KR100913269B1 - 디아릴 황화물 유도체, 그의 염 및 이를 이용한 면역억제제 - Google Patents
디아릴 황화물 유도체, 그의 염 및 이를 이용한 면역억제제 Download PDFInfo
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- KR100913269B1 KR100913269B1 KR1020047004284A KR20047004284A KR100913269B1 KR 100913269 B1 KR100913269 B1 KR 100913269B1 KR 1020047004284 A KR1020047004284 A KR 1020047004284A KR 20047004284 A KR20047004284 A KR 20047004284A KR 100913269 B1 KR100913269 B1 KR 100913269B1
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- South Korea
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- carbon atoms
- group
- formula
- propanediol
- amino
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- -1 Diaryl sulfide derivative Chemical class 0.000 title claims abstract description 60
- 239000003018 immunosuppressive agent Substances 0.000 title claims abstract description 31
- 229960003444 immunosuppressant agent Drugs 0.000 title claims abstract description 9
- 150000003839 salts Chemical class 0.000 title claims description 18
- 230000001861 immunosuppressant effect Effects 0.000 title 1
- UPUNULLOHYJOPV-UHFFFAOYSA-N NC(CC(CCO)O)(C)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl.NC(CC(CCO)O)(C)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl Chemical compound NC(CC(CCO)O)(C)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl.NC(CC(CCO)O)(C)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl UPUNULLOHYJOPV-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 105
- 125000004432 carbon atom Chemical group C* 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 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
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 230000000069 prophylactic effect Effects 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 2
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 206010048908 Seasonal allergy Diseases 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 238000010322 bone marrow transplantation Methods 0.000 claims description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 2
- AVIYEYCFMVPYST-UHFFFAOYSA-N hexane-1,3-diol Chemical compound CCCC(O)CCO AVIYEYCFMVPYST-UHFFFAOYSA-N 0.000 claims 5
- CHJAXFWNKIDMLP-UHFFFAOYSA-N 5-amino-5-[2-chloro-4-[3-(trifluoromethyl)phenyl]sulfanylphenyl]hexane-1,3-diol Chemical compound C1=C(Cl)C(C(N)(CC(O)CCO)C)=CC=C1SC1=CC=CC(C(F)(F)F)=C1 CHJAXFWNKIDMLP-UHFFFAOYSA-N 0.000 claims 2
- CNGHKOUDIMFNEK-UHFFFAOYSA-N 5-amino-5-[4-(3-phenylmethoxyphenyl)sulfanyl-2-(trifluoromethyl)phenyl]hexane-1,3-diol Chemical compound C1=C(C(F)(F)F)C(C(N)(CC(O)CCO)C)=CC=C1SC1=CC=CC(OCC=2C=CC=CC=2)=C1 CNGHKOUDIMFNEK-UHFFFAOYSA-N 0.000 claims 1
- MKSLDLAKJQMWBG-UHFFFAOYSA-N NC(CC(CCO)O)(C)C1=C(C=C(C=C1)SC1=CC(=CC=C1)C(F)(F)F)C(F)(F)F.C(CC)(O)O Chemical compound NC(CC(CCO)O)(C)C1=C(C=C(C=C1)SC1=CC(=CC=C1)C(F)(F)F)C(F)(F)F.C(CC)(O)O MKSLDLAKJQMWBG-UHFFFAOYSA-N 0.000 claims 1
- HZDUWFSJFJOKPT-UHFFFAOYSA-N NC(CC(CCO)O)(C)C1=CC=C(C=C1)SC1=C(C(=CC(=C1)C(F)(F)F)C(F)(F)F)Cl.NC(CC(CCO)O)(C)C1=CC=C(C=C1)SC1=C(C(=CC(=C1)C(F)(F)F)C(F)(F)F)Cl Chemical compound NC(CC(CCO)O)(C)C1=CC=C(C=C1)SC1=C(C(=CC(=C1)C(F)(F)F)C(F)(F)F)Cl.NC(CC(CCO)O)(C)C1=CC=C(C=C1)SC1=C(C(=CC(=C1)C(F)(F)F)C(F)(F)F)Cl HZDUWFSJFJOKPT-UHFFFAOYSA-N 0.000 claims 1
- KEHRNMJKOZRWTO-UHFFFAOYSA-N NC(CC(CCO)O)(C)C1=CC=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1.NC(CC(CCO)O)(C)C1=CC=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1 Chemical compound NC(CC(CCO)O)(C)C1=CC=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1.NC(CC(CCO)O)(C)C1=CC=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1 KEHRNMJKOZRWTO-UHFFFAOYSA-N 0.000 claims 1
- WYSUABICZYQUSP-UHFFFAOYSA-N NC(CC(CCO)O)(CC)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl.NC(CC(CCO)O)(CC)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl Chemical compound NC(CC(CCO)O)(CC)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl.NC(CC(CCO)O)(CC)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl WYSUABICZYQUSP-UHFFFAOYSA-N 0.000 claims 1
- FLTBCWCWSKYNCI-UHFFFAOYSA-N NC(CC(CCO)O)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl.NC(CC(CCO)O)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl Chemical compound NC(CC(CCO)O)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl.NC(CC(CCO)O)C1=C(C=C(C=C1)SC1=CC(=CC=C1)OCC1=CC=CC=C1)Cl FLTBCWCWSKYNCI-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 5
- 208000006313 Delayed Hypersensitivity Diseases 0.000 abstract description 2
- 206010052779 Transplant rejections Diseases 0.000 abstract description 2
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 42
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- 239000000203 mixture Substances 0.000 description 24
- 238000004821 distillation Methods 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 239000011780 sodium chloride Substances 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000012230 colorless oil Substances 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 239000012980 RPMI-1640 medium Substances 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 238000002054 transplantation Methods 0.000 description 6
- 0 *c1ccc(*C2=CC(I)=CCC2)cc1* Chemical compound *c1ccc(*C2=CC(I)=CCC2)cc1* 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo(3.3.1)nonane Chemical compound C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- VIKJHNDCMRRCHY-UHFFFAOYSA-N 1-O-ethyl 3-O-phenyl 2-propylpropanedioate Chemical compound C1(=CC=CC=C1)OC(C(CCC)C(=O)OCC)=O VIKJHNDCMRRCHY-UHFFFAOYSA-N 0.000 description 4
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 4
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- 239000011630 iodine Chemical group 0.000 description 4
- 229910052740 iodine Chemical group 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229910021642 ultra pure water Inorganic materials 0.000 description 4
- 239000012498 ultrapure water Substances 0.000 description 4
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical class OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- ZGCHLAJIRWDGFE-UHFFFAOYSA-N 1-aminopropane-1,1-diol Chemical group CCC(N)(O)O ZGCHLAJIRWDGFE-UHFFFAOYSA-N 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
- KMQWNQKESAHDKD-UHFFFAOYSA-N 2-chloro-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(Cl)=C1 KMQWNQKESAHDKD-UHFFFAOYSA-N 0.000 description 2
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 2
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- 238000011160 research Methods 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- ILMRKBGGQYPOIY-UHFFFAOYSA-N tert-butyl n-[2-[2-chloro-4-[3-(trifluoromethyl)phenyl]sulfanylphenyl]-4,6-dihydroxyhexan-2-yl]carbamate Chemical compound C1=C(Cl)C(C(C)(CC(O)CCO)NC(=O)OC(C)(C)C)=CC=C1SC1=CC=CC(C(F)(F)F)=C1 ILMRKBGGQYPOIY-UHFFFAOYSA-N 0.000 description 1
- CMUTXJXHVDKYAN-UHFFFAOYSA-L tetrabutylazanium difluoride Chemical compound [F-].[F-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC CMUTXJXHVDKYAN-UHFFFAOYSA-L 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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Abstract
Description
Claims (16)
- 하기 화학식1(일반식1)로 표시되는 디아릴 황화물 유도체 또는 약학적으로 허용되는 그의 염(salts):[화학식1]상기 식에서, R1은 할로겐(halogen), 트리할로메틸(trihalomethyl), 하이드록시기(hydroxy), 1 내지 7개의 탄소 원자를 갖는 저급 알킬기(lower alkyl), 페닐기(phenyl), 아르알킬기(aralkyl), 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기(lower alkoxy), 트리플루오로메틸록시기(trifluoromethyloxy), 비치환 또는 플루오르, 염소, 브롬 및 요오드와 같은 할로겐 원소, 트리플루오로메틸, 1 내지 4의 탄소 원자를 갖는 저급 알킬기, 또는 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기를 벤젠 링의 어느 위치에라도 갖는 페녹시기(phenoxy), 사이클로헥실메틸록시기(cyclohexylmethyloxy), 비치환 또는 플루오르, 염소, 브롬 및 요오드와 같은 할로겐 원소, 트리플루오로메틸, 1 내지 4의 탄소 원자를 갖는 저급 알킬기, 또는 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기를 벤젠 링의 어느 위치에라도 갖는 아랄킬록시기(aralkyloxy), 피리딜메틸록시기(pyridylmethyloxy), 신나미록시기(cinnamyloxy), 나프틸메틸록시기(naphthylmethyloxy), 페녹시메틸기 (phenoxymethyl), 하이드록시메틸기(hydroxymethyl), 하이드록시에틸기 (hydroxyethyl), 1 내지 4개의 탄소 원자를 갖는 저급 알킬티오기(lower alkylthio), 1 내지 4개의 탄소 원자를 갖는 저급 알킬술피닐기(lower alkylsulfinyl), 1 내지 4개의 탄소 원자를 갖는 저급 알킬술포닐기(lower alkylsulfonyl), 벤질티오기(benzylthio), 아세틸기(acetyl), 니트로기(nitro), 또는 시아노기(cyano)이며;R2는 수소(hydrogen), 할로겐, 트리할로메틸, 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기, 1 내지 7개의 탄소 원자를 갖는 저급 알킬기, 페네틸기(phenethyl), 또는 벤질록시기(benzyloxy)이며;R3는 수소, 할로겐, 트리플루오로메틸, 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기, 하이드록시기, 벤질록시기, 1 내지 7개의 탄소 원자를 갖는 저급 알킬기, 페닐기, 또는 1 내지 4개의 탄소 원자를 갖는 저급 알콕시 메틸기이며;X는 황(S), 일산화황(SO), 또는 이산화황(SO2)이며;n은 1 내지 4의 정수이다.
- 제 2항에 있어서, R3는 염소(chlorine)임을 특징으로 하는 디아릴 황화물 유도체 또는 약학적으로 허용되는 그의 염(salts).
- 제 2항에 있어서, R3는 트리플루오로메틸(trifluoromethyl)임을 특징으로 하는 디아릴 황화물 유도체 또는 약학적으로 허용되는 그의 염(salts).
- 제 5항에 있어서, R3는 염소(chlorine)임을 특징으로 하는 디아릴 황화물 유도체 또는 약학적으로 허용되는 그의 염(salts).
- 제 5항에 있어서, R3는 트리플루오로메틸(trifluoromethyl)임을 특징으로 하는 디아릴 황화물 유도체 또는 약학적으로 허용되는 그의 염(salts).
- 제 1항에 있어서, 일반식 (1)의 화합물은 1) 2-아미노-2-[4-(3-벤질록시페닐티오)-2-클로로페닐]프로필-1,3-프로파네디올 (2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-1,3-propanediol); 2) 2-아미노-2-[4-(3-벤질록시페닐티오)페닐]프로필-1,3-프로파네디올 (2-amino-2-[4-(3-benzyloxyphenylthio)phenyl]propyl-1,3-propanediol); 3) 2-아미노-2-[4-(3-벤질록시페닐티오)-2-클로로페닐]에틸-1,3-프로파네디올 (2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol); 4) 2-아미노-2-[4-(3-벤질록시페닐티오)-2-클로로페닐]부틸-1,3-프로파네디올 (2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]butyl-1,3-propanediol); 5) 2-아미노-2-[4-(3-(3′-클로로벤질록시)페닐티오)-2-클로로페닐]프로필-1,3-프로파네디올 (2-amino-2-[4-(3-(3′-benzyloxy)phenylthio)-2-chlorophenyl]propyl-1,3-propanediol); 6) 2-아미노-2-[4-(3-벤질록시페닐티오)-2-트리플루오로메틸페닐]프로필-1,3-프로파네디올 (2-amino-2-[4-(3-benzyloxyphenylthio)-2-trifluoromethylphenyl]propyl-1,3-propanediol); 7) 2-아미노-2-[4-(3,5-비스트리플루오로메틸-2-클로로페닐티오)페닐]프로필-1,3-프로파네디올 (2-amino-2-[4-(3,5-bistrifluoromethyl-2-chlorophenylthio)phenyl]propyl-1,3-propanediol); 8) 2-아미노-2-[4-(3-비스트리플루오로메틸페닐티오)페닐]프로필-1,3-프로파네디올 (2-amino-2-[4-(3-bistrifluoromethylphenylthio)phenyl]propyl-1,3-propanediol); 9) 2-아미노-2-[2-클로로-4-(3-트리플루오로메틸페닐티오)페닐]프로필-1,3-프로파네디올(2-amino-2-[2-chloro-4-(3-trifluoromethylphenylthio)phenyl]propyl-1,3-propanediol; 또는 10) 2-아미노-2-[2-트리플루오로메틸-4-(3-트리플루오로메틸페닐티오)페닐]프로필-1,3-프로파네디올(2-amino-2-[2-trifluoromethyl-4-(3-trifluoromethylphenylthio)phenyl]propyl-1,3-propanediol)임을 특징으로 하는 디아릴 황화물 유도체 또는 약학적으로 허용되는 그의 염(salts).
- 하기 화학식1(일반식1)로 표시되는 디아릴 황화물 유도체 또는 약학적으로 허용되는 그의 염(salts)을 활성 성분으로 포함하는 면역억제제:[화학식1]상기 식에서, R1은 할로겐(halogen), 트리할로메틸(trihalomethyl), 하이드록시기(hydroxy), 1 내지 7개의 탄소 원자를 갖는 저급 알킬기(lower alkyl), 페닐기(phenyl), 아르알킬기(aralkyl), 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기(lower alkoxy), 트리플루오로메틸록시기(trifluoromethyloxy), 비치환 또는 플루오르, 염소, 브롬 및 요오드와 같은 할로겐 원소, 트리플루오로메틸, 1 내지 4의 탄소 원자를 갖는 저급 알킬기, 또는 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기를 벤젠 링의 어느 위치에라도 갖는 페녹시기(phenoxy), 사이클로헥실메틸록시기(cyclohexylmethyloxy), 비치환 또는 플루오르, 염소, 브롬 및 요오드와 같은 할로겐 원소, 트리플루오로메틸, 1 내지 4의 탄소 원자를 갖는 저급 알킬기, 또는 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기를 벤젠 링의 어느 위치에라도 갖는 아랄킬록시기(aralkyloxy), 피리딜메틸록시기(pyridylmethyloxy), 신나미록시기(cinnamyloxy), 나프틸메틸록시기(naphthylmethyloxy), 페녹시메틸기(phenoxymethyl), 하이드록시메틸기(hydroxymethyl), 하이드록시에틸기(hydroxyethyl), 1 내지 4개의 탄소 원자를 갖는 저급 알킬티오기(lower alkylthio), 1 내지 4개의 탄소 원자를 갖는 저급 알킬술피닐기(lower alkylsulfinyl), 1 내지 4개의 탄소 원자를 갖는 저급 알킬술포닐기(lower alkylsulfonyl), 벤질티오기(benzylthio), 아세틸기(acetyl), 니트로기(nitro), 또는 시아노기(cyano)이며;R2는 수소(hydrogen), 할로겐, 트리할로메틸, 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기, 1 내지 7개의 탄소 원자를 갖는 저급 알킬기, 페네틸기(phenethyl), 또는 벤질록시기(benzyloxy)이며;R3는 수소, 할로겐, 트리플루오로메틸, 1 내지 4개의 탄소 원자를 갖는 저급 알콕시기, 하이드록시기, 벤질록시기, 1 내지 7개의 탄소 원자를 갖는 저급 알킬기, 페닐기, 또는 1 내지 4개의 탄소 원자를 갖는 저급 알콕시 메틸기이며;X는 황(S), 일산화황(SO), 또는 이산화황(SO2)이며;n은 1 내지 4의 정수이다.
- 제 9항 내지 11항 중 어느 한 항에 있어서, 상기 면역억제제는 자가면역 질환에 대한 예방제 또는 치료제로서 제공되는 것임을 특징으로 하는 면역억제제.
- 제 9항 내지 제 11항 중 어느 한 항에 있어서, 상기 면역억제제는 류마치스 관절염에 대한 예방제 또는 치료제로써 제공되는 것임을 특징으로 하는 면역억제제.
- 제 9항 내지 11항 중 어느 한 항에 있어서, 상기 면역억제제는 건선(psoriasis) 또는 아토피성 피부염(atopic dermatitis)에 대한 예방제 또는 치료제로서 제공되는 것임을 특징으로 하는 면역억제제.
- 제 9항 내지 11항 중 어느 한 항에 있어서, 상기 면역억제제는 기관지 천식(bronchial asthma) 또는 화분증(pollinosis)에 대한 예방제 또는 치료제로서 제공되는 것임을 특징으로 하는 면역억제제.
- 제 9항 내지 11항 중 어느 한 항에 있어서, 상기 면역억제제는 기관 또는 골수 이식에서의 거부반응에 대한 예방제 또는 치료제로서 제공되는 것임을 특징으로 하는 면역억제제.
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BR112021001376A2 (pt) | 2018-07-27 | 2021-04-20 | Priothera Limited | preparação farmacêutica, e usos de 2-amino-2-[4-(3-benziloxifeniltio)-2-clorofenil]etil-propano-1,3-diol, ou um sal farmaceuticamente aceitável do mesmo |
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EP1002792A1 (en) * | 1997-04-04 | 2000-05-24 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-aminopropane-1,3-diol compounds, medicinal use thereof, and intermediates in synthesizing the same |
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KR101003877B1 (ko) * | 2002-09-19 | 2010-12-30 | 교린 세이야꾸 가부시키 가이샤 | 아미노알코올 유도체와 그 부가염 및 면역 억제제 |
Also Published As
Publication number | Publication date |
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JP4917589B2 (ja) | 2012-04-18 |
CN1329372C (zh) | 2007-08-01 |
EP1431284B1 (en) | 2007-11-21 |
BRPI0212894B8 (pt) | 2021-05-25 |
MXPA04002679A (es) | 2004-07-30 |
EP1431284A4 (en) | 2006-03-01 |
DK1431284T3 (da) | 2008-02-18 |
ES2292809T3 (es) | 2008-03-16 |
US6960692B2 (en) | 2005-11-01 |
WO2003029205A1 (fr) | 2003-04-10 |
BRPI0212894B1 (pt) | 2019-07-30 |
JP2009040794A (ja) | 2009-02-26 |
KR20040037107A (ko) | 2004-05-04 |
EP1431284A1 (en) | 2004-06-23 |
BR0212894A (pt) | 2004-10-13 |
CY1107272T1 (el) | 2012-11-21 |
CA2461212A1 (en) | 2003-04-10 |
JP4217620B2 (ja) | 2009-02-04 |
CN1561331A (zh) | 2005-01-05 |
JPWO2003029205A1 (ja) | 2005-01-13 |
CA2461212C (en) | 2010-08-17 |
US20040254222A1 (en) | 2004-12-16 |
AU2002332289B2 (en) | 2007-05-10 |
DE60223699T2 (de) | 2008-10-30 |
PT1431284E (pt) | 2008-01-21 |
DE60223699D1 (en) | 2008-01-03 |
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