TW215055B

TW215055B -

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Publication number: TW215055B
Authority: TW; Taiwan
Prior art keywords: benzyl; phenyl; methyl; methoxyphenyl; patent application
Prior art date: 1990-07-02

Application number

TW080105466A

Other languages

English (en)

Chinese (zh)

Original Assignee

Vertex Pharma

Priority date

1990-07-02

Filing date

1991-07-15

Publication date

1993-10-21

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=24186237&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TW215055(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1991-07-15 Application filed by Vertex Pharma filed Critical Vertex Pharma

1993-10-21 Application granted granted Critical

1993-10-21 Publication of TW215055B publication Critical patent/TW215055B/zh

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150000001875 compounds Chemical class 0.000 claims abstract description 95
230000001506 immunosuppresive effect Effects 0.000 claims abstract description 29
230000000694 effects Effects 0.000 claims abstract description 22
102000018679 Tacrolimus Binding Proteins Human genes 0.000 claims abstract description 17
108010027179 Tacrolimus Binding Proteins Proteins 0.000 claims abstract description 16
239000003018 immunosuppressive agent Substances 0.000 claims abstract description 13
210000000056 organ Anatomy 0.000 claims abstract description 11
108090000623 proteins and genes Proteins 0.000 claims abstract description 9
102000004169 proteins and genes Human genes 0.000 claims abstract description 8
206010052779 Transplant rejections Diseases 0.000 claims abstract description 5
241000124008 Mammalia Species 0.000 claims abstract description 4
-1 2-indolyl Chemical group 0.000 claims description 248
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 47
238000011049 filling Methods 0.000 claims description 43
239000000203 mixture Substances 0.000 claims description 33
125000000217 alkyl group Chemical group 0.000 claims description 19
239000003814 drug Substances 0.000 claims description 17
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
238000006243 chemical reaction Methods 0.000 claims description 15
125000003342 alkenyl group Chemical group 0.000 claims description 13
239000000126 substance Substances 0.000 claims description 12
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 11
UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
229910052786 argon Inorganic materials 0.000 claims description 9
239000007789 gas Substances 0.000 claims description 9
230000002401 inhibitory effect Effects 0.000 claims description 9
229910052717 sulfur Inorganic materials 0.000 claims description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
125000001424 substituent group Chemical group 0.000 claims description 7
206010062016 Immunosuppression Diseases 0.000 claims description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical group C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 claims description 6
238000007639 printing Methods 0.000 claims description 6
230000001363 autoimmune Effects 0.000 claims description 5
229910052799 carbon Inorganic materials 0.000 claims description 5
239000001257 hydrogen Substances 0.000 claims description 5
229910052739 hydrogen Inorganic materials 0.000 claims description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
239000001301 oxygen Substances 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 5
229910052705 radium Inorganic materials 0.000 claims description 5
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
230000028993 immune response Effects 0.000 claims description 4
229940125721 immunosuppressive agent Drugs 0.000 claims description 4
125000004430 oxygen atom Chemical group O* 0.000 claims description 4
125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 3
150000001412 amines Chemical class 0.000 claims description 3
125000004429 atom Chemical group 0.000 claims description 3
125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 3
238000012856 packing Methods 0.000 claims description 3
125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
229910052692 Dysprosium Inorganic materials 0.000 claims description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims description 2
229910052736 halogen Inorganic materials 0.000 claims description 2
150000002367 halogens Chemical class 0.000 claims description 2
125000000623 heterocyclic group Chemical group 0.000 claims description 2
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
125000001151 peptidyl group Chemical group 0.000 claims description 2
230000001629 suppression Effects 0.000 claims description 2
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
ZONYXWQDUYMKFB-UHFFFAOYSA-N flavanone Chemical compound O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 claims 6
125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 5
HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical group [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 claims 4
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 3
125000001041 indolyl group Chemical group 0.000 claims 3
125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 claims 2
241000283973 Oryctolagus cuniculus Species 0.000 claims 2
125000002541 furyl group Chemical group 0.000 claims 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
125000006178 methyl benzyl group Chemical group 0.000 claims 2
125000004076 pyridyl group Chemical group 0.000 claims 2
229920002554 vinyl polymer Polymers 0.000 claims 2
125000003163 2-(2-naphthyl)ethyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(C([H])=C([H])C2=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 1
125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims 1
125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
125000006483 4-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1I)C([H])([H])* 0.000 claims 1
125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 1
240000008564 Boehmeria nivea Species 0.000 claims 1
240000006162 Chenopodium quinoa Species 0.000 claims 1
241000270722 Crocodylidae Species 0.000 claims 1
241000252234 Hypophthalmichthys nobilis Species 0.000 claims 1
229910052769 Ytterbium Inorganic materials 0.000 claims 1
150000001336 alkenes Chemical class 0.000 claims 1
125000004946 alkenylalkyl group Chemical group 0.000 claims 1
125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
239000001273 butane Substances 0.000 claims 1
125000004122 cyclic group Chemical group 0.000 claims 1
125000006182 dimethyl benzyl group Chemical group 0.000 claims 1
125000001207 fluorophenyl group Chemical group 0.000 claims 1
229910052500 inorganic mineral Inorganic materials 0.000 claims 1
125000002346 iodo group Chemical group I* 0.000 claims 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims 1
238000004898 kneading Methods 0.000 claims 1
239000011707 mineral Substances 0.000 claims 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
125000006502 nitrobenzyl group Chemical group 0.000 claims 1
JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
125000006187 phenyl benzyl group Chemical group 0.000 claims 1
125000004346 phenylpentyl group Chemical group C1(=CC=CC=C1)CCCCC* 0.000 claims 1
125000004344 phenylpropyl group Chemical group 0.000 claims 1
238000004321 preservation Methods 0.000 claims 1
125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
210000004761 scalp Anatomy 0.000 claims 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 claims 1
125000001544 thienyl group Chemical group 0.000 claims 1
125000003944 tolyl group Chemical group 0.000 claims 1
125000001701 trimethoxybenzyl group Chemical group 0.000 claims 1
ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 claims 1
210000004885 white matter Anatomy 0.000 claims 1
NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 claims 1
208000023275 Autoimmune disease Diseases 0.000 abstract description 12
238000002054 transplantation Methods 0.000 abstract description 9
238000011282 treatment Methods 0.000 abstract description 9
229940124589 immunosuppressive drug Drugs 0.000 abstract description 3
230000006044 T cell activation Effects 0.000 abstract description 2
102000003813 Cis-trans-isomerases Human genes 0.000 abstract 1
108090000175 Cis-trans-isomerases Proteins 0.000 abstract 1
101710103508 FK506-binding protein Proteins 0.000 abstract 1
101710104425 FK506-binding protein 2 Proteins 0.000 abstract 1
101710104423 FK506-binding protein 3 Proteins 0.000 abstract 1
101710104333 FK506-binding protein 4 Proteins 0.000 abstract 1
101710104342 FK506-binding protein 5 Proteins 0.000 abstract 1
101710149710 FKBP-type 16 kDa peptidyl-prolyl cis-trans isomerase Proteins 0.000 abstract 1
101710121306 FKBP-type 22 kDa peptidyl-prolyl cis-trans isomerase Proteins 0.000 abstract 1
101710180800 FKBP-type peptidyl-prolyl cis-trans isomerase FkpA Proteins 0.000 abstract 1
101710104030 Long-type peptidyl-prolyl cis-trans isomerase Proteins 0.000 abstract 1
101710114693 Outer membrane protein MIP Proteins 0.000 abstract 1
101710116692 Peptidyl-prolyl cis-trans isomerase Proteins 0.000 abstract 1
101710111764 Peptidyl-prolyl cis-trans isomerase FKBP10 Proteins 0.000 abstract 1
101710111749 Peptidyl-prolyl cis-trans isomerase FKBP11 Proteins 0.000 abstract 1
101710111747 Peptidyl-prolyl cis-trans isomerase FKBP12 Proteins 0.000 abstract 1
101710111757 Peptidyl-prolyl cis-trans isomerase FKBP14 Proteins 0.000 abstract 1
101710111682 Peptidyl-prolyl cis-trans isomerase FKBP1A Proteins 0.000 abstract 1
101710111689 Peptidyl-prolyl cis-trans isomerase FKBP1B Proteins 0.000 abstract 1
101710147154 Peptidyl-prolyl cis-trans isomerase FKBP2 Proteins 0.000 abstract 1
101710147149 Peptidyl-prolyl cis-trans isomerase FKBP3 Proteins 0.000 abstract 1
101710147152 Peptidyl-prolyl cis-trans isomerase FKBP4 Proteins 0.000 abstract 1
102100020739 Peptidyl-prolyl cis-trans isomerase FKBP4 Human genes 0.000 abstract 1
101710147150 Peptidyl-prolyl cis-trans isomerase FKBP5 Proteins 0.000 abstract 1
101710147138 Peptidyl-prolyl cis-trans isomerase FKBP7 Proteins 0.000 abstract 1
101710147137 Peptidyl-prolyl cis-trans isomerase FKBP8 Proteins 0.000 abstract 1
101710147136 Peptidyl-prolyl cis-trans isomerase FKBP9 Proteins 0.000 abstract 1
101710174853 Peptidyl-prolyl cis-trans isomerase Mip Proteins 0.000 abstract 1
101710200991 Peptidyl-prolyl cis-trans isomerase, rhodopsin-specific isozyme Proteins 0.000 abstract 1
101710092145 Peptidyl-prolyl cis-trans isomerase-like 1 Proteins 0.000 abstract 1
101710092146 Peptidyl-prolyl cis-trans isomerase-like 2 Proteins 0.000 abstract 1
101710092148 Peptidyl-prolyl cis-trans isomerase-like 3 Proteins 0.000 abstract 1
101710092149 Peptidyl-prolyl cis-trans isomerase-like 4 Proteins 0.000 abstract 1
101710113444 Probable parvulin-type peptidyl-prolyl cis-trans isomerase Proteins 0.000 abstract 1
101710090737 Probable peptidyl-prolyl cis-trans isomerase Proteins 0.000 abstract 1
101710133309 Putative peptidyl-prolyl cis-trans isomerase Proteins 0.000 abstract 1
101710124237 Short-type peptidyl-prolyl cis-trans isomerase Proteins 0.000 abstract 1
210000001185 bone marrow Anatomy 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
239000000243 solution Substances 0.000 description 39
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
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210000004027 cell Anatomy 0.000 description 25
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
201000010099 disease Diseases 0.000 description 22
238000000034 method Methods 0.000 description 20
238000012360 testing method Methods 0.000 description 20
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
239000002253 acid Substances 0.000 description 14
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
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PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound 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 description 9
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HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
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229960002930 sirolimus Drugs 0.000 description 7
QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 7
208000024891 symptom Diseases 0.000 description 7
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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210000003734 kidney Anatomy 0.000 description 6
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VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
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238000003786 synthesis reaction Methods 0.000 description 6
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