ES2255610T3 - Antagonistas de los receptores de crf. - Google Patents
Antagonistas de los receptores de crf.Info
- Publication number
- ES2255610T3 ES2255610T3 ES02718405T ES02718405T ES2255610T3 ES 2255610 T3 ES2255610 T3 ES 2255610T3 ES 02718405 T ES02718405 T ES 02718405T ES 02718405 T ES02718405 T ES 02718405T ES 2255610 T3 ES2255610 T3 ES 2255610T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- dichlorophenyl
- compounds
- compound
- hexahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000005557 antagonist Substances 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 304
- -1 halo C1-C6 alkoxy Chemical group 0.000 claims abstract description 120
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 33
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052757 nitrogen Chemical group 0.000 claims abstract description 19
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 18
- 150000002367 halogens Chemical class 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 15
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 15
- 125000003118 aryl group Chemical group 0.000 claims abstract description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 12
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 229940002612 prodrug Drugs 0.000 claims abstract description 9
- 239000000651 prodrug Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 238000011282 treatment Methods 0.000 claims description 47
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 36
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 claims description 31
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 claims description 29
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 150000001412 amines Chemical class 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 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 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 4
- 208000020401 Depressive disease Diseases 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- QAAQDIUDQAOWTK-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)-7-(2-ethylbutyl)-10-methyl-2,7,9,11-tetrazatricyclo[6.3.1.04,12]dodeca-1(11),8(12),9-triene Chemical group C=12C3=NC(C)=NC=1N(CC(CC)CC)CCC2CN3C1=CC=C(Cl)C=C1Cl QAAQDIUDQAOWTK-UHFFFAOYSA-N 0.000 claims description 3
- CNBNLEBKVWQZNX-UHFFFAOYSA-N 6-butyl-7-(cyclopropylmethyl)-2-(2,4-dichlorophenyl)-10-methyl-2,7,9,11-tetrazatricyclo[6.3.1.04,12]dodeca-1(12),8,10-triene Chemical group CCCCC1CC(C=23)CN(C=4C(=CC(Cl)=CC=4)Cl)C3=NC(C)=NC=2N1CC1CC1 CNBNLEBKVWQZNX-UHFFFAOYSA-N 0.000 claims description 3
- VYUMTEKEJKJMQG-UHFFFAOYSA-N 7-(2,4-dichlorophenyl)-10-methyl-2-pentan-3-yl-2,9,11-triazatricyclo[6.3.1.04,12]dodeca-1(11),8(12),9-triene Chemical group C=12C3=NC(C)=NC=1N(C(CC)CC)CC2CCC3C1=CC=C(Cl)C=C1Cl VYUMTEKEJKJMQG-UHFFFAOYSA-N 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- DCLWIFOQEHQVQZ-UHFFFAOYSA-N C=12C3=NC(C)=NC=1N(CCCC)C(CCCC)CC2CN3C1=CC=C(Cl)C=C1Cl Chemical group C=12C3=NC(C)=NC=1N(CCCC)C(CCCC)CC2CN3C1=CC=C(Cl)C=C1Cl DCLWIFOQEHQVQZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 150000002902 organometallic compounds Chemical class 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- PHNRYLGTWPVWGK-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)-7-(2-methoxyethyl)-10-methyl-2,7,9,11-tetrazatricyclo[6.3.1.04,12]dodeca-1(11),8(12),9-triene Chemical group C=12C3=NC(C)=NC=1N(CCOC)CCC2CN3C1=CC=C(Cl)C=C1Cl PHNRYLGTWPVWGK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- MVSXPVRYNDCRJQ-UHFFFAOYSA-N 7-(cyclopropylmethyl)-2-(2,4-dichlorophenyl)-10-methyl-6-propoxy-2,7,9,11-tetrazatricyclo[6.3.1.04,12]dodeca-1(12),8,10-triene Chemical group CCCOC1CC(C=23)CN(C=4C(=CC(Cl)=CC=4)Cl)C3=NC(C)=NC=2N1CC1CC1 MVSXPVRYNDCRJQ-UHFFFAOYSA-N 0.000 claims description 2
- WJQCZTYTCMWBGD-UHFFFAOYSA-N 7-(cyclopropylmethyl)-2-(2,4-dichlorophenyl)-10-methyl-6-propyl-2,7,9,11-tetrazatricyclo[6.3.1.04,12]dodeca-1(12),8,10-triene Chemical group CCCC1CC(C=23)CN(C=4C(=CC(Cl)=CC=4)Cl)C3=NC(C)=NC=2N1CC1CC1 WJQCZTYTCMWBGD-UHFFFAOYSA-N 0.000 claims description 2
- WMBGNRWVJYODMA-UHFFFAOYSA-N C=12C3=NC(C)=NC=1N(C(CCC)CCC)CC2CCN3C1=CC=C(C(F)(F)CF)C=C1C(F)(F)F Chemical group C=12C3=NC(C)=NC=1N(C(CCC)CCC)CC2CCN3C1=CC=C(C(F)(F)CF)C=C1C(F)(F)F WMBGNRWVJYODMA-UHFFFAOYSA-N 0.000 claims description 2
- GFRXIUZQVJCISJ-UHFFFAOYSA-N C=12C3=NC(C)=NC=1N(C(CCC)CCC)CCC2CN3C1=CC=C(C(F)(F)CF)C=C1C(F)(F)F Chemical group C=12C3=NC(C)=NC=1N(C(CCC)CCC)CCC2CN3C1=CC=C(C(F)(F)CF)C=C1C(F)(F)F GFRXIUZQVJCISJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- IOMQSAPFIUXPEO-UHFFFAOYSA-N chembl176145 Chemical group C=12C3=NC(C)=NC=1N(C(CC)CC)CC2CCN3C1=CC=C(Cl)C=C1Cl IOMQSAPFIUXPEO-UHFFFAOYSA-N 0.000 claims description 2
- YALBAQFFCQQJKN-UHFFFAOYSA-N chembl178176 Chemical group C1=2C3=NC(C)=NC=2N(C=2C(=CC(Cl)=CC=2)Cl)CC1CCN3CC1CC1 YALBAQFFCQQJKN-UHFFFAOYSA-N 0.000 claims description 2
- ATYWTDSKRJOYQU-UHFFFAOYSA-N chembl179608 Chemical group C=12C3=NC(C)=NC=1N(C(CCC)CCC)CCC2CN3C1=CC=C(Cl)C=C1Cl ATYWTDSKRJOYQU-UHFFFAOYSA-N 0.000 claims description 2
- DAHAIPSBEBRKTA-UHFFFAOYSA-N chembl180116 Chemical group C=12C3=NC(C)=NC=1N(C(CC)CC)CCC2CN3C1=CC=C(Cl)C=C1Cl DAHAIPSBEBRKTA-UHFFFAOYSA-N 0.000 claims description 2
- VJJBGPHBOZISOV-UHFFFAOYSA-N chembl369510 Chemical group C=12C3=NC(C)=NC=1N(C(CCC)CCC)CC2CCN3C1=CC=C(Cl)C=C1Cl VJJBGPHBOZISOV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 2
- BOTTWHRLZDCVOZ-UHFFFAOYSA-N 7-(2,4-dichlorophenyl)-2-(2-ethylbutyl)-10-methyl-2,7,9,11-tetrazatricyclo[6.3.1.04,12]dodeca-1(11),9-diene Chemical group C12C3N=C(C)N=C1N(CC(CC)CC)CC2CCN3C1=CC=C(Cl)C=C1Cl BOTTWHRLZDCVOZ-UHFFFAOYSA-N 0.000 claims 1
- 210000000936 intestine Anatomy 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 80
- 239000000460 chlorine Substances 0.000 description 78
- 239000002904 solvent Substances 0.000 description 76
- 239000011541 reaction mixture Substances 0.000 description 73
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 70
- 239000000203 mixture Substances 0.000 description 66
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 61
- 235000019439 ethyl acetate Nutrition 0.000 description 60
- 239000007787 solid Substances 0.000 description 60
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 58
- 239000007832 Na2SO4 Substances 0.000 description 57
- 229910052938 sodium sulfate Inorganic materials 0.000 description 57
- 235000011152 sodium sulphate Nutrition 0.000 description 57
- 238000003818 flash chromatography Methods 0.000 description 55
- 239000000741 silica gel Substances 0.000 description 55
- 229910002027 silica gel Inorganic materials 0.000 description 55
- 239000000284 extract Substances 0.000 description 52
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
- 239000003921 oil Substances 0.000 description 45
- 235000019198 oils Nutrition 0.000 description 45
- 238000005481 NMR spectroscopy Methods 0.000 description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
- 239000012043 crude product Substances 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000012267 brine Substances 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 description 21
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 208000035475 disorder Diseases 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 14
- 238000007254 oxidation reaction Methods 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 208000002193 Pain Diseases 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 12
- 230000003647 oxidation Effects 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 229940098779 methanesulfonic acid Drugs 0.000 description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 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 8
- 206010047700 Vomiting Diseases 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- CLJMMQGDJNYDER-UHFFFAOYSA-N heptan-4-amine Chemical compound CCCC(N)CCC CLJMMQGDJNYDER-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 229940044551 receptor antagonist Drugs 0.000 description 8
- 239000002464 receptor antagonist Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- 229910019213 POCl3 Inorganic materials 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 229940125773 compound 10 Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 5
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 239000000010 aprotic solvent Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 229940127573 compound 38 Drugs 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000005658 halogenation reaction Methods 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 5
- 239000001301 oxygen Chemical group 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
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- 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Psychiatry (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0110566A GB0110566D0 (en) | 2001-04-30 | 2001-04-30 | Chemical compounds |
| GB0110566 | 2001-04-30 | ||
| GB0110579 | 2001-04-30 | ||
| GB0110579A GB0110579D0 (en) | 2001-04-30 | 2001-04-30 | Chemical compounds |
| GB0117423A GB0117423D0 (en) | 2001-07-17 | 2001-07-17 | Chemical compounds |
| GB0117423 | 2001-07-17 | ||
| GB0203203 | 2002-02-11 | ||
| GB0203203A GB0203203D0 (en) | 2002-02-11 | 2002-02-11 | Chemical compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2255610T3 true ES2255610T3 (es) | 2006-07-01 |
Family
ID=27447943
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES02718405T Expired - Lifetime ES2255610T3 (es) | 2001-04-30 | 2002-04-30 | Antagonistas de los receptores de crf. |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US7329667B2 (https=) |
| EP (1) | EP1383498B1 (https=) |
| JP (1) | JP2004528342A (https=) |
| KR (1) | KR20040015205A (https=) |
| CN (1) | CN1512883A (https=) |
| AR (1) | AR033296A1 (https=) |
| AT (1) | ATE320254T1 (https=) |
| AU (1) | AU2002249474B2 (https=) |
| BR (1) | BR0209035A (https=) |
| CA (1) | CA2446497A1 (https=) |
| CZ (1) | CZ20032945A3 (https=) |
| DE (1) | DE60209885T2 (https=) |
| ES (1) | ES2255610T3 (https=) |
| HU (1) | HUP0304035A2 (https=) |
| IL (1) | IL158063A0 (https=) |
| MX (1) | MXPA03009930A (https=) |
| NO (1) | NO20034837L (https=) |
| NZ (1) | NZ528364A (https=) |
| PL (1) | PL366854A1 (https=) |
| TW (1) | TWI236908B (https=) |
| WO (1) | WO2002087573A1 (https=) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0308208D0 (en) | 2003-04-09 | 2003-05-14 | Glaxo Group Ltd | Chemical compounds |
| ES2540964T3 (es) | 2009-06-08 | 2015-07-15 | Takeda Pharmaceutical Company Limited | Compuestos de dihidropirrolonaftiridinona como inhibidores de JAK |
| RU2498986C2 (ru) * | 2011-07-20 | 2013-11-20 | Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) | ТЕТРАЦИАНОЗАМЕЩЕННЫЕ 1,4,9b-ТРИАЗАФЕНАЛЕНЫ И СПОСОБ ИХ ПОЛУЧЕНИЯ |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6403599B1 (en) | 1995-11-08 | 2002-06-11 | Pfizer Inc | Corticotropin releasing factor antagonists |
| ZA973884B (en) * | 1996-05-23 | 1998-11-06 | Du Pont Merck Pharma | Tetrahydropteridines and pyridylpiperazines for treatment of neurological disorders |
| EP1129096B1 (en) * | 1998-11-12 | 2003-05-21 | Neurocrine Biosciences, Inc. | Crf receptor antagonists and methods relating thereto |
| IL142893A0 (en) | 1998-11-12 | 2002-04-21 | Neurocrine Biosciences Inc | Fused polyclic heterocyclic compounds and pharmaceutical compositions containing the same |
| GB0117395D0 (en) | 2001-07-17 | 2001-09-05 | Glaxo Group Ltd | Chemical compounds |
-
2002
- 2002-04-30 ES ES02718405T patent/ES2255610T3/es not_active Expired - Lifetime
- 2002-04-30 DE DE60209885T patent/DE60209885T2/de not_active Expired - Fee Related
- 2002-04-30 PL PL02366854A patent/PL366854A1/xx not_active Application Discontinuation
- 2002-04-30 HU HU0304035A patent/HUP0304035A2/hu unknown
- 2002-04-30 CZ CZ20032945A patent/CZ20032945A3/cs unknown
- 2002-04-30 CA CA002446497A patent/CA2446497A1/en not_active Abandoned
- 2002-04-30 AU AU2002249474A patent/AU2002249474B2/en not_active Ceased
- 2002-04-30 KR KR10-2003-7014159A patent/KR20040015205A/ko not_active Withdrawn
- 2002-04-30 US US10/476,441 patent/US7329667B2/en not_active Expired - Fee Related
- 2002-04-30 AR ARP020101598A patent/AR033296A1/es unknown
- 2002-04-30 CN CNA028107454A patent/CN1512883A/zh active Pending
- 2002-04-30 TW TW091108900A patent/TWI236908B/zh not_active IP Right Cessation
- 2002-04-30 BR BR0209035-0A patent/BR0209035A/pt not_active IP Right Cessation
- 2002-04-30 MX MXPA03009930A patent/MXPA03009930A/es active IP Right Grant
- 2002-04-30 WO PCT/GB2002/001981 patent/WO2002087573A1/en not_active Ceased
- 2002-04-30 NZ NZ528364A patent/NZ528364A/en unknown
- 2002-04-30 JP JP2002584918A patent/JP2004528342A/ja active Pending
- 2002-04-30 EP EP02718405A patent/EP1383498B1/en not_active Expired - Lifetime
- 2002-04-30 AT AT02718405T patent/ATE320254T1/de not_active IP Right Cessation
- 2002-04-30 IL IL15806302A patent/IL158063A0/xx unknown
-
2003
- 2003-10-29 NO NO20034837A patent/NO20034837L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA03009930A (es) | 2004-01-29 |
| TWI236908B (en) | 2005-08-01 |
| EP1383498B1 (en) | 2006-03-15 |
| CN1512883A (zh) | 2004-07-14 |
| CZ20032945A3 (cs) | 2004-02-18 |
| AU2002249474B2 (en) | 2006-01-12 |
| JP2004528342A (ja) | 2004-09-16 |
| WO2002087573A1 (en) | 2002-11-07 |
| NO20034837L (no) | 2003-12-09 |
| NO20034837D0 (no) | 2003-10-29 |
| US20040235871A1 (en) | 2004-11-25 |
| HUP0304035A2 (hu) | 2004-04-28 |
| ATE320254T1 (de) | 2006-04-15 |
| PL366854A1 (en) | 2005-02-07 |
| DE60209885T2 (de) | 2006-08-10 |
| KR20040015205A (ko) | 2004-02-18 |
| IL158063A0 (en) | 2004-03-28 |
| CA2446497A1 (en) | 2002-11-07 |
| AR033296A1 (es) | 2003-12-10 |
| DE60209885D1 (de) | 2006-05-11 |
| BR0209035A (pt) | 2004-08-10 |
| EP1383498A1 (en) | 2004-01-28 |
| NZ528364A (en) | 2005-12-23 |
| US7329667B2 (en) | 2008-02-12 |
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