HRP950071A2 - 6-substituted mycophenolic acids and derivatives - Google Patents

Info

Publication number

HRP950071A2

HRP950071A2 HR08/198,725A HRP950071A HRP950071A2 HR P950071 A2 HRP950071 A2 HR P950071A2 HR P950071 A HRP950071 A HR P950071A HR P950071 A2 HRP950071 A2 HR P950071A2

Authority

HR

Croatia

Prior art keywords

formula

methyl

compound

dihydro

lower alkyl

Prior art date

1994-02-18

Links

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• 239000002253 acid Substances 0.000 title claims description 56
• 150000007513 acids Chemical class 0.000 title description 2
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
• 150000001875 compounds Chemical class 0.000 claims description 391
• 238000006243 chemical reaction Methods 0.000 claims description 308
• -1 fluorovinyl Chemical group 0.000 claims description 131
• 125000000217 alkyl group Chemical group 0.000 claims description 101
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 90
• 238000000034 method Methods 0.000 claims description 66
• 150000003839 salts Chemical class 0.000 claims description 48
• 239000000203 mixture Substances 0.000 claims description 46
• 125000003545 alkoxy group Chemical group 0.000 claims description 22
• 229910052736 halogen Inorganic materials 0.000 claims description 22
• 150000002367 halogens Chemical class 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• 125000006239 protecting group Chemical group 0.000 claims description 16
• 125000003342 alkenyl group Chemical group 0.000 claims description 15
• 125000004432 carbon atom Chemical group C* 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 13
• 229920002554 vinyl polymer Chemical group 0.000 claims description 13
• 125000002947 alkylene group Chemical group 0.000 claims description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 12
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 12
• 125000003118 aryl group Chemical group 0.000 claims description 11
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
• 229920006395 saturated elastomer Polymers 0.000 claims description 9
• 238000006460 hydrolysis reaction Methods 0.000 claims description 8
• 125000000623 heterocyclic group Chemical group 0.000 claims description 7
• 125000004001 thioalkyl group Chemical group 0.000 claims description 7
• 241000124008 Mammalia Species 0.000 claims description 6
• 125000004429 atom Chemical group 0.000 claims description 6
• 230000007062 hydrolysis Effects 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
• 125000005282 allenyl group Chemical group 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• 125000002837 carbocyclic group Chemical group 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 125000001072 heteroaryl group Chemical group 0.000 claims description 4
• 230000009467 reduction Effects 0.000 claims description 4
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 4
• NSNYRVZKQPZWCL-UXBLZVDNSA-N (e)-6-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-3,4-dimethylhex-4-enoic acid Chemical compound OC1=C(C\C=C(/C)C(C)CC(O)=O)C(CC)=C(C)C2=C1C(=O)OC2 NSNYRVZKQPZWCL-UXBLZVDNSA-N 0.000 claims description 3
• 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 description 3
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 208000035475 disorder Diseases 0.000 claims description 3
• 230000032050 esterification Effects 0.000 claims description 3
• 238000005886 esterification reaction Methods 0.000 claims description 3
• XRYDHCHHAPNIMK-RUDMXATFSA-N (e)-6-(4-hydroxy-6,7-dimethyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoic acid Chemical compound OC(=O)CCC(/C)=C/CC1=C(C)C(C)=C2COC(=O)C2=C1O XRYDHCHHAPNIMK-RUDMXATFSA-N 0.000 claims description 2
• NLJZQYJXPYKUHI-BJMVGYQFSA-N (e)-6-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(CC)=C(C)C2=C1C(=O)OC2 NLJZQYJXPYKUHI-BJMVGYQFSA-N 0.000 claims description 2
• RUKYKVNICQOEGH-KPKJPENVSA-N 2-[(2e)-2-[2-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)ethylidene]cyclopentyl]acetic acid Chemical compound CCC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C1/CCCC1CC(O)=O RUKYKVNICQOEGH-KPKJPENVSA-N 0.000 claims description 2
• RIVUKEOKLWTYKC-JXMROGBWSA-N 2-[(e)-4-(4-hydroxy-6,7-dimethyl-3-oxo-1h-2-benzofuran-5-yl)but-2-en-2-yl]cyclopentane-1-carboxylic acid Chemical compound CC=1C(C)=C2COC(=O)C2=C(O)C=1C\C=C(/C)C1CCCC1C(O)=O RIVUKEOKLWTYKC-JXMROGBWSA-N 0.000 claims description 2
• MMFWNNZUSNUVPO-DHZHZOJOSA-N CC=1C(C)=C2COC(=O)C2=C(O)C=1C\C=C(/C)C1=CC=CC=C1C(O)=O Chemical compound CC=1C(C)=C2COC(=O)C2=C(O)C=1C\C=C(/C)C1=CC=CC=C1C(O)=O MMFWNNZUSNUVPO-DHZHZOJOSA-N 0.000 claims description 2
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
• 230000002757 inflammatory effect Effects 0.000 claims description 2
• 229910052740 iodine Inorganic materials 0.000 claims description 2
• 230000002062 proliferating effect Effects 0.000 claims description 2
• 230000001185 psoriatic effect Effects 0.000 claims description 2
• 230000003612 virological effect Effects 0.000 claims description 2
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
• 208000004998 Abdominal Pain Diseases 0.000 claims 1
• 208000002881 Colic Diseases 0.000 claims 1
• 230000003647 oxidation Effects 0.000 claims 1
• 238000007254 oxidation reaction Methods 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 17
• 201000010099 disease Diseases 0.000 abstract description 15
• HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical class OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 abstract description 15
• HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 abstract description 13
• 229960000951 mycophenolic acid Drugs 0.000 abstract description 10
• RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 abstract description 2
• 229960004866 mycophenolate mofetil Drugs 0.000 abstract description 2
• 239000003814 drug Substances 0.000 abstract 1
• 229940124597 therapeutic agent Drugs 0.000 abstract 1
• 238000002360 preparation method Methods 0.000 description 144
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 131
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 111
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 82
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 70
• 239000002904 solvent Substances 0.000 description 65
• 239000000243 solution Substances 0.000 description 56
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
• 150000002148 esters Chemical class 0.000 description 48
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 43
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
• 150000001299 aldehydes Chemical class 0.000 description 39
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 33
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
• 125000005907 alkyl ester group Chemical group 0.000 description 25
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
• 239000002585 base Substances 0.000 description 24
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 21
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
• 230000000694 effects Effects 0.000 description 16
• 239000003960 organic solvent Substances 0.000 description 16
• 238000002560 therapeutic procedure Methods 0.000 description 16
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 14
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 14
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 14
• 239000003795 chemical substances by application Substances 0.000 description 14
• 230000015572 biosynthetic process Effects 0.000 description 13
• 150000004820 halides Chemical class 0.000 description 13
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
• 239000013543 active substance Substances 0.000 description 12
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
• 238000002844 melting Methods 0.000 description 12
• 230000008018 melting Effects 0.000 description 12
• 150000007530 organic bases Chemical class 0.000 description 12
• 238000000746 purification Methods 0.000 description 12
• 239000011541 reaction mixture Substances 0.000 description 12
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 11
• 150000002905 orthoesters Chemical class 0.000 description 11
• 239000000725 suspension Substances 0.000 description 11
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
• WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
• 150000003254 radicals Chemical class 0.000 description 10
• 239000000741 silica gel Substances 0.000 description 10
• 229910002027 silica gel Inorganic materials 0.000 description 10
• 238000012360 testing method Methods 0.000 description 10
• 125000002252 acyl group Chemical group 0.000 description 9
• 229910052783 alkali metal Inorganic materials 0.000 description 9
• 125000005842 heteroatom Chemical group 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
• 239000005711 Benzoic acid Substances 0.000 description 8
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
• 150000001336 alkenes Chemical class 0.000 description 8
• 235000010233 benzoic acid Nutrition 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 8
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
• 239000003018 immunosuppressive agent Substances 0.000 description 8
• 239000012442 inert solvent Substances 0.000 description 8
• 230000005764 inhibitory process Effects 0.000 description 8
• 239000007788 liquid Substances 0.000 description 8
• 230000004048 modification Effects 0.000 description 8
• 238000012986 modification Methods 0.000 description 8
• 150000002902 organometallic compounds Chemical class 0.000 description 8
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
• 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 8
• QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 7
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
• 230000000840 anti-viral effect Effects 0.000 description 7
• 239000000460 chlorine Substances 0.000 description 7
• 229940125721 immunosuppressive agent Drugs 0.000 description 7
• 238000002955 isolation Methods 0.000 description 7
• IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 7
• 230000035755 proliferation Effects 0.000 description 7
• 230000002829 reductive effect Effects 0.000 description 7
• 239000012312 sodium hydride Substances 0.000 description 7
• 229910000104 sodium hydride Inorganic materials 0.000 description 7
• 239000000126 substance Substances 0.000 description 7
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• 230000009471 action Effects 0.000 description 6
• XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 6
• 210000003719 b-lymphocyte Anatomy 0.000 description 6
• 239000003054 catalyst Substances 0.000 description 6
• 239000003638 chemical reducing agent Substances 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• 230000001506 immunosuppresive effect Effects 0.000 description 6
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
• 125000002524 organometallic group Chemical group 0.000 description 6
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
• 229910052763 palladium Inorganic materials 0.000 description 6
• 239000000047 product Substances 0.000 description 6
• 229910052701 rubidium Inorganic materials 0.000 description 6
• 238000000926 separation method Methods 0.000 description 6
• NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 6
• 239000007787 solid Substances 0.000 description 6
• 239000003826 tablet Substances 0.000 description 6
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
• 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 5
• 229930105110 Cyclosporin A Natural products 0.000 description 5
• 108010036949 Cyclosporine Proteins 0.000 description 5
• 239000007818 Grignard reagent Substances 0.000 description 5
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
• 208000031481 Pathologic Constriction Diseases 0.000 description 5
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
• 206010052779 Transplant rejections Diseases 0.000 description 5
• 150000001408 amides Chemical class 0.000 description 5
• 230000003110 anti-inflammatory effect Effects 0.000 description 5
• 230000000259 anti-tumor effect Effects 0.000 description 5
• 229910052801 chlorine Inorganic materials 0.000 description 5
• 238000002425 crystallisation Methods 0.000 description 5
• 230000008025 crystallization Effects 0.000 description 5
• 238000004821 distillation Methods 0.000 description 5
• 238000000605 extraction Methods 0.000 description 5
• 150000004795 grignard reagents Chemical class 0.000 description 5
• 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 description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
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