TW474917B - Indolin-2-one derivatives having specific antagonistic activity on vasopressin 2 receptors, process for their preparation and the pharmaceutical compositions containing them - Google Patents

Info

Publication number

TW474917B

TW474917B TW085112955A TW85112955A TW474917B TW 474917 B TW474917 B TW 474917B TW 085112955 A TW085112955 A TW 085112955A TW 85112955 A TW85112955 A TW 85112955A TW 474917 B TW474917 B TW 474917B

Authority

TW

Taiwan

Prior art keywords

ethoxy

compound

spiro

group

cyclohexane

Prior art date

1995-10-24

Links

• Espacenet
• Global Dossier
• Discuss

• KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 title claims abstract description 32
• 229960003726 vasopressin Drugs 0.000 title claims abstract description 30
• GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 title claims abstract description 27
• 238000000034 method Methods 0.000 title claims description 58
• 238000002360 preparation method Methods 0.000 title claims description 47
• 108010004977 Vasopressins Proteins 0.000 title claims description 24
• 102000002852 Vasopressins Human genes 0.000 title claims description 23
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 14
• 230000003042 antagnostic effect Effects 0.000 title claims 2
• 125000004095 oxindolyl group Chemical class N1(C(CC2=CC=CC=C12)=O)* 0.000 title abstract description 3
• 230000008569 process Effects 0.000 title description 2
• -1 for example Chemical compound 0.000 claims abstract description 108
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 34
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
• 239000001257 hydrogen Substances 0.000 claims abstract description 22
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 19
• 239000003814 drug Substances 0.000 claims abstract description 9
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
• 125000003277 amino group Chemical group 0.000 claims abstract description 5
• 150000001875 compounds Chemical class 0.000 claims description 221
• 239000000203 mixture Substances 0.000 claims description 85
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 70
• 239000002904 solvent Substances 0.000 claims description 55
• 150000003839 salts Chemical class 0.000 claims description 44
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
• JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 38
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 29
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
• 150000001412 amines Chemical class 0.000 claims description 24
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
• 239000002253 acid Substances 0.000 claims description 19
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 15
• 239000004480 active ingredient Substances 0.000 claims description 15
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 15
• 150000004677 hydrates Chemical class 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 125000000623 heterocyclic group Chemical group 0.000 claims description 9
• XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 claims description 9
• 101800000989 Oxytocin Proteins 0.000 claims description 8
• XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 claims description 8
• 102100031951 Oxytocin-neurophysin 1 Human genes 0.000 claims description 8
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
• 229960001723 oxytocin Drugs 0.000 claims description 8
• HQABUPZFAYXKJW-UHFFFAOYSA-N N-butylamine Natural products CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 7
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 239000001301 oxygen Substances 0.000 claims description 6
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 5
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
• 125000005843 halogen group Chemical group 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 239000007800 oxidant agent Substances 0.000 claims description 5
• 239000012312 sodium hydride Substances 0.000 claims description 5
• 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
• 125000003003 spiro group Chemical group 0.000 claims description 5
• 125000003545 alkoxy group Chemical group 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 201000010099 disease Diseases 0.000 claims description 4
• 229910052757 nitrogen Inorganic materials 0.000 claims description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
• FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 claims description 3
• 229910052783 alkali metal Inorganic materials 0.000 claims description 3
• 150000001450 anions Chemical class 0.000 claims description 3
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
• 230000033228 biological regulation Effects 0.000 claims description 3
• 239000010949 copper Substances 0.000 claims description 3
• 150000007857 hydrazones Chemical class 0.000 claims description 3
• LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 claims description 3
• 230000000269 nucleophilic effect Effects 0.000 claims description 3
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 3
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
• 229960005235 piperonyl butoxide Drugs 0.000 claims description 3
• 239000002798 polar solvent Substances 0.000 claims description 3
• 230000009467 reduction Effects 0.000 claims description 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
• RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
• IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 2
• 239000000460 chlorine Substances 0.000 claims description 2
• 229910052801 chlorine Inorganic materials 0.000 claims description 2
• 229910052802 copper Inorganic materials 0.000 claims description 2
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 2
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• 150000004681 metal hydrides Chemical class 0.000 claims description 2
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• 150000004706 metal oxides Chemical class 0.000 claims description 2
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 2
• OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical group CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 claims 2
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
• NPWMTBZSRRLQNJ-VKHMYHEASA-N (3s)-3-aminopiperidine-2,6-dione Chemical compound N[C@H]1CCC(=O)NC1=O NPWMTBZSRRLQNJ-VKHMYHEASA-N 0.000 claims 1
• 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims 1
• YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 claims 1
• 101100074846 Caenorhabditis elegans lin-2 gene Proteins 0.000 claims 1
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• 229920002770 condensed tannin Polymers 0.000 claims 1
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• QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 claims 1
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