% | +33% |
ISATX247(10mg/kg) | +1% | +10% |
ISATX247(15mg/kg) | -19% | -11% |
参数 | ISATX247 | 环孢菌素 |
3H-胸腺嘧啶摄取 | 160.54 | 565.52 |
PCNA表达 | 197.72 | 453.88 |
IL-2产生 | 103.35 | 504.80 |
IFN-产生 | 102.67 | 465.65 |
TNF-产生 | 90.58 | 508.29 |
CD 71表达 | 149.84 | 486.82 |
CD 25表达 | 121.00 | 431.53 |
CD 11a表达 | 204.40 | 598.90 |
CD 95表达 | 129.98 | 392.97 |
CD 154表达 | 160.87 | 975.10 |
Claims (36)
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US34620101P | 2001-10-19 | 2001-10-19 | |
US60/346,201 | 2001-10-19 | ||
US37059602P | 2002-04-05 | 2002-04-05 | |
US60/370,596 | 2002-04-05 | ||
PCT/CA2002/001559 WO2003033526A2 (en) | 2001-10-19 | 2002-10-17 | Synthesis of cyclosporin analogs |
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