SA04250400B1 - مشتقات الهيدرونوبول hydronopol كمؤازرات agonists في مستقبلات orl1 البشرية - Google Patents
مشتقات الهيدرونوبول hydronopol كمؤازرات agonists في مستقبلات orl1 البشرية Download PDFInfo
- Publication number
- SA04250400B1 SA04250400B1 SA4250400A SA04250400A SA04250400B1 SA 04250400 B1 SA04250400 B1 SA 04250400B1 SA 4250400 A SA4250400 A SA 4250400A SA 04250400 A SA04250400 A SA 04250400A SA 04250400 B1 SA04250400 B1 SA 04250400B1
- Authority
- SA
- Saudi Arabia
- Prior art keywords
- group
- compound
- mixture
- methyl
- phenyl
- Prior art date
Links
- RCRVMCSPZAMFKV-UHFFFAOYSA-N 2-(6,6-dimethyl-4-bicyclo[3.1.1]heptanyl)ethanol Chemical class C1C2C(C)(C)C1CCC2CCO RCRVMCSPZAMFKV-UHFFFAOYSA-N 0.000 title abstract description 16
- 108010020615 nociceptin receptor Proteins 0.000 title abstract description 9
- 239000000556 agonist Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- -1 alkyl hydrogen Chemical compound 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 1
- 239000003223 protective agent Substances 0.000 claims 1
- 108020003175 receptors Proteins 0.000 abstract description 39
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 108090000622 Nociceptin Proteins 0.000 abstract description 8
- 208000035475 disorder Diseases 0.000 abstract description 8
- 102000048266 Nociceptin Human genes 0.000 abstract description 5
- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000002195 synergetic effect Effects 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
- 238000000034 method Methods 0.000 description 53
- 239000000243 solution Substances 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 239000000047 product Substances 0.000 description 44
- 239000010410 layer Substances 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 102000005962 receptors Human genes 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000012044 organic layer Substances 0.000 description 34
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000003921 oil Substances 0.000 description 22
- 235000019198 oils Nutrition 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 230000009466 transformation Effects 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- 239000007858 starting material Substances 0.000 description 16
- 241001465754 Metazoa Species 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 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 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000012230 colorless oil Substances 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 206010012735 Diarrhoea Diseases 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- 229940127240 opiate Drugs 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000003643 water by type Substances 0.000 description 12
- 238000000746 purification Methods 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000004817 gas chromatography Methods 0.000 description 10
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 210000003608 fece Anatomy 0.000 description 9
- 150000002924 oxiranes Chemical class 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 230000004927 fusion Effects 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 210000001072 colon Anatomy 0.000 description 7
- 125000004494 ethyl ester group Chemical group 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000460 chlorine Substances 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
- 229960004132 diethyl ether Drugs 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 5
- 108090000137 Opioid Receptors Proteins 0.000 description 5
- 102000003840 Opioid Receptors Human genes 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 239000012045 crude solution Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 238000010298 pulverizing process Methods 0.000 description 5
- LDWAIHWGMRVEFR-UHFFFAOYSA-N ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)methanol Natural products C1C2C(C)(C)C1CCC2CO LDWAIHWGMRVEFR-UHFFFAOYSA-N 0.000 description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 4
- 230000003187 abdominal effect Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000003637 basic solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000008602 contraction Effects 0.000 description 4
- 238000007405 data analysis Methods 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- PZJSZBJLOWMDRG-UHFFFAOYSA-N furan-2-ylboronic acid Chemical compound OB(O)C1=CC=CO1 PZJSZBJLOWMDRG-UHFFFAOYSA-N 0.000 description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- FPVZWDQWFCGSFY-UHFFFAOYSA-N spiro[4.5]decan-4-one Chemical compound O=C1CCCC11CCCCC1 FPVZWDQWFCGSFY-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RVPMRQANEKMAPR-OQWPWLHSSA-N (2R)-2-hydroxy-2-phenylacetic acid (1R,2R)-2-(methylamino)cyclohexan-1-ol Chemical compound CN[C@@H]1CCCC[C@H]1O.OC(=O)[C@H](O)C1=CC=CC=C1 RVPMRQANEKMAPR-OQWPWLHSSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- IDDIHRHQBLIGLT-UHFFFAOYSA-N 8-[2-(6,6-dimethyl-4-bicyclo[3.1.1]heptanyl)ethyl]-1-[3-(trifluoromethyl)phenyl]-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound CC1(C)C(CC2)CC1C2CCN(CC1)CCC1(C(NC1)=O)N1C1=CC=CC(C(F)(F)F)=C1 IDDIHRHQBLIGLT-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 235000005979 Citrus limon Nutrition 0.000 description 3
- 244000131522 Citrus pyriformis Species 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- QVZZPLDJERFENQ-NKTUOASPSA-N bassianolide Chemical compound CC(C)C[C@@H]1N(C)C(=O)[C@@H](C(C)C)OC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C(C)C)OC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C(C)C)OC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C(C)C)OC1=O QVZZPLDJERFENQ-NKTUOASPSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 230000010339 dilation Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000009610 hypersensitivity Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 3
- 229960000681 leflunomide Drugs 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229910052814 silicon oxide Inorganic materials 0.000 description 3
- 230000009278 visceral effect Effects 0.000 description 3
- HILGAVODIXBHHR-RNFRBKRXSA-N (1r,2r)-2-(methylamino)cyclohexan-1-ol Chemical compound CN[C@@H]1CCCC[C@H]1O HILGAVODIXBHHR-RNFRBKRXSA-N 0.000 description 2
- JRKPNHLSQGAUDY-UHFFFAOYSA-N 1,3,8-triazaspiro[4.5]decan-4-one Chemical class O=C1NCNC11CCNCC1 JRKPNHLSQGAUDY-UHFFFAOYSA-N 0.000 description 2
- YIVVJAACVHKQEU-UHFFFAOYSA-N 1-[2-(6,6-dimethyl-4-bicyclo[3.1.1]heptanyl)ethyl]-4-(3-fluoroanilino)piperidine-4-carbonitrile Chemical compound CC1(C)C(CC2)CC1C2CCN(CC1)CCC1(C#N)NC1=CC=CC(F)=C1 YIVVJAACVHKQEU-UHFFFAOYSA-N 0.000 description 2
- ROASWXHQKUCZIV-UHFFFAOYSA-N 1-[2-(6,6-dimethyl-4-bicyclo[3.1.1]heptanyl)ethyl]piperidin-4-one Chemical compound CC1(C)C(CC2)CC1C2CCN1CCC(=O)CC1 ROASWXHQKUCZIV-UHFFFAOYSA-N 0.000 description 2
- SIUBLLCTAWTCMD-UHFFFAOYSA-N 2-(6,6-dimethyl-4-bicyclo[3.1.1]heptanyl)-1-methylsulfonylethanol Chemical compound C1C2C(C)(C)C1CCC2CC(O)S(C)(=O)=O SIUBLLCTAWTCMD-UHFFFAOYSA-N 0.000 description 2
- RVSUMNQMPHVRDU-UHFFFAOYSA-N 8-[2-(6,6-dimethyl-4-bicyclo[3.1.1]heptanyl)ethyl]-3-[3-(methylamino)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CN(CCC2C3CC(C3(C)C)CC2)CCC21C(=O)N(CCCNC)CN2C1=CC=CC=C1 RVSUMNQMPHVRDU-UHFFFAOYSA-N 0.000 description 2
- 208000000103 Anorexia Nervosa Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- 241000271559 Dromaiidae Species 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 206010016717 Fistula Diseases 0.000 description 2
- 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 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 235000012093 Myrtus ugni Nutrition 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 102100028646 Nociceptin receptor Human genes 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 241001629697 Panicum turgidum Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 241000220317 Rosa Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 244000061461 Tema Species 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000005341 cation exchange Methods 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000003890 fistula Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000002808 molecular sieve Substances 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
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- ULSBMKGFFFMGOI-UHFFFAOYSA-N tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11OC1 ULSBMKGFFFMGOI-UHFFFAOYSA-N 0.000 description 2
- HPBYMYSKRQWROI-UHFFFAOYSA-N tert-butyl 4-[[benzyl(methyl)amino]methyl]-4-methoxypiperidine-1-carboxylate Chemical compound C=1C=CC=CC=1CN(C)CC1(OC)CCN(C(=O)OC(C)(C)C)CC1 HPBYMYSKRQWROI-UHFFFAOYSA-N 0.000 description 2
- XCRHXSARHPZOGG-UHFFFAOYSA-N tert-butyl 4-methoxy-4-(methylaminomethyl)piperidine-1-carboxylate Chemical compound CNCC1(OC)CCN(C(=O)OC(C)(C)C)CC1 XCRHXSARHPZOGG-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 208000009935 visceral pain Diseases 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Natural products CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- CWPWAQJHDDRCKP-UHFFFAOYSA-N 1,3,5-trimethyl-2-(2,4,6-trimethylphenyl)benzene Chemical compound CC1=CC(C)=CC(C)=C1C1=C(C)C=C(C)C=C1C CWPWAQJHDDRCKP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BRFNNXWPTMQZRE-UHFFFAOYSA-N 1-[2-(trifluoromethyl)phenyl]piperidin-4-ol Chemical compound C1CC(O)CCN1C1=CC=CC=C1C(F)(F)F BRFNNXWPTMQZRE-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- NADNERWNWVUWEZ-UHFFFAOYSA-N 1-formylpiperidine-3-carboxamide Chemical compound NC(=O)C1CCCN(C=O)C1 NADNERWNWVUWEZ-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- WYLSGWZVDHQRNX-UHFFFAOYSA-N 2-(3,4-dimethoxy-n-(4-methylphenyl)sulfonylanilino)-n-(2,4-dimethylpentan-3-yl)acetamide Chemical compound C1=C(OC)C(OC)=CC=C1N(CC(=O)NC(C(C)C)C(C)C)S(=O)(=O)C1=CC=C(C)C=C1 WYLSGWZVDHQRNX-UHFFFAOYSA-N 0.000 description 1
- HILGAVODIXBHHR-UHFFFAOYSA-N 2-(methylamino)cyclohexan-1-ol Chemical compound CNC1CCCCC1O HILGAVODIXBHHR-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 1
- MYHNUQVKTSTVDI-UHFFFAOYSA-N 2-methyl-2-[(2-methylpropan-2-yl)oxy]propane;potassium Chemical compound [K].CC(C)(C)OC(C)(C)C MYHNUQVKTSTVDI-UHFFFAOYSA-N 0.000 description 1
- LPLLVINFLBSFRP-UHFFFAOYSA-N 2-methylamino-1-phenylpropan-1-one Chemical compound CNC(C)C(=O)C1=CC=CC=C1 LPLLVINFLBSFRP-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 1
- 101150011812 AADAC gene Proteins 0.000 description 1
- 108700022183 Ala(2)-MePhe(4)-Gly(5)- Enkephalin Proteins 0.000 description 1
- 102100032047 Alsin Human genes 0.000 description 1
- 101710187109 Alsin Proteins 0.000 description 1
- 241000272522 Anas Species 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 241000272517 Anseriformes Species 0.000 description 1
- 101100372587 Arabidopsis thaliana VHA-c2 gene Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241001132374 Asta Species 0.000 description 1
- 206010048909 Boredom Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- 101150026868 CHS1 gene Proteins 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 241000321369 Cephalopholis fulva Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 238000006066 Comins reaction Methods 0.000 description 1
- 244000293323 Cosmos caudatus Species 0.000 description 1
- 235000005956 Cosmos caudatus Nutrition 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 241000252206 Cypriniformes Species 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 101710200331 Cytochrome b-245 chaperone 1 Proteins 0.000 description 1
- 102100037186 Cytochrome b-245 chaperone 1 Human genes 0.000 description 1
- 101710119396 Cytochrome b-245 chaperone 1 homolog Proteins 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 101150105088 Dele1 gene Proteins 0.000 description 1
- 235000008247 Echinochloa frumentacea Nutrition 0.000 description 1
- 108010092674 Enkephalins Proteins 0.000 description 1
- 241001505295 Eros Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- QMXOFBXZEKTJIK-UHFFFAOYSA-N Glycinol Natural products C1=C(O)C=C2OCC3(O)C4=CC=C(O)C=C4OC3C2=C1 QMXOFBXZEKTJIK-UHFFFAOYSA-N 0.000 description 1
- 101000958041 Homo sapiens Musculin Proteins 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 1
- 241001303829 Lavia Species 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 244000141359 Malus pumila Species 0.000 description 1
- 101100380295 Mus musculus Asah1 gene Proteins 0.000 description 1
- 241000234295 Musa Species 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 241000772415 Neovison vison Species 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102000016978 Orphan receptors Human genes 0.000 description 1
- 108070000031 Orphan receptors Proteins 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 240000000220 Panda oleosa Species 0.000 description 1
- 235000016496 Panda oleosa Nutrition 0.000 description 1
- 240000004072 Panicum sumatrense Species 0.000 description 1
- 206010034016 Paronychia Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- UZHDGDDPOPDJGM-UHFFFAOYSA-N Stigmatellin A Natural products COC1=CC(OC)=C2C(=O)C(C)=C(CCC(C)C(OC)C(C)C(C=CC=CC(C)=CC)OC)OC2=C1O UZHDGDDPOPDJGM-UHFFFAOYSA-N 0.000 description 1
- 241000897276 Termes Species 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010064921 Urinary tract inflammation Diseases 0.000 description 1
- LDWAIHWGMRVEFR-DJLDLDEBSA-N [(1r,4r,5r)-6,6-dimethyl-4-bicyclo[3.1.1]heptanyl]methanol Chemical compound C1[C@H]2C(C)(C)[C@@H]1CC[C@H]2CO LDWAIHWGMRVEFR-DJLDLDEBSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- PYMYPHUHKUWMLA-WISUUJSJSA-N aldehydo-L-xylose Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WISUUJSJSA-N 0.000 description 1
- 229930195726 aldehydo-L-xylose Natural products 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000000320 amidine group Chemical group 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 235000021016 apples Nutrition 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- MKJDUHZPLQYUCB-UHFFFAOYSA-N decan-4-one Chemical compound CCCCCCC(=O)CCC MKJDUHZPLQYUCB-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 230000000741 diarrhetic effect Effects 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- OYFJQPXVCSSHAI-QFPUQLAESA-N enalapril maleate Chemical compound OC(=O)\C=C/C(O)=O.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 OYFJQPXVCSSHAI-QFPUQLAESA-N 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- IBRZMAIAORVEIM-UHFFFAOYSA-N formylcarbamic acid Chemical compound OC(=O)NC=O IBRZMAIAORVEIM-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000011874 heated mixture Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 102000046949 human MSC Human genes 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 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
- 239000010977 jade Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 235000020130 leben Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 229930013686 lignan Natural products 0.000 description 1
- 235000009408 lignans Nutrition 0.000 description 1
- 150000005692 lignans Chemical class 0.000 description 1
- 239000010871 livestock manure Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- AGADEVQOWQDDFX-UHFFFAOYSA-N methyl 3-oxopropanoate Chemical compound COC(=O)CC=O AGADEVQOWQDDFX-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical group CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- GEOWCLRLLWTHDN-UHFFFAOYSA-N phenyl formate Chemical compound O=COC1=CC=CC=C1 GEOWCLRLLWTHDN-UHFFFAOYSA-N 0.000 description 1
- 125000002265 phtalazinyl group Chemical group 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- XIMLAVRHZBUYBE-UHFFFAOYSA-N piperidin-2-one;hydrate;hydrochloride Chemical compound O.Cl.O=C1CCCCN1 XIMLAVRHZBUYBE-UHFFFAOYSA-N 0.000 description 1
- QUUYRYYUKNNNNS-UHFFFAOYSA-N piperidine-1-carboximidamide Chemical compound NC(=N)N1CCCCC1 QUUYRYYUKNNNNS-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- PWZUUYSISTUNDW-VAFBSOEGSA-N quinestrol Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@]4(O)C#C)C)CC2=CC=3OC1CCCC1 PWZUUYSISTUNDW-VAFBSOEGSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 235000008001 rakum palm Nutrition 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 102220047090 rs6152 Human genes 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 208000026775 severe diarrhea Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- ZIQRIAYNHAKDDU-UHFFFAOYSA-N sodium;hydroiodide Chemical compound [Na].I ZIQRIAYNHAKDDU-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 229940081330 tena Drugs 0.000 description 1
- VWRUTYUXELSNEV-UHFFFAOYSA-N tert-butyl 4-[[benzyl(methyl)amino]methyl]-4-hydroxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(O)CN(C)CC1=CC=CC=C1 VWRUTYUXELSNEV-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 235000015961 tonic Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960000716 tonics Drugs 0.000 description 1
- VLCQZHSMCYCDJL-UHFFFAOYSA-N tribenuron methyl Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC(=O)N(C)C1=NC(C)=NC(OC)=N1 VLCQZHSMCYCDJL-UHFFFAOYSA-N 0.000 description 1
- 125000001680 trimethoxyphenyl group Chemical group 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- YRYSAWZMIRQUBO-UHFFFAOYSA-N trimethylsulfoxonium Chemical compound C[S+](C)(C)=O YRYSAWZMIRQUBO-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Classifications
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/04—Auxiliary arrangements, e.g. for control of pressure or for circulation of fluids
- H01M8/04223—Auxiliary arrangements, e.g. for control of pressure or for circulation of fluids during start-up or shut-down; Depolarisation or activation, e.g. purging; Means for short-circuiting defective fuel cells
- H01M8/04268—Heating of fuel cells during the start-up of the fuel cells
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M8/00—Fuel cells; Manufacture thereof
- H01M8/04—Auxiliary arrangements, e.g. for control of pressure or for circulation of fluids
- H01M8/04082—Arrangements for control of reactant parameters, e.g. pressure or concentration
- H01M8/04089—Arrangements for control of reactant parameters, e.g. pressure or concentration of gaseous reactants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/30—Hydrogen technology
- Y02E60/50—Fuel cells
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Manufacturing & Machinery (AREA)
- Sustainable Development (AREA)
- Sustainable Energy (AREA)
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Electric Propulsion And Braking For Vehicles (AREA)
- Fuel Cell (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102009040815 | 2009-09-10 | ||
| PCT/EP2010/004662 WO2011029499A1 (de) | 2009-09-10 | 2010-07-30 | Verfahren zum kaltstarten eines brennstoffzellensystems und brennstoffzellensystem eines kraftfahrzeugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SA04250400B1 true SA04250400B1 (ar) | 2008-03-29 |
Family
ID=43571166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SA4250400A SA04250400B1 (ar) | 2009-09-10 | 2004-12-08 | مشتقات الهيدرونوبول hydronopol كمؤازرات agonists في مستقبلات orl1 البشرية |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US9583774B2 (enExample) |
| EP (1) | EP2476155B1 (enExample) |
| JP (1) | JP5571792B2 (enExample) |
| CN (1) | CN102484272B (enExample) |
| DE (1) | DE102009049761A1 (enExample) |
| SA (1) | SA04250400B1 (enExample) |
| WO (1) | WO2011029499A1 (enExample) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE202012006090U1 (de) * | 2012-06-22 | 2012-08-31 | Siemens Aktiengesellschaft | Anordnung mit einer statischen Ein-/Rückspeiseeinheit und mit einer Verbrennungsmotor-Generatoreinheit |
| DE102013006756A1 (de) | 2013-04-19 | 2014-10-23 | Daimler Ag | Verfahren zum Betreiben eines Kraftfahrzeugs und Kraftfahrzeug mit einem Brennstoffzellensystem |
| DE102013012147A1 (de) | 2013-07-19 | 2015-01-22 | Daimler Ag | Verfahren zum Steuern eines Startvorgangs einer Brennstoffzelle |
| DE102013017342A1 (de) | 2013-10-18 | 2014-07-24 | Daimler Ag | Kühleinrichtung für einen Energiespeicher in einem Kraftwagen sowie Verfahren zum Betreiben einer solchen Kühleinrichtung |
| CN104716360B (zh) * | 2013-12-13 | 2017-09-15 | 中国科学院大连化学物理研究所 | 一种燃料电池系统直接启动方法 |
| DE102014201440B4 (de) * | 2014-01-27 | 2025-04-30 | Volkswagen Aktiengesellschaft | Kraftfahrzeugbordnetz mit optimierter Durchschaltfunktion |
| KR101592705B1 (ko) | 2014-06-11 | 2016-02-19 | 현대자동차주식회사 | 연료전지 시스템 및 그 제어 방법 |
| DE102015109502B4 (de) | 2014-06-20 | 2024-04-25 | Ford Global Technologies, Llc | Vorrichtung und Verfahren zum Erwärmen eines Brennstoffzellenstapels |
| KR101620172B1 (ko) * | 2014-07-03 | 2016-05-13 | 현대자동차주식회사 | 차량의 냉시동 방법 |
| KR101664559B1 (ko) | 2014-09-25 | 2016-10-10 | 현대자동차주식회사 | 연료전지 차량의 냉시동 운전 장치 및 방법 |
| KR101628507B1 (ko) * | 2014-10-29 | 2016-06-08 | 현대자동차주식회사 | 연료전지 차량의 시동 제어방법 |
| DE102014016076A1 (de) | 2014-10-29 | 2015-08-13 | Audi Ag | DC/DC-Wandler für ein Kraftfahrzeug |
| DE102015201405A1 (de) * | 2015-01-28 | 2016-07-28 | Bayerische Motoren Werke Aktiengesellschaft | Kraftfahrzeug und Verfahren zum Aufwärmen eines Brennstoffzellensystems eines Kraftfahrzeugs |
| KR101611123B1 (ko) * | 2015-02-16 | 2016-04-08 | 현대자동차주식회사 | 연료전지 출력 추정방법 |
| BR112018001872B1 (pt) * | 2015-07-28 | 2022-05-10 | Nissan Motor Co., Ltd | Sistema de célula de combustível |
| KR101836611B1 (ko) | 2016-04-07 | 2018-03-09 | 현대자동차주식회사 | 연료전지차량의 시동 제어방법 |
| KR101905951B1 (ko) * | 2016-04-18 | 2018-10-08 | 현대자동차주식회사 | 연료전지차량의 시동 제어 방법 |
| US11135931B2 (en) * | 2019-05-28 | 2021-10-05 | GM Global Technology Operations LLC | System for charging a battery electric vehicle or a plugin hybrid vehicle using a mobile fuel cell |
| CN111409502B (zh) * | 2020-03-25 | 2021-07-23 | 中极氢能汽车(长治)有限公司 | 氢燃料电池汽车及其在低温环境下的电机能量管理方法 |
| CN111785992B (zh) * | 2020-07-22 | 2021-05-14 | 吉林大学 | 一种燃料电池车辆混合低温冷启动控制方法 |
| DE102020128273A1 (de) * | 2020-10-28 | 2022-04-28 | Audi Aktiengesellschaft | Verfahren für einen Froststart einer Brennstoffzellenvorrichtung, Brennstoffzellenvorrichtung sowie Kraftfahrzeug mit einer Brennstoffzellenvorrichtung |
| CN112713289B (zh) * | 2020-12-25 | 2022-04-15 | 中国第一汽车股份有限公司 | 一种燃料电池控制方法、装置、设备及存储介质 |
| DE102021106835A1 (de) | 2021-03-19 | 2022-09-22 | Audi Aktiengesellschaft | Verfahren zum Betreiben einer Brennstoffzellenvorrichtung, Brennstoffzellenvorrichtung sowie Brennstoffzellen-Fahrzeug |
| KR20230077495A (ko) | 2021-11-25 | 2023-06-01 | 현대자동차주식회사 | 연료전지시스템 제어 장치 및 방법 |
| DE102023112597A1 (de) * | 2023-05-12 | 2024-11-14 | Schaeffler Technologies AG & Co. KG | Elektrisches Antriebssystem mit Batterieschutzfunktion durch Abführen mehr Wärmeenergie |
| CN118983471B (zh) * | 2024-10-22 | 2024-12-13 | 长春慧程科技有限公司 | 一种智能化汽车冷启动控制方法 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003109636A (ja) * | 2001-09-30 | 2003-04-11 | Equos Research Co Ltd | 燃料電池スタック |
| JP4626125B2 (ja) | 2003-03-14 | 2011-02-02 | 日産自動車株式会社 | 燃料電池システム |
| JP2005302446A (ja) | 2004-04-08 | 2005-10-27 | Nissan Motor Co Ltd | 燃料電池電源装置 |
| JP4752342B2 (ja) | 2005-06-15 | 2011-08-17 | 株式会社デンソー | 燃料電池システム |
| US20060280977A1 (en) | 2005-06-09 | 2006-12-14 | Denso Corporation | Fuel cell system |
| US7883809B2 (en) * | 2005-08-03 | 2011-02-08 | GM Global Technology Operations LLC | Rapid startup of a fuel cell power module using motor drive |
| US20070243428A1 (en) * | 2005-11-29 | 2007-10-18 | Richards Christopher J | Method of commencing operation of an electrochemical fuel cell stack from freeze-start conditions |
| JP2007317516A (ja) | 2006-05-26 | 2007-12-06 | Canon Inc | 燃料電池及び燃料電池装置 |
| US20070292724A1 (en) * | 2006-06-16 | 2007-12-20 | Gilchrist Ian T | System and method to start a fuel cell stack during a cold-start condition |
| JP2008103228A (ja) | 2006-10-20 | 2008-05-01 | Toyota Motor Corp | 燃料電池システム |
| DE102007026003B4 (de) | 2007-06-04 | 2025-12-11 | Cellcentric Gmbh & Co. Kg | Brennstoffzellensystem mit verbesserten Kaltstarteigenschaften sowie Verfahren |
| WO2009010113A1 (de) | 2007-07-18 | 2009-01-22 | Daimler Ag | Vorrichtung und verfahren zum aufwärmen einer brennstoffzelle in einer startphase |
| DE102007033429B4 (de) | 2007-07-18 | 2022-07-14 | Cellcentric Gmbh & Co. Kg | Vorrichtung und Verfahren zum Aufwärmen einer Brennstoffzelle in einer Startphase |
| JP5315661B2 (ja) | 2007-10-17 | 2013-10-16 | トヨタ自動車株式会社 | 燃料電池搭載車両、燃料電池の制御装置、制御方法 |
-
2004
- 2004-12-08 SA SA4250400A patent/SA04250400B1/ar unknown
-
2009
- 2009-10-17 DE DE102009049761A patent/DE102009049761A1/de not_active Withdrawn
-
2010
- 2010-07-30 WO PCT/EP2010/004662 patent/WO2011029499A1/de not_active Ceased
- 2010-07-30 US US13/395,037 patent/US9583774B2/en active Active
- 2010-07-30 JP JP2012528236A patent/JP5571792B2/ja active Active
- 2010-07-30 CN CN201080040223.0A patent/CN102484272B/zh active Active
- 2010-07-30 EP EP10742735.3A patent/EP2476155B1/de active Active
Also Published As
| Publication number | Publication date |
|---|---|
| EP2476155B1 (de) | 2016-10-12 |
| CN102484272A (zh) | 2012-05-30 |
| WO2011029499A1 (de) | 2011-03-17 |
| EP2476155A1 (de) | 2012-07-18 |
| US20120183814A1 (en) | 2012-07-19 |
| US9583774B2 (en) | 2017-02-28 |
| DE102009049761A1 (de) | 2011-03-17 |
| JP5571792B2 (ja) | 2014-08-13 |
| CN102484272B (zh) | 2014-07-30 |
| JP2013504988A (ja) | 2013-02-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SA04250400B1 (ar) | مشتقات الهيدرونوبول hydronopol كمؤازرات agonists في مستقبلات orl1 البشرية | |
| TWI239957B (en) | Tyrosine kinase inhibitors | |
| US10329297B2 (en) | Compounds for the inhibition of indoleamine-2,3-dioxygenase | |
| US9637498B2 (en) | Substituted thieno[2,3-C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4 | |
| EP3378861B1 (en) | Acrylic acid derivative, preparation method and use in medicine thereof | |
| CN112566886A (zh) | 螺环化合物 | |
| US9056876B2 (en) | Substituted 1H-pyrazolo[3′,4′,4,5]thieno[2,3-b]pyridin-3-amine analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4 | |
| JP6293784B2 (ja) | 炎症性障害の治療のための新規ジヒドロピリミジノイソキノリノン及びその医薬組成物（ｇｐｒ８４アンタゴニスト） | |
| US10745384B2 (en) | Indazole derivatives as αv integrin antagonists | |
| HU230382B1 (hu) | Xantinszármazékok, előállításuk és alkalmazásuk gyógyszerként | |
| SA518391033B1 (ar) | مركبات أمينو ترايازول به استبدال مفيدة باعتبارها مثبطات إنزيم كيتيناز بشري | |
| US20140364409A1 (en) | Substituted pyrazolo[3',4':4,5]thieno[2,3-c]pyridazin-3-amine analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m4 | |
| CN106164076B (zh) | 作为ros1抑制剂的化合物 | |
| UA119848C2 (uk) | Трициклічні гетероцикли як інгібітори білків бет | |
| MX2013005897A (es) | Derivados de benzopirazina sustituidos como inhibidores de cinasa del receptor del factor de crecimiento de fibroblasto (fgfr) para el tratamiento de enfermedades cancerigenas. | |
| EP1692129A1 (de) | Ketolactam-verbindungen und ihre verwendung | |
| TW201605833A (zh) | 作為ｐ９７錯合物抑制劑的稠合嘧啶 | |
| WO2018089358A1 (en) | Azole amides and amines as alpha v integrin inhibitors | |
| US20140206676A1 (en) | Substituted 4-(1h-pyrazol-4-yl)benzyl analogues as positive allosteric modulators of machr m1 receptors | |
| BR112020008157A2 (pt) | compostos espirocíclicos como moduladores do receptor farnesoide x | |
| US20160102090A1 (en) | Substituted 3-benzylquinoxalin-4(3h)-one analogs as positive allosteric modulators of muscarinic acetycholine receptor m1 | |
| US8138333B2 (en) | Sulfonyl-indole derivatives | |
| AU2006298164A1 (en) | Novel fused pyrrole derivative | |
| US10947203B2 (en) | 1,4,5-substituted 1,2,3-triazole analogues as antagonists of the pregnane X receptor | |
| DE102004027359A1 (de) | Pyridin-2-onverbindungen und deren Verwendung |