CN1777575B - 作为1-磷酸-鞘氨醇受体调节剂的氨基-丙醇衍生物 - Google Patents
作为1-磷酸-鞘氨醇受体调节剂的氨基-丙醇衍生物 Download PDFInfo
- Publication number
- CN1777575B CN1777575B CN2004800110595A CN200480011059A CN1777575B CN 1777575 B CN1777575 B CN 1777575B CN 2004800110595 A CN2004800110595 A CN 2004800110595A CN 200480011059 A CN200480011059 A CN 200480011059A CN 1777575 B CN1777575 B CN 1777575B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- phenyl
- group
- formula
- 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
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical class CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 title description 3
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 title 1
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 title 1
- 229940075993 receptor modulator Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical group 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- -1 methoxyl group Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 230000002757 inflammatory effect Effects 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 230000001737 promoting effect Effects 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 206010052779 Transplant rejections Diseases 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 206010062016 Immunosuppression Diseases 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 230000001506 immunosuppresive effect Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 230000002519 immonomodulatory effect Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000002924 anti-infective effect Effects 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- NIDWUZTTXGJFNN-UHFFFAOYSA-N 3-bromopropoxybenzene Chemical compound BrCCCOC1=CC=CC=C1 NIDWUZTTXGJFNN-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000002354 daily effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 238000000527 sonication Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229940046731 calcineurin inhibitors Drugs 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000013081 microcrystal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- VGUWZCUCNQXGBU-UHFFFAOYSA-N 3-[(4-methylpiperazin-1-yl)methyl]-5-nitro-1h-indole Chemical compound C1CN(C)CCN1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 VGUWZCUCNQXGBU-UHFFFAOYSA-N 0.000 description 1
- VVOYROSONSLQQK-UHFFFAOYSA-N 3-[2-[2-cyclopentyl-6-(4-dimethylphosphorylanilino)purin-9-yl]ethyl]phenol Chemical compound C1=CC(P(C)(=O)C)=CC=C1NC1=NC(C2CCCC2)=NC2=C1N=CN2CCC1=CC=CC(O)=C1 VVOYROSONSLQQK-UHFFFAOYSA-N 0.000 description 1
- IYIFPVSMCPNPLQ-UHFFFAOYSA-N 3h-1,2,3-benzodioxaphosphepine Chemical compound O1OPC=CC2=CC=CC=C21 IYIFPVSMCPNPLQ-UHFFFAOYSA-N 0.000 description 1
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 1
- SPXOTSHWBDUUMT-UHFFFAOYSA-M 4-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=C(S([O-])(=O)=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-M 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HWTDMFJYBAURQR-UHFFFAOYSA-N 80-82-0 Chemical compound OS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O HWTDMFJYBAURQR-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=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 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 1
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 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 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 208000021709 Delayed Graft Function Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 101100347633 Drosophila melanogaster Mhc gene Proteins 0.000 description 1
- 206010060742 Endocrine ophthalmopathy Diseases 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[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 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 208000003084 Graves Ophthalmopathy Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000693265 Homo sapiens Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 1
- 101000693269 Homo sapiens Sphingosine 1-phosphate receptor 3 Proteins 0.000 description 1
- 101000653759 Homo sapiens Sphingosine 1-phosphate receptor 5 Proteins 0.000 description 1
- 101000914496 Homo sapiens T-cell antigen CD7 Proteins 0.000 description 1
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 1
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 1
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 108010064600 Intercellular Adhesion Molecule-3 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 102100037871 Intercellular adhesion molecule 3 Human genes 0.000 description 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 1
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 1
- 241001417092 Macrouridae Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 1
- 101000686985 Mouse mammary tumor virus (strain C3H) Protein PR73 Proteins 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- FQMMCMNBYLGQCG-UHFFFAOYSA-N N-[(tert-butylamino)-[di(propan-2-yl)amino]phosphoryl]-2-methylpropan-2-amine Chemical compound C(C)(C)(C)NP(=O)(N(C(C)C)C(C)C)NC(C)(C)C FQMMCMNBYLGQCG-UHFFFAOYSA-N 0.000 description 1
- HIEKJRVYXXINKH-ADVKXBNGSA-N N1([C@H]2CC[C@H](C[C@H]2OC)/C=C(\C)[C@H]2OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@]3(O)O[C@@H]([C@H](C[C@H]3C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]2C)=O)CC)C=NN=N1 Chemical compound N1([C@H]2CC[C@H](C[C@H]2OC)/C=C(\C)[C@H]2OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@]3(O)O[C@@H]([C@H](C[C@H]3C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]2C)=O)CC)C=NN=N1 HIEKJRVYXXINKH-ADVKXBNGSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000013901 Nephropathies and tubular disease Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- GDVNLLJNADMLLR-BBRMVZONSA-N Spergualin Chemical compound NCCCNCCCCNC(=O)[C@H](O)NC(=O)C[C@@H](O)CCCCN=C(N)N GDVNLLJNADMLLR-BBRMVZONSA-N 0.000 description 1
- 229940127530 Sphingosine 1-Phosphate Receptor Modulators Drugs 0.000 description 1
- 102100025750 Sphingosine 1-phosphate receptor 1 Human genes 0.000 description 1
- 102100025747 Sphingosine 1-phosphate receptor 3 Human genes 0.000 description 1
- 102100029802 Sphingosine 1-phosphate receptor 5 Human genes 0.000 description 1
- 235000009233 Stachytarpheta cayennensis Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102100027208 T-cell antigen CD7 Human genes 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 1
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 206010044541 Traumatic shock Diseases 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 208000024711 extrinsic asthma Diseases 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- RZTAMFZIAATZDJ-UHFFFAOYSA-N felodipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-UHFFFAOYSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000010659 intrinsic asthma Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000001875 irritant dermatitis Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 201000010666 keratoconjunctivitis Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 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 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229950000844 mizoribine Drugs 0.000 description 1
- 229950007856 mofetil Drugs 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960001302 ridaforolimus Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 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 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000617 superantigen Toxicity 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[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 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/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)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/094—Esters of phosphoric acids with arylalkanols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
Description
本发明涉及氨基-丙醇衍生物、它们的制备方法、它们的用途和含有它们的药物组合物。
更具体而言,本发明提供了游离形式或盐形式的式I化合物:
其中:
R1是C1-6烷基;被羟基、C1-2烷氧基或1至6个氟原子取代的C1-6烷基;C2-6链烯基;或C2-6炔基;
X、Y各自独立地是O、CH2或C=O;
R2是苯基;萘基;C3-6环烷基;杂芳基;杂环基;苯基C1-2烷基;C3-6环烷基C1-2烷基;杂芳基C1-2烷基;杂环基C1-2烷基;
其中每一个可以被1至5个取代基环取代,所述取代基选自羟基、卤素、C1-4烷基、被1至5个氟原子取代的C1-4烷基、C3-6环烷基、C1-4烷氧基、被1至5个氟原子取代的C1-4烷氧基、C3-6环烷氧基、C3-6环烷基C1-2烷基、氰基、苯基和被羟基、卤素、C1-4烷基、被1至5个氟原子取代的C1-4烷基、C1-4烷氧基、被1至5个氟原子取代的C1-4烷氧基或氰基取代的苯基;
R3是Z-X2,其中Z是CH2、CHF或CF2,且X2是OH或式(a)的残基:
其中Z1是直连键、CH2、CHF、CF2或O,R8和R9各自独立地是H或任选地被1、2或3个卤素原子取代的C1-4烷基;且
R4和R5各自独立地是H;任选地被1、2或3个卤素原子取代的C1-4烷基;或酰基;
R6和R7各自独立地是H;羟基;卤素;C1-4烷基;C1-6环烷基;C1-4烷氧基;
C1-6环烷氧基;C3-6环烷基C1-2烷基;或氰基;且
n是2或3。
烷基或烷基部分可以是直链或支链。链烯基可以是例如乙烯基。炔基可以是例如丙炔-2-基。酰基可以是残基R-CO,其中R是C1-6烷基、C3-6环烷基、苯基或苯基C1-4烷基。卤素可以是氟、氯或溴,优选氟或氯。当烷基被羟基取代时,优选的是在末端碳原子上取代。苯基C1-2烷基可以是例如苄基。
杂芳基可以是包含1至4个选自N、O和S的杂原子的5至8元芳族环,例如吡啶基、嘧啶基、吡嗪基、呋喃基、噁唑基、异噁唑基、噻吩基、噻唑基、异噻唑基、吡咯基、咪唑基或吡唑基.
杂环基是指包含1至4个选自N、O和S的杂原子的3至8元、优选5至8元的饱和或不饱和的杂环,例如四氢呋喃基、四氢吡喃基、吖丙啶基、哌啶基、吡咯烷基、哌嗪基。该杂环基也可以与任选取代的芳基或杂芳基例如苯基稠合,其中Y与所述的芳基或杂芳基键合;实例包括例如苯并[1,3]间二氧杂环戊烯基。
式I化合物可以以游离形式或以盐形式存在,所述盐形式例如与例如无机酸的加成盐,如盐酸盐、氢溴酸盐或硫酸盐,与有机酸的盐,如乙酸盐、富马酸盐、马来酸盐、苯甲酸盐、柠檬酸盐、苹果酸盐、甲磺酸盐或苯磺酸盐。水合物或溶剂合物形式的式I化合物及其盐也是本发明的一部分。
当式I化合物在分子中具有不对称中心时,得到各种旋光异构体。本发明也包括对映体、外消旋物、非对映异构体以及它们的混合物。例如,带有R1、R3和NR4R5的中心碳原子可以具有R或S构型。具有以下三维构型的化合物一般是优选的:
此外,当式I化合物包括几何异构体时,本发明包括顺式-化合物、反式-化合物以及它们的混合物。相似的考虑也适用于含有以上提及的不对称碳原子或不饱和键的起始原料,例如以下所示的式II、III或IV的化合物。
在式I化合物中,单独地或以任一亚组合形式优选以下含义:
1.X是O;
2.Y是O或S;
3.R1是CH3或CH2-OH;
4.R2是苯基;被1或2个选自卤素、C1-2烷基或C1-2烷氧基的取代基取代的苯基;氰基苯基;萘基;或苯并[1,3]间二氧杂环戊烯-5-基;
5.R3是CH2-OH或CH2-OPO3H2;
6.R4和R5各自是氢;
7.R6是氢、甲氧基、甲基或氯;和
8.R7是氢、甲氧基、甲基或氯。
本发明还包括制备式I化合物的方法,该方法包括:
a)对于其中R3是Z-X2,X2是OH的式I化合物,除去式II化合物中存在的保护基:
其中X、n、R1、R2和R4如以上所定义,R’3是Z-X2,其中X2是OH,且R’5是氨基保护基,或者
b)对于其中R3是Z-X2,X2是式(a)的残基的式I化合物,除去式III化合物中存在的保护基:
其中X、n、R1、R2、R4和R’5如以上所定义,且R”3是Z-X2,其中X2是式(a’)的残基:
其中Z1如以上所定义,且R’8或R’9各自是可水解或可氢解的基团,或者R’8和R’9一起形成任选地与环(例如苯环)稠合的二价桥连基,
并且,如果需要,将所获得的游离形式的式I化合物转化成所需的盐形式,反之亦然。
方法步聚a)可根据本领域已知的方法进行。氨基保护基的除去可根据本领域已知的方法方便地进行,例如通过水解例如在酸性介质中如使用盐酸水解。氨基保护基的实例有例如“Protective Groups in OrganicSynthesis”T.W.Greene,J.Wiley&Sons NY,第2版,第7章,1991以及其中的参考文献中所公开的那些保护基,例如苄基、对-甲氧基苄基、甲氧基甲基、四氢吡喃基、三烷基硅烷基、酰基、叔丁氧基-羰基、苄氧基羰基、9-芴基甲氧基羰基、三氟乙酰基等。
在式(a’)的基团中,R’8或R’9均可以具有例如叔丁基、苯基或苄基的含义,或者一起形成环体系,如1,5-二氢-2,4,3-苯并二氧杂磷杂(benzodioxaphosphepin)中的环体系。
方法步聚b)可根据本领域已知的方法进行,例如通过水解进行,例如当R’6和R’7各自是可水解基团时在碱性介质中如使用氢氧化物如氢氧化钡水解,或者当R’6和R’7各自是叔丁基时在酸性介质中水解。其还可通过氢解作用来进行,例如在催化剂如Pd/C存在下氢解,然后水解,例如在酸性介质如HCl中水解。用作起始原料的式II和III的化合物和它们的盐也是新的,并且是本发明的一部分。
本发明还包括制备式II化合物的方法,该方法包括转变式IV的化合物:
其中R1、R’3、R4和R’5如以上所定义,
以引入所需的基团-(CH2)n-Y-R2,例如通过烷基化引入。式IV化合物的烷基化可根据本领域已知的方法进行,例如通过亲核取代,例如通过与烷基化剂R2-Y-(CH2)n-X3反应,其中X3是甲磺酸根、甲苯磺酸根、三氟甲磺酸根、硝基苯磺酸根(nosylate)、氯、溴或碘。烷基化也可以通过按照Mitsunobu方案使用R2-Y-(CH2)n-OH(例如如Hughes,Organic Preparation andPrecedures International 28,127-164,1996或D.L.Hughes,Org.React.42,335,1992中所述)在溶液中进行或按照固相支持合成进行,例如通过使式IV化合物附着于树脂上。或者,可以使用例如键合于树脂如聚苯乙烯上的三苯膦或偶氮甲酸二乙酯(diethyl azocarboxylate)。
其中R’8和R’9形成环体系的式III化合物可以如下制备:
其中X、Y、n、R1、R2、R4和R’5如以上所定义。
在对起始原料的制备没有进行具体描述的情况下,这些化合物是已知的或可以通过与本领域已知方法类似的方法或如下文实施例中所公开的那样进行制备。
以下的实施例是本发明的举例说明。熔点未经校正。
RT=室温
THF=四氢呋喃
DMF=二甲基甲酰胺
MTBE=甲基叔丁基醚
AcOEt=乙酸乙酯
实施例1:(R)-2-氨基-4-{4-[2-(4-氯-苯氧基)-乙氧基]-苯基}-2-甲基-丁烷-1-醇盐酸盐:
向(R)-(3-{4-[2-(4-氯-苯氧基)-乙氧基]-苯基}-1-羟甲基-1-甲基-丙基)-氨基甲酯叔丁基酯(38mg,0.063mmol)中加入4M的在干燥二噁烷(1mL)中的HCl.将澄清的无色溶液在防潮下搅拌2小时.然后,将该溶液蒸发至干,将部分结晶的残余物用干燥乙醚(5mL)吸收.声波振荡10分钟,得到无色晶体沉淀.滤出产物,用冷乙醚洗涤(3×1mL),并在真空中干燥,得到不吸湿的无色微晶粉末形式的标题化合物:HPLC:tR=3.17分钟,ESI+MS:m/z=350/352(MH+)。
(R)-(3-{4-[2-(4-氯-苯氧基)-乙氧基]-苯基}-1-羟甲基-1-甲基-丙基)-氨基甲酯叔丁基酯可以根据以下方法制备:
向[(R)-1-羟基-4-(4-羟基-苯基)-2-甲基-丁-2-基]-氨基甲酯叔丁基酯(100mg,0.34mmol)和1-(2-溴乙氧基)-4-氯苯(120mg,0.51mmol,1.5当量)在无水DMF(2.5mL)中的溶液中加入不含水的碳酸铯(166mg,0.51mmol,1.5当量)。将得到的混悬液在60℃、防潮下搅拌过夜。冷却至RT后,滤出固体,并用DMF洗涤(2×1mL)。将合并的滤液在高真空中蒸发,得到深橙色糖浆状物。通过快速色谱法(FlashMaster II,MTBE/己烷梯度:45分钟内0%MTBE→40%MTBE,随后40%MTBE 15分钟)纯化,得到无色晶体:HPLC:tR=5.45分钟,ESI+MS:m/z=450/452。
按照实施例1的方法但使用适当的起始原料,可以制备其中R2和R6如表1中所示的式A化合物:
表1
实施例11:2-氨基-4-{4-[2-苯氧基-乙氧基]-苯基}-2-乙氧基-丁烷-1-醇盐酸盐:
向4-[2-(4-羟甲基-2-甲基-4,5-二氢-噁唑-4-基)-乙基]-苯酚(300mg,1.27mmol)在DMF(5mL)中的溶液中加入Cs2CO3(1.2g,3.83mmol)和2-苯氧基乙基溴(770mg,1.27mmol)。将反应混合物在85℃下搅拌4小时。然后加入AcOEt和水,分离有机层,水相用AcOEt萃取(3×50mL)。将合并的有机萃取物用盐水洗涤,用MgSO4干燥并蒸发至干.通过快速色谱法(AcOEt/Hx9∶1)纯化,得到无色油状物形式的(2-甲基-4-{2-[4-(2-苯氧基-乙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基)-甲醇.向(2-甲基-4-{2-[4-(2-苯氧基-乙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基)-甲醇(50mg,0.14mmol)在乙醇(2mL)中的溶液中加入浓HCl(2mL).将反应混合物在85℃下搅拌2小时,然后浓缩至干.将残余物重新溶解在AcOEt中并用己烷使其沉淀.滤出固体,用干燥乙醚洗涤并在真空中干燥,得到无色粉末形式的2-氨基-4-{4-[2-苯氧基-乙氧基]-苯基}-2-乙氧基-丁烷-1-醇盐酸盐.ESI+MS:m/z=332.3(M+H)+。
按照实施例11的方法但使用适当的起始原料,可以制备其中R2如表2中所示的式B化合物:
表2
实施例26:(+/-)磷酸单-(2-氨基-4-{4-[2-苯氧基-乙氧基]-苯基}-2-乙氧基-丁烷)酯:
向(2-甲基-4-{2-[4-(2-苯氧基-乙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基)-甲醇(200mg,0.56mmol)和四唑(197mg,2.81mmol,5当量,用甲苯重结晶得到)在干燥THF(5mL)中的溶液中加入N,N-二异丙基氨基磷酸二叔丁酯(di-tert-butyl-N,N-diisopropylphosphoramide)(561mg,2.25mmol,4当量)。在RT、氩气下搅拌3小时后,在0℃、剧烈搅拌下缓慢加入H2O2(30%,10当量)。将反应混合物再搅拌30分钟,然后加入饱和硫代硫酸钠溶液(5mL)。分离有机层,水相用乙醚萃取(3×20mL)。将合并的有机萃取物用盐水洗涤,用MgSO4干燥并蒸发至干。通过快速色谱法(AcOEt/己烷1∶1)纯化,得到无色晶体形式的磷酸二叔丁基酯2-甲基-4-{2-[4-(2-苯氧基-乙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基甲基酯。最后,向磷酸二叔丁基酯2-甲基-4-{2-[4-(2-苯氧基-乙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基甲基酯(150mg,0.27mmol)在乙醇(5mL)中的溶液中加入浓HCl(5mL)。将反应混合物在50℃下搅拌2小时,然后浓缩至干。将残余物重新溶解在AcOEt中,用己烷使其沉淀。滤出固体,用干燥乙醚洗涤并在真空中干燥,得到无色粉末形式的磷酸单-(2-氨基-4-{4-[2-苯氧基-乙氧基]-苯基}-2-乙氧基-丁烷)酯。ESI+MS:m/z=410.2(M-H)+。
按照实施例26的方法但使用适当的起始原料,可以制备其中R2如表3中所示的式C化合物:
表3
实施例36:磷酸(R)-单-(2-氨基-4-{4-[2-(4-氯-苯氧基)-乙氧基]-苯基}-2-甲基-丁基)酯:
将[3-{4-[2-(4-氯-苯氧基)-乙氧基]-苯基}-1-(二叔丁氧基-磷酰氧基-甲基)-1-甲基-丙基]-氨基甲酸叔丁基酯(44mg,0.069mmol)溶解在4M的在二噁烷(2mL)中的HCl中。搅拌2小时后,蒸发略微混浊的溶液。将无色半固体残余物用干燥乙醚(5mL)进行声波振荡,得到无色沉淀。滤出固体,用干燥乙醚洗涤并将其真空干燥,得到灰白色粉末:HPLC:tR=3.11分钟,ESI+MS:m/z=430/432(M-H+)。
[3-{4-[2-(4-氯-苯氧基)-乙氧基]-苯基}-1-(二叔丁氧基-磷酰氧基-甲 基)-1-甲基-丙基]-氨基甲酸叔丁基酯根据以下方法制备:
向(R)-(3-{4-[2-(4-氯-苯氧基)-乙氧基]-苯基}-1-羟甲基-1-甲基-丙基)-氨基甲酯叔丁基酯(40mg,0.089mmol,实施例1a)和四唑(19mg,0.27mmol,3当量,用甲苯重结晶得到)在干燥THF(1mL)中的溶液中加入N,N-二乙基-氨基磷酸二叔丁酯(36μL,0.13mmol,1.5当量)。将反应混合物在RT、氩气下搅拌2小时。然后,在0℃、剧烈搅拌下注入H2O2(30%,91μL,0.89mmol,10当量)。将反应混合物再搅拌30分钟,然后加入饱和硫代硫酸钠溶液(1mL)。分离有机层,水相用乙醚萃取(3×1mL)。将合并的有机萃取物用盐水洗涤,用MgSO4干燥并蒸发至干。通过快速色谱法(FlashMaster II,MTBE/己烷梯度:在45分钟内0%MTBE→50%MTBE,然后50%MTBE15分钟)纯化粗物质,得到无色晶体:HPLC:tR=6.64分钟,ESI+MS:m/z=642/644(MH+)。
按照实施例36的方法但使用适当的起始原料,可以制备其中R2和R6如表4中所示的式D化合物:
表4
实施例44:2-氨基-2-{2-[4-(3-苯氧基-丙氧基)-苯基]-乙基}-丙烷-1,3-二醇盐酸盐:
向4-[2-(4-羟甲基-2-甲基-4,5-二氢-噁唑-4-基)-乙基]-苯酚(300mg,1.27mmol)在DMF(5mL)中的溶液中加入Cs2CO3(1.2g,3.83mmol)和(3-溴-丙氧基)-苯(273mg,1.27mmol)。将反应混合物在85℃下搅拌4小时。然后加入AcOEt和水,分离有机层,水相用AcOEt萃取(3×50mL)。将合并的有机萃取物用盐水洗涤,用MgSO4干燥并蒸发至干。通过快速色谱法(AcOEt/己烷9∶1)纯化,得到无色油状物形式的(2-甲基-4-{2-[4-(3-苯氧基-丙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基)-甲醇。向(2-甲基-4-{2-[4-(3-苯氧基-丙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基)-甲醇(50mg,0.135mmol)在乙醇(2mL)中的溶液中加入浓HCl(2mL)。将反应混合物在85℃下搅拌2小时,然后浓缩至干。将残余物重新溶解在AcOEt中,用己烷使其沉淀。滤出固体,用干燥乙醚洗涤并在真空中干燥,得到无色粉末形式的2-氨基-2-{2-[4-(3-苯氧基-丙氧基)-苯基]-乙基}-丙烷-1,3-二醇盐酸盐。ESI+MS:m/z=370.4(M+H)+。
按照实施例44的方法但使用适当的起始原料,可以制备其中R2和Y如表5中所示的式E化合物:
表5
实施例52:(R)-2-氨基-2-甲基-4-[4-(3-苯氧基-丙氧基)-苯基]-丁烷-1-醇盐酸盐:
向{(R)-1-羟甲基-1-甲基-3-[4-(3-苯氧基-丙氧基)-苯基]-丙基}-氨基甲酸叔丁基酯(50mg,0.11mmol)中加入4M的在干燥二噁烷(1mL)中的HCl。将无色澄清溶液在防潮下搅拌2小时。然后,将溶液蒸发至干,将部分结晶的残余物用干燥乙醚(5mL)吸收。声波振荡10分钟,得到无色晶体沉淀。滤出产物,用冷乙醚洗涤(3×1mL),在真空中干燥,得到不吸湿的无色微晶粉末形式的标题化合物。ESI+MS:m/z=330.4(MH+)。
{(R)-1-羟甲基-1-甲基-3-[4-(3-苯氧基-丙氧基)-苯基]-丙基}-氨基甲酸叔丁基酯可以根据以下方法制备:
向[(R)-1-羟基-4-(4-羟基-苯基)-2-甲基-丁-2-基]氨基甲酸叔丁基酯(100mg,0.34mmol)和(3-溴-丙氧基)-苯(109.6mg,0.51mmol,1.5当量)在无水DMF(2.5mL)中的溶液中加入不含水的碳酸铯(166mg,0.51mmol,1.5当量)。将得到的混悬液在60℃、防潮下搅拌过夜。冷却至RT后,滤出固体,用DMF洗涤(2×1mL)。将合并的滤液在高真空中蒸发,得到深橙色糖浆状物。通过快速色谱法(FlashMaster II,MTBE/己烷梯度:在45分钟内0%MTBE→40%MTBE,然后40%MTBE 15分钟)纯化,得到无色晶体:ESI+MS:m/z=430.4.
实施例53:(R)-2-氨基-4-{4-[3-(5-溴-2-甲氧基-苯氧基)-丙氧基]-苯基}-2-甲基-丁烷-1-醇盐酸盐:
如实施例52中所述使用4-溴-2-(3-溴-丙氧基)-1-甲氧基-苯代替(3-溴-丙氧基)-苯制备标题化合物。ESI+MS:m/z=439.3(M+H)+。
实施例54:(+/-)单磷酸单-{2-氨基-2-羟甲基-4-[4-(3-苯氧基-丙氧基)-苯基]-丁基}酯:
向(2-甲基-4-{2-[4-(3-苯氧基-丙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基)-甲醇(200mg,0.54mmol)和四唑(189mg,2.70mmol,5当量,用甲苯重结晶得到)在干燥THF(5mL)中的溶液中加入N,N-二异丙基氨基磷酸二叔丁酯(538.5mg,2.16mmol,4当量)。在RT、氩气下搅拌3小时后,在0℃、剧烈搅拌下缓慢加入H2O2(30%,10当量)。将反应混合物再搅拌30分钟,然后加入饱和硫代硫酸钠溶液(5mL)。分离有机层,水相用乙醚萃取(3×20mL)。将合并的有机萃取物用盐水洗涤,用MgSO4干燥并蒸发至干。通过快速色谱法(AcOEt/己烷1∶1)纯化,得到无色晶体形式的(+/-)磷酸二叔丁基酯2-甲基-4-{2-[4-(3-苯氧基-丙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基甲基酯。最后,向磷酸二叔丁基酯2-甲基-4-{2-[4-(3-苯氧基-丙氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基甲基酯(50mg,0.089mmol)在乙醇(5mL)中的溶液中加入浓HCl(5mL)。将反应混合物在50℃下搅拌2小时,然后浓缩至干。将残余物重新溶解在AcOEt中,用己烷使其沉淀。滤出固体,用干燥乙醚洗涤并在真空中干燥,得到无色粉末形式的(+/-)单磷酸单-{2-氨基-2-羟甲基-4-[4-(3-苯氧基-丙氧基)-苯基]-丁基}酯。ESI+MS:m/z=426.4(M-H)+。
按照实施例54的方法但使用适当的起始原料,可以制备其中R2、R10和Y如表6中所示的式F化合物。
表6
游离形式或可药用盐形式的式I化合物显示出有价值的药理学性质,例如调节淋巴细胞再循环的特性,例如如体外和体内试验所证明,并因此适用于治疗。
A.体外
如以下测定法中所测定的那样,式I化合物对各个人S1P受体具有结合亲和力:
1-磷酸-鞘氨醇(S1P)受体特性
用人S1P受体EDG-1(S1P1)、EDG-3(S1P3)、EDG-5(S1P2)、EDG-6(S1P4)和EDG-8(S1P5)试验了化合物的激活剂活性。通过对化合物诱导的GTP[γ-35S]与膜蛋白的结合能力进行定量来评估功能受体活化,所述膜蛋白由稳定表达适当人S1P受体的转染CHO或RH7777细胞制备得到。所用的测定技术是SPA(基于闪烁亲近的测定法)。简言之,将DMSO溶解的化合物连续稀释,在50mM Hepes、100mM NaCl、10mM MgCl2、10μM GDP、0.1%无脂肪BSA和0.2nM GTP[γ-35S](1200Ci/mmol)存在下加至SPA-珠粒(Amersham-Pharmacia)固定的表达膜蛋白的S1P受体中(10-20μg/孔)。于RT下在96孔微量滴定板中孵育120分钟后,通过离心步聚分离出未结合的GTP[γ-35S]。用TOPcount读板仪(Packard)对膜结合的GTP[γ-35S]引发的SPA珠粒的发光进行定量。使用标准曲线拟合软件计算EC50。在本测定法中,式I化合物对S1P1受体具有<50nM的结合亲和力。
实施例 | S1P<sub>1</sub>EC<sub>50</sub>[nM] | S1P<sub>3</sub>EC<sub>50</sub>[nM] | S1P<sub>4</sub>EC<sub>50</sub>[nM] | S1P<sub>5</sub>EC<sub>50</sub>[nM] |
36 | 0.6Agon. | 15Agon. | >1000 | 14Agon. |
38 | 8.6Agon. | >1000 | 28Agon. | 11.7Agon. |
42 | 5.5Agon. | >1000 | 8.2Agon. | 6.3Agon. |
43 | 8Agon. | 340Agon. | 43Agon. | 0.5Agon. |
56 | 8.5Agon. | >10000Agon. | 1.6Agon. | 16.5Agon |
Agon.=激动剂
B.体内:血液淋巴细胞减少
通过管饲法向大鼠口服施用式I的化合物或赋形剂。在第1天和施用后2、6、24、48和72小时于大鼠尾部采血进行血液学分析,由第1天的血样得到个体的基线值。在本测定法中,当以0.03至3mg/kg的剂量施用时,式I化合物使外周血液淋巴细胞减少。例如,得到以下结果:外周血液淋巴细胞减少50%以上
实施例1:0.03mg/kg口服6小时后,0.02mg/kg口服24小时后。
实施例3:0.01mg/kg口服6小时后,<0.03mg/kg口服48小时后。
实施例7:0.03mg/kg口服6小时后,0.02mg/kg口服48小时后。
实施例9:0.2mg/kg口服6小时后,>1mg/kg口服48小时后。
实施例53:0.1mg/kg口服6小时后,0.5mg/kg口服48小时后。
因此,式I化合物可用于治疗和/或预防由淋巴细胞相互作用介导的疾病或病症,例如在移植中,如急性或慢性细胞、组织或器官同种异体移植物或异种移植物排斥反应或移植物功能恢复延迟(delayed graft function)、移植物抗宿主病、自身免疫性疾病例如类风湿性关节炎、系统性红斑狼疮、桥本甲状腺炎、多发性硬化症、重症肌无力、I型或II型糖尿病以及与之有关的病症、脉管炎、恶性贫血、干燥综合征、葡萄膜炎、银屑病、格雷夫斯眼病(Graves ophthalmopathy)、局限性脱发等、变应性疾病例如变应性哮喘、特应性皮炎、变应性鼻炎/结膜炎、变应性接触性皮炎、任选地伴有潜在异常反应的炎性疾病例如炎性肠病、局限性回肠炎或溃疡性结肠炎、内源性哮喘、炎性肺损伤、炎性肝损伤、炎性肾小球损伤、动脉粥样硬化、骨关节炎、刺激性接触性皮炎以及进一步的湿疹性皮炎、脂溢性皮炎、免疫介导病症的皮肤症状、炎性眼病、角膜结膜炎、心肌炎或肝炎、局部缺血/再灌注损伤例如心肌梗塞、中风、消化道缺血、肾衰竭或出血性休克、外伤性休克、血管生成、阿尔茨海默病、癌症例如乳腺癌、T细胞淋巴瘤或T细胞白血病、感染性疾病例如中毒性休克(例如超抗原诱发的)、败血症性休克、成人型呼吸窘迫综合征或病毒感染例如AIDS、病毒性肝炎、慢性细菌感染或老年性痴呆。细胞、组织或实体器官移植物的实例包括例如胰岛、干细胞、骨髓、角膜组织、神经元组织、心脏、肺、联合心肺、肾脏、肝脏、肠、胰腺、气管或食管。对于以上用途,所需剂量当然将随着施用方式、所治疗的具体病症以及所需效果的不同而变化。
一般而言,表明在约0.03至2.5mg/kg体重的日剂量下全身性施用可获得令人满意的结果。在较大的哺乳动物例如人中,适用的日剂量是约0.5mg至约100mg,该日剂量可以方便地例如以每天不超过4次的分剂量或以缓释形式被施用。用于口服施用的合适的单位剂量形式包含约0.1至50mg活性成分。
式I化合物可以以任何常规途径施用,特别是经肠、例如口服施用,例如以片剂或胶囊剂形式经肠施用,或者经胃肠外施用,例如以注射用溶液或混悬液形式经胃肠外施用,经局部施用,例如以洗剂、凝胶剂、软膏剂或乳膏剂形式或以鼻用或栓剂形式经局部施用。包含游离形式或可药用盐形式的式I化合物以及至少一种可药用载体或稀释剂的药物组合物可按照常规方法通过与可药用载体或稀释剂混合来制备。
式I化合物可以以游离形式或可药用盐形式施用,例如如上所述的可药用盐形式。这类盐可通过常规方法制备并具有与游离化合物同样数量级的活性。
根据上述内容,本发明还提供了:
1.1在需要这种治疗的个体中预防或治疗由淋巴细胞介导的病症或疾病例如以上所述的那些病症或疾病的方法,该方法包括向所述个体施用有效量的式I化合物或其可药用盐;
1.2在需要这种治疗的个体中预防或治疗急性或慢性移植物排斥反应或T细胞介导的炎性或自身免疫性疾病例如以上所述的那些的方法,该方法包括向所述个体施用有效量的式I化合物或其可药用盐;
2.用作药物的游离形式或可药用盐形式的式I化合物,其例如在以上1.1或1.2项下所述的任一方法中用作药物。
3.一种药物组合物,其包含游离形式或可药用盐形式的式I化合物以及合适的可药用的稀释剂或载体,其例如用于以上1.1或1.2项下所述的任一方法中。
4.式I化合物或其可药用盐,其用于制备用于以上1.1或1.2项下所述的任一方法中的药物组合物。
式I化合物可以作为单独的活性成分施用或例如作为辅剂与其它药物联合施用,所述的其它药物例如免疫抑制剂或免疫调节剂或其它抗炎剂,例如用于治疗或预防同种异体移植物或异种移植物急性或慢性排斥反应或炎性或自身免疫性病症的上述药物,或化学治疗剂例如恶性细胞抗增殖剂。例如,式I化合物可以与以下物质组合使用:钙调磷酸酶抑制剂,例如环孢菌素A、FK 506或ISATX247;mTOR抑制剂,例如雷帕霉素、40-O-(2-羟乙基)-雷帕霉素、CCI779、ABT578、AP23573、AP23464、AP23675、AP23841、TAFA-93、比利莫司(biolimus)7或比利莫司9;具有免疫抑制性质的子囊霉素,例如ABT-281、ASM981等;皮质类固醇;环磷酰胺;硫唑嘌呤;甲氨蝶呤;来氟洛米;咪唑立宾;霉酚酸;霉酚酸酯;15-去氧斯潘格宁或其免疫抑制同系物、类似物或衍生物;免疫抑制单克隆抗体,例如抗白细胞受体例如MHC、CD2、CD3、CD4、CD7、CD8、CD25、CD28、CD40、CD45、CD58、CD80、CD86或它们的配体的单克隆抗体;其它免疫调节化合物,例如具有至少一部分CTLA4或其突变体的胞外结构域、例如具有至少与非-CTLA4蛋白序列结合的CTLA4或其突变体、例如CTLA4Ig(例如称为ATCC 68629)或其突变体、例如LEA29Y的胞外部分的重组结合分子;粘附分子抑制剂,例如LFA-1拮抗剂、ICAM-1或-3拮抗剂、VCAM-4拮抗剂或VLA-4拮抗剂;或化学治疗剂,例如紫杉醇、吉西他滨、顺铂、阿霉素或5-氟脲嘧啶;或抗感染剂。
当式I化合物与其它免疫抑制/免疫调节、抗炎、化学治疗或抗感染疗法联合施用时,共同施用的免疫抑制、免疫调节、抗炎、化学治疗或抗感染化合物的剂量当然将随所共同使用的药物的类型、例如它是甾类化合物还是钙调磷酸酶抑制剂、所用的具体药物、所治疗的病症等的不同而变化。根据上述内容,另一方面,本发明提供了:
5.如上所述的方法,该方法包括共同施用例如并行或相继施用治疗有效且无毒量的式I化合物和至少一种第二种药物物质,例如免疫抑制、免疫调节、抗炎或化学治疗药物,例如以上所述的那些。
6.药物组合,例如套药包,其包括a)第一种活性剂,其是本文所公开的游离形式或可药用盐形式的式I化合物,和b)至少一种联用活性剂,例如免疫抑制、免疫调节、抗炎、化学治疗或抗感染药物。该套药包可以包括关于其施用的说明书。
本文所用的术语“共同施用”或“联合施用”等意指包括向单个患者施用所选择的治疗剂,并旨在包括活性剂不必须通过相同施用途径或同时被施用的治疗方案。
本文所用的术语“药物组合”是指通过将一种以上的活性成分相混合或组合而得到的产物,它包括活性成分的固定组合和非固定组合。术语“固定组合”是指活性成分例如式I的化合物与联用活性剂以单一实体或剂量形式被同时施用于患者。术语“非固定组合”是指活性成分例如式I化合物与联用活性剂作为分开的实体被同时、并行或无特定时间限制地相继施用于患者,其中所述施用在患者体内提供治疗有效水平的2种化合物。后者也适用于组合疗法(cocktail therapy),例如施用3种或更多种活性成分。
Claims (9)
1.游离形式或盐形式的式I化合物:
其中:
R1是C1-6烷基;被羟基、C1-2烷氧基或1至6个氟原子取代的C1-6烷基;C2-6链烯基;或C2-6炔基;
X是O;
Y是O或S;
R2是苯基;萘基;C3-6环烷基;杂芳基;杂环基;苯基C1-2烷基;C3-6环烷基C1-2烷基;杂芳基C1-2烷基;杂环基C1-2烷基;
其中每一个可以被1至5个取代基环取代,所述取代基选自羟基、卤素、C1-4烷基、被1至5个氟原子取代的C1-4烷基、C3-6环烷基、C1-4烷氧基、被1至5个氟原子取代的C1-4烷氧基、C3-6环烷氧基、C3-6环烷基C1-2烷基、氰基、苯基和被羟基、卤素、C1-4烷基、被1至5个氟原子取代的C1-4烷基、C1-4烷氧基、被1至5个氟原子取代的C1-4烷氧基或氰基取代的苯基;
R3是Z-X2,其中Z是CH2、CHF或CF2,且X2是OH或式(a)的残基:
其中Z1是直连键、CH2、CHF、CF2或O,R8和R9各自独立地是H或任选地被1、2或3个卤素原子取代的C1-4烷基;且
R4和R5各自独立地是H;任选地被1、2或3个卤素原子取代的C1-4烷基;或酰基;
R6和R7各自独立地是H;羟基;卤素;C1-4烷基;C1-6环烷基;C1-4烷氧基;
C1-6环烷氧基;C3-6环烷基C1-2烷基;或氰基;且
n是2或3。
2.权利要求1的游离形式或盐形式的式I化合物,其中R2是苯基;被1或2个卤素、C1-2烷基或C1-2烷氧基取代的苯基;氰基苯基;萘基;或苯并[1,3]间二氧杂环戊烯-5-基。
3.权利要求1或2的游离形式或盐形式的化合物,其中R6和R7各自独立地是氢、甲氧基、甲基或氯。
4.权利要求1的游离形式或盐形式的化合物,其中R1是CH3或CH2-OH。
5.权利要求1的游离形式或盐形式的化合物,其中每一R4和R5是氢。
6.权利要求1的游离形式或盐形式的化合物,其中R3是CH2-OH或CH2-OPO3H2。
7.一种药物组合物,其包含权利要求1至6中任意一项的化合物或其可药用盐以及适合的可药用的稀释剂或载体。
8.一种药物组合物,其包含权利要求1至6中任意一项的游离形式或可药用盐形式的化合物和至少一种联用活性剂。
9.根据权利要求1的化合物或其可药用盐的用途,用于制备预防或治疗淋巴细胞介导的病症或疾病、预防或治疗急性或慢性移植物排斥反应或T细胞介导的炎性或自身免疫性疾病的药物.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0309944 | 2003-04-30 | ||
GB0309944.7 | 2003-04-30 | ||
GB0329505.2 | 2003-12-19 | ||
GB0329500A GB0329500D0 (en) | 2003-12-19 | 2003-12-19 | Organic compounds |
GB0329500.3 | 2003-12-19 | ||
GB0329505A GB0329505D0 (en) | 2003-12-19 | 2003-12-19 | Organic compounds |
PCT/EP2004/004569 WO2004096752A1 (en) | 2003-04-30 | 2004-04-29 | Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1777575A CN1777575A (zh) | 2006-05-24 |
CN1777575B true CN1777575B (zh) | 2010-05-12 |
Family
ID=33424535
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2004800110595A Expired - Fee Related CN1777575B (zh) | 2003-04-30 | 2004-04-29 | 作为1-磷酸-鞘氨醇受体调节剂的氨基-丙醇衍生物 |
Country Status (11)
Country | Link |
---|---|
US (1) | US7625950B2 (zh) |
EP (1) | EP1622860B1 (zh) |
JP (1) | JP4603531B2 (zh) |
CN (1) | CN1777575B (zh) |
AT (1) | ATE547395T1 (zh) |
AU (1) | AU2004234066B2 (zh) |
BR (1) | BRPI0410025A (zh) |
CA (1) | CA2523582A1 (zh) |
ES (1) | ES2383298T3 (zh) |
MX (1) | MXPA05011596A (zh) |
WO (1) | WO2004096752A1 (zh) |
Families Citing this family (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1546110A4 (en) | 2002-07-30 | 2008-03-26 | Univ Virginia | ACTIVE COMPOUNDS IN THE SIGNALING OF SPHINGOSINE 1-PHOSPHATE |
ATE547395T1 (de) * | 2003-04-30 | 2012-03-15 | Novartis Pharma Gmbh | Aminopropanol-derivate als modulatoren des sphingosin-1-phosphat-rezeptors |
GB0313612D0 (en) * | 2003-06-12 | 2003-07-16 | Novartis Ag | Organic compounds |
CA2535704C (en) * | 2003-08-28 | 2012-12-11 | Novartis Ag | Aminopropanol derivatives |
WO2005041899A2 (en) | 2003-11-03 | 2005-05-12 | University Of Virginia Patent Foundation | Orally available sphingosine 1-phosphate receptor agonists and antagonists |
GB0329498D0 (en) * | 2003-12-19 | 2004-01-28 | Novartis Ag | Organic compounds |
US8039674B2 (en) | 2004-06-23 | 2011-10-18 | Ono Pharmaceutical Co., Ltd. | Compound having S1P receptor binding potency and use thereof |
KR101178318B1 (ko) * | 2004-07-16 | 2012-08-29 | 교린 세이야꾸 가부시키 가이샤 | 효과적인 의약의 사용법 및 부작용 발현의 방어에 관한방법 |
KR20070058455A (ko) | 2004-08-13 | 2007-06-08 | 프래시스 파마슈티컬즈 인코포레이티드 | 스핑고신-1-포스페이트(s1p) 수용체 활성을 조절하기위한 방법 및 조성물 |
EP1806338B1 (en) | 2004-10-12 | 2016-01-20 | Kyorin Pharmaceutical Co., Ltd. | Process for producing 2-amino-2-[2-[4-(3-benzyloxy-phenylthio)-2-chlorophenyl[ethyl]-1,3-propanediol hydrochloride and hydrates thereof. and intermediates the production thereof |
AU2006214314B2 (en) | 2005-02-14 | 2012-02-09 | University Of Virginia Patent Foundation | Sphingosine 1- phos phate agonists comprising cycloalkanes and 5 -membered heterocycles substituted by amino and phenyl groups |
GB0513431D0 (en) | 2005-06-30 | 2005-08-10 | Kherion Technology Ltd | Prophylactic compositions and uses |
AU2006300485B2 (en) * | 2005-10-07 | 2011-08-25 | Kyorin Pharmaceutical Co., Ltd. | Therapeutic agent for liver disease containing 2-amino-1,3-propanediol derivative as active ingredient and therapeutic method for liver disease |
ES2369520T3 (es) | 2005-12-15 | 2011-12-01 | Mitsubishi Tanabe Pharma Corporation | Compuesto amínico y su uso para propósitos médicos. |
JP2009528274A (ja) | 2006-01-27 | 2009-08-06 | ユニバーシティ オブ バージニア パテント ファンデーション | 神経因性疼痛の治療法 |
TWI389683B (zh) * | 2006-02-06 | 2013-03-21 | Kyorin Seiyaku Kk | A therapeutic agent for an inflammatory bowel disease or an inflammatory bowel disease treatment using a 2-amino-1,3-propanediol derivative as an active ingredient |
CA2641718A1 (en) | 2006-02-09 | 2007-08-16 | University Of Virginia Patent Foundation | Bicyclic sphingosine 1-phosphate analogs |
US8097644B2 (en) | 2006-03-28 | 2012-01-17 | Allergan, Inc. | Indole compounds having sphingosine-1-phosphate (S1P) receptor antagonist |
US8232319B2 (en) | 2006-08-08 | 2012-07-31 | Kyorin Pharmaceutical Co., Ltd. | Amino phosphate derivative and S1P receptor modulator having same as an active ingredient |
NZ574012A (en) | 2006-08-08 | 2012-02-24 | Kyorin Seiyaku Kk | Aminoalcohol derivative and immunosuppressant containing the same as active ingredient |
EP2097397A1 (en) | 2006-11-21 | 2009-09-09 | University Of Virginia Patent Foundation | Tetralin analogs having sphingosine 1-phosphate agonist activity |
CA2669124A1 (en) | 2006-11-21 | 2008-05-29 | University Of Virginia Patent Foundation | Benzocycloheptyl analogs having sphingosine 1-phosphate receptor activity |
EP2099741A2 (en) | 2006-11-21 | 2009-09-16 | University Of Virginia Patent Foundation | Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity |
US8524917B2 (en) | 2007-01-11 | 2013-09-03 | Allergan, Inc. | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity |
CN101730677B (zh) * | 2007-06-14 | 2014-07-16 | 田边三菱制药株式会社 | 胺化合物及其药物应用 |
BRPI0817397A2 (pt) | 2007-09-24 | 2015-04-07 | Allergan Inc | Compostos indol contendo grupos arila ou heteroarila com atividade biológica do receptor de esfingosina-1-fosfato (sip) |
WO2009099174A1 (ja) | 2008-02-07 | 2009-08-13 | Kyorin Pharmaceutical Co., Ltd. | アミノアルコール誘導体を有効成分とする炎症性腸疾患の治療剤又は予防剤 |
AU2009244538A1 (en) | 2008-05-08 | 2009-11-12 | Allergan, Inc. | Therapeutically useful substituted 1, 7-diphenyl-l, 2, 3, 5, 6, 7-hexahydropyrido [ 3, 2, 1-I J ] quinoline compounds |
US8143291B2 (en) | 2008-05-09 | 2012-03-27 | Allergan, Inc. | Indole compounds bearing aryl or heteroaryl groups having sphingosine-1-phosphate (S1P) receptor biological activity |
KR20180023049A (ko) | 2008-07-23 | 2018-03-06 | 아레나 파마슈티칼스, 인크. | 자가면역성 및 염증성의 장애의 치료에 유용한 치환된 1,2,3,4-테트라히드로시클로펜타[b]인돌-3-일)아세트산 유도체 |
EP2342205B1 (en) | 2008-08-27 | 2016-04-20 | Arena Pharmaceuticals, Inc. | Substituted tricyclic acid derivatives as s1p1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders |
RU2012119249A (ru) * | 2009-10-23 | 2013-11-27 | Аллерган, Инк. | Соединения кумарина в качестве модуляторов рецепторов для терапевтического использования |
BR122013016024A2 (pt) * | 2009-12-10 | 2016-05-10 | Novartis Ag | composições, usos, kit e processos de preparação relacionados com derivados halogenados de fty720 |
EP4148045A1 (en) | 2010-01-27 | 2023-03-15 | Arena Pharmaceuticals, Inc. | Intermediate compounds for the preparation of (r)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b] indol-3-yl)acetic acid and salts thereof |
SG10201501575VA (en) | 2010-03-03 | 2015-04-29 | Arena Pharm Inc | Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof |
CN102260178A (zh) * | 2010-05-25 | 2011-11-30 | 中国医学科学院药物研究所 | 羟基丙二醇类衍生物、其制备方法和其药物组合物与用途 |
JP6895378B2 (ja) | 2015-01-06 | 2021-06-30 | アリーナ ファーマシューティカルズ, インコーポレイテッド | S1p1受容体に関連する状態の処置方法 |
EP3939965A1 (en) | 2015-06-22 | 2022-01-19 | Arena Pharmaceuticals, Inc. | Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid for use in sipi receptor-associated disorders |
CN110520124A (zh) | 2017-02-16 | 2019-11-29 | 艾尼纳制药公司 | 用于治疗原发性胆汁性胆管炎的化合物和方法 |
WO2018151834A1 (en) | 2017-02-16 | 2018-08-23 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of inflammatory bowel disease with extra-intestinal manifestations |
KR20210074291A (ko) | 2018-09-06 | 2021-06-21 | 아레나 파마슈티칼스, 인크. | 자가면역 및 염증성 장애의 치료에 유용한 화합물 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0778263A1 (en) * | 1994-08-22 | 1997-06-11 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzene compound and medicinal use thereof |
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 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2309868A (en) * | 1996-01-30 | 1997-08-06 | Sony Corp | Radio receiver detects FCCH synchronising signal |
ES2243370T3 (es) | 1997-04-10 | 2005-12-01 | PHARMACIA & UPJOHN COMPANY LLC | Composiciones poliaromaticas para el tratamiento de infecciones por virus herpes. |
ATE314383T1 (de) | 2001-03-26 | 2006-01-15 | Novartis Pharma Gmbh | 2-amino-propanol derivate |
JP2002316985A (ja) * | 2001-04-20 | 2002-10-31 | Sankyo Co Ltd | ベンゾチオフェン誘導体 |
US6960692B2 (en) * | 2001-09-27 | 2005-11-01 | Kyorin Pharmaceutical Co., Ltd. | Diaryl sulfide derivative, addition salt thereof, and immunosuppressant |
WO2003029184A1 (fr) * | 2001-09-27 | 2003-04-10 | Kyorin Pharmaceutical Co., Ltd. | Derive d'ether de diaryle, son sel d'addition et son immunosuppresseur |
JP4166218B2 (ja) | 2002-09-13 | 2008-10-15 | ノバルティス アクチエンゲゼルシャフト | アミノ−プロパノール誘導体 |
ATE547395T1 (de) * | 2003-04-30 | 2012-03-15 | Novartis Pharma Gmbh | Aminopropanol-derivate als modulatoren des sphingosin-1-phosphat-rezeptors |
-
2004
- 2004-04-29 AT AT04730206T patent/ATE547395T1/de active
- 2004-04-29 WO PCT/EP2004/004569 patent/WO2004096752A1/en active Search and Examination
- 2004-04-29 AU AU2004234066A patent/AU2004234066B2/en not_active Ceased
- 2004-04-29 CA CA002523582A patent/CA2523582A1/en not_active Abandoned
- 2004-04-29 ES ES04730206T patent/ES2383298T3/es not_active Expired - Lifetime
- 2004-04-29 CN CN2004800110595A patent/CN1777575B/zh not_active Expired - Fee Related
- 2004-04-29 US US10/554,556 patent/US7625950B2/en not_active Expired - Fee Related
- 2004-04-29 MX MXPA05011596A patent/MXPA05011596A/es active IP Right Grant
- 2004-04-29 EP EP04730206A patent/EP1622860B1/en not_active Expired - Lifetime
- 2004-04-29 JP JP2006505327A patent/JP4603531B2/ja not_active Expired - Fee Related
- 2004-04-29 BR BRPI0410025-5A patent/BRPI0410025A/pt not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0778263A1 (en) * | 1994-08-22 | 1997-06-11 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzene compound and medicinal use thereof |
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 |
Also Published As
Publication number | Publication date |
---|---|
ATE547395T1 (de) | 2012-03-15 |
JP4603531B2 (ja) | 2010-12-22 |
CA2523582A1 (en) | 2004-11-11 |
AU2004234066A1 (en) | 2004-11-11 |
BRPI0410025A (pt) | 2006-04-25 |
US20060211658A1 (en) | 2006-09-21 |
US7625950B2 (en) | 2009-12-01 |
MXPA05011596A (es) | 2006-01-23 |
AU2004234066B2 (en) | 2008-02-21 |
ES2383298T3 (es) | 2012-06-20 |
WO2004096752A1 (en) | 2004-11-11 |
EP1622860A1 (en) | 2006-02-08 |
JP2006524660A (ja) | 2006-11-02 |
EP1622860B1 (en) | 2012-02-29 |
CN1777575A (zh) | 2006-05-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1777575B (zh) | 作为1-磷酸-鞘氨醇受体调节剂的氨基-丙醇衍生物 | |
CN100516024C (zh) | 氨基-丙醇衍生物 | |
CN100358861C (zh) | 作为1-磷酸鞘氨醇受体调节剂的氨基-丙醇衍生物 | |
EP1622866B1 (en) | Aminopropanol derivatives as sphingosine-1-phosphate receptor modulators | |
EP1377593B1 (en) | 2-amino-propanol derivatives | |
CN100575335C (zh) | 氨基-丙醇衍生物 | |
US20070135501A1 (en) | Amino acid derivatives | |
AU2002257719A1 (en) | 2-amino-propanol derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100512 Termination date: 20130429 |