ES2234683T3 - Derivados de isoquinolina y quinazolina con actividad combinada sobre los receptores 5ht1a, 5ht1b y 5ht1d. - Google Patents
Derivados de isoquinolina y quinazolina con actividad combinada sobre los receptores 5ht1a, 5ht1b y 5ht1d.Info
- Publication number
- ES2234683T3 ES2234683T3 ES00971423T ES00971423T ES2234683T3 ES 2234683 T3 ES2234683 T3 ES 2234683T3 ES 00971423 T ES00971423 T ES 00971423T ES 00971423 T ES00971423 T ES 00971423T ES 2234683 T3 ES2234683 T3 ES 2234683T3
- Authority
- ES
- Spain
- Prior art keywords
- formula
- isoquinoline
- mmol
- dihydro
- pyrrolo
- 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
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title abstract description 10
- 101150015707 HTR1A gene Proteins 0.000 title description 7
- 230000000694 effects Effects 0.000 title description 5
- 101150050738 HTR1B gene Proteins 0.000 title description 2
- 101100321769 Takifugu rubripes htr1d gene Proteins 0.000 title description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical class N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 44
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 97
- 150000003839 salts Chemical class 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 208000035475 disorder Diseases 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- SNLLQMROANTIQN-UHFFFAOYSA-N (2-fluorophenyl)-[8-(4-methylpiperazin-1-yl)-2,3-dihydropyrrolo[3,2-g]isoquinolin-1-yl]methanone Chemical compound C1CN(C)CCN1C(C1=C2)=NC=CC1=CC1=C2N(C(=O)C=2C(=CC=CC=2)F)CC1 SNLLQMROANTIQN-UHFFFAOYSA-N 0.000 claims description 4
- TXRGJNXLUOJBIV-UHFFFAOYSA-N (5-methyl-1-phenylpyrazol-4-yl)-[8-(4-methylpiperazin-1-yl)-2,3-dihydropyrrolo[3,2-g]isoquinolin-1-yl]methanone Chemical compound C1CN(C)CCN1C(C1=C2)=NC=CC1=CC1=C2N(C(=O)C2=C(N(N=C2)C=2C=CC=CC=2)C)CC1 TXRGJNXLUOJBIV-UHFFFAOYSA-N 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- WNSSKIBDALBFGI-UHFFFAOYSA-N 4-[5-ethyl-4-[8-(4-methylpiperazin-1-yl)-2,3-dihydropyrrolo[3,2-g]isoquinoline-1-carbonyl]pyrazol-1-yl]benzonitrile Chemical compound CCC1=C(C(=O)N2C3=CC4=C(N5CCN(C)CC5)N=CC=C4C=C3CC2)C=NN1C1=CC=C(C#N)C=C1 WNSSKIBDALBFGI-UHFFFAOYSA-N 0.000 claims description 4
- LRCDTMLNXFWKPD-UHFFFAOYSA-N 4-[5-methyl-4-[8-(4-methylpiperazin-1-yl)-2,3-dihydropyrrolo[3,2-g]isoquinoline-1-carbonyl]pyrazol-1-yl]benzonitrile Chemical compound C1CN(C)CCN1C(C1=C2)=NC=CC1=CC1=C2N(C(=O)C2=C(N(N=C2)C=2C=CC(=CC=2)C#N)C)CC1 LRCDTMLNXFWKPD-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Chemical group 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 230000009286 beneficial effect Effects 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 208000020401 Depressive disease Diseases 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 15
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 2
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000007787 solid Substances 0.000 description 51
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 206010012812 Diffuse cutaneous mastocytosis Diseases 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000012458 free base Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- AUTQZLTYBFUXAS-UHFFFAOYSA-N 8-(4-methylpiperazin-1-yl)-2,3-dihydro-1h-pyrrolo[3,2-g]isoquinoline Chemical compound C1CN(C)CCN1C(C1=C2)=NC=CC1=CC1=C2NCC1 AUTQZLTYBFUXAS-UHFFFAOYSA-N 0.000 description 13
- 239000007832 Na2SO4 Substances 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- -1 benzoxazinonyl Chemical group 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
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- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 7
- 102000017911 HTR1A Human genes 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- KVSPNWILRSCUBM-UHFFFAOYSA-N 1-benzyl-2,3-dihydroindole-6-carboxylic acid Chemical compound C12=CC(C(=O)O)=CC=C2CCN1CC1=CC=CC=C1 KVSPNWILRSCUBM-UHFFFAOYSA-N 0.000 description 6
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 6
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 235000015320 potassium carbonate Nutrition 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 6
- BMFJTABNNAHEMU-UHFFFAOYSA-N (1-benzyl-2,3-dihydropyrrolo[3,2-g]isoquinolin-8-yl) trifluoromethanesulfonate Chemical compound C1=2C=C3C(OS(=O)(=O)C(F)(F)F)=NC=CC3=CC=2CCN1CC1=CC=CC=C1 BMFJTABNNAHEMU-UHFFFAOYSA-N 0.000 description 5
- IUMWRNTXTBKDJU-UHFFFAOYSA-N 1-(4-methylpiperazin-1-yl)isoquinolin-7-amine Chemical compound C1CN(C)CCN1C1=NC=CC2=CC=C(N)C=C12 IUMWRNTXTBKDJU-UHFFFAOYSA-N 0.000 description 5
- ILHDYUNGKWCIMT-UHFFFAOYSA-N 1-[4-(2,3-dihydro-1h-pyrrolo[3,2-g]isoquinolin-8-yl)piperazin-1-yl]-2,2,2-trifluoroethanone Chemical compound C1CN(C(=O)C(F)(F)F)CCN1C(C1=C2)=NC=CC1=CC1=C2NCC1 ILHDYUNGKWCIMT-UHFFFAOYSA-N 0.000 description 5
- DALXNJWWXTVOMV-UHFFFAOYSA-N 8-(1-methylpiperidin-4-yl)-2,3-dihydro-1h-pyrrolo[3,2-g]isoquinoline Chemical compound C1CN(C)CCC1C(C1=C2)=NC=CC1=CC1=C2NCC1 DALXNJWWXTVOMV-UHFFFAOYSA-N 0.000 description 5
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 5
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- 239000003208 petroleum Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 4
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- 239000013078 crystal Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- YWVHPLJGOVNNFC-UHFFFAOYSA-N 1-[4-(1-benzyl-2,3-dihydropyrrolo[3,2-g]isoquinolin-8-yl)piperazin-1-yl]-2,2,2-trifluoroethanone Chemical compound C1CN(C(=O)C(F)(F)F)CCN1C(C1=C2)=NC=CC1=CC1=C2N(CC=2C=CC=CC=2)CC1 YWVHPLJGOVNNFC-UHFFFAOYSA-N 0.000 description 3
- SMQYSUSOYTUZGX-UHFFFAOYSA-N 1-benzyl-3,7-dihydro-2h-pyrrolo[3,2-g]isoquinolin-8-one Chemical compound C1=2C=C3C(O)=NC=CC3=CC=2CCN1CC1=CC=CC=C1 SMQYSUSOYTUZGX-UHFFFAOYSA-N 0.000 description 3
- GUOORCLHTNPIRK-UHFFFAOYSA-N 1-benzyl-8-(1-methylpiperidin-4-yl)-2,3-dihydropyrrolo[3,2-g]isoquinoline Chemical compound C1CN(C)CCC1C(C1=C2)=NC=CC1=CC1=C2N(CC=2C=CC=CC=2)CC1 GUOORCLHTNPIRK-UHFFFAOYSA-N 0.000 description 3
- HJFLTTNCURQAAZ-UHFFFAOYSA-N 1-benzyl-8-(4-methylpiperazin-1-yl)-2,3-dihydropyrrolo[3,2-g]isoquinoline Chemical compound C1CN(C)CCN1C(C1=C2)=NC=CC1=CC1=C2N(CC=2C=CC=CC=2)CC1 HJFLTTNCURQAAZ-UHFFFAOYSA-N 0.000 description 3
- GIHJEPQSWKNECR-UHFFFAOYSA-N 1-benzyl-8-piperazin-1-yl-2,3-dihydropyrrolo[3,2-g]isoquinoline Chemical compound C=1C=CC=CC=1CN(C1=CC2=3)CCC1=CC2=CC=NC=3N1CCNCC1 GIHJEPQSWKNECR-UHFFFAOYSA-N 0.000 description 3
- IEYFLGMSECLVHN-UHFFFAOYSA-N 1-benzyl-8-piperidin-4-yl-2,3-dihydropyrrolo[3,2-g]isoquinoline Chemical compound C=1C=CC=CC=1CN(C1=CC2=3)CCC1=CC2=CC=NC=3C1CCNCC1 IEYFLGMSECLVHN-UHFFFAOYSA-N 0.000 description 3
- KFIFDNVCVVUCAQ-UHFFFAOYSA-N 2-(4-methylpiperazin-1-yl)-4H-pyrrolo[3,2-g]isoquinoline Chemical compound CN1CCN(CC1)C=1C=C2CC=3C=CN=CC=3C=C2N=1 KFIFDNVCVVUCAQ-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- YMUSRAUKLHCTOF-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-6-nitroquinazoline Chemical compound C1CN(C)CCN1C1=NC=NC2=CC=C([N+]([O-])=O)C=C12 YMUSRAUKLHCTOF-UHFFFAOYSA-N 0.000 description 3
- UIMGUNWHHBSISY-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)quinazolin-6-amine Chemical compound C1CN(C)CCN1C1=NC=NC2=CC=C(N)C=C12 UIMGUNWHHBSISY-UHFFFAOYSA-N 0.000 description 3
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- AEBKXRCZDMCMHT-UHFFFAOYSA-N 8-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydropyrrolo[3,2-g]isoquinoline-1-carbaldehyde Chemical compound C1CN(C(=O)C(F)(F)F)CCN1C(C1=C2)=NC=CC1=CC1=C2N(C=O)CC1 AEBKXRCZDMCMHT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
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- 125000001072 heteroaryl group Chemical group 0.000 description 3
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Classifications
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- 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
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9926304.8A GB9926304D0 (en) | 1999-11-05 | 1999-11-05 | Novel compounds |
| GB9926304 | 1999-11-05 | ||
| GB0017880A GB0017880D0 (en) | 2000-07-20 | 2000-07-20 | Novel compounds |
| GB0017880 | 2000-07-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2234683T3 true ES2234683T3 (es) | 2005-07-01 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES00971423T Expired - Lifetime ES2234683T3 (es) | 1999-11-05 | 2000-11-02 | Derivados de isoquinolina y quinazolina con actividad combinada sobre los receptores 5ht1a, 5ht1b y 5ht1d. |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US20050239797A1 (enExample) |
| EP (1) | EP1228043B1 (enExample) |
| JP (1) | JP2003513075A (enExample) |
| AT (1) | ATE286883T1 (enExample) |
| AU (1) | AU1028601A (enExample) |
| DE (1) | DE60017446T2 (enExample) |
| ES (1) | ES2234683T3 (enExample) |
| PE (1) | PE20010956A1 (enExample) |
| UY (1) | UY26426A1 (enExample) |
| WO (1) | WO2001032626A1 (enExample) |
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| EP1283199A4 (en) | 2000-05-16 | 2003-12-17 | Takeda Chemical Industries Ltd | MELANINE CONCENTRATING HORMONE ANTAGONISTS |
| DE10315571A1 (de) | 2003-04-05 | 2004-10-14 | Merck Patent Gmbh | Pyrazolverbindungen |
| DE10315573A1 (de) | 2003-04-05 | 2004-10-14 | Merck Patent Gmbh | Substituierte Pyrazole |
| DE10315569A1 (de) * | 2003-04-05 | 2004-10-14 | Merck Patent Gmbh | Substituierte Pyrazolverbindungen |
| GB0316915D0 (en) * | 2003-07-18 | 2003-08-20 | Glaxo Group Ltd | Compounds |
| BRPI0412259B1 (pt) | 2003-07-22 | 2019-08-20 | Astex Therapeutics Limited | Compostos de 1H-pirazol 3,4-dissubstituídos como moduladores de quinases dependentes de ciclina (CDK), seus usos, processo para a preparação dos mesmos e composição farmacêutica |
| WO2005067933A1 (en) * | 2004-01-16 | 2005-07-28 | F. Hoffmann-La Roche Ag | 1-benzyl-5-piperazin-1-yl-3,4 dihydro-1h-quinazolin-2-one derivatives and the respective 1h-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzo(d) (1,3)oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-ht) for the treatment of diseases of the central nervous system |
| US9066903B2 (en) * | 2006-02-28 | 2015-06-30 | The United States Of America As Represented By The Department Of Veterans Affairs | Pharmacological treatment of Parkinson's disease |
| US20090099175A1 (en) * | 2006-03-01 | 2009-04-16 | Arrington Mark P | Phosphodiesterase 10 inhibitors |
| WO2008115593A1 (en) | 2007-03-21 | 2008-09-25 | The University Of Montana | 1-[(2'-substituted)-piperazin-1'-yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents |
| EP2669270B1 (en) | 2011-01-28 | 2018-01-03 | Sato Pharmaceutical Co., Ltd. | Indole-related compounds as urat1 inhibitors |
| US10092574B2 (en) | 2012-09-26 | 2018-10-09 | Valorisation-Recherche, Limited Partnership | Inhibitors of polynucleotide repeat-associated RNA foci and uses thereof |
| KR101709127B1 (ko) * | 2015-06-16 | 2017-02-22 | 경동제약 주식회사 | Dpp-iv 억제제의 제조를 위한 신규 중간체, 이의 제조방법 및 이를 이용한 dpp-iv 억제제의 제조방법 |
| CN112480007B (zh) * | 2020-12-08 | 2022-11-18 | 宿迁市科莱博生物化学有限公司 | 一种1，3-二甲基-1h-吡唑-4-羧酸的合成方法 |
| WO2025190395A2 (en) * | 2024-03-14 | 2025-09-18 | Pharmaengine, Inc. | Mta-cooperative prmt5 inhibitor |
Family Cites Families (8)
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| US3932412A (en) * | 1970-12-07 | 1976-01-13 | Sandoz, Inc. | 1-(4-Hydroxyalkylpiperazino)-isoquinoline nitrates |
| US3778440A (en) * | 1970-12-07 | 1973-12-11 | Sandoz Ag | 1-substituted amino-isoquinolines and nitrates thereof |
| IL112248A0 (en) * | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
| WO1998047868A1 (en) * | 1997-04-18 | 1998-10-29 | Smithkline Beecham Plc | Heterocycle-containing urea derivatives as 5ht1a, 5ht1b and 5ht1d receptor antagonists |
| JP2001524116A (ja) * | 1997-04-18 | 2001-11-27 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | ５ｈｔ１ａ、５ｈｔ１ｂおよび５ｈｔ１ｄ受容体アンタゴニスト活性を合わせ持つインドール誘導体 |
| US6340759B1 (en) * | 1997-10-02 | 2002-01-22 | Eisai Co., Ltd. | Fused pyridine derivatives |
| WO1999031086A1 (en) * | 1997-12-12 | 1999-06-24 | Smithkline Beecham Plc | Quinolinepiperazine and quinolinepiperidine derivatives, their preparation and their use as combined 5-ht1a, 5-ht1b and 5-ht1d receptor antagonists |
| WO2000006575A2 (en) * | 1998-07-28 | 2000-02-10 | Smithkline Beecham Plc | Azabicyclic compounds |
-
2000
- 2000-11-02 AT AT00971423T patent/ATE286883T1/de not_active IP Right Cessation
- 2000-11-02 ES ES00971423T patent/ES2234683T3/es not_active Expired - Lifetime
- 2000-11-02 AU AU10286/01A patent/AU1028601A/en not_active Abandoned
- 2000-11-02 EP EP00971423A patent/EP1228043B1/en not_active Expired - Lifetime
- 2000-11-02 DE DE60017446T patent/DE60017446T2/de not_active Expired - Fee Related
- 2000-11-02 WO PCT/EP2000/010908 patent/WO2001032626A1/en not_active Ceased
- 2000-11-02 JP JP2001534778A patent/JP2003513075A/ja active Pending
- 2000-11-03 UY UY26426A patent/UY26426A1/es not_active Application Discontinuation
- 2000-11-03 PE PE2000001176A patent/PE20010956A1/es not_active Application Discontinuation
-
2005
- 2005-06-13 US US11/151,008 patent/US20050239797A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| DE60017446D1 (de) | 2005-02-17 |
| DE60017446T2 (de) | 2006-03-02 |
| EP1228043A1 (en) | 2002-08-07 |
| WO2001032626A1 (en) | 2001-05-10 |
| AU1028601A (en) | 2001-05-14 |
| EP1228043B1 (en) | 2005-01-12 |
| US20050239797A1 (en) | 2005-10-27 |
| UY26426A1 (es) | 2001-05-31 |
| ATE286883T1 (de) | 2005-01-15 |
| PE20010956A1 (es) | 2001-09-15 |
| JP2003513075A (ja) | 2003-04-08 |
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