CN105209485A - 肽化合物 - Google Patents
肽化合物 Download PDFInfo
- Publication number
- CN105209485A CN105209485A CN201480026613.0A CN201480026613A CN105209485A CN 105209485 A CN105209485 A CN 105209485A CN 201480026613 A CN201480026613 A CN 201480026613A CN 105209485 A CN105209485 A CN 105209485A
- Authority
- CN
- China
- Prior art keywords
- pro
- lys
- gly
- ser
- tbu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 123
- 150000001875 compounds Chemical class 0.000 title abstract description 175
- 150000003839 salts Chemical class 0.000 claims abstract description 85
- 239000003814 drug Substances 0.000 claims abstract description 83
- 230000036961 partial effect Effects 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 53
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- 238000002360 preparation method Methods 0.000 claims description 35
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 34
- 206010012601 diabetes mellitus Diseases 0.000 claims description 34
- SCIFESDRCALIIM-VIFPVBQESA-N N-methyl-L-phenylalanine Chemical compound C[NH2+][C@H](C([O-])=O)CC1=CC=CC=C1 SCIFESDRCALIIM-VIFPVBQESA-N 0.000 claims description 31
- 208000008589 Obesity Diseases 0.000 claims description 31
- 235000020824 obesity Nutrition 0.000 claims description 30
- 230000002265 prevention Effects 0.000 claims description 15
- 230000004913 activation Effects 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 10
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 10
- 239000012190 activator Substances 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 claims 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 2
- 239000000370 acceptor Substances 0.000 claims 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 abstract description 9
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 abstract 1
- 230000003213 activating effect Effects 0.000 abstract 1
- 108010036598 gastric inhibitory polypeptide receptor Proteins 0.000 abstract 1
- -1 sec.-propyl Chemical group 0.000 description 258
- 239000011347 resin Substances 0.000 description 233
- 229920005989 resin Polymers 0.000 description 233
- 239000000243 solution Substances 0.000 description 213
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 159
- 239000002585 base Substances 0.000 description 154
- 238000006243 chemical reaction Methods 0.000 description 127
- 239000000203 mixture Substances 0.000 description 124
- 238000005406 washing Methods 0.000 description 112
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 85
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 83
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 80
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 77
- 150000001408 amides Chemical class 0.000 description 64
- 150000003053 piperidines Chemical class 0.000 description 58
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 55
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 55
- 238000012360 testing method Methods 0.000 description 53
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 52
- 238000010828 elution Methods 0.000 description 52
- 238000004128 high performance liquid chromatography Methods 0.000 description 52
- 238000001556 precipitation Methods 0.000 description 52
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 50
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 46
- 229940024606 amino acid Drugs 0.000 description 44
- 230000000694 effects Effects 0.000 description 43
- 235000001014 amino acid Nutrition 0.000 description 42
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 239000001301 oxygen Substances 0.000 description 37
- 229910052760 oxygen Inorganic materials 0.000 description 37
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 35
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 33
- 125000005843 halogen group Chemical group 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 33
- VVQIIIAZJXTLRE-QMMMGPOBSA-N (2s)-2-amino-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound CC(C)(C)OC(=O)NCCCC[C@H](N)C(O)=O VVQIIIAZJXTLRE-QMMMGPOBSA-N 0.000 description 32
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 32
- 102100040918 Pro-glucagon Human genes 0.000 description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 30
- 238000001035 drying Methods 0.000 description 30
- 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 29
- 239000008103 glucose Substances 0.000 description 29
- 230000002829 reductive effect Effects 0.000 description 29
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 28
- 239000000843 powder Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 28
- 102000005962 receptors Human genes 0.000 description 28
- 108020003175 receptors Proteins 0.000 description 28
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 27
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 27
- 239000007864 aqueous solution Substances 0.000 description 27
- 238000010511 deprotection reaction Methods 0.000 description 27
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 27
- 229940100630 metacresol Drugs 0.000 description 27
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 27
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 26
- 230000004087 circulation Effects 0.000 description 26
- 238000001914 filtration Methods 0.000 description 26
- 238000001819 mass spectrum Methods 0.000 description 26
- 239000006228 supernatant Substances 0.000 description 26
- 230000008961 swelling Effects 0.000 description 26
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 26
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 25
- 239000003795 chemical substances by application Substances 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 23
- 150000001413 amino acids Chemical group 0.000 description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 21
- 239000003112 inhibitor Substances 0.000 description 20
- 125000006239 protecting group Chemical group 0.000 description 20
- 210000004369 blood Anatomy 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 19
- 230000037396 body weight Effects 0.000 description 18
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 17
- 239000000556 agonist Substances 0.000 description 17
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 210000004899 c-terminal region Anatomy 0.000 description 16
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 238000009833 condensation Methods 0.000 description 13
- 230000005494 condensation Effects 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 235000013305 food Nutrition 0.000 description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 125000002769 thiazolinyl group Chemical group 0.000 description 12
- WDGICUODAOGOMO-DHUJRADRSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(tritylamino)pentanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)CC(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WDGICUODAOGOMO-DHUJRADRSA-N 0.000 description 11
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 11
- 108060001084 Luciferase Proteins 0.000 description 11
- 239000005089 Luciferase Substances 0.000 description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 11
- 125000003710 aryl alkyl group Chemical group 0.000 description 11
- 230000008878 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 102000051325 Glucagon Human genes 0.000 description 10
- 108060003199 Glucagon Proteins 0.000 description 10
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 10
- 230000032050 esterification Effects 0.000 description 10
- 238000005886 esterification reaction Methods 0.000 description 10
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 10
- 229960004666 glucagon Drugs 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 125000003396 thiol group Chemical group [H]S* 0.000 description 10
- 206010006895 Cachexia Diseases 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 9
- 230000003203 everyday effect Effects 0.000 description 9
- 235000012631 food intake Nutrition 0.000 description 9
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 8
- 208000001145 Metabolic Syndrome Diseases 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 206010020772 Hypertension Diseases 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 6
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 6
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 230000005496 eutectics Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 5
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 5
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 description 5
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- PYGSKMBEVAICCR-UHFFFAOYSA-N hexa-1,5-diene Chemical group C=CCCC=C PYGSKMBEVAICCR-UHFFFAOYSA-N 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 5
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000007410 oral glucose tolerance test Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 208000004611 Abdominal Obesity Diseases 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 4
- 208000002705 Glucose Intolerance Diseases 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 206010056997 Impaired fasting glucose Diseases 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 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 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 230000003579 anti-obesity Effects 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 150000007524 organic acids Chemical group 0.000 description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 4
- 201000009104 prediabetes syndrome Diseases 0.000 description 4
- 229940044601 receptor agonist Drugs 0.000 description 4
- 239000000018 receptor agonist Substances 0.000 description 4
- 230000000630 rising effect Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- 206010003571 Astrocytoma Diseases 0.000 description 3
- 239000005485 Azilsartan Substances 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 3
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 101150020692 Gipr gene Proteins 0.000 description 3
- 108010063919 Glucagon Receptors Proteins 0.000 description 3
- 102100040890 Glucagon receptor Human genes 0.000 description 3
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 3
- 108010063738 Interleukins Proteins 0.000 description 3
- 102000015696 Interleukins Human genes 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- 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 3
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- 101150090155 R gene Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940100389 Sulfonylurea Drugs 0.000 description 3
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 3
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 239000006035 Tryptophane Substances 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 125000005116 aryl carbamoyl group Chemical group 0.000 description 3
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 3
- 229960002731 azilsartan Drugs 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 201000010989 colorectal carcinoma Diseases 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000013613 expression plasmid Substances 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 229960002870 gabapentin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 3
- 201000008980 hyperinsulinism Diseases 0.000 description 3
- 208000006575 hypertriglyceridemia Diseases 0.000 description 3
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 3
- 239000000859 incretin Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- 125000001786 isothiazolyl group Chemical group 0.000 description 3
- 229960002623 lacosamide Drugs 0.000 description 3
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 230000002969 morbid Effects 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 229960004799 tryptophan Drugs 0.000 description 3
- 108700026215 vpr Genes Proteins 0.000 description 3
- QVINPSQORHCFEX-UHFFFAOYSA-N $l^{1}-oxidanylsulfonylbenzene Chemical compound [O]S(=O)(=O)C1=CC=CC=C1 QVINPSQORHCFEX-UHFFFAOYSA-N 0.000 description 2
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 2
- QNLWMPLUWMWDMQ-YTTGMZPUSA-N (2s)-3-[4-(2-carbazol-9-ylethoxy)phenyl]-2-[2-(4-fluorobenzoyl)anilino]propanoic acid Chemical compound N([C@@H](CC=1C=CC(OCCN2C3=CC=CC=C3C3=CC=CC=C32)=CC=1)C(=O)O)C1=CC=CC=C1C(=O)C1=CC=C(F)C=C1 QNLWMPLUWMWDMQ-YTTGMZPUSA-N 0.000 description 2
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical class CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 2
- RXBYRTSOWREATF-UHFFFAOYSA-N 1,2,3,4-tetrahydroacridine Chemical compound C1=CC=C2C=C(CCCC3)C3=NC2=C1 RXBYRTSOWREATF-UHFFFAOYSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 229940099409 11 Beta hydroxysteroid dehydrogenase inhibitor Drugs 0.000 description 2
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 2
- NFTMKHWBOINJGM-UHFFFAOYSA-N 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-4-[[4-(tetrazol-1-yl)phenoxy]methyl]-1,3-thiazole Chemical compound N1=CC(CC)=CN=C1N1CCC(C=2SC=C(COC=3C=CC(=CC=3)N3N=NN=C3)N=2)CC1 NFTMKHWBOINJGM-UHFFFAOYSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- FJEJHJINOKKDCW-INIZCTEOSA-N 3-[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-[(2s)-1-methoxypropan-2-yl]oxy-n-(5-methylpyrazin-2-yl)benzamide Chemical compound C=1C(C(=O)NC=2N=CC(C)=NC=2)=CC(O[C@@H](C)COC)=CC=1OC(N=C1)=CN=C1C(=O)N1CCC1 FJEJHJINOKKDCW-INIZCTEOSA-N 0.000 description 2
- AJJISMLYIMQAKP-OAHLLOKOSA-N 5-[4-[(2r)-4-(3-fluoro-4-methylsulfonylphenoxy)butan-2-yl]piperidin-1-yl]-3-propan-2-yl-1,2,4-oxadiazole Chemical compound CC(C)C1=NOC(N2CCC(CC2)[C@H](C)CCOC=2C=C(F)C(=CC=2)S(C)(=O)=O)=N1 AJJISMLYIMQAKP-OAHLLOKOSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 229940127110 AZD1656 Drugs 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 2
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 108010018763 Biotin carboxylase Proteins 0.000 description 2
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 2
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 description 2
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 description 2
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 description 2
- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Canagliflozin Chemical compound CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 description 2
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 2
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- 125000000028 D-cysteine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C(S[H])([H])[H] 0.000 description 2
- 239000004287 Dehydroacetic acid Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 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
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000010228 Erectile Dysfunction Diseases 0.000 description 2
- 229920003149 Eudragit® E 100 Polymers 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- 229940100607 GPR119 agonist Drugs 0.000 description 2
- 102100039997 Gastric inhibitory polypeptide receptor Human genes 0.000 description 2
- 101800001586 Ghrelin Proteins 0.000 description 2
- 102400000442 Ghrelin-28 Human genes 0.000 description 2
- 229940123232 Glucagon receptor agonist Drugs 0.000 description 2
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 2
- 102000030595 Glucokinase Human genes 0.000 description 2
- 108010021582 Glucokinase Proteins 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 101000886866 Homo sapiens Gastric inhibitory polypeptide receptor Proteins 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 2
- 108010019598 Liraglutide Proteins 0.000 description 2
- 101710151321 Melanostatin Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 102000007072 Nerve Growth Factors Human genes 0.000 description 2
- 102400000064 Neuropeptide Y Human genes 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 239000005480 Olmesartan Substances 0.000 description 2
- 102400000319 Oxyntomodulin Human genes 0.000 description 2
- 101800001388 Oxyntomodulin Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- GSINGUMRKGRYJP-VZWAGXQNSA-N Remogliflozin Chemical compound C1=CC(OC(C)C)=CC=C1CC1=C(C)N(C(C)C)N=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 GSINGUMRKGRYJP-VZWAGXQNSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- JLRNKCZRCMIVKA-UHFFFAOYSA-N Simfibrate Chemical compound C=1C=C(Cl)C=CC=1OC(C)(C)C(=O)OCCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 JLRNKCZRCMIVKA-UHFFFAOYSA-N 0.000 description 2
- 206010054184 Small intestine carcinoma 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
- 229940123051 Somatostatin receptor agonist Drugs 0.000 description 2
- 201000002661 Spondylitis Diseases 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 102000003673 Symporters Human genes 0.000 description 2
- 108090000088 Symporters Proteins 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 206010046543 Urinary incontinence Diseases 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- DJJHHSKPECQNIQ-UHFFFAOYSA-N [O]C(=O)N1CCCCC1 Chemical compound [O]C(=O)N1CCCCC1 DJJHHSKPECQNIQ-UHFFFAOYSA-N 0.000 description 2
- DWDAZFJBSZTCCM-UHFFFAOYSA-N [O]C1CCCCC1 Chemical compound [O]C1CCCCC1 DWDAZFJBSZTCCM-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 2
- 229960001667 alogliptin Drugs 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 159000000013 aluminium salts Chemical class 0.000 description 2
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 229940125682 antidementia agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 2
- 229960004046 apomorphine Drugs 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 159000000009 barium salts Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 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 2
- 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 2
- 239000011230 binding agent Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000003327 cancerostatic effect Effects 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- MVCQKIKWYUURMU-UHFFFAOYSA-N cetilistat Chemical compound C1=C(C)C=C2C(=O)OC(OCCCCCCCCCCCCCCCC)=NC2=C1 MVCQKIKWYUURMU-UHFFFAOYSA-N 0.000 description 2
- 229950002397 cetilistat Drugs 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 239000011280 coal tar Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 229960003850 dabigatran Drugs 0.000 description 2
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 235000019258 dehydroacetic acid Nutrition 0.000 description 2
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 2
- 229940061632 dehydroacetic acid Drugs 0.000 description 2
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 2
- 230000001610 euglycemic effect Effects 0.000 description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- AFLFKFHDSCQHOL-IZZDOVSWSA-N gft505 Chemical compound C1=CC(SC)=CC=C1C(=O)\C=C\C1=CC(C)=C(OC(C)(C)C(O)=O)C(C)=C1 AFLFKFHDSCQHOL-IZZDOVSWSA-N 0.000 description 2
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- CBFCDTFDPHXCNY-UHFFFAOYSA-N icosane Chemical compound CCCCCCCCCCCCCCCCCCCC CBFCDTFDPHXCNY-UHFFFAOYSA-N 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 2
- 229960002701 liraglutide Drugs 0.000 description 2
- 108010033243 lisinopril drug combination hydrochlorothiazide Proteins 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 108700008455 metreleptin Proteins 0.000 description 2
- 229960000668 metreleptin Drugs 0.000 description 2
- 229960003404 mexiletine Drugs 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- PXZWGQLGAKCNKD-DPNMSELWSA-N molport-023-276-326 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 PXZWGQLGAKCNKD-DPNMSELWSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000002632 myometrial effect Effects 0.000 description 2
- ZUSSTQCWRDLYJA-UHFFFAOYSA-N n-hydroxy-5-norbornene-2,3-dicarboximide Chemical compound C1=CC2CC1C1C2C(=O)N(O)C1=O ZUSSTQCWRDLYJA-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- GNZCSGYHILBXLL-UHFFFAOYSA-N n-tert-butyl-6,7-dichloro-3-methylsulfonylquinoxalin-2-amine Chemical compound ClC1=C(Cl)C=C2N=C(S(C)(=O)=O)C(NC(C)(C)C)=NC2=C1 GNZCSGYHILBXLL-UHFFFAOYSA-N 0.000 description 2
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000003900 neurotrophic factor Substances 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000002664 nootropic agent Substances 0.000 description 2
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229960005117 olmesartan Drugs 0.000 description 2
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical compound OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 2
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 2
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229960005095 pioglitazone Drugs 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 2
- 229960004197 prasugrel Drugs 0.000 description 2
- 229960001233 pregabalin Drugs 0.000 description 2
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 2
- WPDCHTSXOPUOII-UHFFFAOYSA-N propan-2-yl 4-[5-methoxy-6-[(2-methyl-6-methylsulfonylpyridin-3-yl)amino]pyrimidin-4-yl]oxypiperidine-1-carboxylate Chemical compound N1=CN=C(OC2CCN(CC2)C(=O)OC(C)C)C(OC)=C1NC1=CC=C(S(C)(=O)=O)N=C1C WPDCHTSXOPUOII-UHFFFAOYSA-N 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 201000001514 prostate carcinoma Diseases 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229940126844 remogliflozin Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- 108010068072 salmon calcitonin Proteins 0.000 description 2
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 2
- 108010033693 saxagliptin Proteins 0.000 description 2
- 229960004937 saxagliptin Drugs 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229960004058 simfibrate Drugs 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 239000002594 sorbent Substances 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ATGUDZODTABURZ-UHFFFAOYSA-N thiolan-2-ylideneazanium;chloride Chemical compound Cl.N=C1CCCS1 ATGUDZODTABURZ-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229960004418 trolamine Drugs 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 2
- 229960001254 vildagliptin Drugs 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000019156 vitamin B Nutrition 0.000 description 2
- 239000011720 vitamin B Substances 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000016261 weight loss Diseases 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 229940063159 zestoretic Drugs 0.000 description 2
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical compound N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 2
- UDAFSIIPPBYMBU-UHFFFAOYSA-N $l^{1}-oxidanyl(morpholin-4-yl)methanone Chemical compound [O]C(=O)N1CCOCC1 UDAFSIIPPBYMBU-UHFFFAOYSA-N 0.000 description 1
- QDGIAPPCJRFVEK-UHFFFAOYSA-N (1-methylpiperidin-4-yl) 2,2-bis(4-chlorophenoxy)acetate Chemical compound C1CN(C)CCC1OC(=O)C(OC=1C=CC(Cl)=CC=1)OC1=CC=C(Cl)C=C1 QDGIAPPCJRFVEK-UHFFFAOYSA-N 0.000 description 1
- SGNVTRHWJGTNKV-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 11-(2,5-dioxopyrrol-1-yl)undecanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCCCCCCN1C(=O)C=CC1=O SGNVTRHWJGTNKV-UHFFFAOYSA-N 0.000 description 1
- PVGATNRYUYNBHO-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(2,5-dioxopyrrol-1-yl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCN1C(=O)C=CC1=O PVGATNRYUYNBHO-UHFFFAOYSA-N 0.000 description 1
- VLARLSIGSPVYHX-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 6-(2,5-dioxopyrrol-1-yl)hexanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCN1C(=O)C=CC1=O VLARLSIGSPVYHX-UHFFFAOYSA-N 0.000 description 1
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- KSDDQEGWVBODMD-OULINLAESA-N (2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-amino-3-sulfanylpropanoyl]amino]-4-carboxybutanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]-4-carboxybutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-oxobutanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]-3-hydroxybutanoyl]amino]-4-carboxybutanoyl]amino]hexanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CS)CC1=CC=CC=C1 KSDDQEGWVBODMD-OULINLAESA-N 0.000 description 1
- XEANIURBPHCHMG-SWLSCSKDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-[(1r)-3-oxocyclopentyl]-n-pyrazin-2-ylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC=NC=1)C[C@@H]1CC(=O)CC1 XEANIURBPHCHMG-SWLSCSKDSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- BFNXYSZBURSNHS-UVJOBNTFSA-N (2s)-1-[(2s)-6-amino-2-[[(1s)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid;6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 BFNXYSZBURSNHS-UVJOBNTFSA-N 0.000 description 1
- JSYGLDMGERSRPC-FQUUOJAGSA-N (2s,4s)-4-fluoro-1-[2-[[(1r,3s)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound C1[C@@H](F)C[C@@H](C#N)N1C(=O)CN[C@H]1C[C@@H](CN2N=CN=C2)CC1 JSYGLDMGERSRPC-FQUUOJAGSA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- ZKNJEOBYOLUGKJ-ALCCZGGFSA-N (z)-2-propylpent-2-enoic acid Chemical compound CCC\C(C(O)=O)=C\CC ZKNJEOBYOLUGKJ-ALCCZGGFSA-N 0.000 description 1
- AKHXXQAIVSMYIS-UHFFFAOYSA-N 1,1-dioxo-3-pentyl-6-(trifluoromethyl)-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound FC(F)(F)C1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CCCCC)NC2=C1 AKHXXQAIVSMYIS-UHFFFAOYSA-N 0.000 description 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 1
- JQIZHNLEFQMDCQ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine Chemical compound C1CC=CNN1 JQIZHNLEFQMDCQ-UHFFFAOYSA-N 0.000 description 1
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 1
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 description 1
- HORKYAIEVBUXGM-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoxaline Chemical compound C1=CC=C2NCCNC2=C1 HORKYAIEVBUXGM-UHFFFAOYSA-N 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- PRANGDVEJDGZJZ-UHFFFAOYSA-N 1-$l^{1}-oxidanylpiperidine Chemical compound [O-][N+]1CCCCC1 PRANGDVEJDGZJZ-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- VNBFUGOVQMFIRN-UHFFFAOYSA-N 1-chlorobutan-2-ol Chemical compound CCC(O)CCl VNBFUGOVQMFIRN-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- 125000005955 1H-indazolyl group Chemical group 0.000 description 1
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical compound N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 description 1
- XKLNOVWDVMWTOB-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-carbazole Chemical compound N1C2=CC=CC=C2C2=C1CCCC2 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 1
- LHJGJYXLEPZJPM-UHFFFAOYSA-N 2,4,5-trichlorophenol Chemical compound OC1=CC(Cl)=C(Cl)C=C1Cl LHJGJYXLEPZJPM-UHFFFAOYSA-N 0.000 description 1
- NMRWDFUZLLQSBN-UHFFFAOYSA-N 2,4-dichloro-n-(3,5-dichloro-4-quinolin-3-yloxyphenyl)benzenesulfonamide Chemical compound ClC1=CC(Cl)=CC=C1S(=O)(=O)NC(C=C1Cl)=CC(Cl)=C1OC1=CN=C(C=CC=C2)C2=C1 NMRWDFUZLLQSBN-UHFFFAOYSA-N 0.000 description 1
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical class OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- WGIMXKDCVCTHGW-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCO WGIMXKDCVCTHGW-UHFFFAOYSA-N 0.000 description 1
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 description 1
- DDTQLPXXNHLBAB-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-[3-(trifluoromethyl)phenoxy]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C(C(=O)O)OC1=CC=CC(C(F)(F)F)=C1 DDTQLPXXNHLBAB-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- NCDZABJPWMBMIQ-INIZCTEOSA-N 2-[(3s)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]piperidin-3-yl]acetic acid Chemical compound CCCSC1=NC(N2C[C@H](CC(O)=O)CCC2)=CC=C1C(=O)NC1CCCCC1 NCDZABJPWMBMIQ-INIZCTEOSA-N 0.000 description 1
- NSVFSAJIGAJDMR-UHFFFAOYSA-N 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate Chemical compound CC=1NC(C)=C(C(=O)OCCN(CC=2C=CC=CC=2)C=2C=CC=CC=2)C(C=2C=C(C=CC=2)[N+]([O-])=O)C=1P1(=O)OCC(C)(C)CO1 NSVFSAJIGAJDMR-UHFFFAOYSA-N 0.000 description 1
- YGZFYDFBHIDIBH-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]icosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCC(CO)N(CCO)CCO YGZFYDFBHIDIBH-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- YZQLWPMZQVHJED-UHFFFAOYSA-N 2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester Chemical compound C=1C=CC=C(SC(=O)C(C)C)C=1NC(=O)C1(CC(CC)CC)CCCCC1 YZQLWPMZQVHJED-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- BCSVCWVQNOXFGL-UHFFFAOYSA-N 3,4-dihydro-4-oxo-3-((5-trifluoromethyl-2-benzothiazolyl)methyl)-1-phthalazine acetic acid Chemical compound O=C1C2=CC=CC=C2C(CC(=O)O)=NN1CC1=NC2=CC(C(F)(F)F)=CC=C2S1 BCSVCWVQNOXFGL-UHFFFAOYSA-N 0.000 description 1
- RMNLMKOJDVKOHO-UHFFFAOYSA-N 3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)benzonitrile Chemical compound O1C(=O)CN(C)CC(=O)OB1C1=CC=CC(C#N)=C1 RMNLMKOJDVKOHO-UHFFFAOYSA-N 0.000 description 1
- AEDQNOLIADXSBB-UHFFFAOYSA-N 3-(dodecylazaniumyl)propanoate Chemical compound CCCCCCCCCCCCNCCC(O)=O AEDQNOLIADXSBB-UHFFFAOYSA-N 0.000 description 1
- RIIDAVMUCMIWKP-AWEZNQCLSA-N 3-[(2s)-1-hydroxypropan-2-yl]oxy-n-(1-methylpyrazol-3-yl)-5-(4-methylsulfonylphenoxy)benzamide Chemical compound C=1C(C(=O)NC2=NN(C)C=C2)=CC(O[C@H](CO)C)=CC=1OC1=CC=C(S(C)(=O)=O)C=C1 RIIDAVMUCMIWKP-AWEZNQCLSA-N 0.000 description 1
- DGENZVKCTGIDRZ-UHFFFAOYSA-N 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1NCC1=CC=CC(OC=2C=CC=CC=2)=C1 DGENZVKCTGIDRZ-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- WZFZJEPHYDDFCT-UHFFFAOYSA-N 3-chloro-2-methyl-n-[4-[2-(3-oxomorpholin-4-yl)ethyl]-1,3-thiazol-2-yl]benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=NC(CCN2C(COCC2)=O)=CS1 WZFZJEPHYDDFCT-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- YMPALHOKRBVHOJ-UHFFFAOYSA-N 3-{5-methoxy-1-[(4-methoxyphenyl)sulfonyl]-1h-indol-3-yl}propanoic acid Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(OC)C=C2C(CCC(O)=O)=C1 YMPALHOKRBVHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000003477 4 aminobutyric acid receptor stimulating agent Substances 0.000 description 1
- IZSNYUXQJVAHFH-UHFFFAOYSA-N 4-$l^{1}-oxidanylmorpholine Chemical compound [O-][N+]1CCOCC1 IZSNYUXQJVAHFH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 1
- IETKPTYAGKZLKY-UHFFFAOYSA-N 5-[[4-[(3-methyl-4-oxoquinazolin-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound N=1C2=CC=CC=C2C(=O)N(C)C=1COC(C=C1)=CC=C1CC1SC(=O)NC1=O IETKPTYAGKZLKY-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 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
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- RXQZLSRIOOYKLF-UHFFFAOYSA-N 5H-pyrazolo[4,3-d]triazine Chemical compound N1=NN=C2C=NNC2=C1 RXQZLSRIOOYKLF-UHFFFAOYSA-N 0.000 description 1
- BKYKPTRYDKTTJY-UHFFFAOYSA-N 6-chloro-3-(cyclopentylmethyl)-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1CCCC1 BKYKPTRYDKTTJY-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 102000011690 Adiponectin Human genes 0.000 description 1
- 108010076365 Adiponectin Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical compound CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 229940118148 Aldose reductase inhibitor Drugs 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 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
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 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
- 108010011485 Aspartame Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 108010028845 BIM 23190 Proteins 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 description 1
- 239000006171 Britton–Robinson buffer Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- HJLYDACAXXYHTJ-UHFFFAOYSA-N C1=CC=C[C]2[N+]([O-])=NN=C21 Chemical compound C1=CC=C[C]2[N+]([O-])=NN=C21 HJLYDACAXXYHTJ-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 description 1
- NTTSSAONTDQRAV-UHFFFAOYSA-N CCC([O])=O Chemical compound CCC([O])=O NTTSSAONTDQRAV-UHFFFAOYSA-N 0.000 description 1
- XQCKXOKBWVXUJH-UHFFFAOYSA-N CCOC([O])=O Chemical compound CCOC([O])=O XQCKXOKBWVXUJH-UHFFFAOYSA-N 0.000 description 1
- 101100268668 Caenorhabditis elegans acc-2 gene Proteins 0.000 description 1
- 101100297347 Caenorhabditis elegans pgl-3 gene Proteins 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 229940122820 Cannabinoid receptor antagonist Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- DTDYFAZVXNSAGJ-UHFFFAOYSA-N ClC(O)C(O)CO.[Na] Chemical compound ClC(O)C(O)CO.[Na] DTDYFAZVXNSAGJ-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 102100025892 Complement C1q tumor necrosis factor-related protein 1 Human genes 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-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
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 1
- 208000002230 Diabetic coma Diseases 0.000 description 1
- 206010012665 Diabetic gangrene Diseases 0.000 description 1
- 102000002148 Diacylglycerol O-acyltransferase Human genes 0.000 description 1
- 108010001348 Diacylglycerol O-acyltransferase Proteins 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 206010061825 Duodenal neoplasm Diseases 0.000 description 1
- DVJAMEIQRSHVKC-BDAKNGLRSA-N Dutogliptin Chemical compound OB(O)[C@@H]1CCCN1C(=O)CN[C@H]1CNCC1 DVJAMEIQRSHVKC-BDAKNGLRSA-N 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 229920003163 Eudragit® NE 30 D Polymers 0.000 description 1
- 229920003141 Eudragit® S 100 Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000017259 Extragonadal germ cell tumor Diseases 0.000 description 1
- BZCALJIHZVNMGJ-HSZRJFAPSA-N Fasiglifam Chemical compound CC1=CC(OCCCS(C)(=O)=O)=CC(C)=C1C1=CC=CC(COC=2C=C3OC[C@@H](CC(O)=O)C3=CC=2)=C1 BZCALJIHZVNMGJ-HSZRJFAPSA-N 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 102100023374 Forkhead box protein M1 Human genes 0.000 description 1
- 229940125827 GPR40 agonist Drugs 0.000 description 1
- 206010017964 Gastrointestinal infection Diseases 0.000 description 1
- 208000036391 Genetic obesity Diseases 0.000 description 1
- 108010016122 Ghrelin Receptors Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- NMWQEPCLNXHPDX-UHFFFAOYSA-N Glybuzole Chemical compound S1C(C(C)(C)C)=NN=C1NS(=O)(=O)C1=CC=CC=C1 NMWQEPCLNXHPDX-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- HNSCCNJWTJUGNQ-UHFFFAOYSA-N Glyclopyramide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC(=O)NN1CCCC1 HNSCCNJWTJUGNQ-UHFFFAOYSA-N 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039256 Growth hormone secretagogue receptor type 1 Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 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 1
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 1
- 102000004384 Histamine H3 receptors Human genes 0.000 description 1
- 108090000981 Histamine H3 receptors Proteins 0.000 description 1
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 description 1
- 101000907578 Homo sapiens Forkhead box protein M1 Proteins 0.000 description 1
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 1
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 206010053712 Hypersomnia-bulimia syndrome Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 206010048865 Hypoacusis Diseases 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- 206010021042 Hypopharyngeal cancer Diseases 0.000 description 1
- 206010056305 Hypopharyngeal neoplasm Diseases 0.000 description 1
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000005726 Inflammatory Breast Neoplasms Diseases 0.000 description 1
- 206010021980 Inflammatory carcinoma of the breast Diseases 0.000 description 1
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- SFBODOKJTYAUCM-UHFFFAOYSA-N Ipriflavone Chemical compound C=1C(OC(C)C)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 SFBODOKJTYAUCM-UHFFFAOYSA-N 0.000 description 1
- 208000009164 Islet Cell Adenoma Diseases 0.000 description 1
- 102000005237 Isophane Insulin Human genes 0.000 description 1
- 108010081368 Isophane Insulin Proteins 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 201000008178 Kleine-Levin syndrome Diseases 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102100032352 Leukemia inhibitory factor Human genes 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- SMNOERSLNYGGOU-UHFFFAOYSA-N Mefruside Chemical compound C=1C=C(Cl)C(S(N)(=O)=O)=CC=1S(=O)(=O)N(C)CC1(C)CCCO1 SMNOERSLNYGGOU-UHFFFAOYSA-N 0.000 description 1
- 102000001796 Melanocortin 4 receptors Human genes 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101100288498 Mus musculus Large1 gene Proteins 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 1
- 108090000742 Neurotrophin 3 Proteins 0.000 description 1
- 102100029268 Neurotrophin-3 Human genes 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- KUEUWHJGRZKESU-UHFFFAOYSA-N Niceritrol Chemical compound C=1C=CN=CC=1C(=O)OCC(COC(=O)C=1C=NC=CC=1)(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 KUEUWHJGRZKESU-UHFFFAOYSA-N 0.000 description 1
- VRAHPESAMYMDQI-UHFFFAOYSA-N Nicomol Chemical compound C1CCC(COC(=O)C=2C=NC=CC=2)(COC(=O)C=2C=NC=CC=2)C(O)C1(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 VRAHPESAMYMDQI-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108090000630 Oncostatin M Proteins 0.000 description 1
- 102000004140 Oncostatin M Human genes 0.000 description 1
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
- 229940123730 Orexin receptor antagonist Drugs 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229940126033 PPAR agonist Drugs 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- CZYWHNTUXNGDGR-UHFFFAOYSA-L Pamidronate disodium Chemical compound O.O.O.O.O.[Na+].[Na+].NCCC(O)(P(O)([O-])=O)P(O)([O-])=O CZYWHNTUXNGDGR-UHFFFAOYSA-L 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 208000018737 Parkinson disease 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
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 206010035004 Pickwickian syndrome Diseases 0.000 description 1
- RZKYEQDPDZUERB-UHFFFAOYSA-N Pindone Chemical group C1=CC=C2C(=O)C(C(=O)C(C)(C)C)C(=O)C2=C1 RZKYEQDPDZUERB-UHFFFAOYSA-N 0.000 description 1
- UJEWTUDSLQGTOA-UHFFFAOYSA-N Piretanide Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1N1CCCC1 UJEWTUDSLQGTOA-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 201000010769 Prader-Willi syndrome Diseases 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 1
- JQCCNTMVGDVJMW-UHFFFAOYSA-N S1NC=CC=C1.ClC Chemical compound S1NC=CC=C1.ClC JQCCNTMVGDVJMW-UHFFFAOYSA-N 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 108091006277 SLC5A1 Proteins 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 229940123495 Squalene synthetase inhibitor Drugs 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 235000006092 Stevia rebaudiana Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 1
- QLYKJCMUNUWAGO-GAJHUEQPSA-N Taranabant Chemical compound N([C@@H](C)[C@@H](CC=1C=CC(Cl)=CC=1)C=1C=C(C=CC=1)C#N)C(=O)C(C)(C)OC1=CC=C(C(F)(F)F)C=N1 QLYKJCMUNUWAGO-GAJHUEQPSA-N 0.000 description 1
- 208000011622 Testicular disease Diseases 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- HXWJFEZDFPRLBG-UHFFFAOYSA-N Timnodonic acid Natural products CCCC=CC=CCC=CCC=CCC=CCCCC(O)=O HXWJFEZDFPRLBG-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- 102100031013 Transgelin Human genes 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 1
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 241000405119 Virga Species 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- KNDHRUPPBXRELB-UHFFFAOYSA-M [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium;chloride Chemical compound [Cl-].C1=CC(CC)=CC=C1C(C)CCC1=CC=C([N+](C)(C)C)C=C1 KNDHRUPPBXRELB-UHFFFAOYSA-M 0.000 description 1
- DBQAKYOUIDOENI-UHFFFAOYSA-M [Br-].C(C1=CC=CC=C1)(=O)[N+]1=CSC=C1 Chemical compound [Br-].C(C1=CC=CC=C1)(=O)[N+]1=CSC=C1 DBQAKYOUIDOENI-UHFFFAOYSA-M 0.000 description 1
- OPLYDSLPKIFDAA-UHFFFAOYSA-M [F-].[S+](=O)(=O)=O Chemical compound [F-].[S+](=O)(=O)=O OPLYDSLPKIFDAA-UHFFFAOYSA-M 0.000 description 1
- ISEFLIBOQOJZIN-UHFFFAOYSA-N [O].CCC=CCC Chemical compound [O].CCC=CCC ISEFLIBOQOJZIN-UHFFFAOYSA-N 0.000 description 1
- DDPNFUUBIAXJES-UHFFFAOYSA-N [O]C(=O)c1ccc2ccccc2c1 Chemical compound [O]C(=O)c1ccc2ccccc2c1 DDPNFUUBIAXJES-UHFFFAOYSA-N 0.000 description 1
- NRAINUFKKPBZQY-UHFFFAOYSA-N [O]C1CC1 Chemical compound [O]C1CC1 NRAINUFKKPBZQY-UHFFFAOYSA-N 0.000 description 1
- GYAPJISEIGCPQO-UHFFFAOYSA-N [O]C1CCC1 Chemical compound [O]C1CCC1 GYAPJISEIGCPQO-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 201000008395 adenosquamous carcinoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- MKOMESMZHZNBIZ-UHFFFAOYSA-M alagebrium Chemical compound [Cl-].CC1=C(C)SC=[N+]1CC(=O)C1=CC=CC=C1 MKOMESMZHZNBIZ-UHFFFAOYSA-M 0.000 description 1
- 208000002353 alcoholic hepatitis Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- DAYKLWSKQJBGCS-NRFANRHFSA-N aleglitazar Chemical compound C1=2C=CSC=2C(C[C@H](OC)C(O)=O)=CC=C1OCCC(=C(O1)C)N=C1C1=CC=CC=C1 DAYKLWSKQJBGCS-NRFANRHFSA-N 0.000 description 1
- 229950010157 aleglitazar Drugs 0.000 description 1
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 1
- 229960002535 alfacalcidol Drugs 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229960003318 alteplase Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000005910 aminocarbonylation reaction Methods 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- CKMXBZGNNVIXHC-UHFFFAOYSA-L ammonium magnesium phosphate hexahydrate Chemical compound [NH4+].O.O.O.O.O.O.[Mg+2].[O-]P([O-])([O-])=O CKMXBZGNNVIXHC-UHFFFAOYSA-L 0.000 description 1
- MZZLGJHLQGUVPN-HAWMADMCSA-N anacetrapib Chemical compound COC1=CC(F)=C(C(C)C)C=C1C1=CC=C(C(F)(F)F)C=C1CN1C(=O)O[C@H](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)[C@@H]1C MZZLGJHLQGUVPN-HAWMADMCSA-N 0.000 description 1
- 229950000285 anacetrapib Drugs 0.000 description 1
- LDXYBEHACFJIEL-HNNXBMFYSA-N anagliptin Chemical compound C=1N2N=C(C)C=C2N=CC=1C(=O)NCC(C)(C)NCC(=O)N1CCC[C@H]1C#N LDXYBEHACFJIEL-HNNXBMFYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 206010002224 anaplastic astrocytoma Diseases 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 125000002078 anthracen-1-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([*])=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000000748 anthracen-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([H])=C([*])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000002961 anti-hyperuricemic effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229960003886 apixaban Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 1
- 229960003856 argatroban Drugs 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000005126 aryl alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 1
- IIOPLILENRZKRV-UHFFFAOYSA-N azosemide Chemical compound C=1C=CSC=1CNC=1C=C(Cl)C(S(=O)(=O)N)=CC=1C1=NN=N[N]1 IIOPLILENRZKRV-UHFFFAOYSA-N 0.000 description 1
- 229960004988 azosemide Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000001119 benign fibrous histiocytoma Diseases 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- BMWITAUNXBHIPO-OZZZDHQUSA-N benzenesulfonic acid;(2s,4s)-4-fluoro-1-[2-[(1-hydroxy-2-methylpropan-2-yl)amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound OS(=O)(=O)C1=CC=CC=C1.OCC(C)(C)NCC(=O)N1C[C@@H](F)C[C@H]1C#N BMWITAUNXBHIPO-OZZZDHQUSA-N 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- ZRROISWUBQJICN-UHFFFAOYSA-N benzoyl naphthalene-1-carboperoxoate Chemical compound C1(=CC=CC2=CC=CC=C12)C(=O)OOC(C1=CC=CC=C1)=O ZRROISWUBQJICN-UHFFFAOYSA-N 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229960002890 beraprost Drugs 0.000 description 1
- YTCZZXIRLARSET-VJRSQJMHSA-M beraprost sodium Chemical compound [Na+].O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC([O-])=O YTCZZXIRLARSET-VJRSQJMHSA-M 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000005885 boration reaction Methods 0.000 description 1
- 208000012172 borderline epithelial tumor of ovary Diseases 0.000 description 1
- 208000017835 brachydactyly-nystagmus-cerebellar ataxia syndrome Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- ILJDFBVQZFJJJS-UHFFFAOYSA-N butyl $l^{1}-oxidanylformate Chemical compound CCCCOC([O])=O ILJDFBVQZFJJJS-UHFFFAOYSA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- UFGVUHDWEQMLGF-UHFFFAOYSA-L calcium;2-carboxyphenolate;3,7-dimethyl-2-oxopurin-6-olate Chemical compound [Ca+2].OC1=CC=CC=C1C([O-])=O.CN1C(=O)[N-]C(=O)C2=C1N=CN2C UFGVUHDWEQMLGF-UHFFFAOYSA-L 0.000 description 1
- ZQNPDAVSHFGLIQ-UHFFFAOYSA-N calcium;hydrate Chemical compound O.[Ca] ZQNPDAVSHFGLIQ-UHFFFAOYSA-N 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 229960004349 candesartan cilexetil Drugs 0.000 description 1
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3N=CN=C3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 1
- 239000003536 cannabinoid receptor antagonist Substances 0.000 description 1
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 description 1
- 239000006229 carbon black Substances 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003262 carboxylic acid ester group Chemical group [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 208000022033 carcinoma of urethra Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- 229960004195 carvedilol Drugs 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 description 1
- WGEWUYACXPEFPO-AULYBMBSSA-N chembl2016681 Chemical compound C1C[C@@H](NS(=O)(=O)C(C)(C)C)CC[C@@H]1C(=O)NC1=CC=C(C(F)(F)F)C=N1 WGEWUYACXPEFPO-AULYBMBSSA-N 0.000 description 1
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 1
- SLYFITHISHUGLZ-LWZDQURMSA-N chembl2105635 Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@@H]([C@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@H](C)O)C(=O)N1 SLYFITHISHUGLZ-LWZDQURMSA-N 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 208000012191 childhood neoplasm Diseases 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229930002875 chlorophyll Natural products 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 1
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 230000007665 chronic toxicity Effects 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 description 1
- 229950009226 ciglitazone Drugs 0.000 description 1
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 1
- 229960004588 cilostazol Drugs 0.000 description 1
- 229950003072 clinofibrate Drugs 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 229960001678 colestyramine Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000005171 cycloalkylsulfanyl group Chemical group 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 description 1
- 239000004913 cyclooctene Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 229960003206 cyclopenthiazide Drugs 0.000 description 1
- VCZIFQMEDXLHEA-UHFFFAOYSA-N cyclopentylperoxycyclohexane Chemical compound C1(CCCC1)OOC1CCCCC1 VCZIFQMEDXLHEA-UHFFFAOYSA-N 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- UKPXULFIISGBHG-UHFFFAOYSA-N cyclopropene Chemical compound [CH]1C=C1 UKPXULFIISGBHG-UHFFFAOYSA-N 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 229950004181 dalcetrapib Drugs 0.000 description 1
- 229940018872 dalteparin sodium Drugs 0.000 description 1
- 108010007487 davalintide Proteins 0.000 description 1
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 1
- 229960005227 delapril Drugs 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 229910052805 deuterium Inorganic materials 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
- 238000003745 diagnosis Methods 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- VVWFEDKRKBBKFD-UHFFFAOYSA-N diazocyclooctane Chemical compound [N-]=[N+]=C1CCCCCCC1 VVWFEDKRKBBKFD-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 208000019836 digestive system infectious disease Diseases 0.000 description 1
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical group C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- IRYSOHKKWIRVLX-UHFFFAOYSA-N dimethylamino formate Chemical compound CN(C)OC=O IRYSOHKKWIRVLX-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- ZZFKAZHZSSJSSE-UHFFFAOYSA-L disodium;[(cycloheptylamino)-[hydroxy(oxido)phosphoryl]methyl]-hydroxyphosphinate;hydrate Chemical compound O.[Na+].[Na+].OP(O)(=O)C(P([O-])([O-])=O)NC1CCCCCC1 ZZFKAZHZSSJSSE-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229960001446 distigmine Drugs 0.000 description 1
- GJHSNEVFXQVOHR-UHFFFAOYSA-L distigmine bromide Chemical compound [Br-].[Br-].C=1C=C[N+](C)=CC=1OC(=O)N(C)CCCCCCN(C)C(=O)OC1=CC=C[N+](C)=C1 GJHSNEVFXQVOHR-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 201000000312 duodenum cancer Diseases 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229950003102 efonidipine Drugs 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 1
- JYSJVJJVLNYRKL-QPHHPWFVSA-N elcatonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)C1CCCCCC(=O)OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 JYSJVJJVLNYRKL-QPHHPWFVSA-N 0.000 description 1
- 229960000756 elcatonin Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229940047562 eliquis Drugs 0.000 description 1
- 229950000269 emiglitate Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 229950002375 englitazone Drugs 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960005153 enoxaparin sodium Drugs 0.000 description 1
- 210000003158 enteroendocrine cell Anatomy 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 1
- 229950010170 epalrestat Drugs 0.000 description 1
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 description 1
- RINBGYCKMGDWPY-UHFFFAOYSA-N epitizide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(CSCC(F)(F)F)NS2(=O)=O RINBGYCKMGDWPY-UHFFFAOYSA-N 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000006627 ethoxycarbonylamino group Chemical group 0.000 description 1
- NWWORXYTJRPSMC-QKPAOTATSA-N ethyl 4-[2-[(2r,3r,4r,5s)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]ethoxy]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)C1 NWWORXYTJRPSMC-QKPAOTATSA-N 0.000 description 1
- AKFNKZFJBFQFAA-DIOPXHOYSA-N ethyl 4-[[2-[(2s,4s)-2-cyano-4-fluoropyrrolidin-1-yl]-2-oxoethyl]amino]bicyclo[2.2.2]octane-1-carboxylate Chemical compound C1CC(C(=O)OCC)(CC2)CCC12NCC(=O)N1C[C@@H](F)C[C@H]1C#N AKFNKZFJBFQFAA-DIOPXHOYSA-N 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 208000020603 familial colorectal cancer Diseases 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 229950007405 fasiglifam Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- XOEVKNFZUQEERE-UHFFFAOYSA-N flavoxate hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C)=C(C=3C=CC=CC=3)OC2=C1C(=O)OCCN1CCCCC1 XOEVKNFZUQEERE-UHFFFAOYSA-N 0.000 description 1
- 229960003064 flavoxate hydrochloride Drugs 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 239000000989 food dye Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- JUQAECQBUNODQP-UHFFFAOYSA-N furo[3,2-d]pyrimidine Chemical class C1=NC=C2OC=CC2=N1 JUQAECQBUNODQP-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- FODTZLFLDFKIQH-FSVGXZBPSA-N gamma-Oryzanol (TN) Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)O[C@@H]2C([C@@H]3CC[C@H]4[C@]5(C)CC[C@@H]([C@@]5(C)CC[C@@]54C[C@@]53CC2)[C@H](C)CCC=C(C)C)(C)C)=C1 FODTZLFLDFKIQH-FSVGXZBPSA-N 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 208000018914 glucose metabolism disease Diseases 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 229950005232 glybuzole Drugs 0.000 description 1
- 230000036252 glycation Effects 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229950002888 glyclopyramide Drugs 0.000 description 1
- LTYRAPJYLUPLCI-UHFFFAOYSA-N glycolonitrile Chemical compound OCC#N LTYRAPJYLUPLCI-UHFFFAOYSA-N 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- QWEWGXUTRTXFRF-KBPBESRZSA-N gosogliptin Chemical compound C1C(F)(F)CCN1C(=O)[C@H]1NC[C@@H](N2CCN(CC2)C=2N=CC=CN=2)C1 QWEWGXUTRTXFRF-KBPBESRZSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 150000005235 imidazopyrazines Chemical class 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229950006971 incadronic acid Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 1
- 229960004569 indapamide Drugs 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 201000004653 inflammatory breast carcinoma Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000037493 inherited obesity Diseases 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 description 1
- 229950000991 ipragliflozin Drugs 0.000 description 1
- 229960005431 ipriflavone Drugs 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N iso-butene Natural products CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940062717 keppra Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 208000021788 large intestine disease Diseases 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- 229950011452 lidorestat Drugs 0.000 description 1
- 229950009619 lifibrate Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- CHHXEZSCHQVSRE-UHFFFAOYSA-N lobeglitazone Chemical compound C1=CC(OC)=CC=C1OC1=CC(N(C)CCOC=2C=CC(CC3C(NC(=O)S3)=O)=CC=2)=NC=N1 CHHXEZSCHQVSRE-UHFFFAOYSA-N 0.000 description 1
- 229950007685 lobeglitazone Drugs 0.000 description 1
- 229960005060 lorcaserin Drugs 0.000 description 1
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960000519 losartan potassium Drugs 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- ANEBWFXPVPTEET-UHFFFAOYSA-N manidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ANEBWFXPVPTEET-UHFFFAOYSA-N 0.000 description 1
- 229960003963 manidipine Drugs 0.000 description 1
- 210000004086 maxillary sinus Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229960004678 mefruside Drugs 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- WVJKHCGMRZGIJH-UHFFFAOYSA-N methanetriamine Chemical compound NC(N)N WVJKHCGMRZGIJH-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- JHZWMBRFGLKQSH-UHFFFAOYSA-N methyl $l^{1}-oxidanylformate Chemical compound COC([O])=O JHZWMBRFGLKQSH-UHFFFAOYSA-N 0.000 description 1
- WSYALRNYQFNNGP-WJOKGBTCSA-N methyl (2r)-2-phenyl-2-[4-[4-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]phenyl]piperidin-1-yl]acetate Chemical compound C1CN([C@@H](C(=O)OC)C=2C=CC=CC=2)CCC1C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 WSYALRNYQFNNGP-WJOKGBTCSA-N 0.000 description 1
- IVAQJHSXBVHUQT-ZVHZXABRSA-N methyl (e)-3-(3,5-dimethoxyphenyl)-2-[4-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]phenyl]prop-2-enoate Chemical compound C=1C=C(OC=2C=CC(CC3C(NC(=O)S3)=O)=CC=2)C=CC=1/C(C(=O)OC)=C\C1=CC(OC)=CC(OC)=C1 IVAQJHSXBVHUQT-ZVHZXABRSA-N 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- IQSHMXAZFHORGY-UHFFFAOYSA-N methyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound COC(=O)C=C.CC(=C)C(O)=O IQSHMXAZFHORGY-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- INAAFKWUQOMCDA-UHFFFAOYSA-N methylsulfonyloxy ethanesulfonate Chemical compound CS(=O)(=O)OOS(=O)(=O)CC INAAFKWUQOMCDA-UHFFFAOYSA-N 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229950005805 monteplase Drugs 0.000 description 1
- 108010075698 monteplase Proteins 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 1
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical class OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- WIEDUMBCZQRGSY-UHFFFAOYSA-N n-[[2,6-difluoro-4-[3-(1h-1,2,4-triazol-5-yl)phenyl]phenyl]methyl]-2,3-dihydro-1h-inden-2-amine Chemical compound C=1C(F)=C(CNC2CC3=CC=CC=C3C2)C(F)=CC=1C(C=1)=CC=CC=1C1=NC=NN1 WIEDUMBCZQRGSY-UHFFFAOYSA-N 0.000 description 1
- BDQCDIWFPIDPQU-NDEPHWFRSA-N n-methyl-5-[4-[1-[(1r)-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-1'-carbonyl]cyclopropyl]phenyl]pyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC=C1C1=CC=C(C2(CC2)C(=O)N2C[C@@]3(CC2)C2=CC=CC=C2C(=O)O3)C=C1 BDQCDIWFPIDPQU-NDEPHWFRSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 201000007425 nasal cavity carcinoma Diseases 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229950002774 nateplase Drugs 0.000 description 1
- 208000018389 neoplasm of cerebral hemisphere Diseases 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229940033757 niaspan Drugs 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229960000827 niceritrol Drugs 0.000 description 1
- 229950001071 nicomol Drugs 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 208000021284 ovarian germ cell tumor Diseases 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 229960002016 oxybutynin chloride Drugs 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000026792 palmitoylation Effects 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- 229950003603 pamiteplase Drugs 0.000 description 1
- 108010085108 pamiteplase Proteins 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 201000003913 parathyroid carcinoma Diseases 0.000 description 1
- 208000017954 parathyroid gland carcinoma Diseases 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 201000008006 pharynx cancer Diseases 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- 201000007315 pineal gland astrocytoma Diseases 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229950010267 piragliatin Drugs 0.000 description 1
- 229960001085 piretanide Drugs 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 235000002378 plant sterols Nutrition 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 108010001062 polysaccharide-K Proteins 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- TZIRZGBAFTZREM-MKAGXXMWSA-N pramlintide Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H]1NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)CSSC1)[C@@H](C)O)C(C)C)C1=CC=CC=C1 TZIRZGBAFTZREM-MKAGXXMWSA-N 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 230000002360 prefrontal effect Effects 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- KJAQRHMKLVGSCG-UHFFFAOYSA-N propan-2-ylhydrazine Chemical compound CC(C)NN KJAQRHMKLVGSCG-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 108010076038 prosaptide Proteins 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 208000006078 pseudohypoparathyroidism Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- HNWCOANXZNKMLR-UHFFFAOYSA-N pyridoxamine dihydrochloride Chemical compound Cl.Cl.CC1=NC=C(CO)C(CN)=C1O HNWCOANXZNKMLR-UHFFFAOYSA-N 0.000 description 1
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229940079889 pyrrolidonecarboxylic acid Drugs 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 229950010535 razaxaban Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 1
- 229960003015 rimonabant Drugs 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- CRPGRUONUFDYBG-UHFFFAOYSA-N risarestat Chemical compound C1=C(OCC)C(OCCCCC)=CC=C1C1C(=O)NC(=O)S1 CRPGRUONUFDYBG-UHFFFAOYSA-N 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 229960001148 rivaroxaban Drugs 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- XMSXOLDPMGMWTH-UHFFFAOYSA-N rivoglitazone Chemical compound CN1C2=CC(OC)=CC=C2N=C1COC(C=C1)=CC=C1CC1SC(=O)NC1=O XMSXOLDPMGMWTH-UHFFFAOYSA-N 0.000 description 1
- 229950010764 rivoglitazone Drugs 0.000 description 1
- 229950005789 sarpogrelate Drugs 0.000 description 1
- FFYNAVGJSYHHFO-UHFFFAOYSA-N sarpogrelate Chemical compound COC1=CC=CC(CCC=2C(=CC=CC=2)OCC(CN(C)C)OC(=O)CCC(O)=O)=C1 FFYNAVGJSYHHFO-UHFFFAOYSA-N 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 1
- 229960002639 sildenafil citrate Drugs 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 208000037968 sinus cancer Diseases 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940126121 sodium channel inhibitor Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- WSRBRQQGWDWSON-UHFFFAOYSA-M sodium;3,7-dimethylpurine-2,6-dione;2-hydroxybenzoate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O.CN1C(=O)NC(=O)C2=C1N=CN2C WSRBRQQGWDWSON-UHFFFAOYSA-M 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 239000004059 squalene synthase inhibitor Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- SIARJEKBADXQJG-LFZQUHGESA-N stearoyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCCCCCCCCCCCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 SIARJEKBADXQJG-LFZQUHGESA-N 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Natural products 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 1
- 229910052567 struvite Inorganic materials 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 230000035322 succinylation Effects 0.000 description 1
- 238000010613 succinylation reaction Methods 0.000 description 1
- 125000000213 sulfino group Chemical group [H]OS(*)=O 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229950005022 taranabant Drugs 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- MKTAGSRKQIGEBH-SSDOTTSWSA-N tebanicline Chemical compound C1=NC(Cl)=CC=C1OC[C@@H]1NCC1 MKTAGSRKQIGEBH-SSDOTTSWSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- FXYPBSKJSOBFAC-UHFFFAOYSA-N tert-butyl $l^{1}-oxidanylformate Chemical compound CC(C)(C)OC([O])=O FXYPBSKJSOBFAC-UHFFFAOYSA-N 0.000 description 1
- 230000006209 tert-butylation Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VCVWXKKWDOJNIT-ZOMKSWQUSA-N tesofensine Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3C)[C@@H]2COCC)=CC=C(Cl)C(Cl)=C1 VCVWXKKWDOJNIT-ZOMKSWQUSA-N 0.000 description 1
- 229950009970 tesofensine Drugs 0.000 description 1
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CIJQTPFWFXOSEO-NDMITSJXSA-J tetrasodium;(2r,3r,4s)-2-[(2r,3s,4r,5r,6s)-5-acetamido-6-[(1r,2r,3r,4r)-4-[(2r,3s,4r,5r,6r)-5-acetamido-6-[(4r,5r,6r)-2-carboxylato-4,5-dihydroxy-6-[[(1r,3r,4r,5r)-3-hydroxy-4-(sulfonatoamino)-6,8-dioxabicyclo[3.2.1]octan-2-yl]oxy]oxan-3-yl]oxy-2-(hydroxy Chemical compound [Na+].[Na+].[Na+].[Na+].O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1O)NC(C)=O)O[C@@H]1C(C[C@H]([C@@H]([C@H]1O)O)O[C@@H]1[C@@H](CO)O[C@H](OC2C(O[C@@H](OC3[C@@H]([C@@H](NS([O-])(=O)=O)[C@@H]4OC[C@H]3O4)O)[C@H](O)[C@H]2O)C([O-])=O)[C@H](NC(C)=O)[C@H]1C)C([O-])=O)[C@@H]1OC(C([O-])=O)=C[C@H](O)[C@H]1O CIJQTPFWFXOSEO-NDMITSJXSA-J 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- MTKNGOHFNXIVOS-UHFFFAOYSA-N ticlopidine hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 MTKNGOHFNXIVOS-UHFFFAOYSA-N 0.000 description 1
- 229960002961 ticlopidine hydrochloride Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- IWYJYHUNXVAVAA-OAHLLOKOSA-N trelagliptin Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 description 1
- 229950010728 trelagliptin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940061414 trileptal Drugs 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 239000013559 triple agonist Substances 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 201000000334 ureter transitional cell carcinoma Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 201000003365 uterine corpus sarcoma Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- WQEVDHBJGNOKKO-UHFFFAOYSA-K vanadic acid Chemical compound O[V](O)(O)=O WQEVDHBJGNOKKO-UHFFFAOYSA-K 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 206010055031 vascular neoplasm Diseases 0.000 description 1
- 229950006508 velneperit Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 229940061639 zonegran Drugs 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- 229950005346 zopolrestat Drugs 0.000 description 1
- KYHVTMFADJNSGS-UHFFFAOYSA-N {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1h-indol-1-yl}acetic acid Chemical compound C12=CC=CC=C2N(CC(=O)O)C=C1CC1=NC2=C(F)C(F)=CC(F)=C2S1 KYHVTMFADJNSGS-UHFFFAOYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了对GLP-1受体和GIP受体具有活化作用的新的肽化合物,以及所述肽化合物作为药物的用途。具体地说,提供了含有式(I)所代表的部分序列的肽或其盐,以及含有所述肽或其盐的药物。P1-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17-Ala-Gln-A20-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-A29(I)。其中,每个符号如本文所定义。
Description
[技术领域]
本发明涉及对GLP-1受体和GIP受体具有活化作用的新的肽化合物,以及所述肽化合物作为药物的用途。
[发明背景]
胰高血糖素样肽-1(GLP-1)和葡萄糖依赖性促胰岛素分泌多肽(GIP)两者都是被称为肠促胰岛素的肽。GLP-1和GIP分别从小肠L细胞和K细胞中分泌。
GLP-1通过GLP-1受体起作用,并且已知的是,它具有葡萄糖依赖性促胰岛素分泌作用和摄食抑制作用。另一方面,已知的是,GIP通过GIP受体而具有葡萄糖依赖性促胰岛素分泌作用,不过,它对摄食的影响还不是很清楚。
据报道,与单独给予利拉鲁肽(liraglutide)相比,共同给予GLP-1受体激动剂利拉鲁肽(liraglutide)和GIP受体激动剂N-Ac-GIP,能够更加促进葡糖耐量改善作用和降低体重作用(非专利文献1)。同样,据报道,与单独的GLP-1受体激动剂相比,GLP-1受体/GIP受体共激动肽显示了更强的降血糖作用和降低体重作用(专利文献1)。
同样,基于天然胰高血糖素、GIP或GLP-1的结构,人们尝试寻找具有GLP-1受体/GIP受体共激动剂活性或胰高血糖素/GLP-1受体/GIP受体三重激动剂活性的肽,并且使这些肽作为抗减肥药物或糖尿病的治疗药物(专利文献1至8)。然而,没有文献公开本发明的肽化合物。
[引用列表]
[专利文献]
[专利文献1]W02010/011439
[专利文献2]WO2010/148089
[专利文献3]WO2011/119657
[专利文献4]W02012/088379
[专利文献5]W02012/167744
[专利文献6]WO2013/164483
[专利文献7]WO2013/192129
[专利文献8]WO2013/192130
[非专利文献]
[非专利文献1]ClinicalScience121,107-117(2011)
[发明概述]
[技术问题]
本发明的目的是,提供具有高GLP-1受体/GIP受体共激动活性的新的肽化合物,并且用作预防或治疗肥胖症等等的药物。
[解决问题的方案]
本发明人对于具有优良的GLP-1受体/GIP受体共激动活性并且用作预防或治疗肥胖症等等的药物的新的肽化合物进行了深入的研究,并因此发现,包含如下所示的式(I)所代表的部分序列的肽化合物,等等,具有优良的GLP-1受体/GIP受体共激动活性,从而完成本发明。
相应地,本发明涉及
[1]包含式(I)所代表的部分序列的肽∶
P1-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17-Ala-Gln-A20-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-A29(SEQIDNO:1)
其中
P1是下式代表的基团∶
-RA1,
-CO-RA1,
-CO-ORA1,
-CO-CORA1,
-SO-RA1,
-SO2-RA1,
-SO2-ORA1,
-CO-NRA2RA3,
-SO2-NRA2RA3,或
-C(=NRA1)-NRA2RA3
其中,RA1、RA2和RA3各自独立地是氢原子、任选取代的烃基团或任选取代的杂环基团;
A11是Aib或Ala;
A12是Ala、Ile、Lys、Phe或Pya(4);
A13是Aib、Cha、Leu、αMePhe或α-MeTyr;
A16是Lys或Ser;
A17是Gln或Ile;
A20是Ala或Ser;
A29是Gln或Gly,
或其盐(在下文中,有时缩写为化合物(I));
[2]上述[1]的肽或其盐,其中,P1是氢原子;
[3]上述[1]的肽或其盐,其中,A11是Aib;
[4]上述[1]的肽或其盐,其中,A12是Ile;
[5]上述[1]的肽或其盐,其中,A13是Aib;
[6]上述[1]的肽或其盐,其中,A16是Lys;
[7]上述[1]的肽或其盐,其中,A17是Gln;
[8]上述[1]的肽或其盐,其中,A20是Ala;
[9]上述[1]的肽或其盐,其中,A29是Gly;
[10]上述[1]的肽或其盐,在A29的C端上具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所代表的氨基酸序列;
[11]上述[1]的肽或其盐,其中,P1是氢原子;
A11是Aib;
A12是Ile;
A13是Aib;
A16是Lys;
A17是Gln;
A20是Ala;
A29是Gly;
所述肽在A29的C端上具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所代表的氨基酸序列;
[12]H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其盐;
[13]H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其盐;
[14]H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其盐;
[15]H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2或其盐;
[16]包含上述[1]的肽或其盐的药物;
[17]上述[16]的药物,它是GLP-1受体和GIP受体的活化剂;
[18]上述[16]的药物,它是预防或治疗肥胖症或糖尿病的药物;
[19]预防或治疗哺乳动物的肥胖症或糖尿病的方法,所述方法包括:给予哺乳动物有效量的上述[1]的肽或其盐;
[20]活化哺乳动物的GLP-1受体和GIP受体的方法,所述方法包括:给予哺乳动物有效量的上述[1]的肽或其盐;
[21]上述[1]的肽或其盐用于制备药物的用途,所述药物用于预防或治疗肥胖症或糖尿病;
[22]上述[1]的肽或其盐,用于预防或治疗肥胖症或糖尿病。
[本发明的有利效果]
化合物(I)具有优良的GLP-1受体/GIP受体共激动活性,并且显示出显著的体内抑制摄食和降低体重效果。另外,化合物(I)具有降低高血糖症的危险的作用,并且因为它的低胰高血糖素受体激动活性,所以还用于治疗与糖尿病相关的肥胖症,等等。此外,化合物(I)具有出色的溶解性,所以,所述化合物还具有可以容易配制为药物的优点。
[本发明的详细说明]
下面详细描述本说明书中使用的每个取代基的定义。除非另作说明,否则,每个取代基具有下列定义。
在本说明书中,“卤素原子”的例子包括氟、氯、溴和碘。
在本说明书中,“C1-6烷基”的例子包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基和2-乙基丁基。
在本说明书中,“任选卤代的C1-6烷基”的例子包括任选具有1至7个卤素原子的C1-6烷基,优选1至5个卤素原子。其具体实例包括:甲基、氯甲基、二氟甲基、三氯甲基、三氟甲基、乙基、2-溴乙基、2,2,2-三氟乙基、四氟乙基、五氟乙基、丙基、2,2-二氟丙基、3,3,3-三氟丙基、异丙基、丁基、4,4,4-三氟丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、5,5,5-三氟戊基、己基和6,6,6-三氟己基。
在本说明书中,“C2-6烯基”的例子包括:乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、3-甲基-2-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、4-甲基-3-戊烯基、1-己烯基、3-己烯基和5-己烯基。
在本说明书中,“C2-6炔基”的例子包括:乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基和4-甲基-2-戊炔基。
在本说明书中,“C3-10环烷基”的例子包括:环丙基、环丁基、环戊基、环己基、环庚基、环辛基、二环[2.2.1]庚基、二环[2.2.2]辛基、二环[3.2.1]辛基和金刚烷基。
在本说明书中,“任选卤代的C3-10环烷基”的例子包括任选具有1至7个卤素原子的C3-10环烷基,优选1至5个卤素原子。其具体实例包括:环丙基、2,2-二氟环丙基、2,3-二氟环丙基、环丁基、二氟环丁基、环戊基、环己基、环庚基和环辛基。
在本说明书中,“C3-10环烯基”的例子包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基和环辛烯基。
在本说明书中,“C6-14芳基”的例子包括苯基、1-萘基、2-萘基、1-蒽基、2-蒽基和9-蒽基。
在本说明书中,“C7-16芳烷基”的例子包括苄基、苯乙基、萘甲基和苯丙基。
在本说明书中,“C1-6烷氧基”的例子包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基和己氧基。
在本说明书中,“任选卤代的C1-6烷氧基”的例子包括任选具有1至7个卤素原子的C1-6烷氧基,优选1至5个卤素原子。其具体实例包括甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、2,2,2-三氟乙氧基、丙氧基、异丙氧基、丁氧基、4,4,4-三氟丁氧基、异丁氧基、仲丁氧基、戊氧基和己氧基。
在本说明书中,“C3-10环烷基氧基”的例子包括环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基、环庚基氧基和环辛基氧基。
在本说明书中,“C1-6烷硫基”的例子包括甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、仲丁硫基、叔丁硫基、戊硫基和己硫基。
在本说明书中,“任选卤代的C1-6烷硫基”的例子包括任选具有1至7个卤素原子的C1-6烷硫基,优选1至5个卤素原子。其具体例子包括甲硫基、二氟甲硫基、三氟甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、4,4,4-三氟丁硫基、戊硫基和己硫基。
在本说明书中,“C1-6烷基-羰基”的例子包括乙酰基、丙酰基、丁酰基、2-甲基丙酰基、戊酰基、3-甲基丁酰基、2-甲基丁酰基、2,2-二甲基丙酰基、己酰基和庚酰基。
在本说明书中,“任选卤代的C1-6烷基-羰基”的例子包括任选具有1至7个卤素原子的C1-6烷基-羰基,优选1至5个卤素原子。其具体例子包括乙酰基、氯乙酰基、三氟乙酰基、三氯乙酰基、丙酰基、丁酰基、戊酰基和己酰基。
在本说明书中,“C1-6烷氧基-羰基”的例子包括甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基、仲丁氧羰基、叔丁氧羰基、戊氧羰基和己氧羰基。
在本说明书中,“C6-14芳基-羰基”的例子包括苯甲酰基、1-萘酰基和2-萘酰基。
在本说明书中,“C7-16芳烷基-羰基”的例子包括苯乙酰基和苯基丙酰基。
在本说明书中,“5至14元芳香杂环基羰基”的例子包括烟酰基、异烟酰基、噻吩甲酰基和糠酰基。
在本说明书中,“3至14元非芳香杂环基羰基”的例子包括吗啉基羰基、哌啶基羰基和吡咯烷基羰基。
在本说明书中,“单或二-C1-6烷基-氨基甲酰基”的例子包括甲基氨基甲酰基、乙基氨基甲酰基、二甲基氨基甲酰基、二乙基氨基甲酰基和N-乙基-N-甲基氨基甲酰基。
在本说明书中,“单或二-C7-16芳烷基-氨基甲酰基”的例子包括苄基氨基甲酰基和苯乙基氨基甲酰基。
在本说明书中,“C1-6烷基磺酰基”的例子包括甲磺酰基、乙磺酰基、丙磺酰基、异丙基磺酰基、丁磺酰基、仲丁磺酰基和叔丁磺酰基。
在本说明书中,“任选卤代的C1-6烷基磺酰基”的例子包括任选具有1至7个卤素原子的C1-6烷基磺酰基,优选1至5个卤素原子。其具体例子包括甲磺酰基、二氟甲磺酰基、三氟甲基磺酰基、乙磺酰基、丙磺酰基、异丙基磺酰基、丁磺酰基、4,4,4-三氟丁磺酰基、戊磺酰基和己磺酰基。
在本说明书中,“C6-14芳基磺酰基”的例子包括苯磺酰基、1-萘磺酰基和2-萘磺酰基。
在本说明书中,“取代基”的例子包括:卤素原子、氰基、硝基、任选取代的烃基团、任选取代的杂环基团、酰基、任选取代的氨基、任选取代的氨基甲酰基、任选取代的硫代氨甲酰基、任选取代的氨磺酰基、任选取代的羟基、任选取代的硫烷基(SH)和任选取代的甲硅烷基。
在本说明书中,“烃基团”(“任选取代的烃基团”的包括“烃基团”)的例子包括:C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C3-10环烯基、C6-14芳基和C7-16芳烷基。
在本说明书中,“任选取代的烃基团”的例子包括任选具有选自下列取代基组A的取代基的烃基团。
[取代基组A]
(1)卤素原子,
(2)硝基,
(3)氰基,
(4)氧代,
(5)羟基,
(6)任选卤代的C1-6烷氧基,
(7)C6-14芳氧基(例如,苯氧基、萘氧基),
(8)C7-16芳烷氧基(例如,苄氧基),
(9)5至14元芳香杂环基氧基(例如,吡啶基氧基),
(10)3至14元非芳香杂环基氧基(例如,吗啉基氧基、哌啶基氧基),
(11)C1-6烷基-羰基氧基(例如,乙酰氧基、丙酰基氧基),
(12)C6-14芳基-羰基氧基(例如,苯甲酰氧基、1-萘甲酰氧基、2-萘甲酰氧基),
(13)C1-6烷氧基-羰基氧基(例如,甲氧基羰基氧基、乙氧基羰基氧基、丙氧羰基氧基、丁氧基羰基氧基),
(14)单或二-C1-6烷基-氨甲酰氧基(例如,甲基氨甲酰氧基、乙基氨甲酰氧基、二甲基氨基甲酰基氧基、二乙基氨基甲酰基氧基),
(15)C6-14芳基-氨甲酰氧基(例如,苯基氨甲酰氧基、萘基氨甲酰氧基),
(16)5至14元芳香杂环基羰基氧基(例如,烟酰氧基),
(17)3至14元非芳香杂环基羰基氧基(例如,吗啉基羰基氧基、哌啶基羰基氧基),
(18)任选卤代的C1-6烷基磺酰氧基(例如,甲磺酰氧基、三氟甲基磺酰氧基),
(19)任选被C1-6烷基取代的C6-14芳基磺酰氧基(例如,苯基磺酰基氧基、甲苯磺酰氧基),
(20)任选卤代的C1-6烷硫基,
(21)5至14元芳香杂环基团,
(22)3至14元非芳香杂环基团,
(23)甲酰基,
(24)羧基,
(25)任选卤代的C1-6烷基-羰基,
(26)C6-14芳基-羰基,
(27)5至14元芳香杂环基羰基,
(28)3至14元非芳香杂环基羰基,
(29)C1-6烷氧基-羰基,
(30)C6-14芳氧基-羰基(例如,苯氧羰基、1-萘基氧羰基、2-萘基氧羰基),
(31)C7-16芳烷氧基-羰基(例如,苄氧羰基、苯乙基氧羰基),
(32)氨基甲酰基,
(33)硫代氨甲酰基,
(34)单或二-C1-6烷基-氨基甲酰基,
(35)C6-14芳基-氨基甲酰基(例如,苯氨基甲酰),
(36)5至14元芳香杂环基氨基甲酰基(例如,吡啶基氨基甲酰基、噻吩基氨基甲酰基),
(37)3至14元非芳香杂环基氨基甲酰基(例如,吗啉基氨基甲酰基、哌啶基氨基甲酰基),
(38)任选卤代的C1-6烷基磺酰基,
(39)C6-14芳基磺酰基,
(40)5至14元芳香杂环磺酰基(例如,吡啶基磺酰基、噻吩基磺酰基),
(41)任选卤代的C1-6烷基亚磺酰基,
(42)C6-14芳基亚磺酰基(例如,苯亚磺酰基、1-萘基亚磺酰基、2-萘基亚磺酰基),
(43)5至14元芳香杂环基亚磺酰基(例如,吡啶基亚磺酰基、噻吩基亚磺酰基),
(44)氨基,
(45)单或二-C1-6烷基氨基(例如,甲基氨基、乙胺基、丙氨基、异丙胺基、丁胺基、二甲基氨基、二乙基氨基、二丙基氨基、二丁基氨基、N-乙基-N-甲基氨基),
(46)单或二-C6-14芳氨基(例如,苯基氨基),
(47)5至14元芳香杂环基氨基(例如,吡啶氨基),
(48)C7-16芳烷基氨基(例如,苄基氨基),
(49)甲酰氨基,
(50)C1-6烷基-羰基氨基(例如,乙酰氨基、丙酰氨基、丁酰氨基),
(51)(C1-6烷基)(C1-6烷基-羰基)氨基(例如,N-乙酰基-N-甲基氨基),
(52)C6-14芳基-羰基氨基(例如,苯基羰基氨基、萘基羰基氨基),
(53)C1-6烷氧基-羰基氨基(例如,甲氧羰基氨基、乙氧基羰基氨基、丙氧羰基氨基、丁氧羰基氨基、叔丁氧羰基氨基),
(54)C7-16芳烷氧基-羰基氨基(例如,苄氧羰基氨基),
(55)C1-6烷基磺酰氨基(例如,甲基磺酰氨基、乙基磺酰氨基),
(56)任选被C1-6烷基取代的C6-14芳基磺酰氨基(例如,苯磺酰氨基、甲苯磺酰氨基),
(57)任选卤代的C1-6烷基,
(58)C2-6烯基,
(59)C2-6炔基,
(60)C3-10环烷基,
(61)C3-10环烯基,和
(62)C6-14芳基。
“任选取代的烃基团”中的上述取代基的数目是,例如,1至5个取代基,优选1至3个取代基。当取代基的数目是两个或更多个时,相应的取代基可以相同或不同。
在本说明书中,“杂环基团”(包括“任选取代的杂环基团”的“杂环基团”)的例子包括:(i)芳香杂环基团,(ii)非芳香杂环基团,和(iii)7至10元桥接的杂环基团,作为构成环的原子,除了碳原子之外,每个还包含1至4个选自氮原子、硫原子和氧原子的杂原子。
在本说明书中,“芳香杂环基团”(包括“5至14元芳香杂环基团”)的例子包括5至14元(优选5至10元)芳香杂环基团,作为构成环的原子,除了碳原子之外,它还包含1至4个选自氮原子、硫原子和氧原子的杂原子。
“芳香杂环基团”的例子包括5或6元单环芳香杂环基团,例如,噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、三唑基、四唑基、三嗪基等等;以及
8至14元稠合的多环(优选二或三环)芳香杂环基团,例如,苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并恶唑基、苯并异恶唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、咪唑并吡啶基、噻吩并吡啶基、呋喃并吡啶基、吡咯并吡啶基、吡唑并吡啶基、噁唑并吡啶基、噻唑并吡啶基、咪唑并吡嗪基、咪唑并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、吡咯并嘧啶基、吡唑并嘧啶基、噁唑并嘧啶基、噻唑并嘧啶基、吡唑并三嗪基、萘并[2,3-b]噻吩基、(夹)氧硫蒽基、吲哚基、异氮茚基、1H-吲唑基、嘌呤基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、噌琳基、咔唑基、β-咔啉基、菲啶基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基,等等。
在本说明书中,“非芳香杂环基团”(包括“3至14元非芳香杂环基团”)的例子包括3至14元(优选4至10元)非芳香杂环基团,作为构成环的原子,除了碳原子之外,它还包含1至4个选自氮原子、硫原子和氧原子的杂原子。
“非芳香杂环基团”的优选例子包括3至8元单环非芳香杂环基团,例如,氮丙啶基、氧杂环丙基、硫杂丙环基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢噻吩基、四氢呋喃基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、噁唑啉基、噁唑烷基、吡唑啉基、吡唑烷基、噻唑啉基、噻唑烷基、四氢异噻唑基、四氢噁唑基、四氢异噁唑基、哌啶基、哌嗪基、四氢吡啶基、二氢吡啶基、二氢硫代吡喃基、四氢嘧啶基、四氢哒嗪基、二氢吡喃基、四氢吡喃基、四氢硫吡喃基、吗啉基、硫吗啉基、氮杂环庚烷基、二氮杂基、氮杂基、氧杂环庚烷基、氮杂环辛烷、二氮杂环辛烷,等等;以及
9至14元稠合的多环(优选二或三环)非芳香杂环基团,例如,二氢苯并呋喃基、二氢苯并咪唑基、二氢苯并噁唑基、二氢苯并噻唑基、二氢苯并异噻唑基、二氢萘并[2,3-b]噻吩基、四氢异喹啉基、四氢喹啉基、4H-喹嗪基、二氢吲哚基、异二氢氮茚基、四氢噻吩并[2,3-c]吡啶基、四氢苯并氮杂卓基、四氢喹喔啉基、四氢菲啶基、六氢吩噻嗪基、六氢吩噁嗪基、四氢酞嗪基、四氢萘啶基、四氢喹唑啉基、四氢噌琳基、四氢咔唑基、四氢-β-咔啉基、四氢吖啶基、四氢吩嗪基、四氢硫氧杂蒽基、八氢异喹啉基等等。
在本说明书中,“7至10元桥接的杂环基团”的优选例子包括奎宁环基和7-氮杂双环[2.2.1]庚基。
在本说明书中,“含氮杂环基团”的例子包括含有至少一个氮原子作为环构成原子的“杂环基团”。
在本说明书中,“任选取代的杂环基团”的例子包括任选具有选自上述取代基组A的取代基的杂环基团。
“任选取代的杂环基团”中的取代基的数目是,例如,1至3个取代基。当取代基的数目是两个或更多个时,相应的取代基可以相同或不同。
在本说明书中,“酰基”的例子包括:甲酰基、羧基、氨基甲酰基、硫代氨甲酰基、亚磺基、磺基、氨磺酰基和膦酰基,每个任选具有“1或2个取代基,取代基选自C1-6烷基、C2-6烯基、C3-10环烷基、C3-10环烯基、C6-14芳基、C7-16芳烷基、5至14元芳香杂环基团和3至14元非芳香杂环基团,每个任选具有1至3个取代基,取代基选自卤素原子、任选卤代的C1-6烷氧基、羟基、硝基、氰基、氨基和氨基甲酰基”。
“酰基”的例子还包括烃-磺酰基、杂环磺酰基、烃-亚磺酰基和杂环基亚磺酰基。
本文中,烃-磺酰基是指烃基团键合的磺酰基,杂环磺酰基是指杂环基团键合的磺酰基,烃-亚磺酰基是指烃基团键合的亚磺酰基,杂环基亚磺酰基是指杂环基团键合的亚磺酰基。
“酰基”的优选例子包括:甲酰基、羧基、C1-6烷基-羰基、C2-6烯基-羰基(例如,巴豆酰基)、C3-10环烷基-羰基(例如,环丁羰基、环戊烷羰基、环已羰基、环庚烷羰基)、C3-10环烯基-羰基(例如,2-环己烯羰基)、C6-14芳基-羰基、C7-16芳烷基-羰基、5至14元芳香杂环基羰基、3至14元非芳香杂环基羰基、C1-6烷氧基-羰基、C6-14芳氧基-羰基(例如,苯氧羰基、萘基氧羰基)、C7-16芳烷氧基-羰基(例如,苄氧羰基、苯乙基氧基羰基)、氨基甲酰基、单或二-C1-6烷基-氨基甲酰基、单或二-C2-6烯基-氨基甲酰基(例如,二烯丙基氨基甲酰基)、单或二-C3-10环烷基-氨基甲酰基(例如,环丙基氨甲酰基)、单或二-C6-14芳基-氨基甲酰基(例如,苯氨基甲酰)、单或二-C7-16芳烷基-氨基甲酰基、5至14元芳香杂环基氨基甲酰基(例如,吡啶基氨基甲酰基)、硫代氨甲酰基、单或二-C1-6烷基-硫代氨甲酰基(例如,甲硫基氨基甲酰基、N-乙基-N-甲硫基氨基甲酰基)、单或二-C2-6烯基-硫代氨甲酰基(例如,二烯丙基硫代氨甲酰基)、单或二-C3-10环烷基-硫代氨甲酰基(例如,环丙基硫代氨甲酰基、环己基硫代氨甲酰基)、单或二-C6-14芳基-硫代氨甲酰基(例如,苯基硫代氨基甲酰基)、单或二-C7-16芳烷基-硫代氨甲酰基(例如,苯甲基硫代氨基甲酰基、苯乙基硫代氨基甲酰基)、5至14元芳香杂环基硫代氨甲酰基(例如,吡啶基硫代氨基甲酰基)、亚磺基、C1-6烷基亚磺酰基(例如,甲基亚磺酰基、乙基亚磺酰基)、磺基、C1-6烷基磺酰基、C6-14芳基磺酰基、膦酰基和单或二-C1-6烷基膦酰基(例如,二甲基膦酰基、二乙基膦酰基、二异丙基膦酰基、二丁基膦酰基)。
在本说明书中,“任选取代的氨基”的例子包括:任选具有“1或2个选自C1-6烷基、C2-6烯基、C3-10环烷基、C6-14芳基、C7-16芳烷基、C1-6烷基-羰基、C6-14芳基-羰基、C7-16芳烷基-羰基、5至14元芳香杂环基羰基、3至14元非芳香杂环基羰基、C1-6烷氧基-羰基、5至14元芳香杂环基团、氨基甲酰基、单或二-C1-6烷基-氨基甲酰基、单或二-C7-16芳烷基-氨基甲酰基、C1-6烷基磺酰基和C6-14芳基磺酰基的取代基的氨基,每个取代基任选具有1至3个选自取代基组A的取代基”。
任选取代的氨基的优选例子包括:氨基、单或二-(任选卤代的C1-6烷基)氨基(例如,甲基氨基、三氟甲基氨基、二甲基氨基、乙胺基、二乙基氨基、丙氨基、二丁基氨基)、单或二-C2-6链烯基氨基(例如,二烯丙基氨基)、单或二-C3-10环烷基氨基(例如,环丙基氨基、环己基氨基)、单或二-C6-14芳氨基(例如,苯基氨基)、单或二-C7-16芳烷基氨基(例如,苄基氨基、二苄基)、单或二-(任选卤代的C1-6烷基)-羰基氨基(例如,乙酰氨基、丙酰基氨基)、单或二-C6-14芳基-羰基氨基(例如,苯甲酰氨基)、单或二-C7-16芳烷基-羰基氨基(例如,苄基羰基氨基)、单或二-5至14元芳香杂环基羰基氨基(例如,烟酰氨基、异烟酰氨基)、单或二-3至14元非芳香杂环基羰基氨基(例如,哌啶基羰基氨基)、单或二-C1-6烷氧基-羰基氨基(例如,叔丁氧羰基氨基)、5至14元芳香杂环基氨基(例如,吡啶氨基)、氨甲酰氨基、(单或二-C1-6烷基-氨基甲酰基)氨基(例如,甲基氨甲酰氨基)、(单或二-C7-16芳烷基-氨基甲酰基)氨基(例如,苄基氨甲酰氨基)、C1-6烷基磺酰氨基(例如,甲基磺酰氨基、乙基磺酰氨基)、C6-14芳基磺酰氨基(例如,苯磺酰氨基)、(C1-6烷基)(C1-6烷基-羰基)氨基(例如,N-乙酰基-N-甲基氨基)和(C1-6烷基)(C6-14芳基-羰基)氨基(例如,N-苯甲酰基-N-甲基氨基)。
在本说明书中,“任选取代的氨基甲酰基”的例子包括:任选具有“1或2个选自下列的取代基”的氨基甲酰基:C1-6烷基、C2-6烯基、C3-10环烷基、C6-14芳基、C7-16芳烷基、C1-6烷基-羰基、C6-14芳基-羰基、C7-16芳烷基-羰基、5至14元芳香杂环基羰基、3至14元非芳香杂环基羰基、C1-6烷氧基-羰基、5至14元芳香杂环基团、氨基甲酰基、单或二-C1-6烷基-氨基甲酰基和单或二-C7-16芳烷基-氨基甲酰基,每个取代基任选具有1至3个选自取代基组A的取代基。
任选取代的氨基甲酰基的优选例子包括:氨基甲酰基、单或二-C1-6烷基-氨基甲酰基、单或二-C2-6烯基-氨基甲酰基(例如,二烯丙基氨基甲酰基)、单或二-C3-10环烷基-氨基甲酰基(例如,环丙基氨基甲酰基、环己基氨基甲酰基)、单或二-C6-14芳基-氨基甲酰基(例如、苯氨基甲酰基)、单或二-C7-16芳烷基-氨基甲酰基、单或二-C1-6烷基-羰基-氨基甲酰基(例如,乙酰基氨基甲酰基、丙酰基氨基甲酰基)、单或二-C6-14芳基-羰基-氨基甲酰基(例如,苯甲酰基氨基甲酰基)和5至14元芳香杂环基氨基甲酰基(例如,吡啶基氨基甲酰基)。
在本说明书中,“任选取代的硫代氨甲酰基”的例子包括:任选具有“1或2个选自下列的取代基”的硫代氨甲酰基:C1-6烷基、C2-6烯基、C3-10环烷基、C6-14芳基、C7-16芳烷基、C1-6烷基-羰基、C6-14芳基-羰基、C7-16芳烷基-羰基、5至14元芳香杂环基羰基、3至14元非芳香杂环基羰基、C1-6烷氧基-羰基、5至14元芳香杂环基团、氨基甲酰基、单或二-C1-6烷基-氨基甲酰基和单或二-C7-16芳烷基-氨基甲酰基,每个取代基任选具有1至3个选自取代基组A的取代基。
任选取代的硫代氨甲酰基的优选例子包括:硫代氨甲酰基基团、单或二-C1-6烷基-硫代氨甲酰基(例如,甲基硫代氨甲酰基、乙基硫代氨甲酰基、二甲基硫代氨甲酰基、二乙基硫代氨甲酰基、N-乙基-N-甲基硫代氨甲酰基)、单或二-C2-6烯基-硫代氨甲酰基(例如,二烯丙基硫代氨甲酰基)、单或二-C3-10环烷基-硫代氨甲酰基(例如,环丙基硫代氨甲酰基、环己基硫代氨甲酰基)、单或二-C6-14芳基-硫代氨甲酰基(例如,苯基硫代氨甲酰基)、单或二-C7-16芳烷基-硫代氨甲酰基(例如,苄基硫代氨甲酰基、苯乙基硫代氨甲酰基)、单或二-C1-6烷基-羰基-硫代氨甲酰基(例如,乙酰基硫代氨甲酰基、丙酰基硫代氨甲酰基)、单或二-C6-14芳基-羰基-硫代氨甲酰基(例如,苯甲酰基硫代氨甲酰基)和5至14元芳香杂环基硫代氨甲酰基(例如,吡啶基硫代氨甲酰基)。
在本说明书中,“任选取代的氨磺酰基”的例子包括:任选具有“1或2个选自下列的取代基”的氨磺酰基:C1-6烷基、C2-6烯基、C3-10环烷基、C6-14芳基、C7-16芳烷基、C1-6烷基-羰基、C6-14芳基-羰基、C7-16芳烷基-羰基、5至14元芳香杂环基羰基、3至14元非芳香杂环基羰基、C1-6烷氧基-羰基、5至14元芳香杂环基团、氨基甲酰基、单或二-C1-6烷基-氨基甲酰基和单或二-C7-16芳烷基-氨基甲酰基,每个取代基任选具有1至3个选自取代基组A的取代基。
任选取代的氨磺酰基的优选例子包括:氨磺酰基、单或二-C1-6烷基-氨磺酰基(例如,甲基氨磺酰基、乙基氨磺酰基、二甲氨磺酰基、二乙氨磺酰基、N-乙基-N-甲基氨磺酰基)、单或二-C2-6烯基-氨磺酰基(例如,二烯丙基氨磺酰基)、单或二-C3-10环烷基-氨磺酰基(例如,环丙基氨磺酰基、环己基氨磺酰基)、单或二-C6-14芳基-氨磺酰基基团(例如,苯氨基磺酰)、单或二-C7-16芳烷基-氨磺酰基(例如,苄基氨磺酰基、苯乙基氨磺酰基)、单或二-C1-6烷基-羰基-氨磺酰基(例如,乙酰基氨磺酰基、丙酰基氨磺酰基)、单或二-C6-14芳基-羰基-氨磺酰基(例如,苯甲酰氨磺酰基)和5至14元芳香杂环基氨磺酰基(例如,吡啶基氨磺酰基)。
在本说明书中,“任选取代的羟基”的例子包括:任选具有“1或2个选自下列的取代基”的羟基:C1-6烷基、C2-6烯基、C3-10环烷基、C6-14芳基、C7-16芳烷基、C1-6烷基-羰基、C6-14芳基-羰基、C7-16芳烷基-羰基、5至14元芳香杂环基羰基、3至14元非芳香杂环基羰基、C1-6烷氧基-羰基、5至14元芳香杂环基团、氨基甲酰基、单或二-C1-6烷基-氨基甲酰基、单或二-C7-16芳烷基-氨基甲酰基、C1-6烷基磺酰基和C6-14芳基磺酰基,每个取代基任选具有1至3个选自取代基组A的取代基。
任选取代的羟基的优选例子包括:羟基、C1-6烷氧基、C2-6链烯氧基(例如,烯丙氧基、2-丁烯氧基、2-戊烯氧基、3-己烯氧基)、C3-10环烷基氧基(例如,环己基氧基)、C6-14芳氧基(例如,苯氧基、萘氧基)、C7-16芳烷氧基(例如,苄氧基、苯乙基氧基)、C1-6烷基-羰基氧基(例如,乙酰氧基、丙酰氧基、丁酰氧基、异丁酰氧基、戊酰氧基)、C6-14芳基-羰基氧基(例如,苯甲酰氧基)、C7-16芳烷基-羰基氧基(例如,苄基羰基氧基)、5至14元芳香杂环基羰基氧基(例如,烟酰氧基)、3至14元非芳香杂环基羰基氧基(例如,哌啶基羰基氧基)、C1-6烷氧基-羰基氧基(例如,叔丁氧基羰基氧基)、5至14元芳香杂环基氧基(例如,吡啶基氧基)、氨甲酰氧基、C1-6烷基-氨甲酰氧基(例如,甲基氨甲酰氧基)、C7-16芳烷基-氨甲酰氧基(例如,苄基氨甲酰氧基)、C1-6烷基磺酰氧基(例如,甲磺酰氧基、乙基磺酰基氧基)和C6-14芳基磺酰氧基(例如,苯基磺酰基氧基)。
在本说明书中,“任选取代的硫烷基”的例子包括:任选具有“选自C1-6烷基、C2-6烯基、C3-10环烷基、C6-14芳基、C7-16芳烷基、C1-6烷基-羰基、C6-14芳基-羰基和5至14元芳香杂环基团的取代基的硫烷基,每个取代基任选具有1至3个选自取代基组A的取代基”,以及卤代的硫烷基。
任选取代的硫烷基的优选例子包括:硫烷基(-SH)、C1-6烷硫基、C2-6链烯基硫基(例如、烯丙基硫基、2-丁烯基硫基、2-戊烯基硫基、3-己烯基硫基)、C3-10环烷基硫基(例如,环己基硫基)、C6-14芳硫基(例如,苯硫基、萘硫基)、C7-16芳烷基硫基(例如,苯甲硫基、苯乙基硫基)、C1-6烷基-羰基硫基(例如,乙酰基硫基、丙酰基硫基、丁酰基硫基、异丁酰基硫基、新戊酰硫基)、C6-14芳基-羰基硫基(例如,苯甲酰基硫基)、5至14元芳香杂环基硫基(例如,吡啶基硫基)和卤代的硫基(例如,五氟硫基)。
在本说明书中,“任选取代的甲硅烷基”的例子包括:任选具有“1至3个选自C1-6烷基、C2-6烯基、C3-10环烷基、C6-14芳基和C7-16芳烷基的取代基的甲硅烷基,每个取代基任选具有1至3个选自取代基组A的取代基”。
任选取代的甲硅烷基的优选例子包括:三-C1-6烷基甲硅烷基(例如,三甲基甲硅烷基、叔丁基(二甲基)甲硅烷基)。
下面详细描述式(I)中的每个符号的定义。
P1是下式代表的基团∶
-RA1,
-CO-RA1,
-CO-ORA1,
-CO-CORA1,
-SO-RA1,
-SO2-RA1,
-SO2-ORA1,
-CO-NRA2RA3,
-SO2-NRA2RA3或
-C(=NRA1)-NRA2RA3
其中,RA1、RA2和RA3各自独立地是氢原子、任选取代的烃基团或任选取代的杂环基团。
优选,P1是氢原子。
A11是Aib或Ala。
优选,A11是Aib。
A12是Ala、Ile、Lys、Phe或Pya(4)。
优选,A12是Ile。
在另一个实施方案中,优选,A12是Lys。
A13是Aib、Cha、Leu、αMePhe或αMeTyr。
优选,A13是Aib。
A16是Lys或Ser。
优选,A16是Lys。
A17是Gln或Ile。
优选,A17是Gln。
A20是Ala或Ser。
优选,A20是Ala。
A29是Gln或Gly。
优选,A29是Gly。
化合物(I)可以在式(I)所代表的部分序列中的A29的C端上具有额外的肽序列(C端序列)。
本文中,对C端序列的长度没有特别限制,优选1至11个氨基酸残基,更优选6至11个氨基酸残基。
C端序列的例子可以包括
(i)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(SEQIDNO∶2)所代表的氨基酸序列,
(ii)通过缺失、置换(优选,保守置换)或添加1至11个(优选1至5个)氨基酸而衍生自上述(i)的序列的氨基酸序列,和
(iii)从上述(i)或(ii)的序列的N端开始,包含至少1个(连续)氨基酸残基的部分序列,优选包含6个连续的氨基酸残基。
作为C端序列,特别使用
(1)Gly-,
(2)Gly-Pro-,
(3)Gly-Pro-Ser-,
(4)Gly-Pro-Ser-Ser-(SEQIDNO:3),
(5)Gly-Pro-Ser-Ser-Gly-(SEQIDNO:4),
(6)Gly-Pro-Ser-Ser-Gly-Ala-(SEQIDNO:5),
(7)Gly-Pro-Ser-Ser-Gly-Ala-Pro-(SEQIDNO:6),
(8)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-(SEQIDNO:7),
(9)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-(SEQIDNO:8),
(10)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-(SEQIDNO:9),
(11)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-(SEQIDNO:2),
等等。
优选,C端序列是Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-或Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-。
特别优选,C端序列是
Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-。
具有上述C端序列的化合物(I)具有优良的溶解性。
此外,具有上述C端序列的化合物(I)具有体内高的GLP-1受体和GIP受体活化作用。
化合物(I)的优选例子包括下列肽或其盐。
[化合物A]
化合物(I),其中,P1是氢原子;
A11是Aib;
A12是Ile;
A13是Aib;
A16是Lys;
A17是Gln;
A20是Ala;
A29是Gly;
所述肽在A29的C端上具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所代表的氨基酸序列。
可以按照本来已知的肽合成方法,制备化合物(I)。例如,肽合成方法可以是任何固相合成方法和液相合成方法。简而言之,根据目标序列,使能够构成化合物(I)和其余部分(可以通过两个或多个氨基酸构成)的部分肽或氨基酸重复缩合,可以制备目标肽。当具有目标序列的产物具有保护基时,可以通过除去保护基来制备目标肽。已知的缩合方法和除去保护基的方法的例子包括下面(1)-(5)描述的方法。
(1)M.BodanszkyandM.A.Ondetti:PeptideSynthesis,IntersciencePublishers,NewYork(1966)
(2)SchroederandLuebke:ThePeptide,AcademicPress,NewYork(1965)
(3)NobuoIzumiya,etal.PeptideGosei-no-KisotoJikken(Basicsandexperimentsofpeptidesynthesis),publishedbyMaruzenCo.(1975)
(4)HaruakiYajimaandShunpeiSakakibara:SeikagakuJikkenKoza(BiochemicalExperiment)1,TanpakushitsunoKagaku(ChemistryofProteins)IV,205(1977)
(5)HaruakiYajima,ed.:ZokuIyakuhinnoKaihatsu(AsequeltoDevelopmentofPharmaceuticals),Vol.14,PeptideSynthesis,publishedbyHirokawaShoten
反应之后,可以使用常规纯化方法,例如,溶剂提取、蒸馏、柱色谱、液相色谱、重结晶,等等,联用这些方法,将化合物(I)纯化和分离。当通过上述方法获得的肽是游离形式时,利用已知的方法,它可以转变为合适的盐;反之,当获得盐形式的肽时,利用已知的方法,盐可以转变为游离形式或其它盐。
原料化合物也可以是盐。这种盐的例子包括下面所述的化合物(I)的盐所举例说明的那些盐。
为了保护的氨基酸或肽的缩合,可以使用肽合成所使用的各种活化剂,特别优选三鏻盐、四甲基脲盐、碳二亚胺,等等。三鏻盐的例子包括:苯并三唑-1-基氧基三(吡咯烷基)鏻六氟磷酸盐(PyBOP)、溴三(吡咯烷基)鏻六氟磷酸盐(PyBroP)、7-氮杂苯并三唑-1-基氧基三(吡咯烷基)鏻六氟磷酸盐(PyAOP),四甲基脲盐的例子包括:2-(1H-苯并三唑-1-基)-1,1,3,3-六氟磷酸盐(HBTU)、2-(7-氮杂苯并三唑-1-基)-1,1,3,3-六氟磷酸盐(HATU)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲四氟硼酸盐(TBTU)、2-(5-降冰片烷-2,3-二羧基亚胺)-1,1,3,3-四甲基脲四氟硼酸盐(TNTU)、O-(N-琥珀酰亚胺基)-1,1,3,3-四甲基脲四氟硼酸盐(TSTU),碳二亚胺的例子包括:DCC、N,N'-二异丙基碳二亚胺(DIPCDI)、N-乙基-N'-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI(HCl),等等。为了使用这些进行缩合,优选,加入外消旋化抑制剂(例如,HONB、HOBt、HOAt、HOOBt,等等)。缩合所使用的溶剂可以适当地选自肽缩合反应所使用的那些已知溶剂。例如,可以使用酰胺,例如,无水或含水的N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮等等,卤代烃,例如,二氯甲烷、氯仿等等,醇,例如,三氟乙醇、苯酚等等,亚砜,例如,二甲亚砜等等,叔胺,例如,吡啶等等,醚,例如,二噁烷、四氢呋喃等等,腈,例如乙腈、丙腈等等,酯,例如,乙酸甲酯、乙酸乙酯等等,这些溶剂的合适混合物,等等。反应温度适当地选自肽结合反应所使用的已知温度范围,通常选自大约-20℃至50℃的范围。通常使用过量1.5至6倍的活化氨基酸衍生物。在相合成中,当使用茚三酮反应的试验显示缩合不充分时,通过重复缩合反应(不用除去保护基),可以进行充分缩合。如果缩合仍然不充分,甚至在重复反应之后还是不充分,则可以使用乙酸酐、乙酰基咪唑等等,将未反应的氨基酸酰化,这样就可以避免对随后反应的影响。
起始氨基酸的氨基的保护基的例子包括:Z、Boc、叔戊氧羰基、异冰片基氧羰基、4-甲氧基苄氧羰基、Cl-Z、Br-Z、金刚烷基氧羰基、三氟乙酰基、邻苯二甲酰基、甲酰基、2-硝基苯基氧硫基、二苯基膦基亚硫酰基、Fmoc、三苯甲基,等等。
起始氨基酸的羧基保护基的例子包括:除了上述C1-6烷基、C3-10环烷基、C7-14芳烷基之外,还包括烯丙基、2-金刚烷基、4-硝基苄基、4-甲氧苯甲基、4-氯苄基、苯酰基和苄氧羰基酰肼、叔丁氧羰基酰肼、三苯甲基酰肼,等等。
可以保护丝氨酸或苏氨酸的羟基,例如,通过酯化或醚化进行保护。适合于酯化的基团的例子包括:低级(C2-4)烷酰基,例如,乙酰基等等,芳酰基,例如,苯甲酰基等等,以及衍生自有机酸的基团,等等。另外,适合于醚化的基团的例子包括:苄基、四氢吡喃基、叔丁基(But)、三苯甲基(Trt),等等。
酪氨酸的酚羟基的保护基的例子包括:Bzl、2,6-二氯苄基、2-硝基苄基、Br-Z、叔丁基,等等。
组氨酸的咪唑的保护基的例子包括:Tos、4-甲氧基-2,3,6-三甲基苯磺酰基(Mtr)、DNP、Bom、Bum、Boc、Trt、Fmoc,等等。
精氨酸的胍基的保护基的例子包括:Tos、Z、4-甲氧基-2,3,6-三甲基苯磺酰基(Mtr)、对甲氧基苯磺酰基(MBS)、2,2,5,7,8-五甲基色满-6-磺酰基(Pmc)、均三甲苯-2-磺酰基(Mts)、2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基(Pbf)、Boc、Z、NO2,等等。
赖氨酸的侧链氨基的保护基的例子包括:Z、Cl-Z、三氟乙酰基、Boc、Fmoc、Trt、Mtr、4,4-二甲基-2,6-二氧代环己亚基(Dde),等等。
色氨酸的吲哚基的保护基的例子包括:甲酰基(For)、Z、Boc、Mts、Mtr,等等。
天冬酰胺和谷氨酰胺的保护基的例子包括:Trt、占吨基(Xan)、4,4'-二甲氧基二苯甲基(Mbh)、2,4,6-三甲氧基苄基(Tmob),等等。
起始原料中的活化羧基的例子包括相应的酸酐、叠氮化物、活性酯[与醇(例如,五氯苯酚、2,4,5-三氯酚、2,4-二硝基酚、氰基甲醇、对硝基酚、HONB、N-羟基琥珀酰亚胺、1-羟基苯并三唑(HOBt)、1-羟基-7-氮杂苯并三唑(HOAt))形成的酯]等等。起始原料中的活化氨基的例子包括相应的磷酰胺。
消除(除去)保护基的方法的例子包括:在氢气流中、在催化剂(例如Pd-碳黑或Pd-碳)的存在下进行催化还原;使用无水氟化氢、甲磺酸、三氟甲磺酸、三氟乙酸盐、三甲基甲硅烷基溴(TMSBr)、三甲基甲硅烷基三氟甲磺酸酯、四氟硼酸、三(三氟)硼酸、三溴化硼或其混合物溶液进行酸处理;使用二异丙基乙胺、三乙胺、哌啶、哌嗪等等进行处理;以及在液氨中用钠还原,等等。上述酸处理的消除反应通常在-20℃至40℃的温度下进行;通过加入阳离子净化剂,例如苯甲醚、苯酚、苯甲硫醚、间甲酚和对甲酚、甲硫醚、1,4-丁二硫醇、1,2-乙二硫醇等等,可有效地进行酸处理。此外,用硫苯酚处理,可除去用作组氨酸的咪唑的保护基的2,4-二硝基苯基;在1,2-乙二硫醇、1,4-丁二硫醇等等的存在下,以及用稀氢氧化钠、稀氨等等进行碱处理,进行脱保护,可除去用作色氨酸的吲哚的保护基的甲酰基。
与起始原料的反应无关的官能团的保护和保护基、保护基的消除、与反应有关的官能团的活化等等,可以恰当地选自已知的保护基和已知的方法。
在制备肽的酰胺的方法中,使用酰胺合成的树脂,通过固相合成方法形成,或将羧基端部的氨基酸的α-羧基酰胺化,并将肽链沿着氨基端延长至目标链长,而后,制备只除去肽链的N端α-氨基的保护基的肽,以及只除去肽链的C端羧基的保护基的肽,并使两个肽在上述混合溶剂中缩合。关于缩合反应的详细说明,使用与上面相同的方法。将缩合所获得的保护的肽纯化之后,可以利用上述方法,除去所有的保护基,得到目标粗品多肽。使用各种公知的纯化方法,将这种粗品肽纯化,并将主要级分冷冻干燥,可以制备肽的目标酰胺。
当化合物(I)以构型异构体(例如,对映体、非对映体等等,构象异构体等等)形式存在时,它们也在化合物(I)的范围内,并且根据需要,可以利用本来已知的方法或上述分离和纯化方法进行分离。另外,当化合物(I)是消旋体形式时,可以利用常规光学拆分方法,将它分离为S和R形式。
当化合物(I)包括立体异构体时,单独的两种异构体和每个异构体的混合物也在化合物(I)的范围内。
按照本来已知的方法,并且使用聚乙二醇,可以化学修饰化合物(I)。例如,通过聚乙二醇与化合物(I)的Cys残基、Asp残基、Glu残基、Lys残基等等的共轭结合,可以制备化学修饰的化合物(I)。
例如,聚乙二醇(PEG)修饰的化合物(I)能够产生下列效果:提高生物活性、延长血循环时间、降低免疫原性、提高溶解度和提高对于治疗和诊断方面重要的肽的代谢的耐受性。
对PEG的分子量没有特别限制,通常为大约1K至大约1000K道尔顿,优选,大约10K至大约100K道尔顿,更优选,大约20K至大约60K道尔顿。
本领域众所周知的方法可以用作PEG修饰化合物(I)的方法,例如,可以使用如下所述的方法。
(1)具有活性酯的PEG化的试剂(例如,SUNBRIGHTMEGC-30TS(商标名),NOFCorp.)与化合物(I)的氨基键合。
(2)具有醛的PEG化的试剂(例如,SUNBRIGHTME-300AL(商标名),NOFCorp.)与化合物(I)的氨基键合。
(3)二价交联试剂(例如,GMBS(DojindoLaboratories)、EMCS(DojindoLaboratories)、KMUS(DojindoLaboratories)、SMCC(Pierce))与化合物(I)键合,然后,具有硫醇基的PEG化试剂(例如,SUNBRIGHTME-300-SH(商标名),NOFCorp.)与其键合。
(4)通过SH-引入试剂(例如,D-半胱氨酸残基、L-半胱氨酸残基、Traut's试剂),将硫醇基引入到化合物(I)中,并且使这种硫醇基与具有马来酰亚胺基团的PEG化试剂(例如,SUNBRIGHTME-300MA(商标名),NOFCorp.)反应。
(5)通过SH-引入试剂(例如,D-半胱氨酸残基、L-半胱氨酸残基、Traut's试剂),将硫醇基引入到化合物(I)中,并且使这种硫醇基与具有碘乙酰胺基团的PEG化试剂(例如,SUNBRIGHTME-300IA(商标名),NOFCorp.)反应。
(6)引入ω-氨基羧酸或α-氨基酸,作为与化合物(I)的N端氨基的连接基,并且使衍生自这种连接基的氨基与具有活性酯的PEG化试剂(例如,SUNBRIGHTMEGC-30TS(商标名),NOFCorp.)反应。
(7)引入ω-氨基羧酸或α-氨基酸,作为与化合物(I)的N端氨基的连接基,并且使衍生自这种连接基的氨基与具有醛基的PEG化试剂(例如,SUNBRIGHTME-300AL(商标名),NOFCorp.)反应。
另外,化合物(I)可以是溶剂化物(例如,水合物)或非溶剂化物(例如,非水合物)。
可以用同位素(例如,3H、14C、35S、125I)等等标记化合物(I)。
此外,化合物(I)可以是氘转化形式,在这种形式中,1H转变为2H(D)。
同位素标记或取代的化合物(I),例如,可以用作正电子发射层析成象(PET)所使用的示踪物(PET示踪物),并可用于医疗诊断领域,等等。
对于本文所述的肽,与常规的肽标记一致,左端是N端(氨基端),右端是C端(羧基端)。肽的C端可以是任何酰胺(-CONH2)、羧基(-COOH)、羧酸酯基(-COO-)、烷基酰胺(-CONHRa)和酯(-COORa)。特别优选酰胺(-CONH2)。
化合物(I)可以是盐形式。这种盐的例子包括:金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或酸性氨基酸形成的盐,等等。
金属盐的优选例子包括:碱金属盐,例如,钠盐、钾盐,等等;碱土金属盐,例如,钙盐、镁盐、钡盐,等等;铝盐,等等。
与有机碱形成的盐的优选例子包括:与三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺、N,N-二苄基乙二胺等等形成的盐。
与无机酸形成的盐的优选例子包括:与盐酸、氢溴酸、硝酸、硫酸、磷酸等等形成的盐。
与有机酸形成的盐的优选例子包括:与甲酸、乙酸、三氟乙酸、苯二酸、富马酸、草酸、酒石酸、马来酸、枸橼酸、琥珀酸、苹果酸、甲磺酸、苯磺酸、对甲苯磺酸等等形成的盐。
与碱性氨基酸形成的盐的优选例子包括:与精氨酸、赖氨酸、鸟氨酸等等形成的盐。与酸性氨基酸形成的盐的优选例子包括:与门冬氨酸、谷氨酸等等形成的盐。
在上述盐之中,优选药用盐。例如,当化合物具有酸性官能团时,优选无机盐,例如,碱金属盐(例如,钠盐、钾盐等等)、碱土金属盐(例如,钙盐、镁盐、钡盐等等)等等、铵盐等等,当化合物具有碱性官能团时,例如,优选,与无机酸形成的盐,例如盐酸、氢溴酸、硝酸、硫酸、磷酸等等,或与有机酸形成的盐,例如乙酸、苯二酸、富马酸、草酸、酒石酸、马来酸、枸橼酸、琥珀酸、甲磺酸、对甲苯磺酸等等。
化合物(I)可以是前体药物形式。
前体药物是指下列化合物:在生物体中,在生理条件下,由于酶、胃酸等等所造成的反应而转变为化合物(I)的化合物,简而言之,根据酶的种类,由于氧化、还原、水解等等而转变为化合物(I)的化合物;由于胃酸,通过水解等等而转变为化合物(I)的化合物,等等。
化合物(I)的前体药物的例子包括∶化合物(I)的氨基被酰化、烷基化或磷酸化的化合物(例如,化合物(I)的氨基被二十烷酰化、丙氨酰化、戊基氨基羰基化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲氧基羰基化、四氢呋喃化、吡咯烷基甲基化、戊酰氧基甲基化或叔丁基化的化合物,等等);化合物(I)的羟基被酰化、烷基化、磷酸化或硼酸化的化合物(例如,化合物(I)是的羟基被乙酰化、棕榈酰化、丙酰化、新戊酰化、琥珀酰化、富马酰化、丙氨酰化或二甲基氨基甲基碳酰化的化合物);化合物(I)的羧基被酯化或酰胺化的化合物(例如,化合物(I)的羧基被C1-6烷基酯化、苯基酯化、羧甲基酯化、二甲基氨基甲基酯化、新戊酰氧基甲基酯化、乙氧基羰基氧基乙基酯化、酞基酯化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基酯化、环己基氧基羰基乙基酯化或甲基酰胺化的化合物),等等。除此以外,优选使用化合物(I)的羧基被C1-6烷基(例如,甲基、乙基、叔丁基等等)酯化的化合物。这些化合物可以通过本来已知的方法、由化合物(I)来制备。
A化合物(I)的前体药物也可以是生理条件下转变为化合物(I)的化合物,例如,在下列文献中所描述的那些:IYAKUHINnoKAIHATSU(DevelopmentofPharmaceuticals),Vol.7,DesignofMolecules,p.163-198,PublishedbyHIROKAWASHOTEN(1990)。
在本说明书中,前体药物可以形成盐。这种盐的例子包括化合物(I)的盐所举例说明的那些盐。
化合物(I)可以是晶体。具有定形的晶体或多个晶体形式的混合物也包括在化合物(I)范围内。可以按照本来已知的结晶方法,将化合物(I)结晶,制备晶体。
另外,化合物(I)可以是药用共晶体或共晶体盐。本文中,共晶体或共晶体盐是指由两种或多种具体物质组成的晶体物质,它们在室温下是固体,每个具有不同的物理性能(例如,结构、熔点、熔融热、吸湿性、溶解度、稳定性,等等)。可以利用本来已知的共结晶方法,制备共晶体和共晶体盐。
化合物(I)的晶体的物理化学性能(例如,熔点、溶解度、稳定性)和生物学特性(例如,药物动力学(吸收、分布、代谢、排泄)、效能表达)方面具有优越性,并由此特别用作药物。
化合物(I)和其前体药物(在下文中,有时缩写为本发明的化合物)对GLP-1受体和GIP受体具有活化作用。
本发明的化合物对GLP-1受体和GIP受体具有高活化作用,尤其是体内活化作用。
GLP-1和GIP是被称为肠促胰岛素的胃肠激素,并且具有促进胰腺分泌胰岛素的作用。由于肠促胰岛素与葡萄糖代谢紧密相关,所以,对GLP-1受体和GIP受体具有活化作用的化合物可用于预防或治疗与葡萄糖代谢病症相关的症状,包括肥胖症。
由此,本发明的化合物具有摄食抑制作用、体重增加抑制作用,等等。
另外,本发明的化合物具有优良的溶解度。优选,本发明的化合物在水中的溶解度为1mg/mL或更高,更优选10mg/mL或更高。
本发明的化合物可以用作GLP-1受体和GIP受体的活化剂(GLP-1受体/GIP受体共激动剂)。
在本发明中,GLP-1受体和GIP受体的活化剂(GLP-1受体/GIP受体共激动剂)是指,具有GLP-1受体活化作用(GLP-1受体激动剂作用)和GIP受体活化作用(GIP受体激动剂作用)两种作用的药物。具体地说,GLP-1受体和GIP受体的活化剂(GLP-1受体/GIP受体共激动剂)是指,针对GLP-1受体的EC50值和针对GIP受体的EC50值是1:20至20:1的药物,优选1:5至5:1。
本发明的化合物具有低的胰高血糖素受体活化作用(胰高血糖素受体激动剂),因此,具有低的高血糖症作用。与本发明化合物针对GLP-1受体或GIP受体的EC50值相比较,本发明化合物针对胰高血糖素受体的EC50值是1/1000或更低,优选1/10000或更低。
本发明化合物的毒性低(例如,急性毒性、慢性毒性、遗传毒性、生殖毒性、心脏毒性、致癌性),副作用很小,并且可以安全地给予哺乳动物(例如,人、牛、马、狗、猫、猴子、小鼠、大鼠),作为预防或治疗下面所述的各种疾病的药物,等等。
由于本发明的化合物对GLP-1受体和GIP受体的上述活化作用,所以,本发明的化合物可以用作治疗或预防各种疾病的药物,包括肥胖症。本发明的化合物可以用作预防或治疗下列疾病的药物:例如,症状性肥胖症、基于单纯性肥胖的肥胖症、与肥胖症有关的疾病状态或疾病、进食障碍、糖尿病(例如,I型糖尿病、II型糖尿病、妊娠期的糖尿病、肥胖性糖尿病)、高脂质血症(例如,高甘油三酯血症、高胆固醇血症、高LDL-胆固醇血、低HDL-胆固醇血、饭后高血脂症)、高血压症、心力衰竭、糖尿病的并发症[例如,神经病、肾病、视网膜病、糖尿病性心肌病、白内障、巨血管病、骨质减少、高渗性糖尿病性昏迷、传染病(例如,呼吸道感染、尿路感染、肠胃感染、表皮软组织感染、下肢感染)、糖尿病性坏疽、口干症、听觉减退、脑血管病症、周围血液循环病症]、代谢性综合症(具有三个或多个选自高甘油三酯血症(TG)、低HDL胆固醇血症(HDL-C)、高血压症、腹部肥胖症和葡糖耐量削弱的疾病状态)、肌肉减少,等等。
症状性肥胖症的例子包括:内分泌肥胖症(例如,柯兴氏综合征、甲状腺机能减退、胰岛瘤、肥胖性II型糖尿病、假甲状旁腺机能减退、性腺机能减退)、中心性肥胖症(例如,丘脑下部性肥胖、额叶综合症、克-列二氏综合征)、遗传性肥胖症(例如,Prader-Willi综合症、劳-穆-比三氏综合征)、药物诱导的肥胖症(例如,甾体、吩噻嗪、胰岛素、磺酰脲(SU)药物、β-阻断剂诱导的肥胖症),等等。
与肥胖症有关的疾病状态或疾病的例子包括:葡糖耐量病症、糖尿病(尤其是II型糖尿病、肥胖性糖尿病)、脂类代谢异常(与上述高脂质血症同义)、高血压症、心力衰竭、高尿酸血、脂肪肝(包括非酒精性肝炎)、冠心病(心肌梗塞、心绞痛)、脑梗塞(脑血栓、短暂性大脑缺血性发作)、骨/关节疾病(膝盖骨关节炎、臀骨关节炎、变形性脊椎炎、腰痛)、睡眠无呼吸综合症/Pickwick综合症、月经紊乱(月经周期异常、月经和周期异常、闭经、异常的月经症状)、代谢性综合症,等等。
关于糖尿病的诊断标准,JapanDiabetesSociety在1999年报道了新的诊断标准。
按照该报道,糖尿病是指满足空腹血糖水平(葡萄糖在静脉血中的浓度)为126mg/dl或更高、在75g口服葡萄糖耐量试验(75gOGTT)中的2小时值(葡萄糖在静脉血中的浓度)达到200mg/dl或更高以及随机血糖水平(葡萄糖在静脉血中的浓度)为200mg/dl或更高中的任一项的状态。此外,不适用于上述糖尿病的状态,以及没有显示出“空腹血糖水平(葡萄糖在静脉血中的浓度)低于110mg/dl或在75g口服葡萄糖耐量试验(75gOGTT)中的2小时值(葡萄糖在静脉血中的浓度)低于140mg/dl”的状态,被称作“边界类型”。
此外,关于糖尿病的诊断标准,AmericanDiabetesAssociation(ADA)在1997年以及WorldHealthOrganization(WHO)在1998年报道了新的诊断标准。
按照该报道,糖尿病是指满足空腹血糖水平(葡萄糖在静脉血中的浓度)为126mg/dl或更高以及在75g口服葡萄糖耐量试验中的2小时值(葡萄糖在静脉血中的浓度)达到200mg/dl或更高的状态。
按照上述报道,葡糖耐量削弱是指满足空腹血糖水平(葡萄糖在静脉血中的浓度)低于126mg/dl以及在75g口服葡萄糖耐量试验中的2小时值(葡萄糖在静脉血中的浓度)达到140mg/dl并且低于200mg/dl的状态。按照ADA的报道,空腹血糖水平(葡萄糖在静脉血中的浓度)为110mg/dl或更高并且低于126mg/dl的状态被称作IFG(空腹血糖受损)。另一方面,按照WHO的报道,在75g口服葡萄糖耐量试验中的2小时值(葡萄糖在静脉血中的浓度)低于140mg/dl的IFG(空腹血糖受损)的状态被称作IFG(空腹葡萄糖障碍)。
本发明的化合物还用作预防或治疗按照上述新的诊断标准所确定的糖尿病、边界类型糖尿病、葡糖耐量削弱、IFG(空腹血糖受损)和IFG(空腹葡萄糖障碍)。此外,本发明的化合物可以防止边界类型、葡糖耐量削弱、IFG(空腹血糖受损)或IFG(空腹葡萄糖障碍)发展成为糖尿病。
本发明的化合物具有抑制体重增加的作用,因此,可以用作哺乳动物的体重增加的抑制剂。使用本发明化合物的哺乳动物可以是希望避免体重增加的哺乳动物。哺乳动物可以是具有体重增加的遗传危险的哺乳动物,或可以是受生活方式相关的疾病(例如,糖尿病、高血压症和/或高脂质血症)影响的哺乳动物。体重增加可以归因于过度摄入食物或饮食失衡,或可以是由于并用药物(例如,具有PPARγ激动剂作用的胰岛素增敏剂,例如,曲格列酮、罗格列酮、恩格列酮、环格列酮、吡格列酮,等等)造成的体重增加。或者,体重增加可以是达到肥胖症之前的体重增加,或可以是肥胖症患者的体重增加。本文中,肥胖症的定义为:对于日本人,体重指数(BMI:体重(kg)÷[高度(m)]2)为25或更大(按照JapanSocietyfortheStudyofObesity的标准),对于西方人,BMI为30或更大(按照WHO的标准)。
本发明的化合物还用作预防或治疗代谢性综合症的药物。与患有单一生活方式相关的疾病的患者相比较,在代谢性综合症患者中,心血管疾病的发病率显著提高。由此,为了预防心血管疾病,预防或治疗代谢性综合症是非常重要的。
WHO在1999年、NCEP在2001年宣布了代谢性综合症的诊断标准。按照WHO的诊断标准,患有高胰岛素血症或葡糖耐量异常(作为条件)以及患有内脏肥胖症、血脂异常(高TG或低HDL)和高血压症中的两种或多种疾病的个体被诊断为代谢性综合症(WorldHealthOrganization:Definition,DiagnosisandClassificationofDiabetesMellitusandItsComplications.PartI:DiagnosisandClassificationofDiabetesMellitus,WorldHealthOrganization,Geneva,1999)。按照AdultTreatmentPanelIIIoftheNationalCholesterolEducationProgram的诊断标准(缺血性心脏病的指导方针),在美国,患有内脏肥胖症、高甘油三酯血症、低HDL-胆固醇血、高血压症和葡糖耐量异常中的三种或更多种疾病的个体被诊断为患有代谢性综合症(NationalCholesterolEducationProgram:ExecutiveSummaryoftheThirdReportofNationalCholesterolEducationProgram(NCEP)ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultsTreatmentPanelIII).TheJournaloftheAmericanMedicalAssociation,Vol.285,2486-2497,2001)。
本发明的化合物还可以用作预防或治疗下列疾病的药物:例如,骨质疏松症、恶病体质(例如,癌性恶病质、结核病的恶病体质、糖尿病的恶病体质、与血液病有关的恶病体质、与内分泌病有关的恶病体质、与传染病有关的恶病体质或爱滋病所引起的恶病体质)、脂肪肝、多囊卵巢综合症、肾病(例如,慢性肾衰竭、糖尿病的肾病、肾小球肾炎、肾小球硬化症、肾病综合症、高血压性肾硬化、终末期肾病)、肌肉营养不良、心肌梗塞、心绞痛、脑血管病症(例如,脑梗塞、中风)、阿尔海默氏疾病、帕金森氏症、焦虑症、痴呆、胰岛素耐受性综合症、综合症X、高胰岛素血症、由高胰岛素血症所引起的感觉异常、急性或慢性腹泻、炎性疾病(例如,慢性类风湿性关节炎、变形性脊椎炎、关节炎畸形、腰痛、痛风、手术后或外伤后的炎症、腹胀、神经痛、喉咽炎、膀胱炎、肝炎(包括非酒精性脂肪肝炎)、肺炎、胰腺炎、肠炎、炎症性肠病(包括炎症性的大肠疾病)、溃疡性结肠炎、胃粘膜损伤(包括由阿司匹林所引起的胃粘膜损伤)、小肠粘膜损伤、吸收障碍、睾丸功能障碍、内脏肥胖症综合症和肌肉减少。
此外,本发明的化合物还可以用作预防或治疗各种癌症的药物(尤其是乳腺癌(例如,侵入性导管乳腺癌、非侵入性导管乳腺癌、炎症性乳腺癌,等等)、前列腺癌症(例如,激素依赖性前列腺癌症、非激素依赖性前列腺癌症,等等)、胰腺癌(例如,导管胰腺癌,等等)、胃癌(例如,乳头状腺癌、粘液腺癌、腺鳞癌,等等)、肺癌(例如,非小细胞肺癌、小细胞肺癌、恶性间皮瘤,等等)、结肠癌(例如,胃肠基质肿瘤,等等)、直肠癌(例如,胃肠基质肿瘤,等等)、结肠直肠癌(例如,家族性结肠直肠癌、遗传性的非多发性息肉结肠直肠癌、胃肠基质肿瘤,等等)、小肠癌(例如、非霍奇金氏淋巴瘤、胃肠基质肿瘤,等等)、食道癌、十二指肠癌、舌癌、咽癌(例如,鼻咽癌、口咽癌、下咽癌,等等)、唾腺癌、脑肿瘤(例如,松果体的星形细胞瘤、纤维性星形细胞瘤、扩散性星形细胞瘤、间变性星形细胞瘤,等等)、神经鞘瘤、肝癌(例如,原发性肝癌、肝外的胆管癌,等等)、肾癌(例如,肾细胞癌、肾盂和输尿管的移行细胞癌,等等)、胆管癌、子宫内膜癌、子宫的子宫颈癌、卵巢癌(例如,上皮卵巢癌、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤、低恶性潜能的卵巢肿瘤,等等)、膀胱癌、尿道癌、皮肤癌(例如,眼内(眼睛)黑素瘤、Merkel细胞癌,等等)、血管瘤、恶性淋巴瘤、恶性黑色素瘤、甲状腺癌(例如,甲状腺髓样癌,等等)、甲状旁腺癌、鼻腔癌、静脉窦癌、骨肿瘤(例如,骨肉瘤、Ewing肿瘤、子宫肉瘤、软组织肉瘤,等等)、血管纤维瘤、视网膜肉瘤、阴茎癌、睾丸肿瘤、儿科的实质固态瘤(例如、Wilms'肿瘤、儿童期肾脏肿瘤,等等)、卡波济氏肉瘤、AIDS所引起的卡波济氏肉瘤、上颌窦的肿瘤、纤维组织细胞瘤、平滑肌肉瘤、横纹肌肉瘤、白血病(例如,急性的骨髓性白血病、急性淋巴母细胞性白血病,等等),等等)。
本发明的化合物还可以用于二级预防或抑制上述各种疾病的发展(例如,心血管状况,例如,心肌梗塞,等等)。另外,本发明的化合物还用作摄食抑制剂和体重增加抑制剂。本发明的化合物还可以与膳食疗法(例如,糖尿病的膳食疗法)和锻炼治疗联用。
含有本发明化合物的药物显示出低毒性,并且单独使用本发明的化合物或按照通常用作药物制剂的制备方法的本来已知的方法(例如,日本药典所描述的方法),与药理学可接受的载体混合来获得所述药物,安全地口服或胃肠外给药(例如,局部、直肠、静脉内给药),以药物制剂形式给药,例如,片剂(包括糖衣片、膜糖衣片、舌下片、口腔崩解片)、粉剂、颗粒剂、胶囊剂(包括软胶囊、微囊)、液剂、锭剂、糖浆剂、乳剂、混悬剂、注射剂(例如,皮下注射、静脉注射、肌内注射、腹膜内注射,等等)、外用制剂(例如,经鼻制剂、表皮制剂、软膏剂)、栓剂(例如,直肠栓剂、阴道栓剂)、丸剂、鼻制剂、肺制剂(吸入剂)、输液,等等。
这些制剂可以是控制释放制剂,例如,快速释放制剂、持续释放制剂,等等(例如,持续释放微囊)。
在药物制剂中,本发明化合物的含量为整个制剂的大约0.01-大约100wt%。
可以利用通常用作制剂材料的各种有机或无机载体材料来举例说明上述药用载体,例如,固体制剂使用的赋形剂、润滑剂、粘结剂和崩解剂;或液体药物使用的溶剂、增溶剂、悬浮剂、等渗剂、缓冲剂、抚慰剂,等等。此外,如有必要,还可以恰当地使用合适数量的常规添加剂,例如防腐剂、抗氧化剂、着色剂、甜味剂、吸附剂、湿润剂,等等。
赋形剂的例子包括乳糖、蔗糖、D-甘露糖醇、淀粉、玉米淀粉、结晶纤维素、轻质无水硅酸,等等。
润滑剂的例子包括硬脂酸镁、硬脂酸钙、滑石粉、胶态二氧化硅,等等。
粘结剂的例子包括:结晶纤维素、蔗糖、D-甘露糖醇、糊精、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、淀粉、蔗糖、凝胶、甲基纤维素、羧甲基纤维素钠,等等。
崩解剂的例子包括淀粉、羧甲纤维素、羧甲纤维素钙、羧甲淀粉钠、L-羟丙基纤维素,等等。
溶剂的例子包括注射用水、醇、丙二醇、聚乙二醇、芝麻油、玉米油、橄榄油等等。
增溶剂的例子包括聚乙二醇、丙二醇、D-甘露糖醇、苯甲酸苄酯、乙醇、三氨基甲烷、胆固醇、三乙醇胺、碳酸钠、枸橼酸钠,等等。
悬浮剂的例子包括表面活质,例如,硬脂酰三乙醇胺、月桂基磺酸钠、月桂基氨丙醇酸、磷脂酰胆碱、苯扎氯铵、苄索氯铵、单硬脂酸甘油酯,等等;亲水性聚合物,例如,聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素,等等;等等。
等渗剂的例子包括葡萄糖、D-山梨糖醇、氯化钠、丙三醇、D-甘露糖醇等等。
缓冲剂的例子包括缓冲溶液,例如磷酸盐、乙酸盐、碳酸盐、柠檬酸盐等等。
抚慰剂的例子包括苯甲醇,等等。
防腐剂的例子包括对羟基苯甲酸酯、氯丁醇、苯甲醇、苯乙醇、脱氢乙酸、山梨酸,等等。
抗氧化剂的例子包括亚硫酸盐、抗环血酸、α-生育酚等等。
着色剂的例子包括:水溶性的食品煤焦油染料(例如,食用染料,例如,食品红2号和3号、食品黄4号和5号、食品蓝1号和2号,等等)、不溶于水的色淀类染料(例如,上述水溶性的食品煤焦油染料的铝盐)、天然染料(例如,β-胡罗卜素、叶绿素、氧化铁红),等等。
甜味剂的例子包括糖精钠、甘草甜素二钾、阿斯巴甜、蛇菊等等。
吸附剂的例子包括多孔淀粉、硅酸钙(商标名∶FloriteRE)、偏硅酸铝镁(商标名∶Neusilin)和轻质无水硅酸(商标名∶Sylysia)。
湿润剂的例子包括单硬脂酸丙二醇酯、单油酸山梨醇酐酯、二甘醇月桂酸酯和聚氧乙烯月桂基醚。
在制备口服制剂期间,可以根据屏蔽味道、肠溶性能或持久性的需要来使用包衣。
包衣所使用的包衣基质的例子包括:糖衣基质、水性膜包衣基质、肠溶薄膜包衣基质和缓释薄膜包衣基质。
作为糖衣基质,可以使用蔗糖。此外,选自滑石粉、沉淀碳酸钙、凝胶、阿拉伯胶、支链淀粉、加洛巴蜡等等一或多种物质可以联用。
水性膜包衣基质的例子包括:纤维素聚合物,例如,羟丙基纤维素、羟基丙基甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素,等等;合成聚合物,例如,聚乙烯乙缩醛二乙氨基乙酯、氨基烷基甲基丙烯酸酯共聚物E[EudragitE(商标名)]、聚乙烯吡咯烷酮,等等;以及聚糖,例如,支链淀粉,等等。
肠溶性薄膜包衣基质的例子包括:纤维素聚合物,例如,邻苯二甲酸羟丙基甲基纤维素、羟基丙基甲基醋酸纤维素琥珀酸酯、羧甲基乙基纤维素、邻苯二甲酸醋酸纤维素,等等;丙烯酸类聚合物,例如,甲基丙烯酸共聚物L[EudragitL(商标名)]、甲基丙烯酸共聚物LD[EudragitL-30D55(商标名)]、甲基丙烯酸共聚物S[EudragitS(商标名)]等等;和天然存在的物质,例如,片胶,等等。
缓释薄膜包衣基质的例子包括:纤维素聚合物,例如,乙基纤维素,等等;和丙烯酸类聚合物,例如,氨基烷基甲基丙烯酸酯共聚物RS[EudragitRS(商标名)]、丙烯酸乙酯-甲基丙烯酸甲酯共聚物悬浮液[EudragitNE(商标名)],等等。
可以将两种或多种上述包衣基质以合适的比例混合,而后使用。为了包衣,例如,可以使用光屏试剂,例如二氧化钛、红色氧化铁等等。
根据给药患者、症状、给药方法等等,可以恰当地确定本发明化合物的剂量。例如,当口服给予肥胖症或糖尿病患者(体重60kg)本发明的化合物时,本发明化合物的日剂量为大约0.1至100mg,优选大约1.0至50mg,更优选大约1.0至20mg。当胃肠外给予肥胖症或糖尿病患者(体重60kg)本发明的化合物时,本发明化合物的日剂量为大约0.01至30mg,优选大约0.1至20mg,更优选大约0.5至10mg。可以将这些数量每天分为大约一至几份给予。
例如,可以每天(每天1次、每天2次、每天3次、每天4次、每天5次、每天6次)、每2天、每3天、每4天、每5天、每6天、每周、每周两次、每隔一周、每3周、每月、每2个月、每3个月、每4个月、每5个月或每6个月给予本发明的化合物。
本发明的化合物可以与不会不利地影响本发明化合物的其它药物联用,例如,为了提高本发明化合物的作用(肥胖症、糖尿病等等的治疗效果)、降低本发明化合物的剂量等等的目的。
可以与本发明的化合物联用的药物(在下文中,有时缩写为并用药物)的例子包括:抗肥胖剂、糖尿病的治疗剂、糖尿病的并发症的治疗剂、高脂质血症的治疗剂、抗高血压剂、利尿剂、化疗药物、免疫治疗剂、抗炎症药物、抗血栓形成的药物、骨质疏松症的治疗剂、维生素、抗痴呆药物、勃起功能障碍药物、尿频或尿失禁的治疗药物、排尿困难的治疗剂,等等。并用药物的具体例子包括下面所述的并用药物。
抗肥胖药物的例子包括:一元胺吸收抑制剂(例如,苯丁胺、西布曲明、氯苯咪吲哚、氟西汀、特索芬辛(tesofensine))、血清素2C受体激动剂(例如,氯卡色林(lorcaserin))、血清素6受体拮抗剂、组胺H3受体调节剂、GABA调节剂(例如,托吡酯)、神经肽Y拮抗剂(例如,韦利贝特(velneperit))、大麻素受体拮抗剂(例如,利莫那班、taranabant)、生长素释放肽拮抗剂、生长素释放肽受体拮抗剂、生长素释放肽酰化酶抑制剂、阿片样物质受体拮抗剂(例如,GSK-1521498)、食欲素受体拮抗剂、黑皮质素4受体激动剂、11β-羟甾醇脱氢酶抑制剂(例如,AZD-4017)、胰脂肪酶抑制剂(例如,奥利司他、赛利司他(cetilistat))、β3激动剂(例如,N-5984)、甘油二酯酰基转移酶1(DGAT1)抑制剂、乙酰辅酶A羧化酶(ACC)抑制剂、硬脂酰基-CoA不饱和酶抑制剂、微粒体的甘油三酯转移蛋白抑制剂(例如,R-256918)、钠-葡萄糖协同转运蛋白抑制剂(例如,JNJ-28431754、瑞格列净(remogliflozin))、NFκ抑制剂(例如,HE-3286)、PPAR激动剂(例如,GFT-505、DRF-11605)、磷酸酪氨酸磷酸酶抑制剂(例如、钒酸钠、trodusquemin)、GPR119激动剂(例如,PSN-821、MBX-2982、APD597)、葡糖激酶活化剂(例如,AZD-1656)、瘦素、瘦素衍生物(例如,美曲普汀(metreleptin))、CNTF(睫状神经营养因子)、BDNF(脑衍生神经营养因子)、缩胆囊肽激动剂、糊精制剂(例如,普兰林肽、AC-2307)、神经肽Y激动剂(例如,PYY3-36、PYY3-36的衍生物、obineptide、TM-30339、TM-30335)、胃泌酸调节素(oxyntomodulin)制剂∶FGF21制剂(例如,从牛或猪的胰腺提取的动物FGF21制剂;使用大肠杆菌或酵母遗传合成的人FGF21制剂;FGF21的片段或衍生物)、减食欲剂(例如,P-57),等等。
本文中,作为糖尿病的治疗剂,例如,可以提到胰岛素制剂(例如,从牛或猪的胰腺提取的动物胰岛素制剂;使用大肠杆菌或酵母遗传合成的人胰岛素制剂;锌胰岛素;鱼精蛋白锌胰岛素;胰岛素的片段或衍生物(例如,INS-1)、口服胰岛素制剂)、胰岛素增敏剂(例如,吡格列酮或其盐(优选,盐酸盐)、罗格列酮或其盐(优选,马来酸盐)、Metaglidasen、AMG-131、巴格列酮、MBX-2044、利格列酮、Aleglitazar、西格列羧(Chiglitazar)、洛贝格列酮(Lobeglitazone)、PLX-204、PN-2034、GFT-505、THR-0921、WO007/013694、WO2007/018314、WO2008/093639或WO2008/099794所描述的化合物)、α-葡糖苷酶抑制剂(例如,伏格列醇、阿卡波糖、米格列醇、乙格列酯)、双缩胍(例如,二甲双胍、丁福明或其盐(例如,盐酸盐、富马酸盐、琥珀酸盐))、胰岛素促泌剂(例如,磺酰脲(例如,甲苯磺丁脲、格列本脲、格列齐特、氯磺丙脲、甲磺吖庚脲、醋酸己脲、格列吡脲、格列美脲、格列甲嗪、格列丁唑)、瑞格列奈、那格列萘、米格列奈或其钙盐水合物)、二肽基肽酶IV抑制剂(例如,阿洛利停(Alogliptin)或其盐(优选,苯甲酸盐)、维格列汀(vildagliptin)、西他列汀、沙格列汀(Saxagliptin)、BI1356、GRC8200、MP-513、PF-00734200、PHX1149、SK-0403、ALS2-0426、TA-6666、TS-021、KRP-104、曲格列汀(Trelagliptin)或其盐(优选琥珀酸盐))、β3激动剂(例如,N-5984)、GPR40激动剂(例如,Fasiglifam或其水合物、WO2004/041266、WO2004/106276、WO2005/063729、WO2005/063725、WO2005/087710、WO2005/095338、WO2007/013689或WO2008/001931所描述的化合物)、SGLT2(钠-葡萄糖协同转运蛋白2)抑制剂(例如,Depagliflozin、AVE2268、TS-033、YM543、TA-7284、瑞格列净(Remogliflozin)、ASP1941)、SGLT1抑制剂、11β-羟甾醇脱氢酶抑制剂(例如,BVT-3498、INCB-13739)、脂联素或其激动剂、IKK抑制剂(例如,AS-2868)、瘦素耐受性改善药物、抑生长素受体激动剂、葡糖激酶活化剂(例如,Piragliatin、AZD1656、AZD6370、TTP-355、WO006/112549、WO007/028135、WO008/047821、WO008/050821、WO008/136428或WO008/156757所描述的化合物)、GPR119激动剂(例如,PSN821、MBX-2982、APD597)、FGF21、FGF类似物、acc2抑制剂,等等。
作为糖尿病的并发症的治疗剂,可以提到醛糖还原酶抑制剂(例如,脱瑞司他、依帕司他、唑泊司他、法地司他、CT-112、雷尼司他(AS-3201)、利多司他(lidorestat))、神经营养因子和其增强药物(例如,NGF、NT-3、BDNF、WO01/14372所描述的神经营养产物/分泌促进剂(例如,4-(4-氯苯基)-2-(2-甲基-1-咪唑基)-5-[3-(2-甲基苯氧基)丙基]噁唑)、WO2004/039365所描述的化合物)、PKC抑制剂(例如,甲磺酸鲁伯斯塔)、AGE抑制剂(例如,ALT946、N-苯甲酰基噻唑溴化物(ALT766)、EXO-226、Pyridorin、吡哆胺)、GABA激动剂(例如,加巴喷丁、普加巴林)、血清素和去甲肾上腺素再摄取抑制剂(例如,度洛西汀)、钠通道抑制剂(例如,拉科酰胺(lacosamide))、活性氧净化剂(例如,硫辛酸)、大脑血管扩张剂(例如,tiapuride、慢心律)、抑生长素受体激动剂(例如,BIM23190)、细胞程序死亡信号调节激酶-1(ASK-1)抑制剂,等等。
作为高脂质血症的治疗剂,可以提到HMG-CoA还原酶抑制剂(例如,普伐他汀、西伐他汀、洛伐他汀、阿托伐他汀、氟伐他汀、罗苏伐他汀、匹伐他汀或其盐(例如,钠盐、钙盐))、鲨烯合成酶抑制剂(例如,WO97/10224所描述的化合物,例如,N-[[(3R,5S)-1-(3-乙酰氧基-2,2-二甲丙基)-7-氯-5-(2,3-二甲氧基苯基)-2-氧代-1,2,3,5-四氢-4,1-苯并氧氮杂-3-基]乙酰基]哌啶-4-乙酸)、贝特类(fibrate)化合物(例如,苯扎贝特、氯贝特、双贝特(Simfibrate)、克利贝特)、阴离子交换树脂(例如,考来烯胺)、普罗布考、烟酸药物(例如,烟酸环己醇酯、烟酸戊四醇酯、niaspan)、廿六烷五烯酸乙酯、植物甾醇(例如,黃豆固醇、gamma谷维素(γ-谷维素))、胆固醇吸收抑制剂(例如,zechia)、CETP抑制剂(例如,达塞曲匹(dalcetrapib)、安塞曲匹(anacetrapib))、ω-3脂肪酸制剂(例如,ω-3-脂肪酸乙酯90(ω-3-酸乙酯90)),等等。
抗高血压药的例子包括:血管紧张肽转化酶抑制剂(例如,卡托普利、依那普利、地拉普利、等等)、血管紧张素II拮抗剂(例如,坎地沙坦西酯、坎地沙坦、氯沙坦、氯沙坦钾、依普罗沙坦、丙戊沙坦、替米沙坦、伊贝沙坦、他索沙坦、奥美沙坦、奥美沙坦酯、阿齐沙坦(azilsartan)、阿齐沙坦酯,等等)、钙拮抗剂(例如,马尼地平、硝苯地平、氨氯地平、依福地平、尼卡地平、西尼地平,等等)、β阻断剂(例如,美托洛尔、阿替洛尔、普奈洛尔、卡维地洛、吲哚洛尔,等等)、可乐定,等等。
作为利尿剂,可以提到,例如,黄嘌呤衍生物(例如,可可碱水杨酸钠、可可碱水杨酸钙,等等)、噻嗪制剂(例如,乙噻嗪、环戊噻嗪、三氯噻嗪、双氢氯噻嗪、双氢氟噻嗪、苄基双氢氯噻嗪、戊氟噻嗪、多噻嗪、氯甲噻嗪,等等)、抗醛甾酮制剂(例如,螺甾内酯、三氨蝶啶,等等)、碳酸酐酶抑制剂(例如,乙酰唑胺,等等)、氯苯磺酰胺药物(例如,氯噻酮、美夫西特、吲达帕胺,等等)、阿佐寒米、异山梨醇、依他尼酸、吡咯他尼、布美他尼、利尿磺胺,等等。
化学疗法的例子包括:烷基化剂(例如,环磷酰胺、异环磷酰胺)、代谢拮抗剂(例如,氨甲喋呤、5-氟尿嘧啶)、抗癌剂抗生素(例如,丝裂霉素、多柔比星)、植物衍生的抗癌剂(例如,长春花新碱、去乙酰长春酰胺、紫杉酚)、顺铂、卡铂、依托泊苷,等等。除此以外,优选5-氟尿嘧啶衍生物Furtulon或Neofurtulon等等。
免疫治疗剂的例子包括:微生物或细菌组份(例如,胞壁酰二肽衍生物、溶链菌制剂(Picibanil))、具有免疫增强活性的多糖(例如,蘑菇多糖、西佐喃、云芝多糖K(Krestin))、利用遗传工程方法获得的细胞素(例如,干扰素、白介素(IL))、菌落-刺激因子(例如,粒细胞菌落-刺激因子、红细胞生成素),等等。除此以外,优选白介素,例如IL-1、IL-2、IL-12,等等。
抗炎症药物的例子包括非甾体抗炎症药物,例如,阿司匹林、醋氨酚、消炎痛,等等。
作为抗血栓形成的药物,可以提到,例如,肝素(例如,肝素钠、肝素钙、依诺肝素钠、达肝素钠)、华法林(例如、华法林钾)、抗凝血酶药物(例如,阿加曲班、达比加群(dabigatran))、FXa抑制剂(例如,利伐沙班(rivaroxaban)、阿哌沙班(apixaban)、伊多塞班(edoxaban)、YM150、WO02/06234、WO2004/048363、WO2005/030740、WO2005/058823或WO2005/113504所描述的化合物)、溶解血栓剂(例如,尿激酶、替来激酶(tisokinase)、阿替普酶、那替普酶、孟替普酶、帕米普酶)、血小板聚集抑制剂(例如,盐酸噻氯匹定、氯吡格雷、普拉格雷(prasugrel)、E5555、SHC530348、西洛他唑、廿六烷五烯酸乙酯、贝前列素钠、盐酸沙格雷酯),等等。
骨质疏松症的治疗剂的例子包括:阿法骨化醇、骨化三醇、依降钙素、鲑鱼降钙素、雌三醇、依普黄酮、帕米膦酸二钠、水合阿仑膦酸钠、因卡膦酸二钠、利塞膦酸二钠,等等。
维生素的例子包括维生素B1、维生素B12,等等。
抗痴呆药物的例子包括他克林、多奈哌齐、利凡斯的明、加兰他敏,等等。
勃起功能障碍药物的例子包括阿扑吗啡、柠檬酸西地那非,等等。
尿频或尿失禁的治疗药物的例子包括盐酸黄酮哌酯、盐酸羟丁宁、盐酸丙哌维平,等等。
排尿困难的治疗剂的例子包括:乙酰化胆碱脂酶抑制剂(例如,地斯的明(distigmine)),等等。
此外,在动物模型中或临床上证明具有恶病体质改善作用的药物,即,环加氧酶抑制剂(例如,消炎痛)、黄体酮衍生物(例如,甲地孕酮)、糖皮质激素(例如,地塞米松)、灭吐灵药物、四氢大麻酚药物、改善脂肪代谢的药物(例如,二十碳五烯酸)、生长激素、IGF-1或针对恶病体质诱发因子TNF-α、LIF、IL-6或制瘤素M的抗体,等等,也可以与本发明的化合物联用。
或者,糖化抑制剂(例如,ALT-711)、神经再生促进药物(例如,Y-128、VX853、prosaptide)、抗抑郁剂(例如,地昔帕明、阿米替林、丙咪嗪)、抗癫痫药物(例如,乐命达、曲莱(Trileptal)、左乙拉西坦(Keppra)、唑尼沙胺(Zonegran)、普加巴林、Harkoseride、卡马西平)、抗心律失常药物(例如,慢心律)、乙酰胆碱受体配体(例如,ABT-594)、内皮素受体拮抗剂(例如,ABT-627)、一元胺吸收抑制剂(例如,反胺苯环醇)、麻醉止痛剂(例如,吗啡)、GABA受体激动剂(例如,加巴喷丁、加巴喷丁的MR制剂)、α2受体激动剂(例如,可乐定)、局部止痛剂(例如,辣椒碱)、抗焦虑药物(例如,苯并噻氮)、磷酸二酯酶抑制剂(例如,西地那非)、多巴胺受体激动剂(例如,阿扑吗啡)、咪达唑仑、酮康唑,等等,可以与本发明的化合物联用。
对本发明的化合物和并用药物的给药时间没有限制,可以同时给予它们,或以交错方式给予患者。
这种给药模式的例子包括下列模式∶
(1)给予同时加工本发明的化合物和并用药物所获得的单一制剂,(2)通过相同给药途径,同时给予分别制备的本发明化合物和并用药物的两种制剂,
(3)通过相同给药途径,以交错方式给予分别制备的本发明化合物和并用药物的两种制剂,(4)通过不同给药途径,同时给予分别制备的本发明化合物和并用药物的两种制剂,(5)通过不同给药途径,以交错方式给予分别制备的本发明化合物和并用药物的两种制剂(例如,以本发明的化合物和并用药物的顺序给药,或以这种顺序的倒序形式给药),等等。
基于临床上使用的剂量,可以恰当地确定并用药物的剂量。根据给药患者、症状、给药方法、靶向疾病、联用药等等,可以恰当地确定本发明化合物与并用药物的混合比例。当给药患者是人时,例如,相对于1重量份数的本发明的化合物,可以使用0.01-100重量份数的并用药物。
通过本发明化合物与并用药物的联用,可以实现∶
(1)与单一给予本发明的化合物或并用药物相比较,可以降低本发明的化合物或并用药物的剂量,
(2)根据患者的状况(轻微、严重,等等),可以选择与本发明的化合物联用所使用的药物,
(3)通过选择与本发明化合物的作用和机理不同的并用药物,可以设定更长时间的疗程,
(4)通过选择与本发明化合物的作用和机理不同的并用药物,可以设计持续治疗效果,
(5)通过联合使用本发明化合物与并用药物,可以提供协同效应,等等。
[实施例]
在本说明书中使用的缩写是指下列缩写(表1-1和表1-2)。本文所描述的术语中的短线,例如,α-MePhe等等,可以省略,并且这种省略的状况也代表相同含义。
[表1-1]
[表1-2]
在本说明书中,在用代码表示碱基、氨基酸的情况下,这些代码基于符合IUPAC-IUBCommissiononBiochemicalNomenclature的常规代码,或利用本领域的常规代码,其实例如下所示。对于可以具有旋光异构体的氨基酸,提供L型,除非另有陈述(例如,“Ala”是Ala的L型)。另外,“D-”是指D型(例如,“D-Ala”是Ala的D型),“DL-”是指D型和L型的外消旋体(例如,“DL-Ala”是Ala的DL外消旋体)。
TFA∶三氟乙酸
Gly或G∶甘氨酸
Ala或A∶丙氨酸
Val或V∶缬氨酸
Leu或L∶亮氨酸
Ile或I∶异亮氨酸
Ser或S∶丝氨酸
Thr或T∶苏氨酸
Cys或C∶半胱氨酸
Met或M∶甲硫氨酸
Glu或E∶谷氨酸
Asp或D∶天冬氨酸
Lys或K∶赖氨酸
Arg或R∶精氨酸
His或H∶组氨酸
Phe或F∶苯丙氨酸
Tyr或Y∶酪氨酸
Trp或W∶色氨酸
Pro或P∶脯氨酸
Asn或N∶天冬酰胺
Gln或Q∶谷氨酰胺
pGlu∶焦谷氨酸
α-MeTyr∶α-甲基酪氨酸
在下文中,通过下列参考实施例、实施例、试验实施例和制剂实施例,详细说明本发明,这些实施例仅仅是实施方案,并不具有限制性。另外,在不背离发明范围的条件下,可以修改本发明。
在下面的实施例中,术语“室温”通常表示大约10℃至大约35℃的范围。对于“%”,产率用mol/mol%表示,色谱所使用的溶剂用体积%表示,其它“%”是重量%。
THF∶四氢呋喃
DMF∶N,N-二甲基甲酰胺
WSC∶1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐
HOBt∶1-羟基苯并三唑一水合物
参考实施例1
合成
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(SEQIDNO:10)
将Sieber酰胺树脂(0.69meq/g,362mg)加入到反应管中,然后装填到肽合成仪中。根据Fmoc/DCC/HOBt方案,将氨基酸连续缩合。在最后一步,除去N端Fmoc基团。终止缩合之后,用MeOH洗涤树脂,并减压干燥。结果,获得1025mg(0.244meq/g)目标的保护的肽树脂。
参考实施例2
合成
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂(SEQIDNO:11)
将Sieber酰胺树脂(0.69meq/g,362mg)加入到反应管中,然后装填到肽合成仪中。根据Fmoc/DCC/HOBt方案,将氨基酸连续缩合。在最后一步,除去N端Fmoc基团。终止缩合之后,用MeOH洗涤树脂,并减压干燥。结果,获得1331mg(0.188meq/g)目标的保护的肽树脂。
参考实施例3
合成
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(SEQIDNO:12)
将Sieber酰胺树脂(0.61meq/g,410mg)加入到反应管中,然后装填到肽合成仪中。根据Fmoc/DCC/HOBt方案,将氨基酸连续缩合。为了引入18位和20位Ala和19位Gln(Trt),进行双偶合。在最后一步,除去N端Fmoc基团。终止缩合之后,用MeOH洗涤树脂,并减压干燥。结果,获得1110mg(0.225meq/g)目标的保护的肽树脂。
实施例1
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:13)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.244meq/g,41.0mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Ala、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到83mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向83mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇(ethanedithiol)∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶65/35-55/45线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到22.5mg白色粉末。
质谱:(M+H)+4267.4(计算值∶4267.2)
HPLC洗脱时间∶7.1min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例2
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:14)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.244meq/g,41.0mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到84.5mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向84.5mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶65/35-55/45线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到21.5mg白色粉末。
质谱:(M+H)+4281.5(计算值∶4281.2)
HPLC洗脱时间∶7.2min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例3
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:15)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.244meq/g,41.0mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ser(tBu)-OH(38.3mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Ala、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到73.3mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向73.3mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶65/35-55/45线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到17.1mg白色粉末。
质谱:(M+H)+4283.6(计算值∶4283.2)
HPLC洗脱时间∶7.1min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例4
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:16)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.244meq/g,41.0mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ser(tBu)-OH(38.3mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到63mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向63mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶64/36-54/46线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到14.7mg白色粉末。
质谱:(M+H)+4297.8(计算值∶4297.2)
HPLC洗脱时间∶7.2min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例5
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQIDNO:17)
将参考实施例2制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂(0.188meq/g,53.2mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Ala、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到97mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂。
向97mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶63/37-53/47线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到25.2mg白色粉末。
质谱:(M+H)+4139.2(计算值∶4139.1)
HPLC洗脱时间∶7.3min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例6
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQIDNO:18)
将参考实施例2制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂(0.188meq/g,53.2mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到78.1mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂。
向78.1mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶63/37-53/47线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到18.4mg白色粉末。
质谱:(M+H)+4152.9(计算值∶4153.1)
HPLC洗脱时间∶7.4min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例7
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQIDNO:19)
将参考实施例2制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂(0.188meq/g,53.2mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ser(tBu)-OH(38.3mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL,0.1mmol)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Ala、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到87mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂。
向87mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶65/35-55/45线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到17mg白色粉末。
质谱:(M+H)+4154.8(计算值∶4155.1)
HPLC洗脱时间∶7.3min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例8
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQIDNO:20)
将参考实施例2制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂(0.188meq/g,53.2mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ser(tBu)-OH(38.3mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到76.8mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂。
向76.8mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶63/37-53/47线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到16.6mg白色粉末。
质谱:(M+H)+4169.2(计算值∶4169.1)
HPLC洗脱时间∶7.4min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例9∶
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:21)
将参考实施例3制备的
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、Aib、Lys(Boc)、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到72.4mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向72.4mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶67/33-57/43线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到13.9mg白色粉末。
质谱:(M+H)+4295.8(计算值∶4296.2)
HPLC洗脱时间∶6.9min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例10
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ala-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:22)
将参考实施例3制备的
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、Aib、Ala、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到86.1mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ala-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向86.1mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶66/34-56/44线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到16.2mg白色粉末。
质谱:(M+H)+4238.6(计算值∶4239.2)
HPLC洗脱时间∶7.1min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例11
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Phe-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:23)
将参考实施例3制备的
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、Aib、Phe、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到76.4mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Phe-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向76.4mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶65/35-55/45线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到4.7mg白色粉末。
质谱:(M+H)+4315.1(计算值∶4315.2)
HPLC洗脱时间∶7.2min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例12
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Pya(4)-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:24)
将参考实施例3制备的
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、Aib、Pya(4)*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)**、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶在缩合期间,加入17.4μLDIPEA;**∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到78.4mg的H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Pya(4)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向78.4mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶67/33-57/43线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到15.2mg白色粉末。
质谱:(M+H)+4316.2(计算值∶4316.2)
HPLC洗脱时间∶6.9min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例13
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-αMePhe-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:25)
将参考实施例3制备的
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、αMePhe、Ile、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到69.1mg的H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-αMePhe-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向69.1mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶64/36-54/46线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到14.4mg白色粉末。
质谱:(M+H)+4356.9(计算值∶4357.3)
HPLC洗脱时间∶7.4min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例14
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Cha-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:26)
将参考实施例3制备的
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、Cha、Ile、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到71.5mg的H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Cha-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向71.5mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶63/37-53/47线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到16mg白色粉末。
质谱:(M+H)+4348.7(计算值∶4349.3)
HPLC洗脱时间∶7.5min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例15
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-αMePhe-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:27)
将参考实施例3制备的H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、αMePhe、Lys(Boc)、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到77.9mg的H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-αMePhe-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向77.9mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶65/35-55/45线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到13.4mg白色粉末。
质谱:(M+H)+4371.7(计算值∶4372.3)
HPLC洗脱时间∶7.1min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例16
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Cha-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:28)
将参考实施例3制备的
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、Cha、Lys(Boc)、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到75.1mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Cha-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向75.1mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶65/35-55/45线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到14.7mg白色粉末。
质谱:(M+H)+4364.7(计算值∶4364.3)
HPLC洗脱时间∶7.1min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例17
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-αMeTyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:29)
将参考实施例3制备的
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.225meq/g,44.4mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Lys(Boc)、Asp(OtBu)、Leu、αMeTyr、Ile、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到56.2mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-αMeTyr-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向56.2mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶65/35-55/45线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到1.4mg白色粉末。
质谱:(M+H)+4373.8(计算值∶4373.2)
HPLC洗脱时间∶7.2min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例18
合成
Ac-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:30)
将利用与参考实施例1相似的方法制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.253meq/g,39.5mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。接下来,用哌啶处理,除去N端Fmoc基团,而后将DMF(200μL)、DIPEA(17.4μL)和Ac2O(9.4μL)依次加入到树脂中,并将该混合物摇动90分钟。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,用MeOH洗涤树脂,并减压干燥,得到43mg的
Ac-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向43mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶62/38-52/48线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到7.8mg白色粉末。
质谱:(M+H)+4323.4(计算值∶4323.2)
HPLC洗脱时间∶7.5min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例19
合成
Benzoyl-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:31)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.253meq/g,39.5mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。接下来,用哌啶处理,除去N端Fmoc基团,而后将苯甲酸(12.2mg)、0.5MOxymapure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,并将该混合物摇动过夜。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,用MeOH洗涤树脂,而后减压干燥,得到54.8mg的
Benzoyl-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向54.8mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶60/40-50/50线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到10.1mg白色粉末。
质谱:(M+H)+4385.2(计算值∶4385.2)
HPLC洗脱时间∶7.7min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例20
合成
4PyCO-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:32)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.253meq/g,39.5mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。接下来,用哌啶处理,除去N端Fmoc基团,而后将4-吡啶甲酸(12.3mg)、0.5MOxymapure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,并将该混合物摇动过夜。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,用MeOH洗涤树脂,而后减压干燥,得到62.9mg的4PyCO-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向62.9mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶62/38-52/48线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到13.3mg白色粉末。
质谱:(M+H)+4386.2(计算值∶4386.2)
HPLC洗脱时间∶7.3min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例21
合成
cPrCO-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:33)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.253meq/g,39.5mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。接下来,用哌啶处理,除去N端Fmoc基团,而后将环丙烷甲酸(8.6mg)、0.5MOxymapure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,并将该混合物摇动过夜。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,用MeOH洗涤树脂,而后减压干燥,得到61.8mg的
cPrCO-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向61.8mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶61/39-51/49线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到11.7mg白色粉末。
质谱:(M+H)+4349.2(计算值∶4349.2)
HPLC洗脱时间∶7.6min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例22
合成脒基
-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:34)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.253meq/g,39.5mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。接下来,用哌啶处理,除去N端Fmoc基团,而后将DMF(200μL)、N,N'-二(叔丁氧羰基)-1H-吡唑并-1-甲脒(31mg)和DIPEA(17.4μL)依次加入到树脂中,并将该混合物摇动过夜。过滤该反应溶液,而后将DMF(200μL)、N,N'-二(叔丁氧羰基)-1H-吡唑并-1-甲脒(carboxamidine)(31mg)和DIPEA(17.4μL)依次加入到树脂中,并将该混合物再次摇动过夜。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,用MeOH洗涤树脂,而后减压干燥,得到54.7mg的
BocNHC(=NBoc)-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向54.7mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶62/38-52/48线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到10.7mg白色粉末。
质谱:(M+H)+4323.2(计算值∶4323.2)
HPLC洗脱时间∶7.3min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例23
合成
H-NMeTyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:35)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.253meq/g,39.5mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和NMeTyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到66.2mg的
H-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向66.2mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶63/37-53/47线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到9mg白色粉末。
质谱:(M+H)+4295.1(计算值∶4295.2)
HPLC洗脱时间∶7.2min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例24
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:36)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.244meq/g,41.0mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Ala-OH(31.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Tyr(tBu)、Lys(Boc)*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到66.8mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向66.8mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶66/34-56/44线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到16.1mg白色粉末。
质谱:(M+H)+4374.6(计算值∶4374.2)
HPLC洗脱时间∶6.9min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例25
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQIDNO:37)
将参考实施例1制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂(0.244meq/g,41.0mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Tyr(tBu)、Lys(Boc)*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到55.0mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Gln(Trt)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber酰胺树脂。
向55.0mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶66/34-56/44线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到13.7mg白色粉末。
质谱:(M+H)+4431.5(计算值∶4431.3)
HPLC洗脱时间∶6.9min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
实施例26
合成
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQIDNO:38)
将参考实施例2制备的
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂(0.188meq/g,53.2mg)称量到反应管中,并用DMF溶胀。过滤除去DMF之后,将Fmoc-Gln(Trt)-OH(61.1mg)、0.5MOxymaPure/DMF(200μL)和二异丙基碳二亚胺(15.9μL)依次加入到树脂中,而后将该混合物摇动1.5小时。过滤该反应溶液,然后用DMF洗涤树脂6次。在Kaiser试验中确定阴性之后,向其中加入20%哌啶的DMF溶液,并将该混合物摇动1分钟。过滤该溶液,然后向其中再次加入20%哌啶的DMF溶液,并将该混合物摇动20分钟。过滤该溶液,然后用DMF洗涤树脂10次。重复这种Fmoc氨基酸缩合-Fmoc脱保护循环,连续缩合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Tyr(tBu)、Lys(Boc)*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib和Tyr(tBu)(*∶过夜反应)。用MeOH洗涤树脂,而后减压干燥,得到95.4mg的
H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Gln(Trt)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber酰胺树脂。
向95.4mg所获得的树脂中加入1mL的TFA∶间甲酚∶茴香硫醚∶乙二硫醇∶水∶三异丙基硅烷(80:5:5:5:2.5:2.5),并将该混合物搅拌1.5小时。将二乙醚加入到该反应溶液中,获得沉淀,并将该沉淀重复洗涤三次,离心之后,取出上清液。用50%乙酸水溶液提取残余物,过滤取出树脂,而后进行制备HPLC,使用DaisopakSP-100-5-ODS-P柱(250×20mmI.D.)[溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,流速8mL/min,A/B∶61/39-51/49线性浓度梯度洗脱(60min)]。收集含有目标产物的级分,冷冻干燥,得到20.0mg白色粉末。
质谱:(M+H)+4303.0(计算值∶4303.2)
HPLC洗脱时间∶7.1min
洗脱条件∶
柱∶MerckChromolithPerformanceRP-18e(100×4.6mmI.D.)
洗脱液∶使用溶液A∶0.1%TFA-水,溶液B∶含有0.1%TFA的乙腈,A/B∶95/5-35/65线性浓度梯度洗脱(10min)
流速∶3.0mL/min
试验实施例1
使用胞内cAMP浓度的升高作为指标,评价激动剂针对人GIPR、人GLP-1R和人胰高血糖素R的活性
(1)人GIPR基因的表达质粒的构建
将具有与GenBank登记号U39231的序列相同序列的人GIPR基因克隆到pMSRα-neo载体中,制备hGIPR/pMSRα-neo。
(2)报告质粒-表达细胞的构建
将具有上游cAMP响应序列的萤光素酶报告基因引入到CHO-K1细胞中,构成CRE-LUC/CHO-K1细胞。
(3)报告质粒的构建
将cAMP响应序列和博莱霉素(Zeocin)抗性基因的四个备份引入到pGL3(R2.2)-BasicVector(Promega)中,构成Cre-luc(Zeo)报告质粒。
(4)将人GIPR基因引入到CRE-LUC/CHO-K1细胞中,获得表达细胞
将(1)中获得的质粒hGIPR/pMSRα-neo引入到(2)中获得的CRE-LUC/CHO-K1细胞中,得到转化体。接下来,通过加入GIP,从获得的转化体中选择诱导表达萤光素酶的细胞系,即,hGIPR/CRE-LUC/CHO-K1细胞。
(5)人GLP-1R基因的表达质粒的组成
将具有与GenBank登记号NM_002062的序列相同序列的人GLP-1R基因克隆到pIRESneo3载体中,制备hGLP-1/pIRESneo3。
(6)将人GLP-1R基因和报告质粒引入到CHO-K1细胞中,获得表达细胞
将(3)中获得的Cre-luc(Zeo)和(5)中获得的质粒hGLP-1/pIRESneo3引入到CHO-K1细胞中,得到转化体。接下来,通过加入GLP-1,从获得的转化体中选择诱导表达萤光素酶的细胞系,即,hGLP-1R/CRE-luc/CHO-K1细胞。
(7)人胰高血糖素R基因的表达质粒的构建
将具有与GenBank登记号NM_000160的序列相同序列的人胰高血糖素R基因克隆到pMSRα-neo中,制备hGlucagonR/pMSRα-neo。
(8)将人胰高血糖素R基因引入到CRE-LUC/CHO-K1细胞中,获得表达细胞
将(7)中获得的质粒hGlucagonR/pMSRα-neo引入到(2)中获得的CRE-LUC/CHO-K1细胞中,得到转化体。接下来,通过加入胰高血糖素,从获得的转化体中选择诱导表达萤光素酶的细胞系,即,hGlucagonR/CRE-LUC/CHO-K1细胞。
(9)报告试验
将hGIPR/CRE-LUC/CHO-K1细胞播种在384孔白色板(Corning)中,细胞密度为25μL/孔(5×104个细胞/孔),并在37℃的CO2培养箱中,在含有10%胎牛血清、100U/mL青霉素和100μg/mL链霉素的HamF12培养基中培养过夜。向细胞中加入含有试验化合物的培养基,浓度为5μL/孔,并将得到的细胞在37℃的CO2培养箱中培养4小时,得到1μM的最终浓度。向其中加入PicaGeneLT7.5(ToyoInkCo.,Ltd.),浓度为30μL/孔,并将该混合物在光屏蔽的条件下摇动。30分钟之后,使用板读数器Envision(PerkinElmer),测定萤光素酶活性。将在10nMGIP存在下的萤光素酶活性定义为100%,加入DMSO代替试验化合物的萤光素酶活性定义为0%。用作为指标的胞内cAMP浓度的升高,计算GIPR激动剂活性。结果示于表2中。
利用与上面一样的方法,使用hGLP-1R/CRE-luc/CHO-K1细胞,测定GLP-1R激动剂活性。将在10nMGLP-1存在下的萤光素酶活性定义为100%,加入DMSO代替试验化合物的萤光素酶活性定义为0%。用作为指标的胞内cAMP浓度的升高,计算GLP-1R激动剂活性。结果示于表2中。
利用与上面一样的方法,使用hGlucagonR/CRE-LUC/CHO-K1细胞,测定胰高血糖素R激动剂活性。将在10nM胰高血糖素存在下的萤光素酶活性定义为100%,加入DMSO代替试验化合物的萤光素酶活性定义为0%。用作为指标的胞内cAMP浓度的升高,计算胰高血糖素激动剂活性。结果示于表2中。
如表2所示,本发明的化合物对GLP-1受体和GIP受体具有优良的活化作用。另外,本发明的化合物具有低的胰高血糖素受体活化作用。
[表2]
试验实施例2
2天持续皮下给药试验
利用如下所述的方法,检测试验化合物的摄食抑制活性。
将试验化合物溶于溶剂(50%DMSO)中,使得可以每天10nmol/kg的量持续释放,并将该溶液装在Alzet泵(DURECTCorporation,型号∶1003D)中。将充满给药溶液的泵浸在生理盐水中,进行启动,而后使用。利用下列方法包埋该泵。将8-9周龄的每个雄性C57BL/6J小鼠(20-26℃,允许进食和水,不限量;12小时照明-12小时黑暗周期)麻醉;切开其上背皮肤,并将上述泵包埋在皮下;将切口缝合。称重之后,使该小鼠回到饲养笼中(单独饲养),给予先前称重的食品;测定开始给药之后2天的食物消耗。从开始给药的当天所给予食品的重量中减去剩余食品的量,计算食物消耗。当认为单独接受溶剂的对照组的食物消耗的抑制率为0%时,基于开始给药之后2天的累积食物消耗,评价每个试验化合物的摄食抑制活性。试验化合物的食物摄入抑制率(%)定义为:(对照组的食物消耗-试验化合物给予组的食物消耗)/对照组的食物消耗×100。
如表3所示,本发明的化合物具有优良的食物摄入抑制作用。
[表3]
试验实施例3
在DIO小鼠中,持续2周皮下给药研究
利用如下所述的方法,检测试验化合物的抗肥胖活性。
用高油脂饮食(D12451∶ResearchDiets,Inc.)喂养雄性C57BL/6J小鼠,得到饮食诱导的肥胖症(DIO)小鼠。将试验化合物溶于溶剂(50%DMSO)中,使得可以以1nmol/kg/天持续释放,并将该溶液装在Alzet泵(DURECTCorporation,型号∶1002)中。将充满给药溶液的泵浸在生理盐水中,进行启动,而后使用。利用下列方法包埋该泵。将35-37周大的每个雄性DIO-C57BL/6J小鼠(20-26℃,允许进食和水,不限量;12小时照明-12小时黑暗周期)麻醉;切开其上背的皮肤,并将上述泵包埋在皮下;将切口缝合。称重之后,使该小鼠回到饲养笼中(单独饲养),给予先前称重的食品;开始给药之后,每1至3天测定体重。基于开始给药之后2周的失重率,同时,认为单独接受溶剂的对照组的失重率为0%,评价每个试验化合物的抗肥胖活性。
如表4所示,本发明的化合物具有优良的抗肥胖活性。
[表4]
实施例 | 体重变化 |
2 | -16.3 |
24 | -11.1 |
25 | -11.2 |
26 | -16.2 |
试验实施例4
溶解试验
利用如下所述的方法,检测试验化合物的溶解性。
精确测定大约2mg的试验化合物。在25℃,将不同pH值(Britton-Robinson缓冲剂(pH3、5、7、9))的溶剂(10μL、20μL或40μL)加入到每个试验化合物中,并目测观察溶解状况。
如表5所示,在每个pH值下,所有试验化合物都具有良好的溶解性。
[表5]
制剂实施例1
(1)实施例1的化合物:10.0mg
(2)乳糖:70.0mg
(3)玉米淀粉:50.0mg
(4)可溶性淀粉:7.0mg
(5)硬脂酸镁:3.0mg
将实施例1的化合物(10.0mg)和硬脂酸镁(3.0mg)与可溶性淀粉水溶液(0.07ml)(7.0mg可溶性淀粉)一起造粒,干燥,并与乳糖(70.0mg)和玉米淀粉(50.0mg)混合。将该混合物挤压,得到片剂。
制剂实施例2
(1)实施例1的化合物:5.0mg
(2)氯化钠:20.0mg
(3)蒸馏水:总量达到2mL
将实施例1的化合物(5.0mg)和氯化钠(20.0mg)溶于蒸馏水中,并加入水,达到总量2.0ml。过滤该溶液,并在无菌条件下,装填在2ml小瓶中。将小瓶消毒,并紧紧地密封,得到注射溶液。
[工业实用性]
本发明的化合物具有优良的GLP-1受体/GIP受体共激动剂活性,并用作预防或治疗与GLP-1受体/GIP受体有关的各种疾病的药物,例如,肥胖症。
本文引用的所有出版物、专利和专利申请,以引证的方式结合它们的全部内容。
[自由本文的序列表]
SEQIDNO∶1∶人工序列(合成肽(式(I)))
SEQIDNO∶2∶人工序列(合成肽(C端序列))
SEQIDNO∶3∶人工序列(合成肽(C端序列))
SEQIDNO∶4∶人工序列(合成肽(C端序列))
SEQIDNO∶5∶人工序列(合成肽(C端序列))
SEQIDNO∶6∶人工序列(合成肽(C端序列))
SEQIDNO∶7∶人工序列(合成肽(C端序列))
SEQIDNO∶8∶人工序列(合成肽(C端序列))
SEQIDNO∶9∶人工序列(合成肽(C端序列))
SEQIDNO∶10∶人工序列(合成肽(参考实施例1))
SEQIDNO∶11∶人工序列(合成肽(参考实施例2))
SEQIDNO∶12∶人工序列(合成肽(参考实施例3))
SEQIDNO∶13∶人工序列(合成肽(实施例1))
SEQIDNO∶14∶人工序列(合成肽(实施例2))
SEQIDNO∶15∶人工序列(合成肽(实施例3))
SEQIDNO∶16∶人工序列(合成肽(实施例4))
SEQIDNO∶17∶人工序列(合成肽(实施例5))
SEQIDNO∶18∶人工序列(合成肽(实施例6))
SEQIDNO∶19∶人工序列(合成肽(实施例7))
SEQIDNO∶20∶人工序列(合成肽(实施例8))
SEQIDNO∶21∶人工序列(合成肽(实施例9))
SEQIDNO∶22∶人工序列(合成肽(实施例10))
SEQIDNO∶23∶人工序列(合成肽(实施例11))
SEQIDNO∶24∶人工序列(合成肽(实施例12))
SEQIDNO∶25∶人工序列(合成肽(实施例13))
SEQIDNO∶26∶人工序列(合成肽(实施例14))
SEQIDNO∶27∶人工序列(合成肽(实施例15))
SEQIDNO∶28∶人工序列(合成肽(实施例16))
SEQIDNO∶29∶人工序列(合成肽(实施例17))
SEQIDNO∶30∶人工序列(合成肽(实施例18))
SEQIDNO∶31∶人工序列(合成肽(实施例19))
SEQIDNO∶32∶人工序列(合成肽(实施例20))
SEQIDNO∶33∶人工序列(合成肽(实施例21))
SEQIDNO∶34∶人工序列(合成肽(实施例22))
SEQIDNO∶35∶人工序列(合成肽(实施例23))
SEQIDNO∶36∶人工序列(合成肽(实施例24))
SEQIDNO∶37∶人工序列(合成肽(实施例25))
SEQIDNO∶38∶人工序列(合成肽(实施例26))。
Claims (22)
1.包含式(I)所代表的部分序列的肽:
P1-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17-Ala-Gln-A20-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-A29
其中
P1是下式代表的基团:
-RA1,
-CO-RA1,
-CO-ORA1,
-CO-CORA1,
-SO-RA1,
-SO2-RA1,
-SO2-ORA1,
-CO-NRA2RA3,
-SO2-NRA2RA3或
-C(=NRA1)-NRA2RA3
其中,RA1、RA2和RA3各自独立地是氢原子、任选取代的烃基团或任选取代的杂环基团;
A11是Aib或Ala;
A12是Ala、Ile、Lys、Phe或Pya(4);
A13是Aib、Cha、Leu、αMePhe或αMeTyr;
A16是Lys或Ser;
A17是Gln或Ile;
A20是Ala或Ser;
A29是Gln或Gly,
或其盐。
2.权利要求1的肽或其盐,其中,P1是氢原子。
3.权利要求1的肽或其盐,其中,A11是Aib。
4.权利要求1的肽或其盐,其中,A12是Ile。
5.权利要求1的肽或其盐,其中,A13是Aib。
6.权利要求1的肽或其盐,其中,A16是Lys。
7.权利要求1的肽或其盐,其中,A17是Gln。
8.权利要求1的肽或其盐,其中,A20是Ala。
9.权利要求1的肽或其盐,其中,A29是Gly。
10.权利要求1的肽或其盐,在A29的C端上具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所代表的氨基酸序列。
11.权利要求1的肽或其盐,其中,P1是氢原子;
A11是Aib;
A12是Ile;
A13是Aib;
A16是Lys;
A17是Gln;
A20是Ala;
A29是Gly;
所述肽在A29的C端上具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所代表的氨基酸序列。
12.H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其盐。
13.H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其盐。
14.H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其盐。
15.H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2或其盐。
16.包含权利要求1的肽或其盐的药物。
17.权利要求16的药物,它是GLP-1受体和GIP受体的活化剂。
18.权利要求16的药物,它是预防或治疗肥胖症或糖尿病的药物。
19.预防或治疗哺乳动物的肥胖症或糖尿病的方法,所述方法包括:给予哺乳动物有效量的权利要求1的肽或其盐。
20.活化哺乳动物的GLP-1受体和GIP受体的方法,所述方法包括:给予哺乳动物有效量的权利要求1的肽或其盐。
21.权利要求1的肽或其盐用于制备药物的用途,所述药物用于预防或治疗肥胖症或糖尿病。
22.权利要求1的肽或其盐,用于预防或治疗肥胖症或糖尿病。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013-111893 | 2013-05-28 | ||
JP2013111893 | 2013-05-28 | ||
PCT/JP2014/002772 WO2014192284A1 (en) | 2013-05-28 | 2014-05-27 | Peptide compound |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105209485A true CN105209485A (zh) | 2015-12-30 |
CN105209485B CN105209485B (zh) | 2019-12-10 |
Family
ID=50942304
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480026613.0A Active CN105209485B (zh) | 2013-05-28 | 2014-05-27 | 肽化合物 |
Country Status (36)
Country | Link |
---|---|
US (2) | US10087229B2 (zh) |
EP (1) | EP3004155B1 (zh) |
JP (2) | JP6429799B2 (zh) |
KR (1) | KR102229051B1 (zh) |
CN (1) | CN105209485B (zh) |
AP (1) | AP2015008781A0 (zh) |
AR (1) | AR096440A1 (zh) |
AU (1) | AU2014272500B2 (zh) |
CA (1) | CA2908581C (zh) |
CL (1) | CL2015003031A1 (zh) |
CY (1) | CY1124790T1 (zh) |
DK (1) | DK3004155T3 (zh) |
DO (1) | DOP2015000261A (zh) |
EA (2) | EA035813B1 (zh) |
EC (1) | ECSP15044389A (zh) |
ES (1) | ES2900744T3 (zh) |
GE (1) | GEP201706762B (zh) |
HK (1) | HK1216757A1 (zh) |
HR (1) | HRP20212014T1 (zh) |
HU (1) | HUE057361T2 (zh) |
IL (1) | IL242005B (zh) |
LT (1) | LT3004155T (zh) |
MA (1) | MA38472B1 (zh) |
MX (2) | MX2015015464A (zh) |
MY (1) | MY172744A (zh) |
PE (1) | PE20151770A1 (zh) |
PH (1) | PH12015502391B1 (zh) |
PL (1) | PL3004155T3 (zh) |
PT (1) | PT3004155T (zh) |
SG (1) | SG11201507934PA (zh) |
SI (1) | SI3004155T1 (zh) |
TN (1) | TN2015000451A1 (zh) |
TW (1) | TWI638831B (zh) |
UA (1) | UA118558C2 (zh) |
UY (1) | UY35589A (zh) |
WO (1) | WO2014192284A1 (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109477094A (zh) * | 2016-05-24 | 2019-03-15 | 武田药品工业株式会社 | 肽化合物 |
CN110709414A (zh) * | 2017-03-31 | 2020-01-17 | 武田药品工业有限公司 | Gip受体活化肽 |
WO2022253202A1 (zh) | 2021-06-01 | 2022-12-08 | 南京知和医药科技有限公司 | 一种glp-1r和gipr双重靶向激动作用的多肽衍生物及其制备方法和用途 |
CN117402219A (zh) * | 2022-07-13 | 2024-01-16 | 杭州中美华东制药有限公司 | Glp-1/gip双激动剂及其制备方法和用途 |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR096440A1 (es) | 2013-05-28 | 2015-12-30 | Takeda Pharmaceuticals Co | Compuesto peptídico agonista del receptor del péptido similar al glucagón tipo i (glp-1) y del péptido insulinotrópico dependiente de glucosa (gip) |
JOP20200119A1 (ar) | 2015-01-09 | 2017-06-16 | Lilly Co Eli | مركبات مساعد مشترك من gip وglp-1 |
CN104846061A (zh) * | 2015-05-07 | 2015-08-19 | 中国药科大学 | 一种glp-1受体激动剂的受体亲和力测定方法 |
CN105388239B (zh) * | 2015-12-18 | 2018-01-05 | 兆科药业(合肥)有限公司 | 一种多肽固相合成的监测方法 |
US11285180B2 (en) | 2016-12-06 | 2022-03-29 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods of enhancing the potency of incretin-based drugs in subjects in need thereof |
WO2019140030A1 (en) | 2018-01-12 | 2019-07-18 | Eli Lilly And Company | Combination therapy |
EP3743092A4 (en) | 2018-01-23 | 2021-10-20 | Gila Therapeutics, Inc. | PHARMACEUTICAL PEPTIDE-YY FORMULATIONS, COMPOSITIONS, AND PROCEDURES |
BR112020022027A2 (pt) | 2018-05-04 | 2021-02-02 | Novo Nordisk A/S | derivados de gip e seus usos |
CN110818771B (zh) * | 2018-08-14 | 2023-01-17 | 陈铭 | 使用氨基酸离子液体的羰基硫介导多肽合成 |
JP2022503793A (ja) * | 2018-09-24 | 2022-01-12 | 武田薬品工業株式会社 | Gip受容体アゴニストペプチド化合物及びその使用 |
JP2022500483A (ja) * | 2018-09-24 | 2022-01-04 | 武田薬品工業株式会社 | Gip受容体アゴニストペプチド化合物及びその使用 |
KR20220035199A (ko) * | 2019-08-19 | 2022-03-21 | 일라이 릴리 앤드 캄파니 | 인크레틴 유사체의 제조 방법 |
CN114786706A (zh) | 2019-10-04 | 2022-07-22 | 韩美药品株式会社 | 胰高血糖素、包含glp-1受体和gip受体双重激动剂的组合物、及其治疗用途 |
CN110684082B (zh) | 2019-10-08 | 2021-12-10 | 江苏诺泰澳赛诺生物制药股份有限公司 | Gip和glp-1双激动多肽化合物及药学上可接受的盐与用途 |
EP4126921A2 (en) * | 2020-03-25 | 2023-02-08 | Takeda Pharmaceutical Company Limited | Qd dosing of gip receptor agonist peptide compounds and uses thereof |
BR112023000270A2 (pt) | 2020-07-22 | 2023-01-31 | Novo Nordisk As | Composto, composição farmacêutica, e, peptídeo |
CN116157414A (zh) | 2020-07-22 | 2023-05-23 | 诺和诺德股份有限公司 | Glp-1和gip受体共激动剂 |
TW202330584A (zh) | 2022-01-20 | 2023-08-01 | 丹麥商諾佛 儂迪克股份有限公司 | 前藥及其用途 |
WO2024059674A1 (en) | 2022-09-15 | 2024-03-21 | Eli Lilly And Company | Gip and glp-1 dual agonist compounds |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010011439A2 (en) * | 2008-06-17 | 2010-01-28 | Indiana University Research And Technology Corporation | Gip-based mixed agonists for treatment of metabolic disorders and obesity |
WO2012088379A2 (en) * | 2010-12-22 | 2012-06-28 | Marcadia Biotech, Inc. | Methods for treating metabolic disorders and obesity with gip and glp-1 receptor-active glucagon-based peptides |
Family Cites Families (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA65549C2 (uk) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція |
JP2001504105A (ja) | 1996-11-12 | 2001-03-27 | ノボ ノルディスク アクティーゼルスカブ | Glp―1ペプチドの利用 |
AU3087599A (en) | 1998-03-19 | 1999-10-11 | Bionebraska, Inc. | Human appetite control by glucagon-like peptide receptor binding compounds |
WO2000007617A1 (en) | 1998-07-31 | 2000-02-17 | Novo Nordisk A/S | Use of glp-1 and analogues for preventing type ii diabetes |
DK1137666T5 (da) * | 1998-12-07 | 2009-10-05 | Univ Tulane | GLP-1-analoger |
AU2001256757B2 (en) | 2000-05-16 | 2006-03-09 | Sanwa Kagaku Kenkyusho Co., Ltd. | Agents for preventing or ameliorating insulin resistance and/or obesity |
MXPA04012497A (es) | 2002-07-04 | 2005-07-14 | Zealand Pharma As | Glp-1 y metodos para tratar la diabetes. |
US7897566B2 (en) | 2003-12-16 | 2011-03-01 | Ipsen Pharma S.A.S. | Analogues of GLP-1 |
WO2006049681A2 (en) | 2004-08-30 | 2006-05-11 | Bayer Pharmaceuticals Corporation | Selective neuropeptide y2 receptor agonists |
SG159551A1 (en) | 2005-02-11 | 2010-03-30 | Amylin Pharmaceuticals Inc | Gip analog and hybrid polypeptides with selectable properties |
WO2006136374A2 (en) | 2005-06-20 | 2006-12-28 | Develogen Aktiengesellschaft | Use of gip and/or vitamin d3 analogues thereof for enhancing stem or progenitor cell differentiation into insulin producing cells |
CA2657578A1 (en) | 2006-07-11 | 2008-01-17 | Harkness Pharmaceuticals, Inc. | Methods of treating obesity using satiety factors |
CA2660835A1 (en) | 2006-08-17 | 2008-02-21 | Amylin Pharmaceuticals, Inc. | Dpp-iv resistant gip hybrid polypeptides with selectable propperties |
PE20121528A1 (es) | 2006-09-13 | 2012-12-12 | Smithkline Beecham Corp | Metodos para administrar agentes hipoglucemiantes de larga duracion |
EP1972349A1 (en) | 2007-03-21 | 2008-09-24 | Biocompatibles UK Limited | GLP-1 fusion peptides conjugated to polymer(s), their production and use |
EP2224945B1 (en) | 2007-11-23 | 2012-05-16 | Michael Rothkopf | Methods of enhancing diabetes resolution |
EP2318433A4 (en) | 2008-08-07 | 2012-08-08 | Ipsen Pharma Sas | GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE ANALOGUES (GIP) MODIFIED AT THE N-TERMINAL END |
WO2010068735A1 (en) | 2008-12-10 | 2010-06-17 | Glaxosmithkline Llc. | Pharmaceutical compositions |
WO2010148089A1 (en) | 2009-06-16 | 2010-12-23 | Indiana University Research And Technology Corporation | Gip receptor-active glucagon compounds |
EP2450374B9 (en) | 2009-07-02 | 2016-11-23 | Takeda Pharmaceutical Company Limited | Peptide and use thereof |
EP2528618A4 (en) | 2010-01-27 | 2015-05-27 | Univ Indiana Res & Tech Corp | GLUCAGON ANTAGONISTE AND GIP AGONISTS CONJUGATES AND COMPOSITIONS FOR THE TREATMENT OF METABOLISM DISEASES AND ADIPOSITAS |
AR080592A1 (es) | 2010-03-26 | 2012-04-18 | Lilly Co Eli | Peptido con actividad para el gip-r y glp-1-r, formulacion famaceutica que lo comprende, su uso para preparar un medicamento util para el tratamiento de diabetes mellitus y para inducir la perdida de peso |
EP2694095B1 (en) | 2011-04-05 | 2018-03-07 | Longevity Biotech, Inc. | Compositions comprising glucagon analogs and methods of making and using the same |
BR112013031268B1 (pt) | 2011-06-10 | 2020-05-12 | Novo Nordisk A/S | Polipeptídeos |
KR102002783B1 (ko) * | 2011-06-10 | 2019-07-24 | 베이징 한미 파마슈티컬 컴퍼니 리미티드 | 포도당 의존성 인슐리노트로핀 폴리펩타이드 유사물질, 이의 약학적 조성물 및 응용 |
US20130090285A1 (en) | 2011-06-27 | 2013-04-11 | Phasebio Pharmaceuticals, Inc. | Methods of treatment with glp-1 receptor agonists |
ES2626013T3 (es) * | 2011-09-06 | 2017-07-21 | Novo Nordisk A/S | Derivados de GLP-1 |
EP2830646B1 (en) | 2012-03-27 | 2018-03-07 | NGM Biopharmaceuticals, Inc. | Compositions and methods of use for treating metabolic disorders |
CN104470948B (zh) | 2012-05-03 | 2018-06-15 | 西兰制药公司 | Gip-glp-1双激动剂化合物及方法 |
EP2846823B1 (en) | 2012-05-08 | 2019-12-04 | Novo Nordisk A/S | Double-acylated glp-1 derivatives |
WO2013192310A1 (en) | 2012-06-19 | 2013-12-27 | Massachusetts Institute Of Technology | Mass production and size control of nanoparticles through controlled microvortices |
AR091477A1 (es) | 2012-06-21 | 2015-02-04 | Univ Indiana Res & Tech Corp | Analogos de glucagon que presentan actividad de receptor de gip |
RS57347B1 (sr) | 2012-06-21 | 2018-08-31 | Univ Indiana Res & Tech Corp | Analozi glukagona koji ispoljavaju aktivnost gip receptora |
JP2016503046A (ja) | 2012-12-19 | 2016-02-01 | ノヴォ ノルディスク アー/エス | コレステロール流出活性を有する新規glp−1受容体アゴニスト |
CN104902919B (zh) | 2012-12-21 | 2018-11-20 | 赛诺菲 | Glp1/gip双重激动剂或glp1/gip/胰高血糖素三重激动剂 |
US9714277B2 (en) | 2013-03-14 | 2017-07-25 | Medimmune Limited | Pegylated glucagon and GLP-1 co-agonists for the treatment of obesity |
AR096440A1 (es) | 2013-05-28 | 2015-12-30 | Takeda Pharmaceuticals Co | Compuesto peptídico agonista del receptor del péptido similar al glucagón tipo i (glp-1) y del péptido insulinotrópico dependiente de glucosa (gip) |
EA035688B1 (ru) | 2013-11-06 | 2020-07-27 | Зилэнд Фарма А/С | Соединения, которые представляют собой тройные агонисты глюкагона, glp-1 и gip |
TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重glp-1/昇糖素受體激動劑之艾塞那肽-4衍生物 |
JP2018012644A (ja) | 2014-11-26 | 2018-01-25 | 武田薬品工業株式会社 | ペプチド化合物 |
-
2014
- 2014-05-27 AR ARP140102090A patent/AR096440A1/es unknown
- 2014-05-27 EA EA201591891A patent/EA035813B1/ru unknown
- 2014-05-27 SI SI201431933T patent/SI3004155T1/sl unknown
- 2014-05-27 TW TW103118374A patent/TWI638831B/zh active
- 2014-05-27 PT PT147299762T patent/PT3004155T/pt unknown
- 2014-05-27 MX MX2015015464A patent/MX2015015464A/es active IP Right Grant
- 2014-05-27 AU AU2014272500A patent/AU2014272500B2/en active Active
- 2014-05-27 TN TN2015000451A patent/TN2015000451A1/en unknown
- 2014-05-27 MY MYPI2015703438A patent/MY172744A/en unknown
- 2014-05-27 EP EP14729976.2A patent/EP3004155B1/en active Active
- 2014-05-27 HU HUE14729976A patent/HUE057361T2/hu unknown
- 2014-05-27 GE GEAP201413984A patent/GEP201706762B/en unknown
- 2014-05-27 MA MA38472A patent/MA38472B1/fr unknown
- 2014-05-27 ES ES14729976T patent/ES2900744T3/es active Active
- 2014-05-27 UY UY0001035589A patent/UY35589A/es not_active Application Discontinuation
- 2014-05-27 US US14/780,579 patent/US10087229B2/en active Active
- 2014-05-27 PL PL14729976T patent/PL3004155T3/pl unknown
- 2014-05-27 EA EA202090593A patent/EA202090593A3/ru unknown
- 2014-05-27 AP AP2015008781A patent/AP2015008781A0/xx unknown
- 2014-05-27 JP JP2015555470A patent/JP6429799B2/ja active Active
- 2014-05-27 WO PCT/JP2014/002772 patent/WO2014192284A1/en active Application Filing
- 2014-05-27 US US14/287,514 patent/US9200051B2/en active Active
- 2014-05-27 CA CA2908581A patent/CA2908581C/en active Active
- 2014-05-27 UA UAA201510946A patent/UA118558C2/uk unknown
- 2014-05-27 DK DK14729976.2T patent/DK3004155T3/da active
- 2014-05-27 LT LTEPPCT/JP2014/002772T patent/LT3004155T/lt unknown
- 2014-05-27 SG SG11201507934PA patent/SG11201507934PA/en unknown
- 2014-05-27 PE PE2015002124A patent/PE20151770A1/es unknown
- 2014-05-27 CN CN201480026613.0A patent/CN105209485B/zh active Active
- 2014-05-27 HR HRP20212014TT patent/HRP20212014T1/hr unknown
- 2014-05-27 KR KR1020157032121A patent/KR102229051B1/ko active IP Right Grant
-
2015
- 2015-10-11 IL IL242005A patent/IL242005B/en active IP Right Grant
- 2015-10-13 CL CL2015003031A patent/CL2015003031A1/es unknown
- 2015-10-14 PH PH12015502391A patent/PH12015502391B1/en unknown
- 2015-10-15 DO DO2015000261A patent/DOP2015000261A/es unknown
- 2015-10-21 EC ECIEPI201544389A patent/ECSP15044389A/es unknown
- 2015-11-06 MX MX2019010531A patent/MX2019010531A/es unknown
-
2016
- 2016-04-28 HK HK16104856.7A patent/HK1216757A1/zh unknown
-
2018
- 2018-06-12 JP JP2018111494A patent/JP6570705B2/ja active Active
-
2021
- 2021-12-15 CY CY20211101100T patent/CY1124790T1/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010011439A2 (en) * | 2008-06-17 | 2010-01-28 | Indiana University Research And Technology Corporation | Gip-based mixed agonists for treatment of metabolic disorders and obesity |
WO2012088379A2 (en) * | 2010-12-22 | 2012-06-28 | Marcadia Biotech, Inc. | Methods for treating metabolic disorders and obesity with gip and glp-1 receptor-active glucagon-based peptides |
Non-Patent Citations (1)
Title |
---|
GAULT VA等: "Administration of an acylated GLP-1 and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity.", 《CLINICAL SCIENCE》 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109477094A (zh) * | 2016-05-24 | 2019-03-15 | 武田药品工业株式会社 | 肽化合物 |
CN109477094B (zh) * | 2016-05-24 | 2022-04-26 | 武田药品工业株式会社 | 肽化合物 |
CN110709414A (zh) * | 2017-03-31 | 2020-01-17 | 武田药品工业有限公司 | Gip受体活化肽 |
WO2022253202A1 (zh) | 2021-06-01 | 2022-12-08 | 南京知和医药科技有限公司 | 一种glp-1r和gipr双重靶向激动作用的多肽衍生物及其制备方法和用途 |
CN117402219A (zh) * | 2022-07-13 | 2024-01-16 | 杭州中美华东制药有限公司 | Glp-1/gip双激动剂及其制备方法和用途 |
WO2024012472A1 (zh) * | 2022-07-13 | 2024-01-18 | 杭州中美华东制药有限公司 | Glp-1/gip双激动剂及其制备方法和用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105209485A (zh) | 肽化合物 | |
TWI801373B (zh) | 胜肽化合物 | |
US10501516B2 (en) | Peptide compound | |
EP3856339A1 (en) | Gip receptor agonist peptide compounds and uses thereof | |
WO2016084826A1 (ja) | ペプチド化合物 | |
TWI770085B (zh) | 胜肽化合物 | |
EA042684B1 (ru) | Пептид, активирующий рецептор гип | |
EA044242B1 (ru) | Пептидное соединение | |
BR112015027596B1 (pt) | Peptídeo, sequência, medicamento, e, uso de um peptídeo |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20231229 Address after: Kanagawa, Japan Patentee after: Sike Haiya Pharmaceutical Co.,Ltd. Address before: Osaka, Japan Patentee before: TAKEDA PHARMACEUTICAL Co.,Ltd. |