NO320028B1 - Substituerte 1-Okso- og 1,3-dioksoisoindoliner og deres anvendelse i farmasoytiske preparater for a redusere inflammatoriske cykotin nivaer - Google Patents
Substituerte 1-Okso- og 1,3-dioksoisoindoliner og deres anvendelse i farmasoytiske preparater for a redusere inflammatoriske cykotin nivaer Download PDFInfo
- Publication number
- NO320028B1 NO320028B1 NO20013982A NO20013982A NO320028B1 NO 320028 B1 NO320028 B1 NO 320028B1 NO 20013982 A NO20013982 A NO 20013982A NO 20013982 A NO20013982 A NO 20013982A NO 320028 B1 NO320028 B1 NO 320028B1
- Authority
- NO
- Norway
- Prior art keywords
- acid
- dioxoisoindolin
- oxoisoindolin
- carbamoylbutanoic
- nitro
- Prior art date
Links
- 230000002757 inflammatory effect Effects 0.000 title claims abstract description 12
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 6
- 108090000695 Cytokines Proteins 0.000 claims abstract description 15
- 102000004127 Cytokines Human genes 0.000 claims abstract description 14
- 241000124008 Mammalia Species 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- XMKUEWQZKLDLQQ-UHFFFAOYSA-N 5-amino-2-(4-nitro-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical group C1=CC([N+]([O-])=O)=C2C(=O)N(C(CCC(=O)N)C(O)=O)C(=O)C2=C1 XMKUEWQZKLDLQQ-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- WHGCSJYLVKPHSS-UHFFFAOYSA-N 2-(4-nitro-1,3-dioxoisoindol-2-yl)pentanedioic acid Chemical group C1=CC([N+]([O-])=O)=C2C(=O)N(C(CCC(=O)O)C(O)=O)C(=O)C2=C1 WHGCSJYLVKPHSS-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- XSKMMEVRGHPMSJ-UHFFFAOYSA-N 5-amino-2-(4-amino-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical group C1=CC(N)=C2C(=O)N(C(CCC(=O)N)C(O)=O)C(=O)C2=C1 XSKMMEVRGHPMSJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- XYCTTXSUXYHEGZ-UHFFFAOYSA-N 4-amino-2-(4-amino-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical group C1=CC(N)=C2C(=O)N(C(CC(=O)N)C(O)=O)C(=O)C2=C1 XYCTTXSUXYHEGZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- CASOMQVHZDICDH-UHFFFAOYSA-N 5-amino-2-(4-methyl-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical group CC1=CC=CC2=C1C(=O)N(C(CCC(N)=O)C(O)=O)C2=O CASOMQVHZDICDH-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- GMZFKVRMIVHGOK-UHFFFAOYSA-N 2-(4-methyl-1,3-dioxoisoindol-2-yl)pentanedioic acid Chemical group CC1=CC=CC2=C1C(=O)N(C(CCC(O)=O)C(O)=O)C2=O GMZFKVRMIVHGOK-UHFFFAOYSA-N 0.000 claims description 2
- HNVVLGMTFHERFZ-UHFFFAOYSA-N 4-amino-3-methyl-2-(4-nitro-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical group C1=CC([N+]([O-])=O)=C2C(=O)N(C(C(C)C(N)=O)C(O)=O)C(=O)C2=C1 HNVVLGMTFHERFZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 51
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 abstract description 51
- JVYMXRZSOURPSE-UHFFFAOYSA-N 5-amino-4-(4-amino-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical group C1=CC(N)=C2C(=O)N(C(CCC(O)=O)C(=O)N)C(=O)C2=C1 JVYMXRZSOURPSE-UHFFFAOYSA-N 0.000 abstract description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 abstract 1
- 230000033115 angiogenesis Effects 0.000 description 24
- 206010028980 Neoplasm Diseases 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- 238000011282 treatment Methods 0.000 description 23
- 201000010099 disease Diseases 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 21
- 241000725303 Human immunodeficiency virus Species 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 13
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 13
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 13
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 13
- 201000011510 cancer Diseases 0.000 description 13
- 239000001384 succinic acid Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 210000001744 T-lymphocyte Anatomy 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 108700012920 TNF Proteins 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 208000030507 AIDS Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 208000031886 HIV Infections Diseases 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 230000010076 replication Effects 0.000 description 7
- -1 tetrahydrocortisol Chemical class 0.000 description 7
- 230000004614 tumor growth Effects 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- ROFZMKDROVBLNY-UHFFFAOYSA-N 4-nitro-2-benzofuran-1,3-dione Chemical compound [O-][N+](=O)C1=CC=CC2=C1C(=O)OC2=O ROFZMKDROVBLNY-UHFFFAOYSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 210000002889 endothelial cell Anatomy 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 208000024908 graft versus host disease Diseases 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- JDVPQXZIJDEHAN-UHFFFAOYSA-N succinamic acid Chemical compound NC(=O)CCC(O)=O JDVPQXZIJDEHAN-UHFFFAOYSA-N 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 206010029113 Neovascularisation Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 4
- 206010040070 Septic Shock Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000004037 angiogenesis inhibitor Substances 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 229960002989 glutamic acid Drugs 0.000 description 4
- GTFMAONWNTUZEW-UHFFFAOYSA-N glutaramic acid Chemical compound NC(=O)CCCC(O)=O GTFMAONWNTUZEW-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 201000004792 malaria Diseases 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000035939 shock Effects 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 230000006433 tumor necrosis factor production Effects 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 3
- WSZDWVVHNBZAEC-UHFFFAOYSA-N 4-amino-2-(4-nitro-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC([N+]([O-])=O)=C2C(=O)N(C(CC(=O)N)C(O)=O)C(=O)C2=C1 WSZDWVVHNBZAEC-UHFFFAOYSA-N 0.000 description 3
- 206010006895 Cachexia Diseases 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 230000006820 DNA synthesis Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 208000009329 Graft vs Host Disease Diseases 0.000 description 3
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000001388 Opportunistic Infections Diseases 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 230000018199 S phase Effects 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 239000003974 emollient agent Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 102000057041 human TNF Human genes 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229960004023 minocycline Drugs 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000001613 neoplastic effect Effects 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 230000000451 tissue damage Effects 0.000 description 3
- 231100000827 tissue damage Toxicity 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- KQOKYLBWODYVIR-UHFFFAOYSA-N 2-(4-amino-1,3-dioxoisoindol-2-yl)pentanedioic acid Chemical compound NC1=CC=CC2=C1C(=O)N(C(CCC(O)=O)C(O)=O)C2=O KQOKYLBWODYVIR-UHFFFAOYSA-N 0.000 description 2
- JGYBMOPXWMVNLQ-UHFFFAOYSA-N 4-amino-2-(1,3-dioxo-4-propan-2-ylisoindol-2-yl)-4-oxobutanoic acid Chemical compound CC(C)C1=CC=CC2=C1C(=O)N(C(CC(N)=O)C(O)=O)C2=O JGYBMOPXWMVNLQ-UHFFFAOYSA-N 0.000 description 2
- IFDZOMVNICEWHH-UHFFFAOYSA-N 5-amino-4-(4-nitro-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC([N+]([O-])=O)=C2C(=O)N(C(CCC(O)=O)C(=O)N)C(=O)C2=C1 IFDZOMVNICEWHH-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 101100002068 Bacillus subtilis (strain 168) araR gene Proteins 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 206010014824 Endotoxic shock Diseases 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- AEFLONBTGZFSGQ-VKHMYHEASA-N L-isoglutamine Chemical compound NC(=O)[C@@H](N)CCC(O)=O AEFLONBTGZFSGQ-VKHMYHEASA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010024229 Leprosy Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 102000007327 Protamines Human genes 0.000 description 2
- 108010007568 Protamines Proteins 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000006044 T cell activation Effects 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 230000002491 angiogenic effect Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 101150044616 araC gene Proteins 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000009739 binding Methods 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 210000004087 cornea Anatomy 0.000 description 2
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 229960005304 fludarabine phosphate Drugs 0.000 description 2
- NGGMYCMLYOUNGM-CSDLUJIJSA-N fumagillin Chemical compound C([C@H]([C@H]([C@@H]1[C@]2(C)[C@H](O2)CC=C(C)C)OC)OC(=O)\C=C\C=C\C=C\C=C\C(O)=O)C[C@@]21CO2 NGGMYCMLYOUNGM-CSDLUJIJSA-N 0.000 description 2
- 108091006104 gene-regulatory proteins Proteins 0.000 description 2
- 102000034356 gene-regulatory proteins Human genes 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical group C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000007302 negative regulation of cytokine production Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000002947 procoagulating effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940048914 protamine Drugs 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000005588 protonation Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 230000036303 septic shock Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- NGGMYCMLYOUNGM-UHFFFAOYSA-N (-)-fumagillin Natural products O1C(CC=C(C)C)C1(C)C1C(OC)C(OC(=O)C=CC=CC=CC=CC(O)=O)CCC21CO2 NGGMYCMLYOUNGM-UHFFFAOYSA-N 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- AODPIQQILQLWGS-UHFFFAOYSA-N (3alpa,5beta,11beta,17alphaOH)-form-3,11,17,21-Tetrahydroxypregnan-20-one, Natural products C1C(O)CCC2(C)C3C(O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC21 AODPIQQILQLWGS-UHFFFAOYSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- 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 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical class O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- KYTQRLKXTUZCIH-UHFFFAOYSA-N 2-(1,3-dioxo-4-propan-2-ylisoindol-2-yl)butanedioic acid Chemical compound CC(C)C1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(O)=O)C2=O KYTQRLKXTUZCIH-UHFFFAOYSA-N 0.000 description 1
- XVZAVIHBETVGSQ-UHFFFAOYSA-N 2-(1,3-dioxo-4-propylisoindol-2-yl)butanedioic acid Chemical compound CCCC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(O)=O)C2=O XVZAVIHBETVGSQ-UHFFFAOYSA-N 0.000 description 1
- PLVWEGSABPGFJW-UHFFFAOYSA-N 2-(1-amino-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound C1=CC=C2C(N)N(C(CC(O)=O)C(O)=O)C(=O)C2=C1 PLVWEGSABPGFJW-UHFFFAOYSA-N 0.000 description 1
- YYJRIODZWRNGBD-UHFFFAOYSA-N 2-(1-amino-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound C1=CC=C2C(N)N(C(CCC(O)=O)C(O)=O)C(=O)C2=C1 YYJRIODZWRNGBD-UHFFFAOYSA-N 0.000 description 1
- RHNSEIYTDIYOSC-UHFFFAOYSA-N 2-(1-butyl-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound C1=CC=C2C(CCCC)N(C(CC(O)=O)C(O)=O)C(=O)C2=C1 RHNSEIYTDIYOSC-UHFFFAOYSA-N 0.000 description 1
- VPXSIRYZDVCLNB-UHFFFAOYSA-N 2-(1-butyl-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound C1=CC=C2C(CCCC)N(C(CCC(O)=O)C(O)=O)C(=O)C2=C1 VPXSIRYZDVCLNB-UHFFFAOYSA-N 0.000 description 1
- XTELVOMYAQKLHC-UHFFFAOYSA-N 2-(1-ethyl-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound C1=CC=C2C(CC)N(C(CC(O)=O)C(O)=O)C(=O)C2=C1 XTELVOMYAQKLHC-UHFFFAOYSA-N 0.000 description 1
- CBURZBDLOCAYSJ-UHFFFAOYSA-N 2-(1-ethyl-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound C1=CC=C2C(CC)N(C(CCC(O)=O)C(O)=O)C(=O)C2=C1 CBURZBDLOCAYSJ-UHFFFAOYSA-N 0.000 description 1
- TVUKAZVBQDDPEV-UHFFFAOYSA-N 2-(1-methyl-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound C1=CC=C2C(C)N(C(CC(O)=O)C(O)=O)C(=O)C2=C1 TVUKAZVBQDDPEV-UHFFFAOYSA-N 0.000 description 1
- HARWOAUWXHDTRW-UHFFFAOYSA-N 2-(1-methyl-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound C1=CC=C2C(C)N(C(CCC(O)=O)C(O)=O)C(=O)C2=C1 HARWOAUWXHDTRW-UHFFFAOYSA-N 0.000 description 1
- FLBSTNAYHCCMBD-UHFFFAOYSA-N 2-(1-nitro-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound C1=CC=C2C(=O)N(C(CC(=O)O)C(O)=O)C([N+]([O-])=O)C2=C1 FLBSTNAYHCCMBD-UHFFFAOYSA-N 0.000 description 1
- SDKFMKDRYPLOKB-UHFFFAOYSA-N 2-(1-nitro-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound C1=CC=C2C(=O)N(C(CCC(=O)O)C(O)=O)C([N+]([O-])=O)C2=C1 SDKFMKDRYPLOKB-UHFFFAOYSA-N 0.000 description 1
- PTWHGLJVRQLOAF-UHFFFAOYSA-N 2-(3-oxo-1-propan-2-yl-1h-isoindol-2-yl)butanedioic acid Chemical compound C1=CC=C2C(C(C)C)N(C(CC(O)=O)C(O)=O)C(=O)C2=C1 PTWHGLJVRQLOAF-UHFFFAOYSA-N 0.000 description 1
- YRLKPJRSSATUAL-UHFFFAOYSA-N 2-(3-oxo-1-propan-2-yl-1h-isoindol-2-yl)pentanedioic acid Chemical compound C1=CC=C2C(C(C)C)N(C(CCC(O)=O)C(O)=O)C(=O)C2=C1 YRLKPJRSSATUAL-UHFFFAOYSA-N 0.000 description 1
- WERMFFKHAYXENH-UHFFFAOYSA-N 2-(3-oxo-1-propyl-1h-isoindol-2-yl)butanedioic acid Chemical compound C1=CC=C2C(CCC)N(C(CC(O)=O)C(O)=O)C(=O)C2=C1 WERMFFKHAYXENH-UHFFFAOYSA-N 0.000 description 1
- BKMMKUKELLCLIC-UHFFFAOYSA-N 2-(3-oxo-1-propyl-1h-isoindol-2-yl)pentanedioic acid Chemical compound C1=CC=C2C(CCC)N(C(CCC(O)=O)C(O)=O)C(=O)C2=C1 BKMMKUKELLCLIC-UHFFFAOYSA-N 0.000 description 1
- JGGAJJQYFLPBTA-UHFFFAOYSA-N 2-(3-oxo-7-propan-2-yl-1h-isoindol-2-yl)butanedioic acid Chemical compound CC(C)C1=CC=CC2=C1CN(C(CC(O)=O)C(O)=O)C2=O JGGAJJQYFLPBTA-UHFFFAOYSA-N 0.000 description 1
- WMAKZCILZQLGHS-UHFFFAOYSA-N 2-(3-oxo-7-propan-2-yl-1h-isoindol-2-yl)pentanedioic acid Chemical compound CC(C)C1=CC=CC2=C1CN(C(CCC(O)=O)C(O)=O)C2=O WMAKZCILZQLGHS-UHFFFAOYSA-N 0.000 description 1
- GYLXJKMUPUSVSZ-UHFFFAOYSA-N 2-(3-oxo-7-propyl-1h-isoindol-2-yl)pentanedioic acid Chemical compound CCCC1=CC=CC2=C1CN(C(CCC(O)=O)C(O)=O)C2=O GYLXJKMUPUSVSZ-UHFFFAOYSA-N 0.000 description 1
- NMDGAMYAKJIZPQ-UHFFFAOYSA-N 2-(4-amino-1,3-dioxoisoindol-2-yl)butanedioic acid Chemical compound NC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(O)=O)C2=O NMDGAMYAKJIZPQ-UHFFFAOYSA-N 0.000 description 1
- BGQJBSGIZKROSB-UHFFFAOYSA-N 2-(4-butyl-1,3-dioxoisoindol-2-yl)butanedioic acid Chemical compound CCCCC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(O)=O)C2=O BGQJBSGIZKROSB-UHFFFAOYSA-N 0.000 description 1
- LJFAWJBCIOOZIZ-UHFFFAOYSA-N 2-(4-ethyl-1,3-dioxoisoindol-2-yl)butanedioic acid Chemical compound CCC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(O)=O)C2=O LJFAWJBCIOOZIZ-UHFFFAOYSA-N 0.000 description 1
- JPNGOBFHKWUBEL-UHFFFAOYSA-N 2-(4-methyl-1,3-dioxoisoindol-2-yl)butanedioic acid Chemical compound CC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(O)=O)C2=O JPNGOBFHKWUBEL-UHFFFAOYSA-N 0.000 description 1
- ORDUWGYROYYTAZ-UHFFFAOYSA-N 2-(4-nitro-1,3-dioxoisoindol-2-yl)butanedioic acid Chemical compound C1=CC([N+]([O-])=O)=C2C(=O)N(C(CC(=O)O)C(O)=O)C(=O)C2=C1 ORDUWGYROYYTAZ-UHFFFAOYSA-N 0.000 description 1
- SLIHQYUOOBCMQU-UHFFFAOYSA-N 2-(7-amino-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound NC1=CC=CC2=C1CN(C(CC(O)=O)C(O)=O)C2=O SLIHQYUOOBCMQU-UHFFFAOYSA-N 0.000 description 1
- DVFZIZCDDQITQV-UHFFFAOYSA-N 2-(7-amino-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound NC1=CC=CC2=C1CN(C(CCC(O)=O)C(O)=O)C2=O DVFZIZCDDQITQV-UHFFFAOYSA-N 0.000 description 1
- XXKIWUVNTNBKAG-UHFFFAOYSA-N 2-(7-butyl-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound CCCCC1=CC=CC2=C1CN(C(CC(O)=O)C(O)=O)C2=O XXKIWUVNTNBKAG-UHFFFAOYSA-N 0.000 description 1
- KCMJXUDGFZVBLE-UHFFFAOYSA-N 2-(7-ethyl-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound CCC1=CC=CC2=C1CN(C(CC(O)=O)C(O)=O)C2=O KCMJXUDGFZVBLE-UHFFFAOYSA-N 0.000 description 1
- AFVIQGZDTJYYAY-UHFFFAOYSA-N 2-(7-ethyl-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound CCC1=CC=CC2=C1CN(C(CCC(O)=O)C(O)=O)C2=O AFVIQGZDTJYYAY-UHFFFAOYSA-N 0.000 description 1
- STVHSDXZBYRNSN-UHFFFAOYSA-N 2-(7-methyl-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound CC1=CC=CC2=C1CN(C(CC(O)=O)C(O)=O)C2=O STVHSDXZBYRNSN-UHFFFAOYSA-N 0.000 description 1
- CZSOXNBJESOPRV-UHFFFAOYSA-N 2-(7-methyl-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound CC1=CC=CC2=C1CN(C(CCC(O)=O)C(O)=O)C2=O CZSOXNBJESOPRV-UHFFFAOYSA-N 0.000 description 1
- QGAAJLZWQIATLL-UHFFFAOYSA-N 2-(7-nitro-3-oxo-1h-isoindol-2-yl)butanedioic acid Chemical compound O=C1N(C(CC(=O)O)C(O)=O)CC2=C1C=CC=C2[N+]([O-])=O QGAAJLZWQIATLL-UHFFFAOYSA-N 0.000 description 1
- RZPMMKDWVZJPMQ-UHFFFAOYSA-N 2-(7-nitro-3-oxo-1h-isoindol-2-yl)pentanedioic acid Chemical compound O=C1N(C(CCC(=O)O)C(O)=O)CC2=C1C=CC=C2[N+]([O-])=O RZPMMKDWVZJPMQ-UHFFFAOYSA-N 0.000 description 1
- KLOWCYYNFIUKMV-UHFFFAOYSA-N 4-amino-2-(1,3-dioxo-4-propylisoindol-2-yl)-4-oxobutanoic acid Chemical compound CCCC1=CC=CC2=C1C(=O)N(C(CC(N)=O)C(O)=O)C2=O KLOWCYYNFIUKMV-UHFFFAOYSA-N 0.000 description 1
- CLPYCGWFQRTVJR-UHFFFAOYSA-N 4-amino-2-(1-butyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC=C2C(CCCC)N(C(CC(N)=O)C(O)=O)C(=O)C2=C1 CLPYCGWFQRTVJR-UHFFFAOYSA-N 0.000 description 1
- KFPOJOUMQLYVGQ-UHFFFAOYSA-N 4-amino-2-(1-ethyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC=C2C(CC)N(C(CC(N)=O)C(O)=O)C(=O)C2=C1 KFPOJOUMQLYVGQ-UHFFFAOYSA-N 0.000 description 1
- TXWFFPPYDGKGNS-UHFFFAOYSA-N 4-amino-2-(1-methyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC=C2C(C)N(C(CC(N)=O)C(O)=O)C(=O)C2=C1 TXWFFPPYDGKGNS-UHFFFAOYSA-N 0.000 description 1
- FKNCRAPKSWWHJH-UHFFFAOYSA-N 4-amino-2-(1-nitro-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC=C2C(=O)N(C(CC(=O)N)C(O)=O)C([N+]([O-])=O)C2=C1 FKNCRAPKSWWHJH-UHFFFAOYSA-N 0.000 description 1
- YJVAEMRBOALCAK-UHFFFAOYSA-N 4-amino-2-(4-butyl-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical compound CCCCC1=CC=CC2=C1C(=O)N(C(CC(N)=O)C(O)=O)C2=O YJVAEMRBOALCAK-UHFFFAOYSA-N 0.000 description 1
- ZJIUIECPCFMEGR-UHFFFAOYSA-N 4-amino-2-(4-ethyl-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical compound CCC1=CC=CC2=C1C(=O)N(C(CC(N)=O)C(O)=O)C2=O ZJIUIECPCFMEGR-UHFFFAOYSA-N 0.000 description 1
- GZGWYHVMSPVTPV-UHFFFAOYSA-N 4-amino-2-(4-methyl-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical compound CC1=CC=CC2=C1C(=O)N(C(CC(N)=O)C(O)=O)C2=O GZGWYHVMSPVTPV-UHFFFAOYSA-N 0.000 description 1
- DUBQMVCLIXQMAZ-UHFFFAOYSA-N 4-amino-2-(7-butyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound CCCCC1=CC=CC2=C1CN(C(CC(N)=O)C(O)=O)C2=O DUBQMVCLIXQMAZ-UHFFFAOYSA-N 0.000 description 1
- SESBOAOAHMISPK-UHFFFAOYSA-N 4-amino-2-(7-ethyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound CCC1=CC=CC2=C1CN(C(CC(N)=O)C(O)=O)C2=O SESBOAOAHMISPK-UHFFFAOYSA-N 0.000 description 1
- SRWBJIUCNSXICI-UHFFFAOYSA-N 4-amino-2-(7-methyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound CC1=CC=CC2=C1CN(C(CC(N)=O)C(O)=O)C2=O SRWBJIUCNSXICI-UHFFFAOYSA-N 0.000 description 1
- JYECEBQEZVTVLL-UHFFFAOYSA-N 4-amino-3-(1,3-dioxo-4-propylisoindol-2-yl)-4-oxobutanoic acid Chemical compound CCCC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(N)=O)C2=O JYECEBQEZVTVLL-UHFFFAOYSA-N 0.000 description 1
- DWUXFEUMEBTEQS-UHFFFAOYSA-N 4-amino-3-(1-butyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC=C2C(CCCC)N(C(CC(O)=O)C(N)=O)C(=O)C2=C1 DWUXFEUMEBTEQS-UHFFFAOYSA-N 0.000 description 1
- GHBGLFOQDFLIIH-UHFFFAOYSA-N 4-amino-3-(1-ethyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC=C2C(CC)N(C(CC(O)=O)C(N)=O)C(=O)C2=C1 GHBGLFOQDFLIIH-UHFFFAOYSA-N 0.000 description 1
- PSJQSQXVGHSRDH-UHFFFAOYSA-N 4-amino-3-(1-methyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC=C2C(C)N(C(CC(O)=O)C(N)=O)C(=O)C2=C1 PSJQSQXVGHSRDH-UHFFFAOYSA-N 0.000 description 1
- KAVNWXNGATWEDC-UHFFFAOYSA-N 4-amino-3-(1-nitro-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC=C2C(=O)N(C(CC(O)=O)C(=O)N)C([N+]([O-])=O)C2=C1 KAVNWXNGATWEDC-UHFFFAOYSA-N 0.000 description 1
- YNHQXGZFCAVLPS-UHFFFAOYSA-N 4-amino-3-(4-butyl-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical compound CCCCC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(N)=O)C2=O YNHQXGZFCAVLPS-UHFFFAOYSA-N 0.000 description 1
- ATQTVFLGHXKDJN-UHFFFAOYSA-N 4-amino-3-(4-ethyl-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical compound CCC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(N)=O)C2=O ATQTVFLGHXKDJN-UHFFFAOYSA-N 0.000 description 1
- PPLZIAGPLUZTHN-UHFFFAOYSA-N 4-amino-3-(4-methyl-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical compound CC1=CC=CC2=C1C(=O)N(C(CC(O)=O)C(N)=O)C2=O PPLZIAGPLUZTHN-UHFFFAOYSA-N 0.000 description 1
- ZYANIBLPALGOHP-UHFFFAOYSA-N 4-amino-3-(4-nitro-1,3-dioxoisoindol-2-yl)-4-oxobutanoic acid Chemical compound C1=CC([N+]([O-])=O)=C2C(=O)N(C(CC(O)=O)C(=O)N)C(=O)C2=C1 ZYANIBLPALGOHP-UHFFFAOYSA-N 0.000 description 1
- QEHUAODMRQTLGW-UHFFFAOYSA-N 4-amino-3-(7-ethyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound CCC1=CC=CC2=C1CN(C(CC(O)=O)C(N)=O)C2=O QEHUAODMRQTLGW-UHFFFAOYSA-N 0.000 description 1
- IPKMFRMLEYPICM-UHFFFAOYSA-N 4-amino-3-(7-methyl-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound CC1=CC=CC2=C1CN(C(CC(O)=O)C(N)=O)C2=O IPKMFRMLEYPICM-UHFFFAOYSA-N 0.000 description 1
- PJDGSDCRBKAJDH-UHFFFAOYSA-N 4-amino-3-(7-nitro-3-oxo-1h-isoindol-2-yl)-4-oxobutanoic acid Chemical compound O=C1N(C(CC(O)=O)C(=O)N)CC2=C1C=CC=C2[N+]([O-])=O PJDGSDCRBKAJDH-UHFFFAOYSA-N 0.000 description 1
- AVVBKGKSWJMDFR-UHFFFAOYSA-N 4-amino-4-oxo-2-(3-oxo-1-propan-2-yl-1h-isoindol-2-yl)butanoic acid Chemical compound C1=CC=C2C(C(C)C)N(C(CC(N)=O)C(O)=O)C(=O)C2=C1 AVVBKGKSWJMDFR-UHFFFAOYSA-N 0.000 description 1
- VKQPKDFETQWEBZ-UHFFFAOYSA-N 4-amino-4-oxo-2-(3-oxo-1-propyl-1h-isoindol-2-yl)butanoic acid Chemical compound C1=CC=C2C(CCC)N(C(CC(N)=O)C(O)=O)C(=O)C2=C1 VKQPKDFETQWEBZ-UHFFFAOYSA-N 0.000 description 1
- ZDJPXBIRWFWFII-UHFFFAOYSA-N 4-amino-4-oxo-2-(3-oxo-7-propan-2-yl-1h-isoindol-2-yl)butanoic acid Chemical compound CC(C)C1=CC=CC2=C1CN(C(CC(N)=O)C(O)=O)C2=O ZDJPXBIRWFWFII-UHFFFAOYSA-N 0.000 description 1
- RLUBPUMEMPTGCU-UHFFFAOYSA-N 4-amino-4-oxo-2-(3-oxo-7-propyl-1h-isoindol-2-yl)butanoic acid Chemical compound CCCC1=CC=CC2=C1CN(C(CC(N)=O)C(O)=O)C2=O RLUBPUMEMPTGCU-UHFFFAOYSA-N 0.000 description 1
- FKBPRIMPELADIL-UHFFFAOYSA-N 4-amino-4-oxo-3-(3-oxo-1-propan-2-yl-1h-isoindol-2-yl)butanoic acid Chemical compound C1=CC=C2C(C(C)C)N(C(CC(O)=O)C(N)=O)C(=O)C2=C1 FKBPRIMPELADIL-UHFFFAOYSA-N 0.000 description 1
- BOUIWRNUTIHPBC-UHFFFAOYSA-N 4-amino-4-oxo-3-(3-oxo-1-propyl-1h-isoindol-2-yl)butanoic acid Chemical compound C1=CC=C2C(CCC)N(C(CC(O)=O)C(N)=O)C(=O)C2=C1 BOUIWRNUTIHPBC-UHFFFAOYSA-N 0.000 description 1
- GNKCQSLAVSNNGA-UHFFFAOYSA-N 4-amino-4-oxo-3-(3-oxo-7-propan-2-yl-1h-isoindol-2-yl)butanoic acid Chemical compound CC(C)C1=CC=CC2=C1CN(C(CC(O)=O)C(N)=O)C2=O GNKCQSLAVSNNGA-UHFFFAOYSA-N 0.000 description 1
- NRBCPQSOJXUNCS-UHFFFAOYSA-N 4-amino-4-oxo-3-(3-oxo-7-propyl-1h-isoindol-2-yl)butanoic acid Chemical compound CCCC1=CC=CC2=C1CN(C(CC(O)=O)C(N)=O)C2=O NRBCPQSOJXUNCS-UHFFFAOYSA-N 0.000 description 1
- TWWAWPHAOPTQEU-UHFFFAOYSA-N 4-methyl-2-benzofuran-1,3-dione Chemical compound CC1=CC=CC2=C1C(=O)OC2=O TWWAWPHAOPTQEU-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- HPQVKINWMSDUDM-UHFFFAOYSA-N 5-amino-2-(1,3-dioxo-4-propan-2-ylisoindol-2-yl)-5-oxopentanoic acid Chemical compound CC(C)C1=CC=CC2=C1C(=O)N(C(CCC(N)=O)C(O)=O)C2=O HPQVKINWMSDUDM-UHFFFAOYSA-N 0.000 description 1
- AUDVOVQPBNPQOE-UHFFFAOYSA-N 5-amino-2-(1,3-dioxo-4-propylisoindol-2-yl)-5-oxopentanoic acid Chemical compound CCCC1=CC=CC2=C1C(=O)N(C(CCC(N)=O)C(O)=O)C2=O AUDVOVQPBNPQOE-UHFFFAOYSA-N 0.000 description 1
- ZSSVUSCNBDLWLB-UHFFFAOYSA-N 5-amino-2-(1-amino-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC=C2C(N)N(C(CCC(N)=O)C(O)=O)C(=O)C2=C1 ZSSVUSCNBDLWLB-UHFFFAOYSA-N 0.000 description 1
- VRJZPMOMPXTIRA-UHFFFAOYSA-N 5-amino-2-(1-butyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC=C2C(CCCC)N(C(CCC(N)=O)C(O)=O)C(=O)C2=C1 VRJZPMOMPXTIRA-UHFFFAOYSA-N 0.000 description 1
- CHBVSLSSHQFTAS-UHFFFAOYSA-N 5-amino-2-(1-ethyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC=C2C(CC)N(C(CCC(N)=O)C(O)=O)C(=O)C2=C1 CHBVSLSSHQFTAS-UHFFFAOYSA-N 0.000 description 1
- CFTJNUDKQAMSHV-UHFFFAOYSA-N 5-amino-2-(1-methyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC=C2C(C)N(C(CCC(N)=O)C(O)=O)C(=O)C2=C1 CFTJNUDKQAMSHV-UHFFFAOYSA-N 0.000 description 1
- KRBBAFOXBAZRCY-UHFFFAOYSA-N 5-amino-2-(4-butyl-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical compound CCCCC1=CC=CC2=C1C(=O)N(C(CCC(N)=O)C(O)=O)C2=O KRBBAFOXBAZRCY-UHFFFAOYSA-N 0.000 description 1
- XSMMHSJELJPFSC-UHFFFAOYSA-N 5-amino-2-(4-ethyl-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical compound CCC1=CC=CC2=C1C(=O)N(C(CCC(N)=O)C(O)=O)C2=O XSMMHSJELJPFSC-UHFFFAOYSA-N 0.000 description 1
- KSCACLRGQJXDAB-UHFFFAOYSA-N 5-amino-2-(7-amino-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound O=C1N(C(CCC(=O)N)C(O)=O)CC2=C1C=CC=C2N KSCACLRGQJXDAB-UHFFFAOYSA-N 0.000 description 1
- IVZOIKCYHIILEC-UHFFFAOYSA-N 5-amino-2-(7-butyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound CCCCC1=CC=CC2=C1CN(C(CCC(N)=O)C(O)=O)C2=O IVZOIKCYHIILEC-UHFFFAOYSA-N 0.000 description 1
- QYENXFUDUQFEDV-UHFFFAOYSA-N 5-amino-2-(7-ethyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound CCC1=CC=CC2=C1CN(C(CCC(N)=O)C(O)=O)C2=O QYENXFUDUQFEDV-UHFFFAOYSA-N 0.000 description 1
- ASOZXVYBNIAJDS-UHFFFAOYSA-N 5-amino-2-(7-methyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound CC1=CC=CC2=C1CN(C(CCC(N)=O)C(O)=O)C2=O ASOZXVYBNIAJDS-UHFFFAOYSA-N 0.000 description 1
- JWXSMBGQHOFVJT-UHFFFAOYSA-N 5-amino-2-(7-nitro-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound O=C1N(C(CCC(=O)N)C(O)=O)CC2=C1C=CC=C2[N+]([O-])=O JWXSMBGQHOFVJT-UHFFFAOYSA-N 0.000 description 1
- VBYKESMNUUOSBJ-UHFFFAOYSA-N 5-amino-4-(1,3-dioxo-4-propan-2-ylisoindol-2-yl)-5-oxopentanoic acid Chemical compound CC(C)C1=CC=CC2=C1C(=O)N(C(CCC(O)=O)C(N)=O)C2=O VBYKESMNUUOSBJ-UHFFFAOYSA-N 0.000 description 1
- LKTDYXHMLHJSKE-UHFFFAOYSA-N 5-amino-4-(1,3-dioxo-4-propylisoindol-2-yl)-5-oxopentanoic acid Chemical compound CCCC1=CC=CC2=C1C(=O)N(C(CCC(O)=O)C(N)=O)C2=O LKTDYXHMLHJSKE-UHFFFAOYSA-N 0.000 description 1
- LEZCUUVOJNICQD-UHFFFAOYSA-N 5-amino-4-(1-amino-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC=C2C(N)N(C(CCC(O)=O)C(N)=O)C(=O)C2=C1 LEZCUUVOJNICQD-UHFFFAOYSA-N 0.000 description 1
- JMSJVCDJPPDFKR-UHFFFAOYSA-N 5-amino-4-(1-ethyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC=C2C(CC)N(C(CCC(O)=O)C(N)=O)C(=O)C2=C1 JMSJVCDJPPDFKR-UHFFFAOYSA-N 0.000 description 1
- IPKDRVRPKWDPCI-UHFFFAOYSA-N 5-amino-4-(1-methyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC=C2C(C)N(C(CCC(O)=O)C(N)=O)C(=O)C2=C1 IPKDRVRPKWDPCI-UHFFFAOYSA-N 0.000 description 1
- CXIZBIBLPVPXMG-UHFFFAOYSA-N 5-amino-4-(4-butyl-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical compound CCCCC1=CC=CC2=C1C(=O)N(C(CCC(O)=O)C(N)=O)C2=O CXIZBIBLPVPXMG-UHFFFAOYSA-N 0.000 description 1
- YHBNBIDHJJHGMD-UHFFFAOYSA-N 5-amino-4-(4-ethyl-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical compound CCC1=CC=CC2=C1C(=O)N(C(CCC(O)=O)C(N)=O)C2=O YHBNBIDHJJHGMD-UHFFFAOYSA-N 0.000 description 1
- ZIZZHVNIDWVLGN-UHFFFAOYSA-N 5-amino-4-(4-methyl-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical compound CC1=CC=CC2=C1C(=O)N(C(CCC(O)=O)C(N)=O)C2=O ZIZZHVNIDWVLGN-UHFFFAOYSA-N 0.000 description 1
- USYWQLIFELNXTA-UHFFFAOYSA-N 5-amino-4-(7-amino-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound O=C1N(C(CCC(O)=O)C(=O)N)CC2=C1C=CC=C2N USYWQLIFELNXTA-UHFFFAOYSA-N 0.000 description 1
- JVZJEODDLZUSCJ-UHFFFAOYSA-N 5-amino-4-(7-butyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound CCCCC1=CC=CC2=C1CN(C(CCC(O)=O)C(N)=O)C2=O JVZJEODDLZUSCJ-UHFFFAOYSA-N 0.000 description 1
- YFKYZCYBNWIAGP-UHFFFAOYSA-N 5-amino-4-(7-ethyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound CCC1=CC=CC2=C1CN(C(CCC(O)=O)C(N)=O)C2=O YFKYZCYBNWIAGP-UHFFFAOYSA-N 0.000 description 1
- RXNLJUZQYUZNDX-UHFFFAOYSA-N 5-amino-4-(7-methyl-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound CC1=CC=CC2=C1CN(C(CCC(O)=O)C(N)=O)C2=O RXNLJUZQYUZNDX-UHFFFAOYSA-N 0.000 description 1
- MUVQMLOEDIDSDJ-UHFFFAOYSA-N 5-amino-4-(7-nitro-3-oxo-1h-isoindol-2-yl)-5-oxopentanoic acid Chemical compound O=C1N(C(CCC(O)=O)C(=O)N)CC2=C1C=CC=C2[N+]([O-])=O MUVQMLOEDIDSDJ-UHFFFAOYSA-N 0.000 description 1
- CFHKLVNYNGIZFX-UHFFFAOYSA-N 5-amino-5-oxo-2-(3-oxo-1-propan-2-yl-1h-isoindol-2-yl)pentanoic acid Chemical compound C1=CC=C2C(C(C)C)N(C(CCC(N)=O)C(O)=O)C(=O)C2=C1 CFHKLVNYNGIZFX-UHFFFAOYSA-N 0.000 description 1
- SNFMEBYDQGCREP-UHFFFAOYSA-N 5-amino-5-oxo-2-(3-oxo-1-propyl-1h-isoindol-2-yl)pentanoic acid Chemical compound C1=CC=C2C(CCC)N(C(CCC(N)=O)C(O)=O)C(=O)C2=C1 SNFMEBYDQGCREP-UHFFFAOYSA-N 0.000 description 1
- YFNMIAYPKVQJHC-UHFFFAOYSA-N 5-amino-5-oxo-2-(3-oxo-7-propan-2-yl-1h-isoindol-2-yl)pentanoic acid Chemical compound CC(C)C1=CC=CC2=C1CN(C(CCC(N)=O)C(O)=O)C2=O YFNMIAYPKVQJHC-UHFFFAOYSA-N 0.000 description 1
- TYUNAHWJBFTWPM-UHFFFAOYSA-N 5-amino-5-oxo-4-(3-oxo-1-propan-2-yl-1h-isoindol-2-yl)pentanoic acid Chemical compound C1=CC=C2C(C(C)C)N(C(CCC(O)=O)C(N)=O)C(=O)C2=C1 TYUNAHWJBFTWPM-UHFFFAOYSA-N 0.000 description 1
- LZJGXQWYGDOVQX-UHFFFAOYSA-N 5-amino-5-oxo-4-(3-oxo-1-propyl-1h-isoindol-2-yl)pentanoic acid Chemical compound C1=CC=C2C(CCC)N(C(CCC(O)=O)C(N)=O)C(=O)C2=C1 LZJGXQWYGDOVQX-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- ZOXBWJMCXHTKNU-UHFFFAOYSA-N 5-methyl-2-benzofuran-1,3-dione Chemical compound CC1=CC=C2C(=O)OC(=O)C2=C1 ZOXBWJMCXHTKNU-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000012526 B-cell neoplasm Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 206010063094 Cerebral malaria Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004099 Chlortetracycline Substances 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 206010010755 Conjunctivitis viral Diseases 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 208000037487 Endotoxemia Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000713730 Equine infectious anemia virus Species 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 241000713800 Feline immunodeficiency virus Species 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 101000993347 Gallus gallus Ciliary neurotrophic factor Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010020164 HIV infection CDC Group III Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 1
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102100026236 Interleukin-8 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- PMLJIHNCYNOQEQ-REOHCLBHSA-N L-aspartic 1-amide Chemical compound NC(=O)[C@@H](N)CC(O)=O PMLJIHNCYNOQEQ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 206010024179 Legionella infections Diseases 0.000 description 1
- 208000004023 Legionellosis Diseases 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 201000000090 Microsporidiosis Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 241000711408 Murine respirovirus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010062207 Mycobacterial infection Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 108091093105 Nuclear DNA Proteins 0.000 description 1
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 208000034038 Pathologic Neovascularization Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 208000012641 Pigmentation disease Diseases 0.000 description 1
- 102100035194 Placenta growth factor Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108700005075 Regulator Genes Proteins 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 102000000505 Ribonucleotide Reductases Human genes 0.000 description 1
- 108010041388 Ribonucleotide Reductases Proteins 0.000 description 1
- 241001222774 Salmonella enterica subsp. enterica serovar Minnesota Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010053879 Sepsis syndrome Diseases 0.000 description 1
- 201000010001 Silicosis Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 102100026966 Thrombomodulin Human genes 0.000 description 1
- 108010079274 Thrombomodulin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102100031372 Thymidine phosphorylase Human genes 0.000 description 1
- 108700023160 Thymidine phosphorylases Proteins 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 206010045170 Tumour lysis syndrome Diseases 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 208000005914 Viral Conjunctivitis Diseases 0.000 description 1
- 241000713325 Visna/maedi virus Species 0.000 description 1
- 102100029477 Vitamin K-dependent protein C Human genes 0.000 description 1
- 101710193900 Vitamin K-dependent protein C Proteins 0.000 description 1
- GIUYCYHIANZCFB-UUOKFMHZSA-N [(2r,3s,4r,5r)-5-(6-amino-2-fluoropurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O GIUYCYHIANZCFB-UUOKFMHZSA-N 0.000 description 1
- VRGWBRLULZUWAJ-XFFXIZSCSA-N [(2s)-2-[(1r,3z,5s,8z,12z,15s)-5,17-dihydroxy-4,8,12,15-tetramethyl-16-oxo-18-bicyclo[13.3.0]octadeca-3,8,12,17-tetraenyl]propyl] acetate Chemical compound C1\C=C(C)/CC\C=C(C)/CC[C@H](O)\C(C)=C/C[C@@H]2C([C@@H](COC(C)=O)C)=C(O)C(=O)[C@]21C VRGWBRLULZUWAJ-XFFXIZSCSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000008382 alveolar damage Effects 0.000 description 1
- 210000001132 alveolar macrophage Anatomy 0.000 description 1
- 230000006427 angiogenic response Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000015624 blood vessel development Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 208000019664 bone resorption disease Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical class CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- 210000003711 chorioallantoic membrane Anatomy 0.000 description 1
- 208000019902 chronic diarrheal disease Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000005796 circulatory shock Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- SUYVUBYJARFZHO-UHFFFAOYSA-N dATP Natural products C1=NC=2C(N)=NC=NC=2N1C1CC(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-UHFFFAOYSA-N 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- VRHAQNTWKSVEEC-UHFFFAOYSA-N ethyl 1,3-dioxoisoindole-2-carboxylate Chemical class C1=CC=C2C(=O)N(C(=O)OCC)C(=O)C2=C1 VRHAQNTWKSVEEC-UHFFFAOYSA-N 0.000 description 1
- NUJJHSPYMWDZSJ-UHFFFAOYSA-N ethyl 4-nitro-1,3-dioxoisoindole-2-carboxylate Chemical compound C1=CC([N+]([O-])=O)=C2C(=O)N(C(=O)OCC)C(=O)C2=C1 NUJJHSPYMWDZSJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 230000009791 fibrotic reaction Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229960000936 fumagillin Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- VRGWBRLULZUWAJ-UHFFFAOYSA-N fusaproliferin Natural products C1C=C(C)CCC=C(C)CCC(O)C(C)=CCC2C(C(COC(C)=O)C)=C(O)C(=O)C21C VRGWBRLULZUWAJ-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940096397 interleukin-8 Drugs 0.000 description 1
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229960004196 lymecycline Drugs 0.000 description 1
- AHEVKYYGXVEWNO-UEPZRUIBSA-N lymecycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(=O)NCNCCCC[C@H](N)C(O)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O AHEVKYYGXVEWNO-UEPZRUIBSA-N 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 210000002864 mononuclear phagocyte Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 208000027531 mycobacterial infectious disease Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical class NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000033667 organ regeneration Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 231100000255 pathogenic effect Toxicity 0.000 description 1
- 230000008529 pathological progression Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000004983 pleiotropic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009290 primary effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229930185346 proliferin Natural products 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- LZFIOSVZIQOVFW-UHFFFAOYSA-N propyl 2-hydroxybenzoate Chemical class CCCOC(=O)C1=CC=CC=C1O LZFIOSVZIQOVFW-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 201000003651 pulmonary sarcoidosis Diseases 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000027272 reproductive process Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 235000020046 sherry Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- AODPIQQILQLWGS-GXBDJPPSSA-N tetrahydrocortisol Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CC[C@@H]21 AODPIQQILQLWGS-GXBDJPPSSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000010380 tumor lysis syndrome Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
- A61P37/04—Immunostimulants
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Description
SUBSTITUERTE 1,3 DIOKSOINDOLINER OG DERES ANVENDELSE I FARMASØYTISKE PREPARATER FOR Å REDUSERE INFLAMMATORISKE CYTOKIN-NIVÅER.
Foreliggende oppfinnelse angår 1,3 diokso-isoindoliner som er substituert i 4- eller 5-posisjonen i isoindolin ringen, fremgangsmåten for reduksjon av nivåer av inflammatorisk cytokiner som tumor nekrose faktor-a og behandling av inflammatoriske sykdommer, autoimmune sykdommer, tumorer og cancere hos pattedyr ved administrering derav, og farmasøytiske preparater inneholdende slike derivater.
Tumor nekrose faktor-a (TNFa, er et cytokin som gis primært av mononukleære fagocytter som svar på et antall immunostimu-latorer. Den er et nøkkelcytokin i inflammasjonskaskaden som forårsaker produksjon og/eller frigivning av andre cytokiner og midler. Administrert til dyr eller mennesker forårsaker den inflammasjon, feber, kardiovaskulære effekter, hemorragi, koagulering og faseresponser tilsvarende dem som sees under akutte infeksjoner og sjokktilstander. Eksessive eller ikke regulert TNFa-produksjon er således implikert i et antall sykdomstilstander som alloreaksjoner som poding-mot-vert-sykdom (graft-versus-host disease lik GVHD), demyelinerende sykdommer, hypertensjon, hypertriglyceridamia, diabetes, osteolyse, neoplasi, leukemi, osteomyeli, pancreatitt, trom-botisk sykdom, inflammatorisk tarmsykdom, skleroderma, revraa-toid artritt, osteoartritt og vaskulitt. Anti-TNFa-behand-linger har validert TNFa-inhibering ved reumatoid artritt, inflammatorisk tarmsykdom, endotoksemi og toksisk sjokksyn-drom [Tracey et al., "Nature" 330-: 662-664 (1987) og Hinshaw et al., "Cirk Shock" 30:279-292 (1990)], kakeksi [Dezube et al., "Lancet" 335: (8690), 662 (1990)] og voksen respirato-risk distressyndrom (Adult Respiratory Distress Syndrome = ARDS) der TNFa-konsentrasjonen over 12.000 pg/ml er detek-tert i pulmonære aspirater fra ARDS pasienter [Millar et al, "Lancet" 2 (8665), 712-714 (1989)]. Systemisk infusjon av re-kombinant TNFa resulterte også i forandringer som karakteristisk sees ved ARDS [Ferrai-Baliviera et al., "Arch. Surg". 124 (12), 1400-1405 (1989)]. TNFa synes å være involvert i benresorpsjonssykdommer, inkludert artritt. Når aktivert, vil leukocytter produsere benresorpsjon, en aktivitet som data antyder at TNFa bidrar til [Bertolini et al., "Nature" 319, 516-518 (1986) og Johnson et al., "Endocrinology" 124 (3), 1424-1427 (1989)]. TNFa er også vist å stimulere benresorpsjon og inhiberer bendannelse in vitro og in vivo ved stimu-lering av osteoklastdannelse og -aktivering kombinert med inhibering av osteoblast funksjonen. Ved poding-mot-vert-reaksjon er økede serum TNFa nivåer assosiert med hovedkomp-likasjonen etter akutt, allogen benmargtransplantasjon [Hol-ler at al . , "Blood", 75(4), 1011-1016 (1990)].
Parasittiske infeksjoner kan kontrolleres ved TNFa som malaria- eller legionellainfeksjon. Cerebral malaria er et letalt hyperakutt nevrologisk syndrom assosiert med høye blodnivåer av TNFa og den mest alvorlige komplikasjon som opptrer hos malariapasienter. Nivåer av TNFa korrelert direkte med alvo-ret av sykdommen og prognosen hos pasienter med akutte malaria angrep [Grau et al., "N. Engl. J. Med." 320 (24), 1586-1591 (1989)].
Angiogenese, prosessen med ny blodkarutvikiing og -dannelse, spiller en viktig rolle i tallrike fysiologiske evenementer,
både normale og patologiske. Angiogenese inntrer i respons på spesifikke signaler og involverer en kompleks prosess som ka-rakteriseres ved infiltrering av det basale lamina med vasku-lære, endoteliale celler som respons på ett eller flere
angiogeniske vekstsignaler, migrering av de endoteliale celler mot kilden for signalet eller signalene, og etterfølgende proliferering og dannelse av kapillarrør. Blodstrømmen gjennom den nydannede kapillar initieres etter at endotelialcel-lene kommer i kontakt med og forbinder seg med en på forhånd eksisterende kapillær.
Makrofag indusert angiogenese er kjent og medieres av TNFa.
[Leibovich et al, "Nature" 329, 630-632 (1987) vist ved TNFa induseres in vivo kapillær blodkardannelse i rotte kornea og utviklingen av kylling-korioallantoiske membraner ved meget lave doser og antyder at TNFa er en kandidat for indusering av angiogenese ved inflammasjon, sårheling og tumorvekst. TNFa produksjonen er også assosiert med cancerøse tilstander som tumorlysis-syndromet, gjenopptreden av blærecancer og særlig indusert tumorer [Ching et al., "Brit. J. Cancer",
(1955) 72, 339-343, og Koch, "Progress in Medicianl Che-mistry", 22, 166-242 (1985)].
Den naturlig forekomne balanse mellom endogene stimulatorer og inhibitorer av angiogenese er en der inhibitoriske influ-enser dominerer, se Rastinejad et al, 1989, "Cell" 56:345-355. I de sjeldne tilfelle der neovaskularisering inntrer under normale fysiologiske betingelser som sårheling, organre-generering, embryonisk utvikling og hunnlige reproduktive prosesser, er angiogenese stringent regulert og spatialt og temporalt begrenset. Under betingelser med patologisk angiogenese som den som karakteriserer fast tumorvekst, faller disse regulatoriske kontroller.
Ikke regulert angiogenese blir patologisk og opprettholder progresjonen av mange neoplastiske og ikke-neoplastiske sykdommer. Et antall alvorlige sykdommer domineres ved anormal neovaskulerisering inkludert fast tumorvekst og metastaser, artritt, enkelte typer øyelidelser og psoriasis, se for eksempel overblikk hos Moses et al., 1991, "Biotech.", 9:630-634, Folkman et al., 1995, "N. Engl. J. Med.", 333:1757-1763; Auerbach et al., 1985, "J. Microvasc. Res." 29:401-411; Folkman, 1985, "Advances in Cancer Research" eds. Klein and Wein-house, Academic Press, New York, pp. 175-203; Patz, 1982,
"Am. J. Opthalmol." 94:715-743; and Folkman et al., 1983, Science 221:719-725. I et antall patologiske tilstander bidrar angiogenese prosessen til sykdomstilstanden. For eksempel er det samlet signifikante data som antyder at veksten av faste tumorer er avhengig av angiogenese, se Folkman and Klagsbrun, 1987, Science 235:442-447.
Opprettholdelsen av avaskulariteten i kornea, linser og det trabekulære nettverk er avgjørende for synet så vel som for okulær fysiologi, se for eksempel oversikter av Waltman et al., 1978, "Am. J. Ophthal." 85:704-710 og Gartner et al., 1978, "Surv. Ophthal." 22:291-312. I dag er behandlingen av disse sykdommer, særlig når først neovaskularisering er inn-trådt, utilstrekkelig, og det resulterer ofte i blindhet.
En inhibitor av angiogenese vil ha en viktig terapeutisk rolle i å begrense bidragene i denne prosess til den patologiske progresjon av de underliggende sykdomstilstander så vel som å tilveiebringe verdifulle midler for å studere deres etiologi. For eksempel kan midler som inhiberer tumorneovaskularise-ring, spille en viktig rolle ved inhibering av metastatisk tumorvekst.
Komponentene av angiogenese i forbindelse med vaskulær endotelial celle- proliferering, migrering og invasjon, er funnet å være regulert delvis av polypeptide vekstfaktorer. Forsøk i kultur antyder at endoteliale celler som er eksponert til et medium inneholdende egnete vekstfaktorer, kan induseres til å evokere noen av eller alle angiogene responser. Diverse poly-peptider med endoteliale in vitro vekst fremmende aktivitet er identifisert. Eksempler inkluderer sure og basiske fibro-blastvekstfaktorer, transformeringsvekstfaktorer a og |3, pla-teavledete endotelial cellevekstfaktor, granulocytisk koloni-stimulerende faktor, interleukin-8, hepatocyt vekstfaktor, proliferin, vaskulær endotelial vekstfaktor og plasental vekstfaktor, se for eksempel en oversikt av Folkman et al., 1995, "New Engl. J. Med." 333:1757:1763.
Flere typer forbindelser har vært benyttet for å forhindre angiogenese. Taylor et al. har benyttet protamin for å inhibere angiogenese, se Taylor et al., "Nature" 297:307 (1982). Toksisiteten for protamin begrenser dets praktiske anvendelse som terapeutikum. Folkman et al. har beskrevet bruken av heparin og steorider for å kontrollere angiogenese, se Folkman et al., "Science" 221:719 (1983) og U.S. Pat. nr. 5.001.116 og 4.994.443. Steroider som tetrahydrocortisol som mangler gluko- og mineralkorticoid aktivitet, er funnet å være angiogeniske inhibitorer. Interferon P er også en potent inhibitor av angiogenese som innføres av allogeniske miltceller, se Sidky et al., Cancer Research 47:5155-5161 (1987). Human re-kombinant alfa interferon-oc er rapportert med suksess å være benyttet ved behandling av pulmonære hemangiomatose, en angiogenese indusert sykdom, se White et al., "New England J. Med. 320:1197-1200 (1989).
Andre midler som har vært benyttet for å inhibere angiogenese inkluderer askorbinsyre-eter og relaterte forbindelser, se
japanske Kokai Tokkyo Koho No. 58.131978. Sulfaterte polysak-karider DS 4152 viser også angiogenisk inhibering. Se japansk Kokai Tokkyo Koho No. 63-119500. Et fungalt produkt, fumagil-lin, er et potent angiostatisk middel in vitro. Forbindelsen
er toksisk in vivo, men et syntetisk derivat, AGM 12470, har vært benyttet in vivo for å behandle kollagen II artritt. Fu-
magillin og O-substituert fumagi11inderivater er beskrevet i EPO 0325199A2 og 0357061A1.
I US 5.874.081 beskriver Parish bruken av monoklonale antistoffer for å inhibere angiogenese. I W092/12717 lærer Brem et al at noen tetrasykliner, særlig minosyklin, klortetra-syklin, demeklosyklin, og lymesyklin er brukbare som inhibitorer av angiogenese. I "Cancer Research" 51, 672-675, Jan. 15, 1991, beskriver Brem et al. at minosyklin inhiberer angiogenese i en grad som er sammenlignbar med den til kombi-nasjonterapien av heparin og kortison. I "Cancer Research" 52, 6702-6704, Dec.l, 1992, lærer Teicher et al. at tumorvekst minskes og antallet metastaser reduseres når det anti-angiogeniske middel mot metastaser reduseres når det anti-angiogenetiske middel minosyklin benyttes i forbindelse med cancer kjemoterapi eller strålingsterapi.
Alle de forskjellige celletyper i kroppen kan transformeres til benigne eller malignante tumorceller. Det hyppigste tu-morsetet er lungen fulgt av colorektal, bryst, prostata, blæ-re, pankreas og så ovarie. Andre prevalente typer cancer er leukemi, sentralnervesystemcancer inkludert hjernecancer, me-lanoma, lymfoma, erytroleukemi, uterincancer og hode- og nak-kecancer.
Cancer blir i dag primært behandlet med en eller en kombinasjon av tre typer terapier: kirurgi, bestråling og kjemoterapi. Kirurgi involverer massefjerning av sykt vev. Mens kirurgi noen ganger er effektiv med henblikk på å fjerne tumorer lokalisert ved visse seter, for eksempel bryst, kolon og hud, kan den ikke benyttes ved behandling av tumorer som er lokalisert i andre arealer som ryggrad, heller ikke ved behandling av spredte neoplastiske tilstander som leukemi. Kjemoterapi involverer avbrudd av cellereplikering eller cellemeta-bolisme. Den benyttes som regel ved behandling av leukemi så vel som bryst-, lunge- og testikkelcancer.
Det er fem hovedklasser av kjemoterapeutiske midler som i dag er i bruk ved behandling av cancer: naturlige produkter og deres derivater; antrasykliner, alkyleringsmidler; antiproli-ferativa (også kalt antimetabolitter); og hormonelle midler.
Kjemoterapeutiske midler kalles ofte antineoplastiske midler. Alkyleringsmidlene er antatt å virke ved alkylisering og for-netning av guanin og eventuelt andre baser i DNA og arreste-rer celledeling. Typiske alkyleringsmidler er nitrogensenne-per, etyleniminforbindelser, alkylsulfater, cisplatin og forskjellige nitrosoureaforbindelser. En mangel ved disse forbindelser er at de ikke bare angriper malignante celler men også andre celler som deler seg naturlig som dem i rygg-margen, huden, gastrointestinal mukosa og fetalt vev. Antimetabolitter er karakteristisk reversible eller irreversible enzyminhibitorer eller forbindelser som ellers interfererer med replikasjon, translasjon eller transkripsjon av nuklein-syrer .
Flere syntetiske nukleosider har vært identifisert som viser anticanceraktivitet. Et velkjent nukleosidderivat med sterk anticanceraktivitet er 5-fluoruracil. 5-fluoruracil har vært benyttet klinisk ved behandling av malignante tumorer, inkludert for eksempel carcinomer, sarcomer, hudcancer, cancer i fordøyelsesorganene og brystcancer. 5-fluoruracil forårsaker imidlertid alvorlige ugunstige reaksjoner som kvalme, alope-cia, diarré, stomatit, leukocytiske trombocytopeni, anoreksi, pigmentering og ødem. Derivater av 5-fluoruracil med anticanceraktivitet er beskrevet i US 4.336.381, samt i de japanske publikasjoner 50-50383, 50-50384, 50-64281, 51-146482 og 53-84981. US 4.000.137 beskriver at peroksidatoksidasjonsproduk-tet av inosin, adenosin og cytidin med metanol eller etanol har aktivitet mot lymfocytisk leukemi.
Cytosin arabinosid (også kalt Cytarabin, araC og Cytosar) er en nukleosid analog av deoksycytidin som først ble synteti-sert i 1950 og kom inn i klinisk medisin i 1963. Forbindelsen er i dag et viktig medikament ved behandling av akutt myeloid leukemi. Den er også aktiv mot akutt lymfocytisk leukemi, og i mindre grad er den brukbar mot kronisk myelocytisk leukemi og ikke-Hodgkins lymfom. Primærvirkningen av araC er inhibering av nukleær DNA syntese, se [R. Handschumacher and Y. Cheng, "Purine and Pyrimidine Antimetabolities", Cancer Medi-cine, Chapter XV-1, 3rd edition, edited by J. Holland, et al., Lea and Febigol, publishers]. 5-azacytidin er en cytidin analog som primært benyttes ved behandling av akutt myelocytisk leukemi og myelodysplastisk syndrom.
2-fluoradenosin-5'-fosfat (Fludara, også kalt F-araA) er et av de mest aktive midler ved behandling av kronisk lymfocyt-tisk leukemi. Forbindelsen virker ved å inhibere DNA syntesen. Behandling av celler med F-araA er assosiert med akkumu-lering av celler ved Gl/S fasegrensen og i S-fasen; således er det et cellesyklisk S-fasespesifikt medikament. Innarbei-ding av den aktive metabolitt F-araATP, sinker DNA-kjede-forlengelsen. F-araA er også en potent inhibitor av ribo-nukleotid reduktase, nøkkelenzymet som er ansvarlig for dannelsen av dATP. 2-klordeoksyadenosin er brukbar ved behandling av lavgrad B-celle-neoplasmer som kronisk lymfocyt-tisk leukemi, ikke-Hodgkins lymfom og hårcelleleukemi. Spek-teret av aktivitet tilsvarer den til Fludara. Forbindelsen inhiberer DNA syntese i voksende celler og inhiberer DNA re-parasjoner i hvilende celler.
Selv om et antall kjemoterapeutiske midler har vært identifisert og i dag er i bruk for behandling av cancer, søkes det stadig etter nye midler som er effektive, og som viser lav toksisitet mot friske celler.
TNFa spiller også en rolle på området astma og andre kronisk pulmonære inflammatoriske sykdommer. Avsetningen av silika-partikler fører til silikose, en sykdom med progressiv respi-ratorisk svikt forårsaket av en fibrotisk reaksjon. Forbe-handling med antistoffer mot TNFa blokkerte så å si totalt den silikainduserte lungefibrose hos mus [Pignet et al., "Nature", 344, 245-247 (1990)]. Høye nivåer av TNFa-produksjon (i serum og i isolerte makrofager) er påvist i dyremodeller av silika- og asbestindusert fibrose [Bissonnette et al., "Inflammation" 13(3), 329-339 (1989)]. Alveolære makrofager fra pulmonære sarcoidose-pasienter er også funnet spontant å frigi massive mengder av TNFa sammenlignet med makrofager fra normale donorer [Baughman et al, "J. Lab. Clin. Med." 115(1), 36-42 (1990)].
TNFa er også implikert ved den inflammatoriske respons som
følger reperfusjon, kalt reperfusjonsskade, og er en hovedår-sak til vevsskader etter tap av blodstrøm [Vedder et al, PNAS 87, 2643-2646 (1990)]. Vevsskade kan også inkludere kirurgisk skade og inflammasjon, problemer etter hjertetransplantasjo-ner, systematisk inflammatorisk responssyndrom og multiple organdysfunksjonssyndrom. TNFa endrer også egenskapene hos endoteliale celler og har forskjellige prokoagulante aktiviteter som produksjon av en økning av vevfaktor-prokoagulant-aktiviteten og suppresjon av anti-koagulant protein C-veien så vel som nedregulering av ekspresjonen av trombomodulin [Sherry et al, "J. Cell Biol." 107, 1269-1277 (1988)]. TNFa har pro-inflammatoriske aktiviteter som sammen med dens tidligere produksjon (under de første trinn av et inflammatorisk evenement) gjør den til en sannsynlig mediator for vevsskader i flere viktige lidelser, inkludert, men ikke begrenset til myokardialt infarkt, slag og sirkulatorisk sjokk. Av spesi-fikk betydning kan det være TNFa indusert ekspresjon av ad-hesjonsmolekyler som intracellulært adhesjonsmolekyl (ICAM) eller endotelialt leukocytt adhesjonsmolekyl (ELAM) på endoteliale celler [Munro et al, "Am. J. Path." 135(1), 121-132
(1989)].
TNFa-blokkering med monoklonale anti-TNFa antistoffer er påvist å være fordelaktig ved reumatoid artritt [Elliot et al., "Int. J. Pharmac." 1995 17(2), 141-145]. Høye nivåer av TNFa er assosiert med Chrons sykdom [von Dullemen et al., "Gastro-enterology", 1995 109(1), 129-135], og klinisk fordel er opp-nådd med TNFa-antistoffbehandling.
Moeller beskriver i US 5.231.024, hybridome cellelinjer som syntetiserer høyst spesifikke monoklonale antistoffer (mAb) mot humant tumor nekrosefaktor (TNF). Rubin beskriver i US 4.870.163, hybridomer som produserer monoklonale antistoffer mot human tumornekrosefaktor. Barbanti foreslår i US 5.436.154 at antistoffer mot TNFa og muligens også antistoffer mot TNFP ville være terapeutisk brukbare i de sykdomstil-feller der polypeptidene utøver en patogenisk effekt. For å være terapeutisk brukbar, bør antistoffer mot TNFa være i stand til å nøytralisere de toksiske virkninger av TNFa in vivo. Polyklonale antistoffer kan lett oppnås fra serum av hyperimmuniserte dyr. Disse polyklonale antistoffpreparater er imidlertid ikke optimale for in vivo bruk, fordi de er en blanding av antistoffer inneholdende antistoffer som ikke nøytraliserer TNFa, de er en blanding av antistoffer inneholdende forskjellige antistoffer med forskjellige affinite-ter for den samme epitop, og de er vanskelige å standardisere uttrykt ved potens på grunn av variasjoner fra lot til lot.
Videre <-er det kjent at TNFa er en potent aktivator for re-trovirus replikasjon inkludert aktivering av HIV-1, se [Duh et al., "Proe. Nat. Acad. Sei." 86, 5974-5978 (1989); Poll et al., "Proe. Nat. Acad. Sei." 87, 782-785 (1990); Monto et al., "Blood" 79, 2670 (1990); Clouse et al., "J. Immunol." 142, 431-438 (1989); Poll et al., "AIDS Res. Hum. Retrovi-rus", 191-197 (1992)]. AIDS er resultatet av infeksjon av T lymfocytter med human immunodefekt virus (HIV). Minst 3 typer eller stammer av HIV er identifisert, nemlig HIV-1, HIV-2 og HIV-3. Som en konsekvens av en HIV infeksjon, forringes T-celle mediert immunitet, og infekterte individer manifesterer alvorlige opportunistiske infeksjoner og/eller uvanlige neoplasmer. HIV inngang i T-lymfocytten krever T-lymfpcyttaktiv-ering. Andre viruser som HIV-1, HIV-2 infekterer T-lymfocytter etter T-celleaktivering, og slik virusproteineks-presjon og/eller replikasjon medieres eller opprettholdes av slik T-celleaktivering. Når først en aktiverte T-lymfocytt er infektert med HIV, må T-lymfocytten fortsette å holdes i aktivert tilstand for å tillate HIV-genekspresjon og/eller HIV-replikasjon. Cytokiner og spesielt TNFa er implikert i aktivert T-cellemediert HIV-proteinekspresjon og/eller virusrep-likasjon ved å spille en rolle ved opprettholdelse av T-lymfocyttaktivering. Interferens med cytokinaktivitet som ved prevensjon eller inhibering av cytokin produksjon, særlig TNFa i et HIV-infektert individ, understøtter derfor be-grensningen av opprettholdelsen av T-lymfocytt, forårsaket av HIV infeksjon.
Monocytter, makrofager og relaterte celler som kopfferceller og gliale celler, har også vært implikert ved opprettholdelse av HIV-infeksjon. Disse celler er, på samme måte som T-celler, mål for viral replikasjon og nivå av viral replikasjon er avhengig av aktiveringstilstanden for cellene, se [Rosenberg et al., "The immunopathogensis of HIV Infektion", "Advances in Immunology" 57 (1989)]. Cytokiner som TNFa er vist å aktivere HIV-replikasjon i monocytter og/eller makrofager [Poli et al., "Proe. Nati. Acad. Sei", 87, 782-784
(1990)], og derfor understøtter prevensjon eller inhibering av cytokinproduksjon eller -aktivitet en begrensning av HIV progresjonen for T-celler. Ytterligere studier har identifisert TNFa som en fellesfaktor ved aktivering av HIV in vitro og har gitt en klar virkningsmekanisme via et nukleært regulatorisk protein som finnes i cellecytoplasma [Osborn et al., "PNAS" 86, 2336-2340 (1989)]. Dette antyder at reduksjon av TNFa-syntesen kan ha en antiviral effekt ved HIV infeksjoner, ved å redusere transkripsjonen og derved virusproduksjonen.
AIDS viralreplikasjon av latent HIV i T-celle- og makrofag-linjer kan induseres ved TNFa, se [Folks et al., "PNAS" 86, 2365-2368 (1989)]. En molekylær mekanisme for den virusindu-serende aktivitet er antydet ved evnen til TNFa til å aktivere et genregulatorisk protein (NFkB) som finnes i cellers cytoplasma, noe som fremmer HIV- replikasjon ved å binde til en viral regulatorisk gensekvens (LTR), se [Osborn et al., "PNAS" 86, 2336-2340 (1989)]. TNFa i.AIDS-assosisert kakeksi antydes ved forhøyet serum TNFa og høye nivåer av spontan TNFa-produksjon i perifere blodmonocytter fra pasienter [Wright et al., "J. Immunol." 141(1), 99.104 (1988)]. TNFa affekterer mikrosporidiose (årsak til kronisk diarré hos HIV pasienter) og orale aftøse ulcere hos HIV-pasienter. TNFa har vært implikert i forskjellige roller med virale infeksjoner som cytomegalia-virus (CMV), influensavirus, adenovirus og herpesfamilien av viruser av tilsvarende grunner som de som er angitt. Enkelte viruser som Sendaivirusen og influensa induserer TNFa.
Den nukleære faktor kB (NFKB) er en pleiotropisk transkripsjonen aktivator, se [Lenardo, et al., "Cell" 1989, 58, 227-29] . NFKB har vært implikert som en transkripsjonen aktivator i en varietet av sykdoms- og inflammatoriske tilstander og antas å regulere cytokinnivåene inkludert, men ikke begrenset til TNFa, og også til å være en aktivator av HIV-transkripsjon [Dbaibo, et al., "J. Biol. Chem." 1993, 17762-66; Duh et al., "Proe. Nati. Acad. Sei." 1989, 86, 5974.78; Bachelerie et al., "Nature" 1991, 350, 709-12; Boswas et al., J. Acquired Immune Deficiency Syndrome" 1993, 6, 778-786; Suzuki et al., "Biochem. And Biophys. Res. Comm." 1993, 193, 277-83; Suzuki et al., "Biochem and Biophys. Res. Comm." 1992, 189, 1709-15; Suzuki et al., "Biochem. Mol. Bio. Int." 1993, 31(4), 693-700; Shakhov et al., "Proe. Nati. Acad. Sei." USA 1990, 171, 35-47; og Staal et al., "Proe. Nati. Acad. Sei." USA 1990, 87, 9943-47]. Således kan inhibering av NFKB-bindinger regulere transkripsjonen av ett eller flere cytokingener og ved denne modulering og andre mekanismer være brukbar ved inhibering av et antall sykdomstilstander. Forbindelsene som her beskrevet, kan inhibere virkningen av NFKB i kjernen og er således brukbare ved behandling av et antall sykdommer inkludert, men ikke begrenset til reumatoid artritt, reumatoid spondylitt, osteoartritt, andre artrittiske tilstander, septisk sjokk, sepsis, endotoksisk sjokk, poding-vert-sykdom, wasting, Chrons sykdom, ulcerativ kolitt, multiple sklerose, systemisk lupus erytrematose, ENL i leprosi, HIV, AIDS, og opportunistiske infeksjoner ved AIDS. TNFa- og NFKB nivåene påvirkes av en resiprok feedback-sløyfe. Som antydet ovenfor innvirker forbindelsene ifølge oppfinnelsen på nivåene av både TNFa og NFKB. Selvfølgelig refererer nivåene til aktivitetsnivåene så vel som til konsentrasjonsnivåene eller de absolutte nivåer.
Mange cellulære funksjoner medieres ved nivåene av adenosin 3',5'-syklisk monofosfat (cAMP). Slike cellulære funksjoner kan bidra til inflammatoriske tilstander og sykdommer inkludert astma, inflammasjon og andre tilstander [Lowe and Cheng, "Drugs of the Future", 17(9), 799-807, 1992]. Det har vært vist at en forhøyelse av cAMP i inflammatoriske leukocytter inhiberer deres aktivering og den etterfølgende frigivning av inflammatoriske mediatorer, inkludert TNFa og NFKB. Økede nivåer av cAMP fører også til avslapning av den glatte luftvei-muskel. Fosfodiesteraser kontrollerer nivået av cAMP gjennom hydrolyse, og inhibitorer av fosfodiesteraser er vist å øke cAMP nivåene.
Reduksjon av TNFa-nivåene og/eller økning av cAMP-nivåene utgjør således en verdifull terapeutisk strategi for behandling av mange inflammatoriske, infeksiøse, immunologiske eller malignante sykdommer. Disse inkluderer, men er ikke begrenset til, septisk sjokk, sepsis, endotoksisk sjokk, hemo-dynamisk sjokk og sepsis-syndrom, postischemisk reperfusjonsskade, malaria, mykobakteriell infeksjon, meningitt, psoriasis, kongestiv hjertesvikt, fibrotisk sykdom, kakeksi, pod-ingsawisning, cancer, autoimmun sykdom, opportunistiske infeksjoner ved AIDS, reumatoid artritt, reumatoid spondylitt, osteoartritt, andre artrittiske tilstander, Chrons sykdom, ulcerativ kolitt, multiple sklerose, systemisk lupus erytrematose, ENL i leprosi, strålingsskade og alveolær skade. Tidligere forsøk rettet mot undertrykkelse av effektene av TNFa har spent fra anvendelse av steroider som deksameta-son og prednisolon til bruk av både polyklonale og monoklonale antistoffer [Beutler et al., "Science" 234, 470-474
(1985); WO 92/11383].
Foreliggende oppfinnelse er basert på den oppdagelse at visse klasser av ikke-polypeptid-forbindelser, beskrevet i større detalj her, reduserer nivåene av TNFa, øker cAMP nivåene, inhiberer angiogenese, inhiberer tumorvekst og inhiberer inflammatoriske cytokiner. Foreliggende oppfinnelse angår således 1,3-dioksoindoliner som er substituert i 4-posisjon eller 5-posisjon i isoindolinringen, en metode for å redusere nivåene av tumornekrosefaktor a og andre inflammatoriske cytokiner i et pattedyr ved administrering av slike derivater, og farmasøytiske preparater inneholdende slike derivater. En reduksjon av TNFa-nivåene og/eller økning av cAMP-nivåene og/ eller inhibering av angiogenese in vivo, in vitro og i spise-lige medier, utgjør også verdifulle terapeutiske strategier.
Særlig angår foreliggende oppfinnelse
(a) et 1,3-dioksoindolin med formelen:
der karbonatomet angitt med C<*> utgjør et kiralitetssenter (når n ikke er 0 og R<1> ikke er den samme som R2) ; en av X<1> og X<2> er amino, ni tro, Ci-6 alkyl eller NH-Z, og den andre av X<1> eller X<2> er hydrogen; ;hver av R<1> og R2 uavhengig av den andre er hydroksy eller NH-Z; ;R<3> er hydrogen, Ci_6 alkyl, halo, eller haloalkyl; ;Z er hydrogen, Ci_6 alkyl, formyl eller Ci_6 acyl; og n ;har en verdi lik 0, 1 eller 2; ;forutsatt at hvis X<1> er amino og n er 1 eller 2, er R<1>;og R<2> ikke begge hydroksy; ;(b) salter med formel I. ;Hvis ikke annet er sagt, angir uttrykket alkyl en enverdig, mettet, rett eller forgrenet hydrokarbonkjede inneholdende fra 1 til 6 karbonatomer. Representative for slike alkylgrup-per er metyl, etyl, propyl, isopropyl, butyl, isobutyl, sec-butyl og tert-butyl. Alkoksy henviser til en alkylgruppe bundet til resten av molekylet via et eteroksygenatom. Represen-tanter for slike alkoksygrupper er metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, secbutoksy og tert-butoksy. Halo inkluderer brom, klor, fluor og jod. ;Salter med formel I inkluderer karboksylsyresalter og syreaddisjonssalter av de substituerte 1,3-dioksoindoliner som inneholder et nitrogenatom i stand til protonering. ;Forbindelsene med formel I benyttes, under overvåkning av kvalifiserte profesjonelle for å inhibere de uønskede virkninger av TNFa og andre inflammatoriske cytokiner, inkludert IL-1, IL-6 og IL-12 og/eller for å behandle uønsket angiogenese og tumorvekst. Forbindelsene kan administreres oralt, rektalt eller parenteralt, alene eller i kombinasjon med andre terapeutiske midler, inkludert antibiotika, steroider, kjemoterapeutiske midler osv., til pattedyr som trenger slik behandling; for eksempel ved behandling av cancere, reumatoid artritt, inflammatorisk tarmsykdom, muskulær dystrofi, Chrons sykdom osv. ;Forbindelsene ifølge oppfinnelsen kan også benyttes topisk ved terapi eller profylakse av sykdomstilstander som medieres eller eksaserberes av overdreven TNFa produksjon eller inflammasjon respektivt, som virale infeksjoner, som de som forårsakes av herpesviruser, viral konjunktivitt, psoriasis, atopisk dermatitt osv. ;Forbindelsene kan også benyttes ved veterinær behandling av pattedyr forskjellige fra mennesker og som trenger prevensjon eller inhibering av TNFa produksjon. TNFa-medierte sykdommer for behandling, terapeutisk eller profylaktisk, i dyr inkluderer sykdomstilstander som de som er angitt ovenfor, men særlig virale infeksjoner. Eksempler inkluderer felinimmuno-defekt virus, equin infeksiøst anemivirus, caprin artritt-virus, visnavirus og maedi-virus så vel som andre lentiviru-ser. ;Forbindelsene med formel I kan lett fremstilles via et antall veier. I en utførelsesform tillates en glutaminsyre, glutamin, isoglutamin, aspartinsyre, asparagin eller isoaspargin å reagere med et substituert ftalsyreanhydrid som 1,3-dikokso-isobenzofuran som er ytterligere substituert i 4- eller 5-posisjon: ;der karbonatomet angitt med C<*> utgjør et kiralitetssenter når n ikke er 0 og R<1> ikke er R<2>;
en av X<1> og X<2> er amino, nitro, Ci_6 alkyl eller NH-Z, og
den andre av X<1> eller X<2> er hydrogen;
hver av R<1> og R<2> uavhengig av den andre er hydroksy eller NH-Z;
R<3> er Ci_6 alkyl, halo, eller hydrogen;
Z er hydrogen, aryl eller Ci_6 alkyl; og
n har en verdi lik 0, 1 eller 2;
forutsatt at hvis X<1> er amino og n er 1 eller 2, er R<1>
og R<2> annet enn hydroksy.
Substituerte N-karbetoksyftalimider (se eksempel 1) kan benyttes i stedet for anhydridet.
I en andre utførelsesform benyttes den følgende reaksjon for å fremstille forbindelser med formel I:
Karbonatomet hvortil R<3> er bundet i forbindelsene med formel I, utgjør et kiralitetssenter når n ikke er 0 og R<1>ikke er den samme gruppe som R<2> og gir derved opphav til optiske isomerer. Både blandinger av disse isomerer og de separerte individuelle isomerer selv så vel som diastereomerer, når det er tilstede et andre kiralt senter, som for eksempel i en forgrenet alkylsubstituent med 4 til 6 karbonatomer, ligger innenfor oppfinnelsens ramme. Racematene kan benyttes som så-danne eller kan separeres i de individuelle isomerer meka-nisk, for eksempel ved kromatografi ved bruk av et kiralt ab-sorpsjonsmiddel. Alternativt kan de individuelle isomerer fremstilles stereoselektivt eller separeres kjemisk fra en blanding ved å danne salter med en kiralsyre eller base, for eksempel de individuelle enantiomerer av 10-kamforsulfonsyre, kamforsyre, a-bromkamforsyre, metoksyeddiksyre, vinsyre, diacetylvinsyre, eplesyre, pyrrolidon-5-karboksylsyre og lignende, og så sette fri en eller begge av de oppløste baser, eventuelt under gjentagelse av prosessen, for å oppnå den ene eller begge i det vesentlige frie for den andre, det vil si i en form med en optisk renhet >95%.
Foreliggende oppfinnelse angår også fysiologisk godtakbare, ikke-toksiske syreaddisjonssalter av forbindelsen med formel I som inneholder en gruppe i stand til protonering, for eksempel amino. Slike salter inkluderer de som avledes fra or-ganiske og uorganiske syrer som uten begrensning kan være salt-, hydrobrom-, fosfor-, svovel- eller metansulfonsyre, eddik-, vin-, melke-, rav-, sitron-, eple-, malein-, sorbin-, aconitin-, salicyl-, ftal-, embon-, enantinsyre og lignende.
Representative eksempler på forbindelser som omfattes av oppfinnelsen er: 2-(n-X-1,3-dioksoisoindolin-2-yl)glutarsyre; 2-(n-X-1,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(n-X-1,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(n-X-1,3-dioksoisoindolin-2-yl)ravsyre; 2-(n-X-1,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(n-X-1,3-dioksoisoindolin-2-yl)3-karbamoylpropansyre; 2-(n-X-l-oksoisoindolin-2-yl)glu-tarsyre; 2-(n-X-l-oksoisoindolin-2-yl)4-karbamoylbutansyre; 4-(n-X-l-oksoisoindolin-2-yl)4-karbamoylbutansyre; 2-(n-X-l-oksoisoindolin-2 -yl)ravsyre; 2-(n-X-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; og 3-(n-X-l-oksoisoindolin-2-yl)3-karbamoylpropansyre der n er 3 eller 4 og X er nitro, amino, n-metylamino, metyl, etyl, propyl, isopropyl eller butyl. Spesifikke eksempler er: 2-(3-nitro-l,3-dioksoisoindolin-2-yl)glutarsyre; 2-(3-nitro-l,3-dioksoisoindolin-2-yl)4-karbamoylbutansyre; 4-(3-nitro-l,3-dioksoisoindolin-2-yl)4-karbamoylbutansyre; 2-(3-nitro-l,3-dioksoisoindolin-2-yl)ravsyre; 2- (3-nitro-l,3-dioksoisoindolin-2-yl)3-karbamoylpropansyre; 3- (3-nitro-l,3-dioksoisoindolin-2-yl)3-karbamoylpropansyre; 2-(3-nitro-l-oksoisoindolin-2-yl)glutarsyre; 2-(3-nitro-l-oksoisoindolin-2-yl)karbamoylbutansyre; 4-(3-nitro-l-oksoiso-indolin-2-yl)-4-karbamoylbutansyre; 2-(3-nitro-l-okso-isoindolin-2-yl)ravsyre; 2-(3-nitro-l-oksoisoindolin-2-yl)3-karbamoylpropansyre; 3-(3-nitro-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-nitro-l,3-dioksoisoindolin-2-yl)odipicsyre; 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre, 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-ravsyre; 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-nitro-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-nitro-l-oksoisoindolin-2-yl)glutar-syre; 2-(4-nitro-l-oksoisoindolin-2-yl)4-karbamoylbutansyre; 4- (4-nitro-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-nitro-l-oksoisoindolin-2-yl)ravsyre; 2-(4-nitro-l-oksoiso-indolin-2-yl)3-karbamoylpropansyre; 3-(4-nitro-l-oksoiso-indolin-2-yl)-3-karbamoylpropansyre; 2-(3-amino-l,3-dioksoisoindolin-2-yl)glutarsyre; 2-(3-amino-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-amino-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-amino-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(3-amino-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(3-amino-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-amino-l-oksoisoindolin-2-yl)glutar-syre; 2-(3-amino-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-amino-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-amino-l-oksoisoindolin-2-yl)ravsyre; 2-(3-amino-l-oksoiso-indolin-2-yl)-3-karbamoylpropansyre; 3-(3-amino-l-oksoiso-indolin-2-yl)-3-karbamoylpropansyre; 2-(4-amino-l,3-dioksoisoindolin-2-yl)odipic syre; 2-(4-amino-l,3-dioksoisoindolin-2-yl)4-karbamoylbutansyre; 4-(4-amino-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-amino-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(4-amino-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-amino-l,3-dioksoisoindolin-2-2-yl)-3-karbamoylpropansyre; 2-(4-amino-l-oksoisoindolin-2-yl)glutar-syre; 2-(4-amino-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-amino-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-amino-l-oksoisoindolin-2-yl)ravsyre; 2-(4-amino-l-oksoiso-indolin-2-yl)-3-karbamoylpropansyre; 3-(4-amino-l-oksoiso-indolin-2-yl)-3-karbamoylpropansyre; 2-(3-N-metylamino-l,3-dioksoisoindolin-2-yl)glutarsyre; 2-(3-N-metylamino-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-N-metylamino-l, 3 -dioksoisoindolin-2 -yl) -4-karbamoylbutansyre; 2-(3-N-metylamino-1,3-dioksoisoindolin-2-yl)ravsyre; 2-(3-N-metylamino-l, 3-dioksoisoindolin-2-yl) -3-karbamoylpropansyre; 3-(3-N-metylamino-1,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-N-metylamino-l-oksoisoindolin-2-yl)glutarsyre; 2-(3-N-metylamino-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-N-metylamino-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-N-metylamino-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(3-N-metylamino-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-N-metylamino-l,3-dioksoisoindolin-2-yl)odipic syre; 2-(4-N-metylamino-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-N-metylamino-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-N-metylamino-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(4-N-metylamino-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-N-metylamino-1,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-N-metylamino-l-oksoisoindolin-2-yl)glutarsyre; 2-(4-N-metylamino-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-N-metylamino-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-N-metylamino-l-oksoisoindolin-2-yl)ravsyre; 2-(4-N-metylamino-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-N-metylamino-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-metyl-l,3-dioksoisoindolin-2-yl)glutarsyre; 2-(3-metyl-1,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-metyl-1,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-metyl-1,3-dioksoisoindolin-2-yl)ravsyre; 2-(3-metyl-l,3-dioksoisoindolin-2 -yl) -3-karbamoylpropansyre; 3-(3-metyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-metyl-l-oksoisoindolin-2-yl)glutarsyre; 2-(3-metyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-metyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-metyl-l-oksoisoindolin-2-yl)ravsyre; 2-(3-metyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(3-metyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-metyl-l,3-dioksoisoindolin-2-yl)odipicsyre; 2-(4-metyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-metyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-metyl-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(4-metyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-metyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-metyl-l-oksoisoindolin-2-yl)glutarsyre; 2-(4-metyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-metyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-metyl-l-oksoisoindolin-2-yl)ravsyre; 2-(4-metyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-metyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-etyl-l,3-dioksoisoindolin-2-yl)glutarsyre; 2-(3-etyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-etyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-etyl-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(3-etyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(3-etyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-etyl-l-oksoisoindolin-2-yl)glutarsyre; 2-(3-etyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-etyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-etyl-l-oksoisoindolin-2-yl)ravsyre;
2-(3-etyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(3-etyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-etyl-1,3-dioksoisoindolin-2-yl)odipicsyre; 2-(4-etyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-etyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-etyl-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(4-etyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-etyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-etyl-l-oksoisoindolin-2-yl)glutarsyre; 2-(4-etyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-etyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-etyl-l-oksoisoindolin-2-yl)ravsyre; 2-(4-etyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-etyl-l-okso-isoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-propyl-l,3-dioksoisoindolin-2 -yl) glutarsyre; 2-(3-propyl-l,3-dioksoiso-
indolin-2-.yl) -4-karbamoylbutansyre; 4- (3-propyl-l, 3-diokso-. isoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-propyl-l,3-dioksoisoindolin-2 -yl) ravsyre; 2-(3-propyl-l,3-dioksoisoindolin-2 -yl) -3-karbamoylpropansyre; 3-(3-propyl-l,3-dioksoisoindolin-2 -yl) -3-karbamoylpropansyre; 2-(3-propyl-l-okso-isoindolin-2-yl)glutarsyre; 2-(3-propyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-propyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-propyl-l-oksoisoindolin-2-yl)rav-syre; 2-(3-propyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(3-propyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-propyl-l,3-dioksoisoindolin-2-yl)odipicsyre; 2-(4-propyl-1,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-propyl-1,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-propyl-1,3-dioksoisoindolin-2-yl)ravsyre; 2-(4-propyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-propyl-1,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-propyl-l-oksoisoindolin-2-yl)glutarsyre; 2-(4-propyl-l-oksoiso-indolin-2-yl)-4-karbamoylbutansyre; 4-(4-propyl-l-oksoiso-indolin-2-yl)-4-karbamoylbutansyre; 2-(4-propyl-l-oksoiso-indolin-2-yl)ravsyre; 2-(4-propyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-propyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-isopropyl-l,3-dioksoisoindolin-2-yl)glutarsyre; 2-(3-isopropyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-isopropyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-isopropyl-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(3-isopropyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyer; 3-(3-isopropyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-isopropyl-l-oksoisoindolin-2-yl)glutarsyre; 2-(3-isopropyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-isopropyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(3-isopropyl-l-oksoisoindolin-2-yl)ravsyre;
2- (3-isopropyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3- (3-isopropyl-l-oksoisoindolin-2-yl)-3-kabamoylpropansyre; 2-(4-isopropyl-l,3-dioksoisoindolin-2-yl)odipicsyre; 2-(4-isopropyl-1,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-isopropyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-isopropyl-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(4-isopropyl-l, 3 -dioksoisoindolin-2 -yl) -3-karbamoylpropansyre; 3-
(4-isopropyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-isopropyl-l-oksoisoindolin-2-yl)glutarsyre; 2-(4-isopropyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-isopropyl-l-oksoisoindolin-2-yl)-4-karbamoylburansyre; 2-(4-isopropyl-l-oksoisoindolin-2-yl)ravsyre; 2-(4-isopropyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-isopropyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-butyl-l,3-dioksoisoindolin-2-yl)glutarsyre; 2-(3-butyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-butyl-l,3-dioksoisoindolin-2 -yl) -4-karbamoylbutansyre; 2-(3-butyl-l,3-dioksoisoindolin-2 -yl) ravsyre; 2-(3-butyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(3-butyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(3-butyl-l-oksoisoindolin-2-yl)glutarsyre; 2-(3-butyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(3-butyl-l-oksoisoindolin-2-yl)-4-karba-moylburansyre; 2-(3-butyl-l-oksoisoindolin-2-yl)ravsyre; 2-(3-butyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(3-butyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-butyl-1,3-dioksoisoindolin-2-yl)odipicsyre; 2-(4-butyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-butyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-butyl-l,3-dioksoisoindolin-2-yl)ravsyre; 2-(4-butyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-butyl-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre; 2-(4-butyl-l-oksoiso-indolin-2-yl)glutarsyre; 2-(4-butyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 4-(4-butyl-l-oksoisoindolin-2-yl)-4-karbamoylbutansyre; 2-(4-butyl-l-oksoisoindolin-2-yl)ravsyre; 2-(4-butyl-l-oksoisoindolin-2-yl)-3-karbamoylpropansyre; 3-(4-butyl-l-oksoiso.indolin-2-yl) -3-karbamoylpropansyre.
Disse forbindelser kan benyttes i cancerbehandling, immunmo-dulerende medikamenter, angiogenese inhibering og andre her angitte anvendelser. Orale doseringsformer inkluderer tabletter, kapsler, dragéer og tilsvarende formgitte, pressede far-masøytiske former inneholdende fra 1 til 100 mg medikament per enhetsdose. Isotoniske saltoppløsninger inneholdende fra 20 til 100 mg/ml kan benyttes for parenteral administrering som inkluderer intramuskulær, intratekal, intravenøs og in-tra-arteriell administrering. Rektal administrering kan gjen-nomføres ved bruk av suppositorier som er formulert fra kon-vensjonelle bærere som kakaosmør.
Farmasøytiske preparater omfatter således en eller flere av forbindelsene med formelen I og minst en farmasøytisk aksep-tabel bærer, en diluent eller et drøyemiddel. Ved fremstil-ling av slike preparater blir de aktive bestanddeler vanlig-vis blandet med eller fortynnet med et drøyemiddel og lukket inne i en slik bærer som kan foreligge i form av en kapsel eller en pose. Når drøyemiddelet tjener som diluent, kan dette være et fast, halvfast eller flytende materiale som virker som vehikkel, bærer eller medium for den aktive bestanddel. Således kan preparatene foreligge i form av tabletter, pil-ler, pulvere, eliksirer, suspensjoner, emulsjoner, oppløs-ninger, siruper, myk- og hardgelatinkapsler, suppositorier, sterile injiserbare oppløsninger og sterilt pakkede pulvere. Eksempler på egnede drøyemidler er laktose, dekstrose, sukro-se, sorbitol, mannitol, stivelse, akasiegummi, kalsium sili-kat, mikrokrystallinsk cellulose, polyvinylpyrrolidon, cellulose, vann, sirup og metylcellulose. Formuleringene kan i tillegg inkludere smøremidler som talkum, magnesiumstearat og mineralolje, fuktemidler, emulgerings- og suspensjonsmidler, preserveringsmidler som metyl- og propylhydroksybenzoater, søtningsmidler og smaksmidler.
Preparatene formuleres fortrinnsvis til enhetsdoseform, noe som betyr fysisk diskrete enheter egnet som enhetsdoser, eller en på forhånd bestemt brøkdel av en enhetsdose for administrering i et enkel- eller multippeldoseoppsett til mennesker og andre pattedyr, idet hver enhet inneholder en på forhånd bestemt mengde av det aktive materialet beregnet for å gi den ønskede terapeutiske effekt i forbindelse med et egnet farmasøytisk drøyemiddel. Preparatene kan formuleres for å gi en umiddelbar, opprettholdt eller forsinket frigivning av aktiv bestanddel etter administrering til .pasienten ved å benytte prosedyrer som velkjente i teknikken.
Enzymbundet immunsorbent analyse (ELISA) for TNFa kan gjen-nomføres på konvensjonell måte. PBMC isoleres fra normale donorer ved Ficoll-Hypaque densitets sentrifugering. Celler dyrkes i RPMI supplert med 10% AB+ serum, 2 mM L-glutamin, 100 U/ml penicillin og 100 mg/ml streptomycin. Medikamenter oppløses i dimetylsulfoksid (Sigma Chemical) og fortynnes ytterligere i supplert RPMI. Dimetylsulfoksid konsentrasjonen i nærvær eller fravær av medikamentet i PBMC suspensjonen er 0,25 vektprosent. Medikamenter analyseres som halv-log for-tynninger med utgangspunktet ved 50 mg/ml. Medikamenter settes til PBMC (10<6> celler/ml) i 96 brønners plater 1 time før tilsetting av LPS. PBMC (IO<6> celler/ml) i nærvær eller fravær av medikamenter stimuleres ved behandling med 1 mg/ml LPS fra Salmonella minnesota R595 (List Biological Labs, Campbell, CA). Celler inkuberes så ved 37<2>C i 18-20 timer. Supernatan-ter høstes og analyseres umiddelbart på TNFa nivåer eller holdes dypfryst ved -702C (ikke mer enn 4 dager) til analyse. Konsentrasjonen av TNFa i supernatanten bestemmes ved human TNFa ELISA sett (ENDOGEN, Boston, MA) i henhold til produ-sentens retningslinjer.
De følgende eksempler skal beskrive oppfinnelsens art nærmere uten å ansees som noen begrensning av oppfinnelsens ramme slik den er definert i de vedlagte krav.
EKSEMPEL 1
1-( 4- nitro- l, 3- dioksoisoindolin- 2- yl) propan- 1, 3-dikarboksylsyre
Til den omrørte oppløsning av 10 mmol glutaminsyre og 10,5 mmol natriumkarbonat i 50 ml vann settes 10 mmol etyl 4-nitro-1,3-dioksoisoindolin-2-karboksylat. Den resulterende blanding omrøres 3 timer. Blandingen filtreres. Filtratet surgjøres deretter til pH 1 med 4N saltsyre for å gi 1(4-nitro-1,3-dioksoisoindolin-2-yl)propan-l,3-dikarboksylsyre.
EKSEMPEL 2
1-( 4- metyl- l, 3- dioksoisoindolin- 2- yl) propan- l, 3-dikarboksylsyre
En blanding av 10 mmol glutaminsyre og 10 mmol 4-metyftal-syreanhydrid nedenfor i 20 ml eddiksyre oppvarmes til til-bakeløp. Den avkjølte blanding konsentreres så under vakuum. Resten oppslammes i etylacetat og den resulterende oppslamming filtreres for å gi det ønskede produkt. Som et alterna-tiv til oppslammingsfiltrering, kan kolonnekromatografi benyttes for å rense det ønskede produkt.
EKSEMPEL 3
4-( 4- nitro- l, 3- dioksoisoindolin- 2- yl)- 4- karbamoylbutansyre
En blanding av 20 mmol isoglutamin og 20 mmol 3-nitroftalsyreanhydrid i eddiksyre oppvarmes til tilbakeløp. Den av-kjølte reaksjonsblanding konsentreres og resten renses ved kromatografi for å gi 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre.
EKSEMPEL 4
2-( 4- metyl- l, 3- dioksoisoindolin- 2- yl)- 4- karbamoylbutansyre
En blanding av 10 mmol glutamin og 10 mmol 4-metylisobenzo-furan-1,3-dion i 15 ml eddiksyre oppvarmes til tilbakeløp. Den avkjølte reaksjonsblanding konsentreres og resten renses ved kromatografi for å gi 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre.
EKSEMPEL 5
2-( 4- nitro- l, 3- dioksoisoindolin- 2- yl)- 3- karbamoylbutansyre
En blanding av 10 mmol asparagin og 10 mmol 3-nitroftalsyreanhydrid i 15 ml eddiksyre oppvarmes til tilbakeløp. Den av-kjølte reaksjonsblanding konsentreres og resten renses for å gi 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre .
EKSEMPEL 6
2-/4-amino-l, 3- dioksoisoindolin- 2- yl)- 3- karbamoylpropansyre
En blanding av 7,5 mmol 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre og 200 mg 10% Pd/C i 20 ml dimetylformamid oppvarmes med 60 psi hydrogen i en Parr ryster for å gi 2-(4-amino-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre .
EKSEMPEL 7
2-( 4- nitro- l, 3- dioksoisoindolin- 2- yl)- 4- karbamoylbutansyre
En blanding av 10 mmol glutamin og 10 mmol 3-nitroftalsyreanhydrid i 15 ml eddiksyre oppvarmes til tilbakeløp. Den av-kjølte reaksjonsblanding konsentreres og resten renses ved kromatografi for å gi 2-(4-nitro-l,3-dikosoisoindolin-2-yl)-4-karbamoylbutansyre.
EKSEMPEL 8
2-( 4- amino- l, 3- dioksoisoindolin- 2- yl)- 4- karbamoylbutansyre
En blanding av 5 mmol 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre og 250 mg 10% Pd/C i dimetylformamid hydrogeneres under 60 psi hydrogen i en Parr ryster for å gi 2-(4-amino-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre.
EKSEMPEL 15
1-( 4- nitro- l, 3- dioksoisoindolin- 2- yl) propan- l,3-dikarboksylsyre
En blanding av 3-nitroftalsyreanhydrid (1,5 g, 7,77 mmol) og L-glutaminsyre (1,2 g, 7,77 mmol) i 15 ml DMF oppvarmes til 85<S>C i 6 timer. Blandingen konsentreres under vakuum og resten renses ved kromatografi over silikagel med CH2CI2 : CH3OH 95:5 for å gi 1-(4-nitro-l,3-dioksoisoindolin-2-yl)propan-1,3-dikarboksylsyre (1,51 g, 60%).
<X>H NMR (DMSO-de) 5 8,32 (d, J=7,9 Hz, 1H),.8,21 (d, J=7,3 Hz, 1H), 8,10 (t, J=7,8 Hz, 1H), 4,88-4,82 (dd, J=3,0 og 10,0 Hz, 1H), 2,35-2,20 (m, 4H).
EKSEMPEL 16
1-( 4- amino- l, 3- dioksoisoindolin- 2- yl) propan- l, 3-dikarboksylsyre
En blanding av 1-(4-nitro-l,3-dioksoisoindolin-2-yl)propan-1,3-dikarboksylsyre (1,4 g, 4,34mmol)og 0,14 g 10% Pd/C i 50 ml metanol hydrogeneres ved 50 psi hydrogen i 2 timer. Blandingen filtreres gjennom celitt, og celittputen vaskes med 40 ml metanol. Filtratet konsentreres og resten slammes opp med 25 ml etylacetat og 20 ml heksan for å gi 1-(4-amino-l,3-dioksoisoindolin-2-yl)propan-l,3-dikarbolsylsyre (1,02 g, 80%) med smeltepunkt 198-200<fi>C.
<X>H NMR (DMSO-d6) 8 7,46 (t, J=7,6 Hz, 1H) , 7,02-6,97 (m, 2H) , 6,49 (s, 2H), 4,72-4,68 (m, 1H), 2,38-2,20 (m, 4H); <13>C NMR (DMSO-d6) 8 173,60, 170,60, 168,90, 167,64, 146,64, 135,33, 132,03, 121,56, 110,89, 108,68, 50,56, 30,39, 23,76.
Analyse for: C13H12N2O6;
Beregnet: C 53,43; H 4,14; N 9,59
Funnet: C 53,37; H 4,41; N 9,43
EKSEMPEL 17
2-( 4- nitro- l, 3- dioksoisoindolin- 2- yl)- 4- karbamoylbutansyre
( 40761- 10)
En blanding av 3-nitroftalsyreanhydrid (1,5 g, 7,8 mmol) og L-glutamin (1,14 g, 7,8 mmol) i 15 ml DMF oppvarmes til 85-90aC i 4 timer. Blandingen konsentreres under vakuum og resten oppslammes med 30 ml vann. Den resulterende oppslamming filtreres og faststoffet vaskes med 10 ml vann, tørkes ved 60aC og et trykk mindre enn 1 mm Hg for å gi 2(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre (1,82 g, 73%) med smeltepunkt 182-184aC.
<1>H NMR (DMSO-d6) 8 8,33 (d, J=7,7 Hz, 1H) , 8,22 (d, J=7,0 Hz, 1H) , 8,11 (t, J=7,8 Hz, 1H), 7,19 (s, 1H), 6,73 (s, 1H) , 4,82-4,77 (dd, J=4,6 og 9,8 Hz, 1H), 2,36-2,11 (m, 4H);<13>C NMR (DMSO-de) 8 173,21, 170,03, 165,43, 162,75, 144,45, 136,70, 132,98, 128,83, 127,25, 122,52, 51,87, 31,31, 23,87.
Analyse for: C13N11N3O7;
Beregnet: C 48,60; H 3,45; N 13,08
Funnet: C 48,52; H 3,28; N 13,05
EKSEMPEL 18
2-( 4- amino- l, 3- dioksoisoindolin- 2- yl)- 4- karbamoylbutansyre
( 40761- 18)
En blanding av 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre (1,75 g, 5,45 mmol) og 0,2 g 10% Pd/C i 52 ml metanol hydrogeneres under 50 psi hydrogen i 2 timer. Blandingen filtreres gjennom celitt og celittputen vaskes med 30 ml metanol. Filtratet konsentreres under vakuum og og resten slammes opp med 20 ml etylacetat i 30 minutter. Den resulterende oppslamming filtreres og faststoffet vaskes med 10 ml etylacetat og tørkes (60aC, <1 mmHg) og man oppnår 2-(4-amino-1,3-dioksoisoindolin-2-yl)4-karbamoylbutansyre (1,39 g, 88%) som et gult faststoff med smeltepunkt 165-167<S>C.
<X>H NMR (DMSO-d6) 8 13,08 (b, 1H) , 7,46 (t, J=7,8 Hz, 1H) , 7,22 (s, 1H), 7,02-6,97 (dd, J=4,l og 5,5 Hz, 1H), 6,73 (s, 1H), 6,51 (s, 2H), 4,68-4,62 (dd, J=4,5 og 10,5 Hz, 1H), 2,50-1,99 (m, 4H) ; 13C NMR (DMSO-d6) ( 173,07, 170,75, 168,88, 167,63, 146,66, 135,36, 132,03, 121,58, 110,87, 108,63, 50,74, 31,34, 24,03.
TNFa-inhibering = 46,8 uM
Analyse for: C13H13N305;
Beregnet: C 53,60; H 4,50; N 14,43
Funnet: C 53,71; H 4,40; N 14,31
EKSEMPEL 19
Tabletter som hver inneholder 50 mg 1-(4-nitro-l,3-dioksoisoindolin-2-yl)propan-l,3-dikarboksylsyre kan fremstilles på følgende måte:
De faste bestanddeler tvinges først gjennom en sikt med maskevidde 0,6 mm. Den aktive bestanddel, laktose, talkum, magnesiumstearat og halvparten av stivelsen blandes derefter. Den andre halvpart av stivelsen suspenderes i 40 ml vann, og denne suspensjon settes til en kokende oppløsning av polyety-lenglykol i 100 ml vann. Den resulterende pasta settes til de pulverformige stoffer og blandingen granuleres, hvis nødven-dig under tilsetning av vann. Granulatet tørkes over natten ved 35<2>C, tvinges gjennom en sikt på 1,2 mm maskevidde og presses til tabletter med diameter rundt 6 mm, konkave på begge sider.
EKSEMPEL 20
Tørrfylte gelatinkapsler, hver inneholdende 100 mg 2-(4-nitro-1,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre kan fremstilles på følgende måte:
Natriumlaurylsulfatet siktes inn i 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre gjennom en sikt med maskevidde 0,2 mm og de to komponenter blandes grundig i 10 minutter. Den mikrokrystallinske cellulose tilsettes så gjennom en sikt med maskevidde 0,9 mm og det hele blandes nok en gang grundig i 10 minutter. Til slutt tilsettes magnesiumstearatet gjennom en sikt med maskevidde 0,8 mm og efter blanding i ytterligere 3 minutter innføres blandingen i (langstrakte) størrelse 0 tørrfyll-gelatinkapsler.
EKSEMPEL 21
En 0,2% injeksjonsoppløsning kan fremstilles for eksempel på følgende måte:
2-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre oppløses i 1000 ml vann og filtreres gjennom et mikrofilter. Bufferoppløsningen tilsettes og det hele bringes til 2500 ml med vann. For å preparere enhets doseformer blir porsjoner på 1,0 eller 2,5 ml hver innført i glassampuller (hver inneholdende respektivt 2,0 eller 5,0 mg imid).
Claims (13)
1. En forbindelse, karakterisert ved at den er valgt fra gruppen bestående av et 1,3-dioksoisoindolin med formelen:
der
karbonatomet angitt som C<*> utgjør et kiralitetssenter når n ikke er 0 og når Ri ikke er R<2>;
en av X<1> og X<2> er nitro, Ci_6 alkyl eller NH-Z, og den andre av X<1> eller X<2> er hydrogen;
hver av R<1> og R<2> uavhengig av den andre er hydroksy eller NH-Z;
R3 er hydrogen, CX- 6 alkyl eller halo;
Z er hydrogen, Ci_6 acyl eller Ci_6 alkyl; og n har en verdi lik 0, 1 eller 2;
forutsatt at hvis en av X<1> og X<2> er nitro, og n er 1 eller 2, er R<1> og R2 andre enn hydroksy; og
salter derav.
2. Forbindelse ifølge krav 1, karakterisert ved at R<1> er hydroksy, R<2> er amino, R3 er hydrogen og n er 1 eller 2.
3. Forbindelse ifølge krav 1, karakterisert ved at R<1> er amino, R<2> er hydroksy, R3 er hydrogen og n er 1 eller 2.
4. Forbindelse ifølge krav 1, karakterisert ved at den er 1-(4-nitro-l,3-dioksoisoindolin-2-yl)propan-1,3-dikarboksylsyre.
5. Forbindelse ifølge krav 1, karakterisert ved at den er 1-(4-metyl-l,3-dioksoisoindolin-2-yl)propan-1,3-dikarboksylsyre.
6. Forbindelse ifølge krav 1, karakterisert ved at den er 1-(4-nitro-l,3-dioksoisoindolin-2-yl)-4- karbamoylbutansyre.
7. Forbindelse ifølge krav 1, karakterisert ved at den er 2-(4-metyl-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre.
8. Forbindelse ifølge krav 1, karakterisert ved at den er 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-3-karbamoylbutansyre.
9. Forbindelse ifølge krav 1, karakterisert ved at den er 2-(4-amino-l,3-dioksoisoindolin-2-yl)-3-karbamoylpropansyre.
10. Forbindelse ifølge krav 1, karakterisert ved at den er 2-(4-nitro-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre.
11. Forbindelse ifølge krav 1, karakterisert ved at den er 2-(4-amino-l,3-dioksoisoindolin-2-yl)-4-karbamoylbutansyre.
12. Farmasøytisk preparat, karakterisert ved at det omfatter en mengde av en forbindelse ifølge krav 1 som ved administrering i en enkel- eller multippel dose er tilstrekkelig til å redusere nivåer av inflammatoriske cytokiner hos pattedyr i kombinasjon med en bærer.
13. Forbindelse ifølge krav 1, karakterisert ved at den er en i det vesentlige kiralt ren (R)-isomer, en i det vesentlige kiralt rent (S)-isomer eller en blanding derav.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12494299P | 1999-03-18 | 1999-03-18 | |
PCT/US2000/007029 WO2000055134A1 (en) | 1999-03-18 | 2000-03-17 | Substituted 1-oxo- and 1,3-dioxoisoindolines and their use in pharmaceutical compositions for reducing inflammatory cytokine levels |
Publications (3)
Publication Number | Publication Date |
---|---|
NO20013982D0 NO20013982D0 (no) | 2001-08-16 |
NO20013982L NO20013982L (no) | 2001-11-16 |
NO320028B1 true NO320028B1 (no) | 2005-10-10 |
Family
ID=22417530
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20013982A NO320028B1 (no) | 1999-03-18 | 2001-08-16 | Substituerte 1-Okso- og 1,3-dioksoisoindoliner og deres anvendelse i farmasoytiske preparater for a redusere inflammatoriske cykotin nivaer |
NO20054581A NO20054581L (no) | 1999-03-18 | 2005-10-05 | Substituerte 1-oksoisoindoliner og deres anvendelse i farmasoytiske preparater for a redusere inflammatoriske cykotinnivaer |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20054581A NO20054581L (no) | 1999-03-18 | 2005-10-05 | Substituerte 1-oksoisoindoliner og deres anvendelse i farmasoytiske preparater for a redusere inflammatoriske cykotinnivaer |
Country Status (22)
Country | Link |
---|---|
US (1) | US6380239B1 (no) |
EP (1) | EP1163219B1 (no) |
JP (1) | JP4728487B2 (no) |
KR (1) | KR100672892B1 (no) |
CN (1) | CN1342146A (no) |
AT (1) | ATE306469T1 (no) |
AU (1) | AU771015B2 (no) |
BR (1) | BR0010042A (no) |
CA (1) | CA2361806C (no) |
CZ (1) | CZ20013338A3 (no) |
DE (1) | DE60023123T2 (no) |
DK (1) | DK1163219T3 (no) |
ES (1) | ES2250121T3 (no) |
FI (1) | FI119881B (no) |
HK (1) | HK1042494A1 (no) |
HU (1) | HUP0200499A3 (no) |
NO (2) | NO320028B1 (no) |
NZ (1) | NZ513953A (no) |
RU (1) | RU2001121987A (no) |
TR (1) | TR200102688T2 (no) |
TW (1) | TWI229074B (no) |
WO (1) | WO2000055134A1 (no) |
Families Citing this family (109)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5629327A (en) | 1993-03-01 | 1997-05-13 | Childrens Hospital Medical Center Corp. | Methods and compositions for inhibition of angiogenesis |
US6228879B1 (en) * | 1997-10-16 | 2001-05-08 | The Children's Medical Center | Methods and compositions for inhibition of angiogenesis |
US6429221B1 (en) * | 1994-12-30 | 2002-08-06 | Celgene Corporation | Substituted imides |
US6518281B2 (en) * | 1995-08-29 | 2003-02-11 | Celgene Corporation | Immunotherapeutic agents |
HU228769B1 (en) * | 1996-07-24 | 2013-05-28 | Celgene Corp | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and their use for production of pharmaceutical compositions for mammals to reduce the level of tnf-alpha |
US5635517B1 (en) * | 1996-07-24 | 1999-06-29 | Celgene Corp | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
US7629360B2 (en) * | 1999-05-07 | 2009-12-08 | Celgene Corporation | Methods for the treatment of cachexia and graft v. host disease |
US6458810B1 (en) | 2000-11-14 | 2002-10-01 | George Muller | Pharmaceutically active isoindoline derivatives |
ATE374609T1 (de) * | 2000-11-30 | 2007-10-15 | Childrens Medical Center | Synthese von 4-aminothalidomid enantiomeren |
US7091353B2 (en) | 2000-12-27 | 2006-08-15 | Celgene Corporation | Isoindole-imide compounds, compositions, and uses thereof |
JP4494013B2 (ja) * | 2001-08-06 | 2010-06-30 | ザ チルドレンズ メディカル センター コーポレイション | 窒素置換サリドマイド誘導体の合成及び抗腫瘍活性 |
US7498171B2 (en) | 2002-04-12 | 2009-03-03 | Anthrogenesis Corporation | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
US7323479B2 (en) | 2002-05-17 | 2008-01-29 | Celgene Corporation | Methods for treatment and management of brain cancer using 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline |
US7393862B2 (en) * | 2002-05-17 | 2008-07-01 | Celgene Corporation | Method using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias |
USRE48890E1 (en) | 2002-05-17 | 2022-01-11 | Celgene Corporation | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation |
US7968569B2 (en) * | 2002-05-17 | 2011-06-28 | Celgene Corporation | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
NZ536908A (en) * | 2002-05-17 | 2008-09-26 | Celgene Corp | Treating or preventing cancer comprising administering an effective amount of cytokine inhibitory drug plus a second active ingredient |
US20100129363A1 (en) * | 2002-05-17 | 2010-05-27 | Zeldis Jerome B | Methods and compositions using pde4 inhibitors for the treatment and management of cancers |
US11116782B2 (en) | 2002-10-15 | 2021-09-14 | Celgene Corporation | Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine |
US7189740B2 (en) * | 2002-10-15 | 2007-03-13 | Celgene Corporation | Methods of using 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myelodysplastic syndromes |
US8404717B2 (en) * | 2002-10-15 | 2013-03-26 | Celgene Corporation | Methods of treating myelodysplastic syndromes using lenalidomide |
US8404716B2 (en) | 2002-10-15 | 2013-03-26 | Celgene Corporation | Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine |
US20050203142A1 (en) * | 2002-10-24 | 2005-09-15 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment, modification and management of pain |
US20040087558A1 (en) * | 2002-10-24 | 2004-05-06 | Zeldis Jerome B. | Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain |
US20040091455A1 (en) * | 2002-10-31 | 2004-05-13 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration |
US8034831B2 (en) * | 2002-11-06 | 2011-10-11 | Celgene Corporation | Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies |
US7563810B2 (en) * | 2002-11-06 | 2009-07-21 | Celgene Corporation | Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases |
MXPA05004780A (es) | 2002-11-06 | 2005-10-05 | Celgene Corp | Metodos y composiciones que usan farmacos inhibidores selectivos de citocina para el tratamiento y el manejo de canceres y otros padecimientos. |
BR0316256A (pt) * | 2002-11-18 | 2005-10-04 | Celgene Corp | Métodos de inibir a produção de tnf-alfa e a atividade de pde4, de tratar ou prevenir uma doença ou um distúrbio, de controlar os nìveis de camp em uma célula e de produzir um composto, composição farmacêutica e composto |
JP2006510617A (ja) * | 2002-11-18 | 2006-03-30 | セルジーン・コーポレーション | (+)−3−(3,4−ジメトキシ−フェニル)−3−(1−オキソ−1,3−ジヒドロ−イソインドール−2−イル)−プロピオンアミドの使用方法およびそれを含む組成物 |
CH696542A5 (de) * | 2003-07-09 | 2007-07-31 | Siegfried Ltd | Verfahren zur Herstellung von substituierten 2,6-Dioxopiperidin-3-yl-Verbindungen. |
GB0319069D0 (en) * | 2003-08-14 | 2003-09-17 | Glaxo Group Ltd | Therapeutically useful compounds |
UA83504C2 (en) * | 2003-09-04 | 2008-07-25 | Селджин Корпорейшн | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US20080027113A1 (en) * | 2003-09-23 | 2008-01-31 | Zeldis Jerome B | Methods of Using and Compositions Comprising Immunomodulatory Compounds for Treatment and Management of Macular Degeneration |
US7612096B2 (en) * | 2003-10-23 | 2009-11-03 | Celgene Corporation | Methods for treatment, modification and management of radiculopathy using 1-oxo-2-(2,6-dioxopiperidin-3yl)-4-aminoisoindoline |
US20050100529A1 (en) * | 2003-11-06 | 2005-05-12 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders |
EA200600921A1 (ru) * | 2003-11-06 | 2006-10-27 | Селджин Корпорейшн | Способы и композиции с применением талидомида для лечения и менеджмента рака и других заболеваний |
EP2065383A1 (en) | 2003-11-19 | 2009-06-03 | Signal Pharmaceuticals, Inc. | Indazole compounds and methods of use thereof as protein kinase inhibitors |
US20050143344A1 (en) * | 2003-12-30 | 2005-06-30 | Zeldis Jerome B. | Methods and compositions using immunomodulatory compounds for the treatment and management of central nervous system disorders or diseases |
NZ550026A (en) * | 2004-03-22 | 2009-10-30 | Celgene Corp | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of skin diseases or disorders |
US20050222209A1 (en) * | 2004-04-01 | 2005-10-06 | Zeldis Jerome B | Methods and compositions for the treatment, prevention or management of dysfunctional sleep and dysfunctional sleep associated with disease |
BRPI0418742A (pt) * | 2004-04-14 | 2007-09-11 | Celgene Corp | métodos de tratamento, prevenção ou controle de uma sìndrome mielodisplásica, de redução ou evitação de um efeito adverso associado com a administração de um segundo ingrediente ativo em um paciente sofrendo de um sìndrome mielodisplásica, composição farmacêutica, forma de dosagem unitária única, e, kit |
CA2563810A1 (en) * | 2004-04-23 | 2005-11-10 | Celgene Corporation | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of pulmonary hypertension |
US7405237B2 (en) * | 2004-07-28 | 2008-07-29 | Celgene Corporation | Isoindoline compounds and methods of their use |
ZA200702382B (en) * | 2004-09-03 | 2008-08-27 | Celgene Corp | Processes for the preparation of substituted 2-(2,6-dioxoplperidin-3-yl)-1-oxoisoindolines |
BRPI0518062A (pt) * | 2004-10-28 | 2008-10-28 | Celgene Corp | uso de um modulador de pde4, ou um sal, solvato, ou estereoisÈmero farmaceuticamente aceitável do mesmo, e, composição farmacêutica |
US20060122228A1 (en) * | 2004-11-23 | 2006-06-08 | Zeldis Jerome B | Methods and compositions using immunomodulatory compounds for treatment and management of central nervous system injury |
US20060270707A1 (en) * | 2005-05-24 | 2006-11-30 | Zeldis Jerome B | Methods and compositions using 4-[(cyclopropanecarbonylamino)methyl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione for the treatment or prevention of cutaneous lupus |
CA2612612C (en) | 2005-06-30 | 2014-03-11 | Celgene Corporation | Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds |
CA2613548A1 (en) * | 2005-06-30 | 2007-01-11 | Anthrogenesis Corporation | Repair of tympanic membrane using placenta derived collagen biofabric |
AU2011221383B2 (en) * | 2005-06-30 | 2013-08-01 | Celgene Corporation | Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds |
EP1919500A2 (en) * | 2005-07-13 | 2008-05-14 | Anthrogenesis Corporation | Treatment of leg ulcers using placenta derived collagen biofabric |
US20070021762A1 (en) * | 2005-07-13 | 2007-01-25 | Qing Liu | Ocular plug formed from placenta derived collagen biofabric |
ES2359162T3 (es) | 2005-09-01 | 2011-05-19 | Celgene Corporation | Usos inmunologicos de compuestos inmunomoduladores para vacunas y terapia de enfermedades anti-infecciosas. |
US20080138295A1 (en) * | 2005-09-12 | 2008-06-12 | Celgene Coporation | Bechet's disease using cyclopropyl-N-carboxamide |
US20070066512A1 (en) * | 2005-09-12 | 2007-03-22 | Dominique Verhelle | Methods and compositions using immunomodulatory compounds for the treatment of disorders associated with low plasma leptin levels |
MX343814B (es) | 2005-10-13 | 2016-11-24 | Anthrogenesis Corp | Inmunomodulación usando celulas madre de la placenta. |
KR20080097190A (ko) * | 2005-12-29 | 2008-11-04 | 안트로제네시스 코포레이션 | 태반 줄기세포의 수집과 보존을 위한 개선된 조성물과 이조성물의 이용 방법 |
US20070155791A1 (en) * | 2005-12-29 | 2007-07-05 | Zeldis Jerome B | Methods for treating cutaneous lupus using aminoisoindoline compounds |
US20080064876A1 (en) * | 2006-05-16 | 2008-03-13 | Muller George W | Process for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione |
CL2007002218A1 (es) * | 2006-08-03 | 2008-03-14 | Celgene Corp Soc Organizada Ba | Uso de 3-(4-amino-1-oxo-1,3-dihidro-isoindol-2-il)-piperidina 2,6-diona para la preparacion de un medicamento util para el tratamiento de linfoma de celula de capa. |
WO2008021391A1 (en) * | 2006-08-15 | 2008-02-21 | Anthrogenesis Corporation | Umbilical cord biomaterial for medical use |
WO2008042441A1 (en) * | 2006-10-03 | 2008-04-10 | Anthrogenesis Corporation | Use of umbilical cord biomaterial for ocular surgery |
US8071135B2 (en) | 2006-10-04 | 2011-12-06 | Anthrogenesis Corporation | Placental tissue compositions |
WO2008057162A2 (en) | 2006-10-06 | 2008-05-15 | Anthrogenesis Corporation | Native (telopeptide) placental collagen compositions |
JP2010518812A (ja) * | 2007-02-12 | 2010-06-03 | アンスロジェネシス コーポレーション | 接着性胎盤幹細胞由来の肝細胞および軟骨細胞、ならびにcd34+、cd45−胎盤幹細胞の濃縮細胞集団 |
NZ612888A (en) * | 2007-02-12 | 2015-02-27 | Anthrogenesis Corp | Treatment of inflammatory diseases using placental stem cells |
US7893045B2 (en) | 2007-08-07 | 2011-02-22 | Celgene Corporation | Methods for treating lymphomas in certain patient populations and screening patients for said therapy |
US20090082368A1 (en) * | 2007-09-24 | 2009-03-26 | Painceptor Pharma Corporation | Methods of modulating neurotrophin-mediated activity |
KR20210022148A (ko) | 2007-09-28 | 2021-03-02 | 안트로제네시스 코포레이션 | 인간 태반 관류액 및 인간 태반-유래 중간체 천연 킬러 세포를 사용한 종양 억제 방법 |
US20100311683A1 (en) * | 2007-11-01 | 2010-12-09 | Beach C L | Cytidine analogs for treatment of myelodysplastic syndromes |
EP2235213A2 (en) * | 2007-12-20 | 2010-10-06 | Celgene Corporation | Use of micro-rna as a biomarker of immunomodulatory drug activity |
WO2009105256A2 (en) * | 2008-02-20 | 2009-08-27 | Celgene Corporation | Method of treating cancer by administering an immunomodulatory compound in combination with a cd40 antibody or cd40 ligand |
EP3489352A1 (en) | 2009-03-25 | 2019-05-29 | Celularity, Inc. | Tumor suppression using human placenta-derived intermediate natural killer cells and immunomodulatory compounds |
EP2436387B1 (en) | 2009-05-25 | 2018-07-25 | Celgene Corporation | Pharmaceutical composition comprising crbn for use in treating a disease of the cerebral cortex |
CN101580501B (zh) * | 2009-06-01 | 2011-03-09 | 南京卡文迪许生物工程技术有限公司 | 3-(取代二氢异吲哚酮-2-基)-2,6-哌啶二酮的合成方法及其中间体 |
CA2786266A1 (en) | 2010-01-05 | 2011-07-14 | Celgene Corporation | A combination of an immunomodulatory compound and an artemisinin or a derivative thereof for treating cancer |
MX341050B (es) | 2010-04-07 | 2016-08-05 | Celgene Corp * | Metodos para tratar infeccion viral respiratoria. |
MX2013012083A (es) | 2011-04-18 | 2014-04-16 | Celgene Corp | Biomarcadores para el tratamiento de mieloma multiple. |
KR20140024914A (ko) | 2011-04-29 | 2014-03-03 | 셀진 코포레이션 | 예측인자로 세레브론을 사용하는 암 및 염증성 질환의 치료를 위한 방법 |
WO2013182660A1 (en) | 2012-06-06 | 2013-12-12 | Bionor Immuno As | Hiv vaccine |
ES2872967T3 (es) | 2012-06-29 | 2021-11-03 | Celgene Corp | Métodos para determinar la eficacia de fármacos usando IKZF3 (AIOLOS) |
US9587281B2 (en) | 2012-08-14 | 2017-03-07 | Celgene Corporation | Cereblon isoforms and their use as biomarkers for therapeutic treatment |
AU2014215458A1 (en) | 2013-02-05 | 2015-08-13 | Anthrogenesis Corporation | Natural killer cells from placenta |
AU2014254056B2 (en) | 2013-04-17 | 2019-06-06 | Signal Pharmaceuticals, Llc | Combination therapy comprising a TOR kinase inhibitor and an IMiD compound for treating cancer |
CN103232380A (zh) * | 2013-05-08 | 2013-08-07 | 中国药科大学 | 一种泊马度胺关键中间体的制备方法 |
WO2015007337A1 (en) | 2013-07-19 | 2015-01-22 | Bionor Immuno As | Method for the vaccination against hiv |
EP3160486B1 (en) | 2014-06-27 | 2020-11-18 | Celgene Corporation | Compositions and methods for inducing conformational changes in cereblon other e3 ubiquitin ligases |
RS64038B1 (sr) | 2014-08-22 | 2023-04-28 | Celgene Corp | Postupci za lečenje multiplog mijeloma imunomodulatornim jedinjenjima u kombinaciji sa antitelima |
CN105440013B (zh) * | 2014-08-29 | 2018-10-09 | 杭州和泽医药科技有限公司 | 一种泊马度胺的制备方法 |
SI3313818T1 (sl) | 2015-06-26 | 2024-03-29 | Celgene Corporation | Postopki zdravljenja Kaposijevega sarkoma ali s KSHV povzročenega limfoma, z uporabo imunomodulatornih spojin in uporabe biomarkerjev |
WO2017117118A1 (en) | 2015-12-28 | 2017-07-06 | Celgene Corporation | Compositions and methods for inducing conformational changes in cereblon and other e3 ubiquitin ligases |
CN107365295B (zh) * | 2016-05-11 | 2020-07-07 | 常州制药厂有限公司 | 一种泊马度胺合成工艺的改进方法 |
CN106432045B (zh) * | 2016-06-29 | 2018-12-18 | 深圳海王医药科技研究院有限公司 | 一种泊马度胺杂质的合成方法 |
BR112019011025A2 (pt) | 2016-12-03 | 2019-10-08 | Juno Therapeutics Inc | métodos para modulação de células t car |
PT3618842T (pt) | 2017-05-01 | 2024-01-12 | Juno Therapeutics Inc | Combinação de uma terapia celular e de um composto imunomodulador |
US11413310B2 (en) | 2017-06-02 | 2022-08-16 | Juno Therapeutics, Inc. | Articles of manufacture and methods for treatment using adoptive cell therapy |
MX2019015155A (es) | 2017-06-29 | 2020-08-03 | Juno Therapeutics Inc | Modelo de raton para valorar toxicidades asociadas con inmunoterapias. |
US20200246393A1 (en) | 2017-09-28 | 2020-08-06 | Celularity, Inc. | Tumor suppression using human placenta-derived intermediate natural killer (pink) cells in combination with an antibody |
MA49911A (fr) | 2017-11-01 | 2020-06-24 | Juno Therapeutics Inc | Anticorps et récepteurs antigéniques chimériques spécifiques de l'antigene de maturation des lymphocytes b |
WO2019089858A2 (en) | 2017-11-01 | 2019-05-09 | Juno Therapeutics, Inc. | Methods of assessing or monitoring a response to a cell therapy |
US12006356B2 (en) | 2017-12-15 | 2024-06-11 | Juno Therapeutics, Inc. | Anti-CCT5 binding molecules and chimeric antigen receptors comprising the same |
CA3092037A1 (en) | 2018-02-21 | 2019-08-29 | Celgene Corporation | Bcma-binding antibodies and uses thereof |
CA3117978A1 (en) | 2018-11-08 | 2020-05-14 | Juno Therapeutics, Inc. | Methods and combinations for treatment and t cell modulation |
BR112021009420A2 (pt) | 2018-11-16 | 2021-11-23 | Juno Therapeutics Inc | Métodos de dosagem de células t manipuladas para o tratamento de malignidades de células b |
US20220088070A1 (en) | 2018-11-30 | 2022-03-24 | Juno Therapeutics, Inc. | Methods for treatment using adoptive cell therapy |
EP3917570A1 (en) | 2019-01-29 | 2021-12-08 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1) |
WO2023250400A1 (en) | 2022-06-22 | 2023-12-28 | Juno Therapeutics, Inc. | Treatment methods for second line therapy of cd19-targeted car t cells |
WO2024097905A1 (en) | 2022-11-02 | 2024-05-10 | Celgene Corporation | Methods of treatment with t cell therapy and immunomodulatory agent maintenance therapy |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5855459A (ja) * | 1981-09-26 | 1983-04-01 | Dai Ichi Pure Chem Co Ltd | 光学活性トリプトフアン誘導体の製造法 |
EP0088488B1 (en) * | 1982-01-22 | 1986-10-01 | Beecham Group Plc | Antibacterial agents, their preparation and use |
DE3631229A1 (de) * | 1986-09-13 | 1988-03-24 | Basf Ag | Monoklonale antikoerper gegen humanen tumornekrosefaktor (tnf) und deren verwendung |
GB9109645D0 (en) * | 1991-05-03 | 1991-06-26 | Celltech Ltd | Recombinant antibodies |
GB9028123D0 (en) * | 1990-12-28 | 1991-02-13 | Erba Carlo Spa | Monoclonal antibodies against human tumor necrosis factor alpha |
NL9300354A (nl) * | 1993-02-25 | 1994-09-16 | Futura Nova Bv | Universeel toepasbare celverzamelinrichting. |
US5629327A (en) | 1993-03-01 | 1997-05-13 | Childrens Hospital Medical Center Corp. | Methods and compositions for inhibition of angiogenesis |
HU228769B1 (en) | 1996-07-24 | 2013-05-28 | Celgene Corp | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and their use for production of pharmaceutical compositions for mammals to reduce the level of tnf-alpha |
DE69717831T3 (de) | 1996-07-24 | 2018-08-30 | Celgene Corp. | Substituierte 2-(2,6-dioxopiperidin-3-yl)-phthalimide und -1-oxoisoindoline und verfahren zur reduzierung des tnf-alpha-spiegels |
US5635517B1 (en) | 1996-07-24 | 1999-06-29 | Celgene Corp | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
US5798368A (en) | 1996-08-22 | 1998-08-25 | Celgene Corporation | Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels |
ATE305301T1 (de) | 1996-11-05 | 2005-10-15 | Childrens Medical Center | Mittel zur hemmung von angiogenese enthaltend thalodomid und einen nsaid |
WO1998052919A1 (fr) * | 1997-05-21 | 1998-11-26 | Japan Tobacco Inc. | Derives de phtalimide et produit pharmaceutique contenant ces derives |
-
2000
- 2000-03-17 ES ES00916444T patent/ES2250121T3/es not_active Expired - Lifetime
- 2000-03-17 CZ CZ20013338A patent/CZ20013338A3/cs unknown
- 2000-03-17 NZ NZ513953A patent/NZ513953A/en not_active IP Right Cessation
- 2000-03-17 TR TR2001/02688T patent/TR200102688T2/xx unknown
- 2000-03-17 KR KR1020017011582A patent/KR100672892B1/ko not_active IP Right Cessation
- 2000-03-17 BR BR0010042-0A patent/BR0010042A/pt active Search and Examination
- 2000-03-17 HU HU0200499A patent/HUP0200499A3/hu unknown
- 2000-03-17 AT AT00916444T patent/ATE306469T1/de active
- 2000-03-17 EP EP00916444A patent/EP1163219B1/en not_active Expired - Lifetime
- 2000-03-17 DE DE60023123T patent/DE60023123T2/de not_active Expired - Lifetime
- 2000-03-17 US US09/528,785 patent/US6380239B1/en not_active Expired - Lifetime
- 2000-03-17 JP JP2000605565A patent/JP4728487B2/ja not_active Expired - Fee Related
- 2000-03-17 AU AU37550/00A patent/AU771015B2/en not_active Ceased
- 2000-03-17 RU RU2001121987/04A patent/RU2001121987A/ru unknown
- 2000-03-17 CA CA2361806A patent/CA2361806C/en not_active Expired - Fee Related
- 2000-03-17 DK DK00916444T patent/DK1163219T3/da active
- 2000-03-17 WO PCT/US2000/007029 patent/WO2000055134A1/en active IP Right Grant
- 2000-03-17 CN CN00804440A patent/CN1342146A/zh active Pending
- 2000-05-29 TW TW089104963A patent/TWI229074B/zh not_active IP Right Cessation
-
2001
- 2001-08-16 NO NO20013982A patent/NO320028B1/no not_active IP Right Cessation
- 2001-09-18 FI FI20011839A patent/FI119881B/fi not_active IP Right Cessation
-
2002
- 2002-06-07 HK HK02104317.6A patent/HK1042494A1/zh unknown
-
2005
- 2005-10-05 NO NO20054581A patent/NO20054581L/no unknown
Also Published As
Publication number | Publication date |
---|---|
KR100672892B1 (ko) | 2007-01-23 |
DE60023123T2 (de) | 2006-06-22 |
RU2001121987A (ru) | 2004-02-27 |
JP2002539197A (ja) | 2002-11-19 |
HUP0200499A3 (en) | 2002-12-28 |
FI20011839A (fi) | 2001-09-18 |
NZ513953A (en) | 2001-09-28 |
NO20054581L (no) | 2001-11-16 |
US6380239B1 (en) | 2002-04-30 |
HUP0200499A2 (en) | 2002-06-29 |
CA2361806A1 (en) | 2000-09-21 |
HK1042494A1 (zh) | 2002-08-16 |
ATE306469T1 (de) | 2005-10-15 |
DE60023123D1 (de) | 2006-02-23 |
TWI229074B (en) | 2005-03-11 |
EP1163219B1 (en) | 2005-10-12 |
TR200102688T2 (tr) | 2002-01-21 |
AU771015B2 (en) | 2004-03-11 |
CA2361806C (en) | 2012-03-13 |
NO20013982D0 (no) | 2001-08-16 |
NO20013982L (no) | 2001-11-16 |
WO2000055134A1 (en) | 2000-09-21 |
JP4728487B2 (ja) | 2011-07-20 |
BR0010042A (pt) | 2002-01-15 |
ES2250121T3 (es) | 2006-04-16 |
CZ20013338A3 (cs) | 2002-03-13 |
DK1163219T3 (da) | 2006-02-27 |
FI119881B (fi) | 2009-04-30 |
CN1342146A (zh) | 2002-03-27 |
AU3755000A (en) | 2000-10-04 |
EP1163219A1 (en) | 2001-12-19 |
KR20010109310A (ko) | 2001-12-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1163219B1 (en) | Substituted 1-oxo- and 1,3-dioxoisoindolines and their use in pharmaceutical compositions for reducing inflammatory cytokine levels | |
US5635517A (en) | Method of reducing TNFα levels with amino substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxo-and 1,3-dioxoisoindolines | |
AU745884B2 (en) | 2-(2,6-dioxopiperidin-3-yl)isoindoline derivatives, their preparation and their use as inhibitors of inflammatory cytokines | |
EP1752148B1 (en) | Substituted phenethylsulfones for the treatment of inflammatory, infectious, immunological or malignant disease | |
EP1733726B1 (en) | Pharmaceutically active isoindoline derivatives | |
EP1956017B1 (en) | Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and method of reducing TNF alpha levels | |
US5798368A (en) | Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels | |
AU782634B2 (en) | Substituted acylhydroxamic acids and method of reducing TNFalpha levels | |
NO323449B1 (no) | Substituerte 1.3,4-oksadiazoler samt fremgangsmate for redusering av TNFalfa-nivaer | |
NZ504650A (en) | Non-polypeptide compounds that decrease the levels of TNF-alpha levels, increase cAMP levels and inhibit phosphodiesterase | |
MXPA01009310A (en) | Substituted 1-oxo- and 1,3-dioxoisoindolines and their use in pharmaceutical compositions for reducing inflammatory cytokine levels | |
NO318737B1 (no) | Substituerte 2-(2,6-diokso-3-fluorpiperidin-3-yl)-isoindoliner og deres anvendelse for a redusere TNFa-nivaer | |
MXPA00008645A (en) | 2-(2,6-dioxopiperidin-3-yl)isoindoline derivatives, their preparation and their use as inhibitors of inflammatory cytokines |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM1K | Lapsed by not paying the annual fees |