KR20040016844A - 유로텐신 ⅱ 수용체 길항제인1,2,3,4-테트라하이드로이소퀴놀린 유도체 - Google Patents
유로텐신 ⅱ 수용체 길항제인1,2,3,4-테트라하이드로이소퀴놀린 유도체 Download PDFInfo
- Publication number
- KR20040016844A KR20040016844A KR10-2003-7012299A KR20037012299A KR20040016844A KR 20040016844 A KR20040016844 A KR 20040016844A KR 20037012299 A KR20037012299 A KR 20037012299A KR 20040016844 A KR20040016844 A KR 20040016844A
- Authority
- KR
- South Korea
- Prior art keywords
- dimethoxy
- ethyl
- dihydro
- isoquinolin
- urea
- Prior art date
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- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 239000005557 antagonist Substances 0.000 title claims abstract description 10
- 108050002984 Urotensin II receptors Proteins 0.000 title description 2
- 102000012327 Urotensin II receptors Human genes 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- -1 [1,8] naphthyridin-4-yl Chemical group 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 239000004202 carbamide Substances 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 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 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 6
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- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 102000005962 receptors Human genes 0.000 claims description 5
- 108020003175 receptors Proteins 0.000 claims description 5
- NZJLTTPPHKWCCD-UHFFFAOYSA-N 1-[2-[1-[(4-fluorophenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-(7-methyl-1,8-naphthyridin-4-yl)urea Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(CCNC(=O)NC=2C3=CC=C(C)N=C3N=CC=2)C1CC1=CC=C(F)C=C1 NZJLTTPPHKWCCD-UHFFFAOYSA-N 0.000 claims description 4
- NQKNPCBWMNVULG-UHFFFAOYSA-N 1-[2-[benzyl(methyl)amino]pyridin-4-yl]-3-[2-[1-[(4-fluorophenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]urea Chemical compound C=1C=C(F)C=CC=1CC1C=2C=C(OC)C(OC)=CC=2CCN1CCNC(=O)NC(C=1)=CC=NC=1N(C)CC1=CC=CC=C1 NQKNPCBWMNVULG-UHFFFAOYSA-N 0.000 claims description 4
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 208000035202 High altitude pulmonary edema Diseases 0.000 claims description 4
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002102 aryl alkyloxo group Chemical group 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
- 238000002054 transplantation Methods 0.000 claims description 4
- WLZQSCSPTZZOMK-UHFFFAOYSA-N 1-[2-[1-[(4-fluorophenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-(2-methylquinolin-4-yl)urea Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(CCNC(=O)NC=2C3=CC=CC=C3N=C(C)C=2)C1CC1=CC=C(F)C=C1 WLZQSCSPTZZOMK-UHFFFAOYSA-N 0.000 claims description 3
- UVXNPDXMWNAWLY-UHFFFAOYSA-N 1-[2-[1-[(4-fluorophenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-(5,6,7,8-tetrahydroquinolin-4-yl)urea Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(CCNC(=O)NC=2C=3CCCCC=3N=CC=2)C1CC1=CC=C(F)C=C1 UVXNPDXMWNAWLY-UHFFFAOYSA-N 0.000 claims description 3
- SXOLGZSJYMSVIZ-UHFFFAOYSA-N 1-[2-[1-[(4-fluorophenyl)methyl]-6,8-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-(2-methylquinolin-4-yl)urea Chemical compound C1=2C(OC)=CC(OC)=CC=2CCN(CCNC(=O)NC=2C3=CC=CC=C3N=C(C)C=2)C1CC1=CC=C(F)C=C1 SXOLGZSJYMSVIZ-UHFFFAOYSA-N 0.000 claims description 3
- CBJSOSSLXHWJES-UHFFFAOYSA-N 1-[2-[1-[2-(4-fluorophenyl)ethyl]-6,8-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-(2-methylquinolin-4-yl)urea Chemical compound C1=2C(OC)=CC(OC)=CC=2CCN(CCNC(=O)NC=2C3=CC=CC=C3N=C(C)C=2)C1CCC1=CC=C(F)C=C1 CBJSOSSLXHWJES-UHFFFAOYSA-N 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
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- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 3
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
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- 230000006016 thyroid dysfunction Effects 0.000 claims description 3
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- RFPPNJDJUXZQMC-UHFFFAOYSA-N 1-[(3,4-dichlorophenyl)methyl]-6-methoxy-2-[2-[(2-methylquinolin-4-yl)carbamoylamino]ethyl]-n-propyl-3,4-dihydro-1h-isoquinoline-7-carboxamide Chemical compound C=1C(C)=NC2=CC=CC=C2C=1NC(=O)NCCN1CCC=2C=C(OC)C(C(=O)NCCC)=CC=2C1CC1=CC=C(Cl)C(Cl)=C1 RFPPNJDJUXZQMC-UHFFFAOYSA-N 0.000 claims description 2
- LUXJJPBWULBAJN-UHFFFAOYSA-N 1-[(3,4-dichlorophenyl)methyl]-6-methoxy-n,n-dimethyl-2-[2-[(2-methylquinolin-4-yl)carbamoylamino]ethyl]-3,4-dihydro-1h-isoquinoline-7-carboxamide Chemical compound C1=2C=C(C(=O)N(C)C)C(OC)=CC=2CCN(CCNC(=O)NC=2C3=CC=CC=C3N=C(C)C=2)C1CC1=CC=C(Cl)C(Cl)=C1 LUXJJPBWULBAJN-UHFFFAOYSA-N 0.000 claims description 2
- PHRXGIDEEJSNTP-UHFFFAOYSA-N 1-[(3,4-dichlorophenyl)methyl]-6-methoxy-n-methyl-2-[2-[(2-methylquinolin-4-yl)carbamoylamino]ethyl]-3,4-dihydro-1h-isoquinoline-7-carboxamide Chemical compound C=1C(C)=NC2=CC=CC=C2C=1NC(=O)NCCN1CCC=2C=C(OC)C(C(=O)NC)=CC=2C1CC1=CC=C(Cl)C(Cl)=C1 PHRXGIDEEJSNTP-UHFFFAOYSA-N 0.000 claims description 2
- IVCBFIXLBHFNLJ-UHFFFAOYSA-N 1-[2-(1-benzhydryl-5,8-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-quinolin-4-ylurea Chemical compound C=1C=NC2=CC=CC=C2C=1NC(=O)NCCN1CCC=2C(OC)=CC=C(OC)C=2C1C(C=1C=CC=CC=1)C1=CC=CC=C1 IVCBFIXLBHFNLJ-UHFFFAOYSA-N 0.000 claims description 2
- YFFCIXMDLAWHOY-UHFFFAOYSA-N 1-[2-(1-benzhydryl-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-pyridin-4-ylurea Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)C1C=2C=C(OC)C(OC)=CC=2CCN1CCNC(=O)NC1=CC=NC=C1 YFFCIXMDLAWHOY-UHFFFAOYSA-N 0.000 claims description 2
- ZGZZBOFQGUNQFT-UHFFFAOYSA-N 1-[2-(1-benzhydryl-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-quinolin-4-ylurea Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(CCNC(=O)NC=2C3=CC=CC=C3N=CC=2)C1C(C=1C=CC=CC=1)C1=CC=CC=C1 ZGZZBOFQGUNQFT-UHFFFAOYSA-N 0.000 claims description 2
- MDNNGMLXSHFVGE-UHFFFAOYSA-N 1-[2-(1-benzyl-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-pyridin-4-ylurea Chemical compound C=1C=NC=CC=1NC(=O)NCCN1CCC2=CC=CC=C2C1CC1=CC=CC=C1 MDNNGMLXSHFVGE-UHFFFAOYSA-N 0.000 claims description 2
- BQNRYJHBHWUIJY-UHFFFAOYSA-N 1-[2-(1-benzyl-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-quinolin-4-ylurea Chemical compound C=1C=NC2=CC=CC=C2C=1NC(=O)NCCN1CCC2=CC=CC=C2C1CC1=CC=CC=C1 BQNRYJHBHWUIJY-UHFFFAOYSA-N 0.000 claims description 2
- ATFLTLDVBOARQX-UHFFFAOYSA-N 1-[2-(1-benzyl-5,8-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-pyridin-4-ylurea Chemical compound C=1C=NC=CC=1NC(=O)NCCN1CCC=2C(OC)=CC=C(OC)C=2C1CC1=CC=CC=C1 ATFLTLDVBOARQX-UHFFFAOYSA-N 0.000 claims description 2
- XOIVNJHHLSAOEI-UHFFFAOYSA-N 1-[2-(1-benzyl-5,8-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-quinolin-4-ylurea Chemical compound C=1C=NC2=CC=CC=C2C=1NC(=O)NCCN1CCC=2C(OC)=CC=C(OC)C=2C1CC1=CC=CC=C1 XOIVNJHHLSAOEI-UHFFFAOYSA-N 0.000 claims description 2
- KTOSUZZARDNXEK-UHFFFAOYSA-N 1-[2-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-(2-methylquinolin-4-yl)urea Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(CCNC(=O)NC=2C3=CC=CC=C3N=C(C)C=2)C1CC1=CC=CC=C1 KTOSUZZARDNXEK-UHFFFAOYSA-N 0.000 claims description 2
- HVKBVYFEIOSMSJ-UHFFFAOYSA-N 1-[2-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-pyridin-4-ylurea Chemical compound C=1C=CC=CC=1CC1C=2C=C(OC)C(OC)=CC=2CCN1CCNC(=O)NC1=CC=NC=C1 HVKBVYFEIOSMSJ-UHFFFAOYSA-N 0.000 claims description 2
- LWJKGFMIYZKUDV-UHFFFAOYSA-N 1-[2-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-quinolin-4-ylurea Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(CCNC(=O)NC=2C3=CC=CC=C3N=CC=2)C1CC1=CC=CC=C1 LWJKGFMIYZKUDV-UHFFFAOYSA-N 0.000 claims description 2
- IDOLYTOKBTYTAS-UHFFFAOYSA-N 1-[2-(1-benzyl-6-methoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-pyridin-4-ylurea Chemical compound C=1C=NC=CC=1NC(=O)NCCN1CCC2=CC(OC)=CC=C2C1CC1=CC=CC=C1 IDOLYTOKBTYTAS-UHFFFAOYSA-N 0.000 claims description 2
- FVGJGZTYMUILGK-UHFFFAOYSA-N 1-[2-(1-benzyl-6-methoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-quinolin-4-ylurea Chemical compound C=1C=NC2=CC=CC=C2C=1NC(=O)NCCN1CCC2=CC(OC)=CC=C2C1CC1=CC=CC=C1 FVGJGZTYMUILGK-UHFFFAOYSA-N 0.000 claims description 2
- MQEJLJNQXYVUFF-MUUNZHRXSA-N 1-[2-[(1r)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-(2-methylquinolin-4-yl)urea Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H]1C2=CC(OC)=C(OC)C=C2CCN1CCNC(=O)NC1=CC(C)=NC2=CC=CC=C12 MQEJLJNQXYVUFF-MUUNZHRXSA-N 0.000 claims description 2
- QGNVFJPVQOKCIM-HHHXNRCGSA-N 1-[2-[(1r)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-quinolin-4-ylurea Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H]1C2=CC(OC)=C(OC)C=C2CCN1CCNC(=O)NC1=CC=NC2=CC=CC=C12 QGNVFJPVQOKCIM-HHHXNRCGSA-N 0.000 claims description 2
- WLZQSCSPTZZOMK-MUUNZHRXSA-N 1-[2-[(1r)-1-[(4-fluorophenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-(2-methylquinolin-4-yl)urea Chemical compound C([C@H]1N(CCNC(=O)NC=2C3=CC=CC=C3N=C(C)C=2)CCC=2C=C(C(=CC=21)OC)OC)C1=CC=C(F)C=C1 WLZQSCSPTZZOMK-MUUNZHRXSA-N 0.000 claims description 2
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- RCWNFQOIKSKDCB-UHFFFAOYSA-N 1-[2-[1-(1,3-benzodioxol-5-ylmethyl)-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-quinolin-4-ylurea Chemical compound C1=C2OCOC2=CC(CC2N(CCNC(=O)NC=3C4=CC=CC=C4N=CC=3)CCC=3C=C(C(=CC=32)OC)OC)=C1 RCWNFQOIKSKDCB-UHFFFAOYSA-N 0.000 claims description 2
- QUFCEURLAKMOKZ-UHFFFAOYSA-N 1-[2-[1-[(2,5-dimethoxyphenyl)methyl]-5,8-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-quinolin-4-ylurea Chemical compound COC1=CC=C(OC)C(CC2C3=C(OC)C=CC(OC)=C3CCN2CCNC(=O)NC=2C3=CC=CC=C3N=CC=2)=C1 QUFCEURLAKMOKZ-UHFFFAOYSA-N 0.000 claims description 2
- NEUKZVFYJQBISH-UHFFFAOYSA-N 1-[2-[1-[(2,5-dimethoxyphenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-pyridin-4-ylurea Chemical compound COC1=CC=C(OC)C(CC2C3=CC(OC)=C(OC)C=C3CCN2CCNC(=O)NC=2C=CN=CC=2)=C1 NEUKZVFYJQBISH-UHFFFAOYSA-N 0.000 claims description 2
- HDKOEMTWLBMZQD-UHFFFAOYSA-N 1-[2-[1-[(2,5-dimethoxyphenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethyl]-3-quinolin-4-ylurea Chemical compound COC1=CC=C(OC)C(CC2C3=CC(OC)=C(OC)C=C3CCN2CCNC(=O)NC=2C3=CC=CC=C3N=CC=2)=C1 HDKOEMTWLBMZQD-UHFFFAOYSA-N 0.000 claims description 2
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P11/06—Antiasthmatics
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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Abstract
본원 발명은 신규한 1,2,3,4-테트라하이드로이소퀴놀린 유도체와 관련된 화합물 및 제약학적 조성물의 제조에서 활성 성분으로서 이들의 용도에 관한다. 또한, 본원 발명은 상기 화합물의 제조 공정, 한가지이상의 이들 화합물을 함유하는 제약학적 조성물, 신경호르몬 길항제로서 이들의 용도를 비롯한 관련된 측면에 관한다.
Description
유로텐신 Ⅱ은 소마토스타틴-14에 상당한 서열 상동성을 보유하긴 하지만 이와 상동하지는 않는 환형 11개-아미노산 펩티드이다. 유로텐신 Ⅱ는 어류 척수로부터 처음 분리되고 서열분석되었고(Bern HA, Pearson D, Larson BA, Nishioka RS. Neurohormones from fish tails: the caudal neurosecretory system. I. "Urophysiology" and the caudal neurosecretory system of fishes. Recent Prog. Horm. Res. (1985) 41, 533-552), 이후 다양한 척추동물과 무척추동물 종에서 발견되었다. 사람 유로텐신 Ⅱ는 크로모좀 1p36.21에 위치한 단일 유전자로부터 프레프로-형태로 합성되고, 추정 신호 펩티드 서열이 상이한 2개의 cDNA 절단접합 변이체는 사람 결장 종양과 사람 태반으로부터 분리되었다(GenBank Accession Nr. 095399). 추정 전구호르몬 전환효소 이염기성 절단 부위는 종간에 엄격하게 보존된다. 성숙 11개-아미노산 펩티드는 엄격하게 보존된 C-말단 이황화-결합된 6개-아미노산 루프를 보유하고, 성숙 환형 펩티드의 N-말단 영역은 종간에 변할 수 있다.
유로텐신 Ⅱ는 포유동물에서 강력하고 복잡한 혈역학적 작용을 한다(Douglas SA, Sulpizio AC, piercy V, Sarau HM, Ames RS, Aiyar NV, Ohlstein EH, Willette RN. "Differential vasoconstrictor activity of human urotensin-Ⅱ in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey." Br. J. Pharmacol.(2000) 131, 1262-1274. Douglas, SA, Ashton DJ, Sauermelch CF, Coatney RW, Ohlstein DH, Ruffolo MR, Ohlstein EH, Aiyar NV, Willette R "Human Urotensin-Ⅱ is a potent vasoactive peptide: pharmacological characterization in the rat, mouse, dog and primate." J. Cardiovasc. Pharmacol. (2000) 36, Suppl 1:S163-6). 상기 펩티드는 분리된 포유동물 동맥을 효과적으로 수축시킨다. 이런 혈관수축 효능은 엔도텔린-1의 효능보다 1 크기 자리수 높다. 이들 효과는 GPR-14 또는 SENR이라고 하는 수용체에 결합된 G-단백질에 대한 유로텐신-Ⅱ의 작용을 통하여 적어도 부분적으로 매개되는 것으로 보인다(Ames RS, et al. "Human urotensin-Ⅱ is a potent vasoconstrictor and agonist for the orphan receptor GPR14." Nature. (1999)401,282-6. Mori M, Sugo T, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y,Kurokawa T, Onda H, Nishimura O, Fujino M. "Urotensin Ⅱ is the endogenous ligand of G-proteincoupled orphan receptor, SENR(GPR14)" Biochem. Biophys. Res. Commun. (1999)265,123-9, Liu Q, Pong SS, Zeng Z, et al. "Identification of urotensin Ⅱ as the endogenous ligand for the orphan G-protein-coupled receptor GPR14" Biochem. Biophys. Res. Commun. (1999)266, 174-178). GPR14는 동맥(정맥아님) 평활근, 심방과 심실 심근세포, 췌장, 신장, 뇌에서 발현된다.
혈관수축 작용이외에, 유로텐신 Ⅱ는 심방과 심실 근육 수축에 잠재적인 영향을 준다(Russel FD, Molenaar P, and O'Brien DM "Cardiostimulant effects of urotensin-Ⅱ in human heart in vitro". Br J Pharmacol(2001) 132, 5-9).
유로텐신 Ⅱ는 심장 섬유아세포(Tzandis A, et al., "Urotensin Ⅱ stimulates collagen synthesis by cardiac fibroblasts and hypertrophic signaling cardiomyocytes via G(alpha)q- and Ras-dependent pathways." J. Am. Coll. Cardiol. (2001) 37, 164A.) 및 신생아 근세포(Zou Y, Nagi R, and Yamazaki T, "Urotensin Ⅱ induces hypertrophic response in cultured cardiomyocytes from neonatal rats". FEBS Lett(2001) 508, 57-60)에서 세포 증식, 이동, 콜라겐 합성을 촉진한다. 유로텐신 Ⅱ는 암 세포주에 의해 생산되고, 이의 수용체 역시 이들 세포에서 발현된다(Takahashi K, et al., "Expression of urotensin Ⅱ and urotensin Ⅱ receptor mRNA in various tumor cell lines and secretion of urotensin Ⅱ-like immunoreactivity by SW-13 adrenocortical cells." peptides(2001) 22, 1175-9).
유로텐신 Ⅱ는 췌장에서 글루코오스-촉진된 인슐린 방출을 조절한다(Silvestre RA, et al., "Inhibition of insulin release by urotensin Ⅱ-a study on the perfused rat pancreas". Horm Metab Res(2001) 33, 379-81).
상승된 순환 수준의 유로텐신 Ⅱ는 높은-고도 폐 부종에 민감한 사람 및 신장 이식을 기다리는 환자에서 탐지된다(Gartlon J, et al., "Central Effects of urotensin-Ⅱ following ICV administration in rats". Psychopharmacology(Berlin)(2001) 155, 426-33).
따라서, 유로텐신 Ⅱ의 작용을 차단하는 능력을 가진 물질은 다양한 질환의 치료에 유용할 것으로 기대된다. WO-2001/45694에서는 유로텐신 Ⅱ 수용체 길항제로 유용한 특정 설폰아마이드 및 유로텐신 Ⅱ 불균형과 연관된 질환의 치료에서 이들의 용도를 개시한다. WO-2001/45700에서는 유로텐신 Ⅱ 수용체 길항제로 유용한 특정 피롤리돈 및 유로텐신 Ⅱ 불균형과 연관된 질환의 치료에서 이들의 용도를 개시한다. WO-2001/45711에서는 유로텐신 Ⅱ 수용체 길항제로 유용한 특정 피롤릴과 피리딜 유도체 및 유로텐신 Ⅱ 불균형과 연관된 질환의 치료에서 이들의 용도를 개시한다. WO-2002/00606에서는 유로텐신 Ⅱ 수용체 길항제로 유용한 특정 비페닐 화합물을 개시하고, WO-2002/02530 역시 유로텐신 Ⅱ 수용체 길항제로 유용한 특정 화합물을 개시한다.
본원 발명은 유로텐신 Ⅱ 수용체 길항제인 신규한 1,2,3,4-테트라하이드로이소퀴놀린 유도체 조성물에 관한다. EP 428434에서는 뉴로키닌(neurokinin) 및 물질 P 길항제로서 특정 알킬우레이도피리딘을 개시한다. WO-99/21835에서는 H+-ATPase 및 골 재흡수 저해물질로서 특정 우레이도퀴놀린을 개시한다. WO-01/009088에서는 CCR-3 수용체의 저해물질로서 특정 치환된 헤테로아릴유레아를 개시한다.
본원 발명은 신규한 화학식 I의 1,2,3,4-테트라하이드로이소퀴놀린 유도체 및 제약학적 조성물의 제조에서 활성 성분으로서 이들의 용도에 관한다. 또한, 본원 발명은 화학식 I 화합물의 제조 공정, 한가지이상의 화학식 Ⅰ 화합물을 함유하는 제약학적 조성물, 신경호르몬 길항제로서 이들의 용도를 비롯한 관련된 측면에 관한다.
본원 발명은 화학식 Ⅰ 화합물, 광학적으로 순수한 거울상이성질체나 부분입체이성질체, 거울상이성질체나 부분입체이성질체의 혼합물, 부분입체이성질성 라셈체, 부분입체이성질성 라셈체의 혼합물, 이들의 제약학적으로 수용가능한 염, 용매 복합체, 조직학적 형태에 관한다.
여기서,
X는 -CH2-, -CH2CH2-, -C(CH3)2-이고;
Y는 산소, NH이고;
n은 1이나 2이고;
Z는
2, 6 혹은 8번 위치에서 저급 알킬로 단일-치환되거나 또는 2,6 혹은 2,8번 위치에서 저급 알킬로 이중-치환될 수 있는 퀴놀린-4-일; 7번 위치에서 저급 알킬로 치환될 수 있는 [1,8]나프티리딘-4-일; 2번 위치에서 R7R8N-으로 치환되고 6번 위치에서 수소 혹은 저급 알킬로 추가로 치환될 수 있는 피리딘-4-일이고;
R1은 나프탈렌-1-일; 나프탈렌-2-일; 벤조[1,3]디옥솔-5-일; 벤질, 또는 페닐 고리에서 저급 알킬, 저급 알킬옥시, 트리플루오르메틸, 할로겐, 시아노로 독립적으로 치환되는 단일-, 이중-, 혹은 삼중-치환된 벤질; 페닐, 또는 저급 알킬, 저급 알킬옥시, 트리플루오르메틸, 할로겐, 시아노로 독립적으로 치환되는 단일-, 이중-, 혹은 삼중-치환된 페닐이고;
R2는 수소, 저급 알킬, 아릴, 또는 R1이 E 혹은 Z 기하학적 구조의 스트릴기인 형태이고, 상기 스트릴기에서 페닐 고리는 저급 알킬, 저급 알킬옥시, 트리플루오르메틸, 할로겐, 시아노로 독립적으로 치환되는 단일-, 이중- 혹은 삼중-치환된 페닐이며;
R3, R4, R5, R6은 독립적으로 수소, 시아노, 하이드록시, 저급 알킬옥시, 아르알킬옥시, 저급 알케닐옥시이고, R5는 추가적으로 R7R8NCO이며;
R4와 R5는 서로 결합하여 페닐 고리와 함께, 1개 혹은 2개의 산소 원자를 보유하는 5각형이나 6각형 고리를 형성할 수 있고;
R7과 R8은 독립적으로 수소, 저급 알킬, 아릴, 아르알킬이거나 또는 N과 결합하여 피롤리딘, 피페리딘 혹은 모르폴린 고리를 형성한다.
화학식 I의 정의에서, '저급 알킬'은 1개 내지 7개의 탄소 원자, 바람직하게는 1개 내지 4개의 탄소 원자를 갖는 직쇄나 분지쇄 작용기; 또는 3개 내지 6개의 탄소 원자를 갖는 환형 알킬기를 의미한다. 저급 알킬기의 바람직한 예는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소-부틸, sec-부틸, tert-부틸, n-펜틸, n-헥실, n-헵틸, 사이클로프로필, 사이클로부틸, 사이클로펜틸 또는 사이클로헥실이다.
'저급 알킬옥시'는 저급 알킬-O-의 작용기를 의미하는데, 여기서 '저급 알킬'은 전술한 바와 동일하다. 저급 알킬옥시기의 바람직한 예는 메톡시, 에톡시, 프로폭시, 이소-프로폭시, 부톡시, 이소-부톡시, sec-부톡시, tert-부톡시, 사이클로펜틸옥시, 사이클로헥실옥시이다.
'저급 알케닐옥시'는 저급 알케닐-O-의 작용기를 의미하는데, 여기서 '저급 알케닐'은 2개 내지 5개 탄소 원자를 갖는 직쇄나 분지쇄 알케닐기를 의미한다. 저급 알케닐옥시기의 바람직한 예는 알릴옥시 또는 프로페닐옥시이다.
'아릴'은 1개 이상의 치환체, 바람직하게는 1개 혹은 2개의 치환체를 선택적으로 보유하는 페닐이나 나프틸기를 의미하는데, 이들 치환체 각각은 시아노, 할로겐, 저급 알킬, 저급 알케닐, 저급 알킬옥시, 저급 알케닐옥시, 트리플루오르메틸, 트리플루오르메톡시, 아미노, 카르복시 등에서 독립적으로 선택된다. 아릴기의 바람직한 예는 페닐, 4-메틸페닐, 4-메톡시페닐, 4-시아노페닐, 4-클로로페닐, 4-플루오르페닐, 2-메틸페닐, 2-클로로페닐, 2-플루오르페닐, 2-메톡시페닐, 나프탈렌-1-일, 나프탈렌-2-일이다.
'아르알킬'은 1개의 수소 원자가 상기 정의된 아릴기로 치환되는 저급 알킬기를 의미한다. 아르알킬기의 바람직한 예는 벤질 및 페닐 고리에서 하이드록시, 저급 알킬, 저급 알킬옥시 또는 할로겐으로 치환된 벤질이다.
'아르알킬옥시'는 아르알킬-O-의 작용기를 의미하는데, 여기서 '아르알킬'은 전술한 바와 동일하다. 아르알킬옥시의 바람직한 예는 벤질옥시와 펜에틸옥시이다.
본원 발명에는 화학식 I 화합물의 제약학적으로 수용가능한 염이 포함된다. 여기에는 하이드로할로겐산과 같은 무기산이나 유기산과의 염, 예를 들면 염화수소산이나 브롬화수소산, 황산, 인산, 질산, 구연산, 포름산, 아세트산, 말레산, 주석산, 메틸설폰산, p-톨릴설폰산 등과의 염; 또는 화학식 I 화합물이 산성인 경우에 알칼리나 토류 알칼리 염기와 같은 무기염기와의 염, 예를 들면 나트륨, 칼륨, 칼슘 염 등이 포함된다.
본원 발명에는 화학식 I 화합물의 여러 용매화 복합물이 포함된다. 용매화는 제조 과정동안 달성되거나, 또는 예로써 화학식 I의 초기 무수성 화합물의 흡습성으로 인하여 별도로 진행될 수 있다.
본원 발명에는 화학식 I 화합물의 상이한 조직학적 형태, 예를 들면 화학식 I 화합물의 결정 형태 및 이들의 염과 용매화 복합물 역시 포함된다. 특정 이형체(heteromorph)는 서로 상이한 분해 특성, 안정성 프로필 등을 보이는데, 이들 모두 본원 발명의 범주에 속한다.
화학식 I 화합물은 1개 이상의 비대칭 탄소 원자를 보유할 수 있고, 광학적으로 순수한 거울상이성질체나 부분입체이성질체, 거울상이성질체나 부분입체이성질체의 혼합물, 부분입체이성질성 라셈체, 부분입체이성질성 라셈체의 혼합물 형태로 만들어 질 수 있다. 이런 형태 모두 본원 발명에 포함된다. 이들은 입체선택적 합성, 또는 당분야에 공지된 혼합물 분리 방법, 예를 들면 칼럼 크로마토그래피, 박막 크로마토그래피, HPLC, 결정화 등으로 수득한다.
화학식 I의 바람직한 화합물은 화학식 Ⅱ 화합물이다:
여기서, R1, R2, R3, R4, R5, R6, X, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 Ⅲ 화합물이다:
기서, R1, R2, R3, R4, R5, R6, X, Y, Z는 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 Ⅳ 화합물이다:
여기서, R1, R2, R3, R4, R5, R6, Y, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 Ⅴ 화합물이다:
여기서, R1, R2, R3, R4, R5, R6, Y, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 Ⅵ 화합물이다:
여기서, R1, R2, R3, R4, R5, R6, Y, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 Ⅶ 화합물이다:
여기서, R1, R3, R4, R5, R6, X, Y, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 Ⅷ 화합물이다:
여기서, Ph는 페닐; 독립적으로 수소, 저급 알킬, 저급 알킬옥시, 트리플루오르메틸, 할로겐, 시아노로 치환되는 단일-, 이중- 혹은 삼중-치환된 페닐이고, R3, R4, R5, R6, X, Y, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 Ⅸ 화합물이다:
여기서, R1, R2, X, Y, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 Ⅹ 화합물이다:
여기서, R1, R2, X, Y, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 11 화합물이다:
여기서, R1, R2, X, Y, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 12 화합물이다:
여기서, R1, R2, R3, R4, R5, R6, X, Y, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 ⅩⅢ 화합물이다:
여기서, R1, R2, R3, R4, R5, R6, X, Y, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 ⅩⅣ 화합물이다:
여기서, R1, R2, R3, R4, R5, R6, R7, R8, X, Y, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 ⅩⅤ 화합물이다:
여기서, 1,2,3,4-테트라하이드로이소퀴놀린 고리의 1번 위치는 R 절대 입체화학적 배열을 갖고; R1, R2, R3, R4, R5, R6, X, Z, n은 화학식 I에서와 동일하다.
화학식 I의 다른 바람직한 화합물은 화학식 ⅩⅥ 화합물이다:
여기서, R3, R4, R5, R6은 독립적으로 수소 또는 저급 알킬옥시이고; R1, R2, Z는 화학식 I에서와 동일하다.
화학식 I의 특히 바람직한 화합물의 예는 다음과 같다:
1-{2-[1-(4-플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(3,4-디플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(3-플루오르-4-메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(3,4-디플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(3-플루오르-4-메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(4-플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-(2-{1-[2-(4-플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(2,4-디플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(2,4-디플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-퀴놀린-4-일-유레아;
1-(2-{1-[2-(3,4-디플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(3,4-디플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-퀴놀린-4-일-유레아;
1-(2-{1-[2-(4-플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-퀴놀린-4-일-유레아;
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-7,8-디메톡시-1,3,4,5-테트라하이드로-벤조[c]아제핀-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[(E)-2-(2,4-디플루오르-페닐)-비닐]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[(E)-2-(2,5-디플루오르-페닐)-비닐]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(2,3-디플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(2,4-디플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(2,5-비스-트리플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(2,5-디플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(3,4-디플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(3,4-디메톡시-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(3,5-비스-트리플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{1-[2-(4-플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{6,7-디메톡시-1-[2-(2-메톡시-페닐)-에틸]-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{6,7-디메톡시-1-[2-(3-메톡시-페닐)-에틸]-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{6,7-디메톡시-1-[2-(4-메톡시-페닐)-에틸]-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(2-{6,7-디메톡시-1-[2-(4-트리플루오르메틸-페닐)-에틸]-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;
1-[2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-(2-메틸-퀴놀린-4-일)-유레아;
1-[2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-[3-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필]-3-(2-메틸-퀴놀린-4-일)-유레아;
1-[3-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필]-3-퀴놀린-4-일-유레아;
1-[2-(1-벤조[1,3]디옥솔-5-일메틸-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-(2-메틸-퀴놀린-4-일)-유레아;
1-[2-(1-벤조[1,3]디옥솔-5-일메틸-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[2-(1-벤조[1,3]디옥솔-5-일메틸-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-[2-(1-벤질-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[2-(1-벤질-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-[2-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-(2-메틸-퀴놀린-4-일)-유레아;
1-[2-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[2-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-[2-(1-벤질-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[2-(1-벤질-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-[2-(6,7-디메톡시-1-나프탈렌-2-일메틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[2-(6,7-디메톡시-1-나프탈렌-2-일메틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-[2-(6,7-디메톡시-1-페녹시메틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[3-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필]-3-(2-메틸-퀴놀린-4-일)-유레아;
1-[3-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필]-3-퀴놀린-4-일-유레아;
1-{2-[1-(2,5-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[1-(2,5-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(2,6-디클로로-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(3,4-디플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[1-(3,4-디플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6,7,8-트리메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(5,6,7,8-테트라하이드로-퀴놀린-4-일)-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(3-플루오르-4-메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(3-플루오르-5-트리플루오르메틸-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(4-클로로-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[1-(4-클로로-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[6,7-디메톡시-1-(2,3,4-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[6,7-디메톡시-1-(2,3,4-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[6,7-디메톡시-1-(3,4,5-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[6,7-디메톡시-1-(3,4,5-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[6,7-디메톡시-1-(3,4,5-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[6,7-디메톡시-1-(3-메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[6,7-디메톡시-1-(3-메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[6,7-디메톡시-1-(4-메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[6,7-디메톡시-1-(4-메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{3-[1-(3,4-디플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-퀴놀린-4-일-유레아;
1-{3-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{3-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-퀴놀린-4-일-유레아;
1-{3-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{3-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-퀴놀린-4-일-유레아;
1-{3-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-퀴놀린-4-일-유레아;
1-{2-[5-(3,4-디메톡시-벤질)-7,8-디하이드로-5H-[1,3]디옥솔로[4,5-g]이소퀴놀린-6-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[5-(3,4-디메톡시-벤질)-7,8-디하이드로-5H-[1,3]디옥솔로[4,5-g]이소퀴놀린-6-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[6-(3,4-디메톡시-벤질)-2,3,8,9-테트라하이드로-6H-[1,4]디옥시노[2,3-g]이소퀴놀린-7-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[6-(3,4-디메톡시-벤질)-2,3,8,9-테트라하이드로-6H-[1,4]디옥시노[2,3-g]이소퀴놀린-7-일]-에틸}-3-퀴놀린-4-일-유레아;
1-[2-(1-벤즈하이드릴-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-[2-(1-벤즈하이드릴-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[2-(1-벤즈하이드릴-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-[2-(1-벤질-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;
1-[2-(1-벤질-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(2,5-디메톡시-벤질)-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[6,7-디메톡시-1-(1-페닐-프로필)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;
1-{2-[6,7-디메톡시-1-(1-페닐-프로필)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-4,4-디메틸-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[(R)-1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[(R)-1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;
1-{2-[(R)-1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[7-벤질옥시-1-(3,4-디메톡시-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-{2-[1-(3,4-디메톡시-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;
1-(3,4-디클로로-벤질)-6-메톡시-2-{2-[3-(2-메틸-퀴놀린-4-일)-우레이도]-에틸}-1,2,3,4-테트라하이드로이소퀴놀린-7-카르복실산 메틸아마이드;
1-(3,4-디클로로-벤질)-6-메톡시-2-{2-[3-(2-메틸-퀴놀린-4-일)-우레이도]-에틸}-1,2,3,4-테트라하이드로이소퀴놀린-7-카르복실산 프로필아마이드;
1-(3,4-디클로로-벤질)-6-메톡시-2-{2-[3-(2-메틸-퀴놀린-4-일)-우레이도]-에틸}-1,2,3,4-테트라하이드로이소퀴놀린-7-카르복실산 디메틸아마이드;
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(7-메틸-[1,8]나프티리딘-4-일)-유레아;
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(5,6,7,8-테트라하이드로-퀴놀린-4-일)-유레아;
1-[2-(벤질-메틸-아미노)-피리딘-4-일]-3-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-유레아;
1-[2-(벤질-메틸-아미노)-6-메틸-피리딘-4-일]-3-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-유레아;
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-[2-(메틸-페닐-아미노)-피리딘-4-일]-유레아;
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-피롤리딘-1-일-피리딘-4-일)-유레아;
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸아미노-1-일-피리딘-4-일)-유레아;
퀴놀린-4-일-카르밤산 2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸 에스테르;
퀴놀린-4-일-카르밤산 2-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸 에스테르;
퀴놀린-4-일-카르밤산 2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸 에스테르;
퀴놀린-4-일-카르밤산 3-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;
퀴놀린-4-일-카르밤산 3-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;
퀴놀린-4-일-카르밤산 3-[1-(3,4-디플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;
퀴놀린-4-일-카르밤산 3-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;
퀴놀린-4-일-카르밤산 3-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르.
유로텐신 Ⅱ의 작용을 저해하는 능력으로 인하여, 전술한 화합물은 유로텐신 Ⅱ의 작용으로 인한 혈관수축 증가, 확산, 다른 병적 상태와 연관된 질환의 치료에 사용될 수 있다. 이런 질환의 예는 고혈압, 죽상경화증, 협심증이나 심근 허혈,울혈성 심장 마비, 심부전, 심장 부정맥, 신허혈, 만성 신장 질환, 신부전, 발작, 뇌혈관 연축, 뇌 허혈, 치매, 편두통, 지주막하 출혈, 당뇨병, 당뇨성 혈관경화증, 천식, 만성 폐색성 폐 질환, 높은-고도 폐 부종, 레이노 증후군, 문맥 고혈압, 갑상선 기능장애, 폐 부종, 폐 고혈압, 폐 섬유증 등이다. 이들은 풍선이나 스텐트 혈관성형술이후 재협착, 암, 전립선 비대, 발기 장애, 청력 상실, 흑내장, 만성 기관지염, 천식, 그람 네거티브 패혈증, 쇼크, 겸상적혈구 빈혈, 사구체신염, 신장통, 녹내장, 당뇨합병증, 혈관이나 심장 수술 또는 장기 이식후 합병증, 사이클로스포린 치료의 합병증, 통증, 중독, 정신분열증, 알츠하이머병, 불안, 강박 행동, 간질성 발작, 스트레스, 우울증, 치매, 신경근육 질환, 신경퇴행성 질환, 유로텐신 Ⅱ/유로텐신 Ⅱ 수용체의 조절이상과 관련된 다른 질환의 치료와 예방에도 사용될 수 있다.
이들 조성물은 장영양(enteral)이나 경구 형태, 예를 들면 정제, 당의정, 젤라틴 캡슐, 에멀젼, 용액, 현탁액; 비강 형태, 예를 들면 스프레이; 또는 직장에 좌약 형태로 투여될 수 있다. 이들 화합물은 근육내, 장관외 또는 정맥내 형태, 예를 들면 주사가능 용액 형태로 투여될 수도 있다.
이들 제약학적 조성물은 화학식 I 화합물 및 제약업에 통상적으로 사용되는 무기 및/또는 유기 부형제, 예를 들면 락토오스, 옥수수나 이의 유도체, 활석, 스테아르산 또는 이들 물질의 염과 혼합된 제약학적으로 수용가능한 염을 함유한다.
젤라틴 캡슐의 제조에 식물성 오일, 왁스, 지방, 지질 또는 반-지질 폴리올 등이 사용될 수 있다. 용액과 시럽의 제조에 물, 폴리올, 사카로오스, 글루코오스등이 사용된다. 주사가능물질은 물, 폴리올, 알코올, 글리세린, 식물성 오일, 레시틴, 리포좀 등을 사용하여 제조한다. 좌약은 자연이나 수소첨가된 오일, 왁스, 지방산(지방), 액체나 반-액체 폴리올 등을 사용하여 제조한다.
조성물은 방부제, 안정화 개선물질, 점도 개선이나 조절 물질, 용해도 개선물질, 감미료, 염료, 미각 개선 화합물, 삼투압을 변화시키는 염, 완충액, 항-산화제 등을 추가로 함유할 수 있다.
화학식 I 화합물은 1가지이상의 다른 치료요법적으로 유용한 물질, 예를 들면 펜톨라민, 페녹시벤자민, 아테놀롤, 프로프라놀롤, 티몰롤, 메토프롤롤, 카르테올롤, 카르베딜롤 등과 같은 α-와 β-차단제; 하이드랄라진, 미녹시딜, 디아족시드, 플로세퀴난 등과 같은 혈관확장제; 딜티아젬, 니카르디핀, 니모디핀, 베라파밀, 니페디핀 등과 같은 칼슘-길항제; 실라제프릴, 카프토프릴, 엔알라프릴, 리시노프릴 등과 같은 안지오텐신 전환효소-저해제; 피나시딜, 크로마칼림 등과 같은 칼륨 채널 활성화제; 로사르탄, 발사르탄, 칸데사르탄, 이르베사르탄, 에프로사르탄, 텔미사르탄, 타소사르탄 등과 같은 안지오텐신 수용체 길항제; 하이드로클로로티아지드, 클로로티아지드, 아세톨아마이드, 부메타니드, 푸로세미드, 메톨라존, 클로르탈리돈 등과 같은 이뇨제; 메틸도파, 클로니딘, 구아나벤즈, 레세르핀 등과 같은 교감신경자극차단제; 보센탄, 테조센탄, 다루센탄, 아트라센탄, 엔라센탄, 시탁센탄 등과 같은 엔도텔린 수용체 길항제; 로바스타틴, 프라비스타틴, 플루바스타틴, 아토르바스타틴, 세리바스타틴, 심바스타틴 등과 같은 고지혈증 치료제; 고혈압, 혈관 질환 또는 전술한 다른 질환을 치료하는 다른 치료약물과 병용될 수도 있다.
용량은 넓은 범위에서 변할 수 있지만 특정 상황에 적합하게 조정되어야 한다. 일반적으로, 경구 형태에서 일일 용량은 약 70 ㎏ 성인에서 대략 3 ㎎ 내지 3g, 바람직하게는 대략 10 ㎎ 내지 1 g, 좀더 바람직하게는 5 ㎎ 내지 300 ㎎이다. 적절하게는, 용량은 매일 동량의 1 내지 3회 분량으로 투여된다. 일반적으로, 어린이는 체중과 연령에 적합한 좀더 적은 분량을 복용한다.
화학식 I 화합물은 후술된 반응 순서에 따라 당분야에 공지된 방법으로 만들 수 있다. 단순 명쾌하게 하기 위하여, 화학식 I 화합물을 결과하는 일부 가능 합성 루트만 기술한다.
화학식 I 화합물에 반응식 I 내지 Ⅴ에서 밝힌 일반적 합성 루트를 이용할 수 있다. 일부 경우에는 1개 이상의 다양한 작용기(R1내지 R9, X, Y, Z, n)가 반응식 I 내지 V에서 밝힌 어셈블리와 부적합하여 보호기의 사용이 필요하다. 보호기의 사용은 당분야에 공지된 것이다(참조: Protective Groups in Organic Synthesis, T.W. Greene, Wiley-Interscience, 1981). 보호를 필요로 하는 특정 작용기는 아민(아마이드 또는 카르바메이트로 보호됨), 알코올(에스테르 또는 에테르로 보호됨), 카르복실산(에스테르로 보호됨)이다. 이와 관련하여, 이들 보호기는 필요한 자리에 위치한다고 추정한다.
반응식 I 내지 Ⅲ에서 화학식 I의 1,2,3,4-테트라하이드로이소퀴놀린과 1,2,3,4-테트라하이드로벤즈[c]아제핀은 상업적으로 가용하거나 또는 당분야에 공지된 방법으로 라셈형이나 광학적 활성형태로 제조된다. 가령, 이들은 POCl3이나 PCl5의 작용하에 상응하는 페닐에틸아민이나 페닐프로필아민으로부터 유래된 아마이드의 고리-닫힘 응축 반응, 이후 NaBH4와 같은 환원제 처리로 만들 수 있다(Whaley WM, Govindachari TR "The Preparation of 3,4-dihydroisoquinolines and related compounds by the Bischler-Napieralski reaction." Org. React. (1951) 6, 74-106. Finkelstein J, Chiang E, Brossi A "Synthesis of 1,2,3,4-tetrahydro-1,1,2,3,3,4,4-heptamethyl-6,7-dimethoxyisoquinoline and related compounds as potential hypotensive agents." J. Med. Chem. (1971) 14, 584-588. Ukaji Z, Shimizu Y, Kenmoku Y, Ahmend A, Inomata K "Catalytic asymmetric addition of dialkylzinc to 3,4-dihydroisoquinoline N-oxides utilizing tartaric acid ester as a chiral auxiliary." Bull. Chem. Soc. Jpn. (2000), 73, 447-452. Zheng W, Nikulin VI, Konkar AA, Vansol SS, Shams G, Feller DR, Miller DD "2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c] pyridines: novel selective beta3-adrenoceptor antagonists." J Med Chem(1999), 42, 2287-2294). 거울상이성질에서 실질적으로 순수한 1-치환된-2-테트라하이드로이소퀴놀린과 1-치환된-2-테트라하이드로벤자제핀 유도체는 유사한 방법으로 만들어진다(Polniasz다 R.P. et al., J. Am. Chem. Soc. (1989) 111, 4859-4863). 이런 비대칭 합성의 핵심 단계는Bischler-Napieralski반응으로 수득되는 키랄성 이미늄 이온의 입체선택적 수소화물 환원이다. (R)-1-치환된-2-테트라하이드로이소퀴놀린 유도체의 제조에서 기질에 내재하는 키랄성은 상업적으로 가용한 (R)-(+)-α-펜에틸아민으로부터 유래된다.
반응식 I 또는 Ⅱ에 따라, 화학식 I의 1,2,3,4-테트라하이드로이소퀴놀린이나 1,2,3,4-테트라하이드로벤즈[c]아제핀은 적절히 보호된 아미노알킬 할로겐 화합물(Ⅱ) 또는 하이드로알킬 할로겐 화합물(Ⅲ)로 N-알킬화된다. 보호기를 제거하여 아민(Ⅳ) 또는 알코올(Ⅴ)을 얻는다. 중간물질 Ⅳ와 Ⅴ는 카르보닐디이미다졸과 같은 카르보닐화제로 단계적 처리, 이후 소디움 헥사메틸디실라지드와 같은 강한 염기의 존재하에 적절한 아민(Ⅵ)과의 반응으로 화학식 I의 최종 화합물을 얻는다. 이는 화학식 I에 상응하는 최종 화합물 Ⅶ와 Ⅷ를 제공하는데, 여기서 Y는 각각 NH 또는 O이고, n, X, Z, R1내지 R6은 화학식 I에 정의된 바와 같이 동일하다.
화학식 I 화합물의 대안적 합성 루트는 반응식 Ⅲ에 예시한다. 이런 방식으로, 화학식 Ⅸ의 카르복실산은 가령 DMF와 같은 극성 비양자성 용매에서 DPPA 처리에 의해 상응하는 아실 아지드로 전환된다. 정제되지 않은 아실 아지드는 톨루엔과 같은 불활성 용매에서 열 재배열(thermal rearrangement)하여 상응하는 이소시아산염을 얻는다. 정제되지 않은 이소시아산염은 화학식 Ⅳ의 알킬 아민 또는 화학식 Ⅴ의 알킬 알코올과 반응시켜 표적 화합물 Ⅶ 또는 Ⅷ를 수득하는데, 여기서 n, X, Y, Z, R1내지 R6은 화학식 I에 정의된 바와 같이 동일하다.
화학식 I 화합물의 또 다른 합성 루트는 반응식 Ⅳ에 예시한다. 이런 방식으로, 화학식 I의 1,2,3,4-테트라하이드로이소퀴놀린은 NaHO3이나 디-이소프로필에틸아민과 같은 포집제 염기의 존재하에 THF와 같은 비양자성 용매에서 화학식 Ⅹ 화합물(Russel RK et al. "Thiophene Systems. 9 Thienopyrimidinedione Derivatives as Potential Antihypertensive Agents" J Med Chem 1988, 31, 1786-1793)로 N-알킬화시켜 표적 화합물 ?을 수득하는데, 여기서 n, X, Y, Z, R1내지 R6은 화학식 I에 정의된 바와 같이 동일하다.
화학식 Ⅹ의 필수 중간물질의 제조는 반응식 Ⅴ에 예시하는데, 여기서 Y, Z, n은 화학식 I에 정의된 바와 같이 동일하고 Hal은 염화물과 같은 할로겐 원자를 나타낸다. 화학식 Ⅵ의 상업적으로 가용하거나 공지된 헤테로아릴 아민은 상업적으로 가용하거나 공지된 할로알킬 이소시아산염 또는 할로알킬 클로로포름산염과 반응시킨다. 대안으로, 화학식 Ⅹ 화합물은 헤테로아릴 카르복실산(Ⅸ)으로부터 유래된 시오시아산염의 반응으로 수득한다.
본 발명의 전술한 내용은 다수의 실시예로 좀더 구체적으로 설명하지만, 이들 실시예는 본원 발명의 범주를 한정하지 않는다.
약어
AcOH:아세트산
BSA:소 혈청 알부민
CDI: 카르보닐디이미다졸
DIPEA디이소프로필에틸아민
DMAP4-디메틸아미노피리딘
DMF:디메틸포름아마이드
DMSO디메틸설폭시드
DPPA:디페닐포스포릴아지드
EDC:N-(3-디메틸아미노프로필)-N'-에틸-카르보디이미드
EDTA:에틸렌디아민 테트라-아세트산
EtOAc: 에틸 아세테이트
Et2O:디에틸 에테르
Hex:헥산
HOBT:1-하이드록시벤조트리아졸
HPLC:고성능 액체 크로마토그래피
HV:높은 진공 상태
LC-MS:액체 크로마토그래피-질량 분광법
LAH:리튬 알루미늄 하이브리드
MeOH:메탄올
min:분
MHz:메가헤르츠
NaHMDS:소디움 비스(트리메틸실릴)아마이드
NMR:핵 자기 공명
ppm:100만분의 1
PBS:인산염-완충된 염수
PyBOP:(벤조트리아졸-1-일옥시)-트리피롤리디노포스포늄
헥사플루오르포스페이트
rt:실온
sat.:포화된
TEA:트리에틸아민
TFA:트리플루오르아세트산
THF:테트라하이드로푸란
TLC:박막 크로마토그래피
tR:체류 시간
일반적으로, 반응은 자연 건조된 유리 기구에서 N2가스와 같은 불활성 대기하에 진행된다. 용매는 공급업자로부터 입수된 상태로 사용된다. 증발은 감압 및 50℃ 수조 온도하에 회전 증발기에서 실시한다. LC-MS 특성화는 ESI 이온화 모드를 이용하여 Finnigan HP1100 플랫폼에서 실시하고, 양이온 탐지는 Navigator AQA 검출기로 실시한다. 분석용 액체 크로마토그래피 분리는 0.45 ㎖/min의 유속으로 4.6 x 30 ㎜ 직경의 C18 칼럼 및 0.5% 포름산을 함유하는 물에 6분 구배의 2-95% CH3CN 이동상에서 실시한다. 체류 시간(tR)은 분으로 제시한다. TLC는 사전-코팅된 실리카겔 60 F254 유리-배후 플레이트(MERCK)에서 실시한다. 예비 HPLC는 21 x 60 ㎜ 직경의 C18 칼럼 및 0.5% 포름산을 함유하는 물에 1 구배의 2-95% CH3CN 이동상을 이용하여 Varian/Gilson 플랫폼에서 실시한다.
중간물질의 제조. 실시예 A
실시예 A1. (4-플루오르-벤질)-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
2-(3,5-디메톡시-페닐)-에틸아민
THF(30 ㎖)에 녹인 LiAlH4(1.76 g, 46.4 mmol) 현탁액에 THF(70 ㎖)에 녹인1,3-디메톡시-5-(2-니트로-비닐)-벤젠(2.43 g, 11.6 mmol; Gairaud CB, Lappin GR, J Org Chem 1953, 18, 1) 용액을 0℃에서 방울방울 첨가한다. 혼합물은 상기 온도에서 30분동안, 이후 환류에서 4시간동안 교반한다. 반응 혼합물은 2N NaOH(20 ㎖)를 후속으로 첨가하여 냉각시키고 실온에서 추가로 15분동안 교반한다. 수용액은 EtOAC로 3회 추출한다. 모아긴 유기층은 무수성 MgSO4에서 건조시키고 여과하고 농축시켜 황색 오일로 표제 화합물을 얻는다.
N-[2-(3,5-디메톡시-페닐)-에틸]-2-(4-플루오르-페닐)-아세트아마이드
무수성 DMF(50 ㎖)에 녹인 2-(3,5-디메톡시-페닐)-에틸아민(1.01 g, 5.57 mmol) 용액에 4-플루오르페닐 아세트산(860 ㎎, 5.57 mmol), PyBOP(3.17 g), N-에틸디이소프로필아민(2.2 ㎖, 12.8 mmol)을 첨가한다. 혼합물은 실온에서 14시간동안 교반한다. 물(60 ㎖)을 첨가하고, 혼합물은 EtOAc(4 x 60 ㎖)로 추출한다. 모아진 유기상은 염수로 세척하고 MgSO4에서 건조시키고 여과하고 진공하에 농축시킨다. 잔류물은 실리카겔 칼럼 크로마토그래피(EtOAc/Hex, 7:3)로 정제하여 황색 오일로 표제 화합물을 얻는다.
1-(4-플루오르-벤질)-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
CH3CN(3 ㎖)에 녹인 N-[2-(3,5-디메톡시-페닐)-에틸]-2-(4-플루오르-페닐)-아세트아마이드(404 ㎎, 1.27 mmol) 교반 용액에 POCl3(350 ㎕, 3.82 mmol)을 첨가한다. 반응 혼합물은 환류에서 30분동안 교반한다. 감압하에 농축하여 잔류 오일을 얻고, 이는 MeOH(10 ㎖)에 용해시킨다. 상기 용액에 NaBH4(340 ㎎, 8.61 mmol)를 0℃에서 조금씩 첨가한다. 반응 혼합물은 실온으로 데우고 14시간동안 교반한다. 반응 혼합물은 물(15 ㎖)에 부어넣고 CH2Cl2로 4회 추출한다. 모아진 유기층은 무수성 MgSO4에서 건조시키고 여과하고 감압하에 농축시킨다. 잔류물은 플래시 칼럼 크로마토그래피(CH2Cl2/MeOH, 9:1)로 정제하여 갈색 오일로 표제 화합물을 얻는다.
실시예 A2-A4
다음의 출발 물질은 실시예 A1의 방법으로 얻는다:
A2. 1-(3,4-디메톡시-벤질)-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A3. 1-(3,4-디플루오르-벤질)-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A4. 1-(3-플루오르-4-메톡시-벤질)-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
실시예 A5. 1-[2-(4-플루오르-페닐)-에틸]-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
N-[2-(3,5-디메톡시-페닐)-에틸]-3-(4-플루오르-페닐)-프로피온아마이드
2-(3,5-디메톡시-페닐)-에틸아민(1.20 g, 6.62 mmol)은 무수성 DMF(50 ㎖)에 용해시키고, 3-(4-플루오르페닐) 프로피온산(1.113 g, 6.62 mmol), PyBOP(3.77 g), DIPEA(2.61 ㎖, 15 mmol)를 첨가한다. 혼합물은 실온에서 14시간동안 교반한다. 물(60 ㎖)을 첨가하고, 혼합물은 EtOAc(4 x 60 ㎖)로 추출한다. 모아진 유기상은 염수로 세척하고 MgSO4에서 건조시키고 여과하고 진공하에 농축시킨다. 잔류물은 실리카겔 칼럼 크로마토그래피(EtOAc/Hex, 7:3)로 정제하여 황색 오일로 표제 화합물을 얻는다.
1-[2-(4-플루오르-페닐)-에틸]-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
CH3CN(12 ㎖)에 녹인 N-[2-(3,5-디메톡시-페닐)-에틸]-3-(4-플루오르-페닐)-프로피온아마이드(1.25 g, 3.77 mmol) 교반 용액에 POCl3(1.04 ㎖, 11 mmol)을 첨가한다. 반응 혼합물은 환류에서 30분동안 교반한다. 감압하에 농축하여 잔류 오일을 얻고, 이는 MeOH(35 ㎖)에 용해시킨다. 상기 용액에 NaBH4(1.00 g, 26.4 mmol)를 0℃에서 조금씩 첨가하고, 반응 혼합물은 실온으로 데우고 14시간동안 교반한다. 반응 혼합물은 물(40 ㎖)에 부어넣고 CH2Cl2(4 x 40 ㎖)로 추출한다. 모아진 유기층은 무수성 MgSO4에서 건조시키고 여과하고 감압하에 농축시킨다. 잔류물은 플래시 칼럼 크로마토그래피(CH2Cl2/MeOH, 9:1)로 정제하여 갈색 오일로 표제 화합물을 얻는다.
실시예 A6-A7
다음의 출발 물질은 실시예 A5의 방법으로 얻는다:
A6. 1-[2-(2,4-디플루오르-페닐-에틸]-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A7. 1-[2-(3,4-디플루오르-페닐)-에틸]-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
실시예 A8. 6,7-디메톡시-1-[2-(3-메톡시-페닐)-에틸]-1,2,3,4-테트라하이드로-이소퀴놀린
-[2-(3,4-디메톡시-페닐)-에틸]-3-(3-메톡시-페닐)-프로피온아마이드
THF(20 ㎖)에 녹인 3-(3-메톡시-페닐)-프로피온산(1.19 g, 6.62 mmol)과 3-디메틸아미노-프로필)-에틸-카르보디이미드 염산염(1.33 g, 6.95 mmol)의 현탁액에 2-(3,4-디메톡시-페닐)-에틸아민(1.20 g, 6.62 mmol)을 첨가한다. 혼합물은 실온에서 14시간동안 교반한다. 혼합물은 H2O(100 ㎖)와 EtOAc(100 ㎖)에 부어넣는다. 유기층은 포화된 탄산수소나트륨 용액, 10% 구연산, 포화된 염화나트륨 용액으로 순차적으로 세척한다. 생성된 유기층은 감압하에 농축하여 표제 화합물을 얻는다.
6,7-디메톡시-1-[2-(3-메톡시-페닐)-에틸]-1,2,3,4-테트라하이드로-이소퀴놀린
THF(50 ㎖)에 녹인 N-[2-(3,4-디메톡시-페닐)-에틸]-3-(3-메톡시-페닐)-프로피온-아마이드(2.21 g, 6.44 mmol) 용액에 POCl3(4.91 g, 32.2 mmol)을 첨가하고, 반응 혼합물은 1시간동안 환류시킨다. 실온으로 냉각한 이후, 용매를 감압하에 제거한다. 생성된 오일은 메탄올(20 ㎖)로 처리하고 한번 더 증발시킨다. 잔류물은 0℃로 냉각된 절대 메탄올(40 ㎖)에 용해시키고 NaBH4(1.21 g, 32.0 mmol)를 조금씩 첨가한다. 생성 혼합물은 실온에서 16시간동안 교반하고, 이후 증발시킨다. 잔류물에 물(150 ㎖)을 첨가한다. 수층은 CH2Cl2(3 x 50 ㎖)로 추출한다. 모아진 추출물은 MgSO4에서 건조시키고 농축하여 표제 화합물을 얻는다.
실시예 A9-A45
다음의 출발 물질은 실시예 A8의 방법으로 얻는다:
A9. 1-[(E)-2-(2,3-디플루오르-페닐)-비닐]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A10. 1-[(E)-2-(2,4-디플루오르-페닐)-비닐]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A11. 1-[(E)-2-(2,5-디플루오르-페닐)-비닐]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A12. 1-[2-(2,5-비스-트리플루오르메틸-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A13. 1-[2-(2,5-디플루오르-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A14. 1-[2-(3,4-디플루오르-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A15. 1-[2-(3,4-디메톡시-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A16. 1-[2-(3,5-비스-트리플루오르메틸-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A17. 1-[2-(4-플루오르-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A18. 6,7-디메톡시-1-[2-(2-메톡시-페닐)-에틸]-1,2,3,4-테트라하이드로-이소퀴놀린
A19. 6,7-디메톡시-1-[2-(4-메톡시-페닐)-에틸]-1,2,3,4-테트라하이드로-이소퀴놀린
A20. 6,7-디메톡시-1-[2-(4-트리플루오르메틸-페닐)-에틸]-1,2,3,4-테트라하이드로-이소퀴놀린
A21. 6,7-디메톡시-1-펜에틸-1,2,3,4-테트라하이드로-이소퀴놀린
A22. 1-(2,5-디메톡시-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A23. 1-(2,6-디클로로-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A24. 1-(3,4-디플루오르-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A25. 1-(3,4-디메톡시-벤질)-6,7,8-트리메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A26. 1-(3,4-디메톡시-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A27. 1-(3,4-디메톡시-벤질)-6,7-디메톡시-4,4-디메틸-1,2,3,4-테트라하이드로-이소퀴놀린
A28. 1-(3-플루오르-4-메톡시-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A29. 1-(3-플루오르-5-트리플루오르메틸-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A30. 1-(4-클로로-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A31. 1-(4-플루오르-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A32. 1-벤즈하이드릴-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A33. 1-벤조[1,3]디옥솔-5-일메틸-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A34. 1-벤질-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A35. 6-(3,4-디메톡시-벤질)-2,3,6,7,8,9-헥사하이드로-[1,4]디옥시노[2,3-g]-이소퀴놀린
A36. 6,7-디메톡시-1-(1-페닐-프로필)-1,2,3,4-테트라하이드로-이소퀴놀린
A37. 6,7-디메톡시-1-(2,3,4-트리메톡시-벤질)-1,2,3,4-테트라하이드로-이소퀴놀린
A38. 6,7-디메톡시-1-(3,4,5-트리메톡시-벤질)-1,2,3,4-테트라하이드로-이소퀴놀린
A39. 6,7-디메톡시-1-(3-메톡시-벤질)-1,2,3,4-테트라하이드로-이소퀴놀린
A40. 6,7-디메톡시-1-(4-메톡시-벤질)-1,2,3,4-테트라하이드로-이소퀴놀린
A41. 6,7-디메톡시-1-나프탈렌-2-일메틸-1,2,3,4-테트라하이드로-이소퀴놀린
A42. 6,7-디메톡시-1-페녹시메틸-1,2,3,4-테트라하이드로-이소퀴놀린
A43. 7-벤질옥시-1-(3,4-디메톡시-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A44. 1-(3,4-디메톡시-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A45. 1-(3,4-디메톡시-벤질)-7,8-디메톡시-2,3,4,5-테트라하이드로-1H-벤조[c]아제핀
3-(3,4-디메톡시-페닐)-프로피온아마이드
건조 THF(175 ㎖)에 녹인 3-(3,4-디메톡시-페닐)-프로피온산(10.0 g, 47.6 mmol) 교반 용액에 TEA(7.3 ㎖, 52.4 mmol)를 질소하에 첨가한다. 생성 혼합물은 -10℃로 냉각하고, 이후 에틸 클로로포름산염(5.0 ㎖, 52 mmol)을 방울방울 첨가한다. -10℃에서 교반(20분)한 이후, THF(105 ㎖)에 녹인 수산화암모늄(물에서 25%, 105 ㎖)을 첨가하고, 혼합물은 15℃에서 30분동안, 이후 실온에서 1.5시간동안 첨가한다. 반응 혼합물은 진공하에 농축하고 CH2Cl2로 3회 추출하며, 모아진 유기 추출물은 포화된 수성 NaHCO3과 염수로 세척한다. 유기상은 무수성 MgSO4에서 건조시키고 여과하고 농축시켜 무색 고체로 표제 화합물을 얻는다.
3-(3,4-디메톡시-페닐)-프로필아민
무수성 THF(400 ㎖)에 녹인 3-(3,4-디메톡시-페닐)-프로피온아마이드(11.1 g, 53.0 mmol) 용액은 무수성 THF(170 ㎖)에 녹인 LiAlH4(4.02 g, 106 mmol)의 교반된 차가운 현탁액에 천천히 첨가한다. 첨가의 완결직후, 혼합물은 환류에서 2시간동안 교반한다. 0℃로 냉각한 이후, H2O(5 ㎖)와 NaOH 1N(5 ㎖)을 방울방울 첨가하여 과량의 수소화물을 분해시킨다. 현탁액은 여과 및 증발시킨다. 잔류물은 H2O(40 ㎖)와 CH2Cl2(100 ㎖)간에 분할한다. 유기층은 포화된 수성 NaHCO3과 염수로 세척하고 무수성 MgSO4에서 건조시키고 감압하에 농축시켜 황색 오일로 표제 화합물을 얻는다.
2-(3,4-디메톡시-페닐)-N-[3-(3,4-디메톡시-페닐)-프로필]-아세트아마이드
무수성 THF(70 ㎖)에 녹인 3-(3,4-디메톡시-페닐)-프로필아민(12.5 g, 64.1 mmol)과 TEA(10 ㎖, 71.8 mmol)의 용액은 0℃로 냉각시키고 THF(28 ㎖)에 녹인 (3,4-디메톡시-페닐)-아세틸 염화물(13.8 g, 64.1 mmol)을 방울방울 첨가한다. 질소하에 실온에서 13시간동안 교반한 이후, 포화된 수성 NaHCO3용액을 첨가하고, 반응 혼합물은 EtOAc로 3회 추출한다. 유기상은 무수성 MgSO4에서 건조시키고 여과하고 용매를 증발시킨다. 잔류물은 톨루엔으로 세척하고 건조시켜 베이지색 고체로 표제 화합물을 얻는다.
1-(3,4-디메톡시-벤질)-7,8-디메톡시-2,3,4,5-테트라하이드로-1H-벤조[c]아제핀
무수성 아세토니트릴(185 ㎖)에 녹인 2-(3,4-디메톡시-페닐)-N-[3-(3,4-디메톡시-페닐)-프로필]-아세트아마이드(6.16 g, 16.5 mmol)와 POCl3(4.95 ㎖, 54.1 mmol)의 혼합물은 질소하에 환류에서 4시간동안 교반한다. 냉각후, 반응 혼합물은증발시키고, 잔류물은 MeOH(125 ㎖)에 용해시킨다. 용액은 0℃로 냉각하고 NaBH4(4.31 g, 114 mmol)를 조금씩 첨가한다. 질소하에 0℃에서 2시간동안 교반한 이후, 반응 혼합물은 H2O에 부어넣고 CH2Cl2로 3회 추출한다. 모아진 유기 추출물은 염수로 세척하고 무수성 MgSO4에서 건조시키고 여과하고 농축시켜 정제되지 않은 오일을 얻는다. 플래시 크로마토그래피(CH2Cl2/MeOH: 9:1)로 황색 오일로 표제 화합물을 산출한다.
A46. 1-[2-(2,3-디플루오르-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
3-(2,3-디플루오르-페닐)-프로피온산
에탄올(100 ㎖)에 녹인 2,3-디플루오르-신남산(2.94 g, 16 mmol) 현탁액에 Pd(탄소에서 10%, 50 ㎎)를 첨가하고, 혼합물은 수소(7.5 bar)로 15시간동안 처리한다. 현탁액은 셀리터에 여과하고 용매를 증발시켜 표제 화합물을 얻는다.
1-[2-(2,3-디플루오르-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
상기 화합물은 실시예 A8의 방법에 따라 3-(2,3-디플루오르-페닐)-프로피온산과 2-(3,4-디메톡시-페닐)-에틸아민으로부터 얻는다.
실시예 A47
다음의 출발 물질은 실시예 A46의 방법으로 얻는다:
A47. 1-[2-(2,4-디플루오르-페닐)-에틸]-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
실시예 A48. 1-(3,4-디클로로-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린-7-카르복실산 디메틸아마이드
2-(4-벤질옥시-3-메톡시-페닐)-비닐아민
THF(300 ㎖)에 녹인 LAH(8.0 g, 0.21 mmol)의 교반 현탁액은 얼음 용액조에서 냉각시키고, THF(300 ㎖)에 녹인 4-벤질옥시-3-메톡시니트로스티렌(15.0 g, 52.6 mmol) 용액을 방울방울 첨가한다. 녹색의 반응 혼합물은 0.5시간동안 실온으로 데우고, 이후 4시간동안 환류시킨다. 회색의 반응 혼합물은 물(8 ㎖), 15% 수성 NaOH(8 ㎖), 물(24 ㎖)로 순차적으로 처리한다. 생성된 회색 현탁액은 50℃에서 20분동안 교반한다. 생성된 황색 현탁액은 여과하고, 잔류물은 EtOAc로 세척한다. 모아진 여과액은 증발시켜 황색 오일로 표제 화합물을 얻는데, 이는 추가 정제없이 사용한다.
N-[2-(4-벤질옥시-3-메톡시-페닐)-비닐]-2-(3,4-디클로로-페닐)-아세트아마이드
톨루엔(100 ㎖)에 녹인 3,4-디클로로페닐 아세트산(10.6 g, 51.7 mmol)과 2-(4-벤질옥시-3-메톡시-페닐)-비닐아민(12.1 g, 47 mmol)의 혼합물은 Dean-Strak 장치에서 환류로 17시간동안 가열한다. 반응물은 실온으로 냉각시킨다. 여과하여 황색 결정으로 표제 화합물을 얻는다. 여과액은 Dean-Strak 장치에서 환류로 16시간동안 한번 더 가열하고, 이후 실온으로 냉각시킨다. 여과하여 황색 결정으로 2차 표제 화합물을 얻는다. 이들 2개의 표제화합물은 모으고 추가 정제없이 사용한다.
7-벤질옥시-1-(3,4-디클로로-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
CH3CN(100 ㎖)에 녹인 N-[2-(4-벤질옥시-3-메톡시-페닐)-비닐]-2-(3,4-디클로로-페닐)-아세트아마이드(13.3 g, 30 mmol) 현탁액에 포스포르옥시클로라이드(8.1 ㎖, 13.5 g, 88 mmol)를 실온에서 방울방울 첨가한다. 생성된 백색 현탁액은 환류로 가열하고, 생성된 황색 용액은 환류에서 3시간동안 가열한다. 짙은 황색 용액은 냉각시키고 황색 오일로 증발시킨다. 오일은 MeOH(100 ㎖)에 넣고 증발시켜 오렌지색 고체를 얻는다. 상기 물질은 MeOH(100 ㎖)에 재용해시키고, 용액은 0℃로 냉각한다. NaBH4(3.61 g, 95 mmol)를 조금씩 첨가하는데 가스 발생 및 강한 발열반응이 나타난다. 생성된 백색 현탁액은 실온에서 16시간동안 교반한다. 반응 혼합물은 EtOAc(200 ㎖)와 물(200 ㎖)간에 분할하고, 수상은 EtOAc(3 x 200 ㎖)로 추출한다. 모아진 유기상은 물과 염수로 세척하고 증발시켜 연한 황색 오일로 표제 화합물을 얻는데, 이는 추가 정제없이 사용한다.
1-(3,4-디클로로-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린-7-올
MeOH(150 ㎖)와 1,2-디클로로벤젠(30 ㎖)에 녹인 7-벤질옥시-1-(3,4-디클로로-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린(14.1 g, 30 mmol) 용액에 목탄에서 50% Pd(500 ㎎)을 첨가한다. 반응 용기는 대기압에서 질소, 이후 수소로 씻어낸다. 실온에서 16시간동안 교반한 이후, 반응 혼합물은 Hyflo에 여과하고 증발시켜 베이지색 고체로 표제 화합물을 얻는데, 이는 추가 정제없이 사용한다.
1-(3,4-디클로로-벤질)-7-하이드록시-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-카르복실산 tert-부틸 에스테르
이소프로판올(30 ㎖)에 녹인 1-(3,4-디클로로-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린-7-올(9.6 g, 28 mmol) 용액에 1M 수성 NaOH(30 ㎖)와 di-tert-부틸-중탄산염(6.7 g, 30.8 mmol)을 방울방울 첨가한다. 생성된 갈색 용액은 실온에서 30분동안 교반하고, 생성된 황색 용액은 EtOAc(50 ㎖)와 물(50 ㎖)간에 분할한다. 유기상은 물과 염수로 순차적으로 세척하고 증발시켜 황색 오일로 표제 화합물을 얻는데, 이는 추가 정제없이 사용한다.
1-(3,4-디클로로-벤질)-6-메톡시-7-트리플루오르메탄설포닐옥시-3,4-디하이드로-1H-이소퀴놀린-2-카르복실산 tert-부틸 에스테르
CH2Cl2(100 ㎖)에 녹인 1-(3,4-디클로로-벤질)-7-하이드록시-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-카르복실산 tert-부틸 에스테르(12 g, 27 mmol) 용액에 Et3N(3.8 ㎖, 27 mmol)을 첨가한다. 반응 혼합물은 0℃로 냉각하고 트리플루오르메탄설폰 무수물(4.45 ㎖, 27 mmol)을 첨가한다. 생성된 황색 용액은 실온에서 30분동안 교반하고 포화된 수성 NaHCO3(100 ㎖)에 부어넣는다. 수상은 CH2Cl2(2 x 100 ㎖)로 추출하고, 모아진 유기상은 건조시키고(MgSO4) 여과하고 증발시켜 황색 오일로 표제 화합물을 얻는다. 정제는 MeOH로부터 결정화로 달성한다. 증발된 모액(mother liquor)은 실리카겔 크로마토그래피(헵탄:Et2O, 9:1)직후 추가의 물질을 제공한다.
7-시아노-1-(3,4-디클로로-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-카르복실산 tert-부틸 에스테르
새로이 건조된 4A 분자체에서 DMF(15 ㎖)에 녹인 1-(3,4-디클로로-벤질)-6-메톡시-7-트리플루오르메탄설포닐옥시-3,4-디하이드로-1H-이소퀴놀린-2-카르복실산 tert-부틸 에스테르(10 g, 17 mmol) 용액은 20분동안 아르곤으로 포기하여 산소를 제거한다. 상기 용액은 DMF(15 ㎖)에 녹인 아연 시안화물(4.6 g, 34 mmol)의 산소제거된 현탁액에 아르곤하에 첨가한다. 생성된 연한 갈색 현탁액은 120℃ 오일 용액조에 위치시킨다. 테트라키스(트리페닐포스핀)-팔라듐(1.0 g)을 첨가하고, 갈색 반응 혼합물은 120℃에서 2시간동안 교반한다. 반응 혼합물은 실온으로 냉각하고EtOAc와 포화된 수성 NaHCO3간에 분할한다. 혼합물은 Hyflo에 여과한다. 수상은 EtOAc(3 x 40 ㎖)로 추출한다. 모아진 유기상은 염수로 추출하고 MgSO4에서 건조시키고 여과하고 증발시킨다. 생성된 황색 오일은 부분적으로 고체화된다. 혼합물은 여과하고 Et2O로 세척하여 백색 결정으로 표제 화합물을 얻는다. 여과액 증발 및 실리카겔 크로마토그래피(EtOAc:헵탄, 1:4)로 백색 결정으로 추가의 표제 화합물을 얻는다.
1-(3,4-디클로로-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2,7-디카르복실산 2-tert-부틸 에스테르
벤질 알코올(10 ㎖)에 녹인 7-시아노-1-(3,4-디클로로-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-카르복실산 tert-부틸 에스테르(3.60 g, 8.06 mmol) 용액에 KOH(3.00 g)를 첨가하고, 반응 혼합물은 160℃에서 0.5시간동안 교반한다. 반응 혼합물은 실온으로 냉각하고 2M 수성 HCl로 산성화시킨다. 반응 혼합물은 EtOAc(3 x 20 ㎖)로 분할한다. 모아진 유기상은 염수로 세척하고 MgSO4에서 건조시키고 여과하고 증발시켜 황색 오일을 산출한다. 실리카겔에서 CH2Cl2:MeOH 19:1, 이후 MeOH로 크로마토그래피를 실시하여 황색 고체로 표제 화합물을 얻는다.
1-(3,4-디클로로-벤질)-7-디메틸카르바모일-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-카르복실산 tert-부틸 에스테르
CH2Cl2(10 ㎖)에 녹인 1-(3,4-디클로로-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2,7-디카르복실산 2-tert-부틸 에스테르(1.0 g, 2.1 mmol) 용액에 디메틸아민 염산염(0.35 g, 4.3 mmol), HOBt(65 ㎎, 0.43 mmol), DMAP(52 ㎎, 0.43 mmol), EDC 염산염(493 ㎎, 2.6 mmol)을 첨가한다. 반응 혼합물은 실온에서 16시간동안 교반한다. 미세한 황색 현탁액은 CH2Cl2(10 ㎖)로 희석하고 1M 수성 HCl과 포화된 수성 NaHCO3으로 세척한다. 유기상은 MgSO4에서 건조시키고 여과하고 증발시켜 황색 오일로 표제 화합물을 얻는다.
1-(3,4-디클로로-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린-7-카르복실산 디메틸아마이드
디옥산에서 4M HCl에 녹인 1-(3,4-디클로로-벤질)-7-디메틸카르바모일-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-카르복실산 tert-부틸 에스테르(1.0 g, 2.0 mmol) 용액은 0℃에서 1시간동안 교반한다. 반응 혼합물은 증발시켜 백색 고체로 표제 화합물을 얻는다.
실시예 A49-A50
다음의 출발 물질은 실시예 A48의 방법으로 얻는다:
A49. 1-(3,4-디클로로-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린-7-카르복실산 메틸아마이드
A50. 1-(3,4-디클로로-벤질)-6-메톡시-1,2,3,4-테트라하이드로-이소퀴놀린-7-카르복실산 프로필아마이드
실시예 A51-A52
거울상이성질에서 순수한 출발 물질은 Polniaszek R.P. et al., J. Am. Chem. Soc. (1989) 111, 4859-4863의 방법으로 얻는다:
A51. (R)-1-(3,4-디메톡시-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
A52. (R)-1-(4-플루오르-벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린
중간물질의 제조. 실시예 B.
실시예 B1. (2-브로모-에틸)-카르밤산 tert-부틸 에스테르
1N 수성 NaOH(200 ㎖)에 MeOH(400 ㎖)을 첨가하고, 생성 용액은 20℃로 냉각한다. 브롬화수소산 2-브로모에틸아민(25.0 g, 122 mmol)은 1회분으로 첨가하고, 이후 di-tert-부틸 중탄산염(26.6 g, 122 mmol)을 첨가한다. 반응 혼합물은 2.5시간동안 교반한다. MeOH는 회전 증발기에서 제거하고, 수성 현탁액은 CH2Cl2(2 x 175 ㎖)로 추출한다. 모아진 유기상은 5% 수성 구연산(300 ㎖)으로 추출하고 MgSO4에서 건조시키고 여과하고 증발시켜 표제 화합물을 얻는다.
실시예 B2. (3-클로로-프로필)-카르밤산 tert-부틸 에스테르
상기 물질은 3-클로로프로필아민으로부터 실시예 B1과 유사하게 얻는다.
중간물질의 제조. 실시예 C
실시예 C1. 4-아미노-2-메틸퀴놀린
상기 물질은 상업적으로 가용하다.
실시예 C2. 4-아미노-피리딘
상기 물질은 상업적으로 가용하다.
실시예 C3. 4-아미노-퀴놀린
Shinkai et al., "4-Aminoquinolines: Novel Nociceptin Antagonists with Analgesic Activity", J. Med. Chem. (2000) 43, 4667-4677에서 밝힌 방법에 따라 상용의 4-니트로퀴놀린 N-옥사이드로부터 얻는다.
실시예 C4. 4-아미노-6,7,8,9-테트라하이드로-퀴놀린
6,7,8,9-테트라하이드로-퀴놀린-N-옥사이드
THF(125 ㎖)에 녹인 5,6,7,8-테트라하이드로퀴놀린(2.66 ㎖, 20 mmol) 용액은 0℃로 냉각하고 THF(25 ㎖)에 녹인 m-클로로과산화벤조산(3.8 g, 22 mmol)을 첨가한다. 0.5시간후, 혼합물은 진공하에 증발시키고 CH2Cl2(75 ㎖)에 재용해시킨다. 용액은 NaOH(1M, 20 ㎖)와 구연산(10%, 20 ㎖)으로 세척하고 건조시키고 증발시켜 표제 화합물을 얻는다.
4-니트로-6,7,8,9-테트라하이드로-퀴놀린-N-옥사이드
5,6,7,8-테트라하이드로퀴놀린-N-옥사이드(298 ㎎, 2 mmol)는 HNO3(100%, 0.5 ㎖)과 H2SO4(98%, 0.7 ㎖)의 냉각된 혼합물로 처리한다. 혼합물은 2시간동안 80℃로 가열하고 얼음(100 g)에 부어넣고 CH2Cl2(30 ㎖)로 추출한다. 유기상은 건조시키고 증발시켜 표제 화합물을 얻는다.
4-아미노-6,7,8,9-테트라하이드로-퀴놀린
실시예 C3의 방법에 따라 4-니트로-6,7,8,9-테트라하이드로-퀴놀린-N-옥사이드로부터 얻는다.
실시예 C5. 4-아미노-7-메틸-[1.8]-나프티리딘
Barlin GB, Tan WL, "Potential Antimalarials. I 1,8-naphthyridines", Aust J Chem(1984) 37, 1065-1073. radivov R, Haimova M, Simova E "Synthesis of 4-Amino-3-Pyridiyl and 4-Amino-5-Pyrimidyl Aryl Ketones and Related Compounds via an ortho-Liyhiation reaction", Synthesis(1986), 886-891에서 밝힌 방법에 따라 얻는다.
실시예 C6. 퀴놀린-4-카르복실산
상기 물질은 상업적으로 가용하다.
실시예 C7. 2-메틸-퀴놀린-4-카르복실산
상기 물질은 Brasyunas VB et al., "Synthesis of Quinoline-4-carboxylic acid and its derivatives", Chem. Heterocycl. Compd.(engl. Transl.)(1988) 670-673에서 밝힌 방법에 따라 이사틴(isatin)과 아세톤의 반응으로 얻는다.
실시예 C8. 2-(벤질-메틸-아미노)-이소니코틴산
2-클로로-피리딘-4-카르복실산(300 ㎎, 1.9 mmol), 벤질메틸아민(230 ㎎, 1.9 mmol), 트리에틸아민(192 ㎎, 1.9 mmol)의 혼합물은 12시간동안 120℃로 가열한다. 잔류물은 CH2Cl2(30 ㎖)에 용해시키고 1M NaOH(3 x 5 ㎖)로 추출한다. 수상은 pH 2로 조정하고 EtOAc(6 x 5 ㎖)로 추출한다. 유기상은 모으고 건조시키고(MgSO4) 증발시켜 표제 화합물을 얻는다.
실시예 C9. 2-(벤질-메틸-아미노)-6-메틸-이소니코틴산
상기 물질은 실시예 C8과 유사하게 2-클로로-6-메틸-피리딘-4-카르복실산과 벤질메틸아민을 반응시켜 얻는다.
실시예 C10. 2-(메틸-페닐-아미노)-이소니코틴산
상기 물질은 실시예 C8과 유사하게 2-클로로-피리딘-4-카르복실산과 N-메틸아닐린을 반응시켜 얻는다.
실시예 C11. 2-피롤리딘-1-일-이소니코틴산
상기 물질은 실시예 C8과 유사하게 2-클로로-피리딘-4-카르복실산과 피롤리딘을 반응시켜 얻는다.
중간물질의 제조. 실시예 D
실시예 D1. 1-(2-클로로-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아
THF(480 ㎖)에 녹인 4-아미노-2-메틸퀴놀린(실시예 C1, 12.6 g, 80 mmol) 용액에 2-클로로에틸이소시안산염(10.2 ㎖, 120 mmol)을 실온에서 첨가한다. 반응 혼합물은 실온에서 40시간동안 교반한다. MeOH(100 ㎖)를 첨가하고, 추가로 1시간동안 교반한다. 반응 혼합물은 증발시키고, 잔류물은 CH2Cl2에 넣는다. 유기상은 1N HCl(250 ㎖)와 함께 진탕하고, 생성 침전물은 여과로 수거한다. 고체는 CH2Cl2(100 ㎖), 포화된 NaHCO3(2 x 100 ㎖), 물(4 x 100 ㎖)로 세척한다. 생성 고체는 HV하에 실온에서 14시간동안 건조시켜 표제 화합물을 얻는다.
실시예 D2. 1-(3-클로로-프로필)-3-(2-메틸-퀴놀린-4-일)-유레아
표제 화합물은 실시예 D1 방법과 유사하게 4-아미노-2-메틸퀴놀린(실시예 C1)과 3-클로로프로필이소시안산염으로부터 얻는다.
실시예 D3. 1-(2-클로로-에틸)-3-(퀴놀린-4-일)-유레아
표제 화합물은 실시예 D1 방법과 유사하게 4-아미노-2-퀴놀린(실시예 C3)과 2-클로로에틸이소시안산염으로부터 얻는다.
실시예 D4. 1-(3-클로로-프로필)-3-(퀴놀린-4-일)-유레아
표제 화합물은 실시예 D1 방법과 유사하게 4-아미노-2-퀴놀린(실시예 C3)과 3-클로로프로필이소시안산염으로부터 얻는다.
실시예 D5. 1-(2-클로로-에틸)-3-(피리딘-4-일)-유레아
표제 화합물은 실시예 D1 방법과 유사하게 4-아미노-피리딘(실시예 C2)과 2-클로로에틸이소시안산염으로부터 얻는다.
실시예 D6. 1-(2-클로로-에틸)-3-(7-메틸-[1,8]-나프티리딘-4-일)-유레아
표제 화합물은 실시예 D1 방법과 유사하게 4-아미노-7-메틸-[1,8]-나프티리딘(실시예 C5)과 2-클로로에틸이소시안산염으로부터 얻는다.
최종 산물의 제조
실시예 1
1-{2-[1-(4-플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아
무수성 THF(2.5 ㎖)에 녹인 1-(4-플루오르-벤질)-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린(실시예 A1, 50 ㎎, 0.16 mmol) 용액에 1-(2-클로로-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아(실시예 D1, 43.8 ㎎, 0.16 mmol), TEA(34.6 ㎕, 0.25 mmol), Nal(2.5 ㎎, 0.017 mmol)을 첨가한다. 혼합물은 75℃, 밀봉된 플라스크에서 5일동안 교반한다. 반응 혼합물은 증발시키고, 잔류물은 예비 HPLC로 정제하여 표제 화합물을 얻는다.
LC-MS(MeCN/H2O, 1:1)tR= 0.93 min, m/z = 529.3(M+1)
실시예 2-6
다음의 표에 제시된 추가의 실시예는 실시예 1의 방법에 따라 실시예 A1 내지 A4 및 실시예 D1 또는 D3을 출발 물질로 하여 얻는다.
실시예 7
1-(2-{1-[2-(4-플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아
1-[2-(4-플루오르-페닐)-에틸]-6,8-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린(실시예 A5, 100 ㎎, 0.317 mmol)은 무수성 THF(3.0 ㎖), 1-(2-클로로-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아(실시예 D1, 83.6 ㎎, 0.317 mmol), TEA(66.2 ㎕, 0.475 mmol), Nal(4.8 ㎎, 0.032 mmol)을 첨가한다. 혼합물은 75℃, 밀봉된 플라스크에서 5일동안 교반한다. 반응 혼합물은 증발시키고, 잔류물은 예비 HPLC로 정제하여 표제 화합물을 얻는다.
LC-MS(MeCN/H2O, 1:1)tR= 1.11 min, m/z = 543.5(M+1)
실시예 8-9
다음의 표에 제시된 추가의 실시예는 실시예 7의 방법에 따라 실시예 A5 내지 A7 및 실시예 D1 또는 D3을 출발 물질로 하여 얻는다.
실시예 13
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아
THF(2 ㎖)에 녹인 1-(4-플루오르벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린(실시예 A31,0.16 g, 0.50 mmol) 용액에 1-(2-클로로-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아(실시예 D1, 0.18 g, 0.60 mmol), 고체 NaHCO3(50 ㎎, 0.6 mmol), Nal(15 ㎎, 0.1 mmol)을 첨가한다. 혼합물은 70℃, 밀봉된 플라스크에서 5일동안 교반한다. 혼합물은 증발시키고, 잔류물은 예비 HPLC로 정제하여 표제 화합물을 얻는다.
LC-MS(MeCN/H2O, 1:1)tR= 1.10 min, m/z = 529.19(M+1)
실시예 14-105
다음의 표에 제시된 추가의 실시예는 실시예 13의 방법에 따라 실시예 A1 내지 A52 및 실시예 D1 내지 D5를 출발 물질로 하여 얻는다.
실시예 106
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(7-메틸-[1,8]나프티리딘-4-일)-유레아
실시예 106.1. {2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-카르밤산 tert-부틸 에스테르
THF(40 ㎖)에 녹인 1-(4-플루오르벤질)-6,7-디메톡시-1,2,3,4-테트라하이드로-이소퀴놀린(실시예 A31, 1.05 g, 3.5 mmol) 용액에 (2-브로모-에틸)-카르밤산 tert-부틸 에스테르(실시예 B1, 0.94 g, 4.2 mmol)와 DIPEA를 첨가한다. 반응 혼합물은 70℃, 밀봉된 플라스크에서 5일동안 교반한다. 반응 혼합물은 증발 건조시키고, 잔류물은 예비 HPLC로 정제하여 표제 화합물을 얻는다.
실시예 106.2. 1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(7-메틸-[1,8]-나프티리딘-4-일)-유레아
차가운 AcOH(1 ㎖)에 녹인 {2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-카르밤산 tert-부틸 에스테르(실시예 106.1, 0.22 g, 0.5 mmol)의 교반 용액에 conc. HCl(0.1 ㎖)을 첨가한다. 5분후, 반응 혼합물은 CHCl3(20 ㎖)과 1N NaOH(15 ㎖)간에 분할한다. 유기상은 증발시킨다. 잔류물은 DMSO(2 ㎖)에 넣고 CDI(0.2 g, 0.6 mmol, 1.2 eq.)로 처리한다. 반응 혼합물은 실온에서 3시간동안 교반하고, 이후 4-아미노-7-메틸-[1,8]-나프티리딘(실시예 C5, 0.19 g, 0.6 mmol)을 첨가한다. 생성 용액에 1회분 NaHMDS(2M/THF, 1.25 ㎖, 2.5 mmol)을 첨가한다. 반응 혼합물은 실온에서 30분동안 교반하고, 이후 H2O(0.4 ㎖)를 첨가한다. 반응 혼합물은 증발시키고, 잔류물은 예비 HPLC로 정제하여 표제 화합물을 얻는다.
LC-MS(MeCN/H2O, 1:1)tR= 0.92 min, m/z = 530.3(M+1)
실시예 107. 1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(5,6,7,8-테트라하이드로-퀴놀린-4-일)-유레아
차가운 AcOH(1 ㎖)에 녹인 {2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-카르밤산 tert-부틸 에스테르(실시예 106.1, 0.22 g, 0.5 mmol)의 교반 용액에 conc. HCl(0.1 ㎖)을 첨가한다. 5분후, 반응 혼합물은 CHCl3(20 ㎖)과 1N NaOH(15 ㎖)간에 분할한다. 유기상은 증발시킨다. 잔류물은 DMSO(2 ㎖)에 넣고 CDI(0.2 g, 0.6 mmol, 1.2 eq.)로 처리한다. 반응 혼합물은 실온에서 3시간동안 교반하고, 이후 4-아미노-5,6,7,8-테트라하이드로퀴놀린(실시예 C4, 0.19 g, 0.6 mmol)을 첨가한다. 생성 용액에 1회분 NaHMDS(2M/THF, 1.25 ㎖, 2.5 mmol)을 첨가한다. 반응 혼합물은 실온에서 30분동안 교반하고, 이후 H2O(0.4 ㎖)를 첨가한다. 반응 혼합물은 증발시키고, 잔류물은 예비 HPLC로 정제하여 표제 화합물을 얻는다.
LC-MS(MeCN/H2O, 1:1)tR= 0.92 min, m/z = 519.3(M+1)
실시예 108
1-[2-(벤질-메틸-아미노)-피리딘-4-일]-3-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-유레아
실시예 108.1. 벤질-(4-이소시아나토-피리딘-2-일)-메틸-아민
DMF(10 ㎖)에 녹인 2-(벤질-메틸-아미노)-이소니코틴산(실시예 C8, 780 ㎎, 3.2 mmol) 용액에 트리에틸아민(360 ㎎, 3.5 mmol)을 0℃에서 첨가한다. 5분후, DPPA(975 ㎎, 3.5 mmol)를 첨가하고 0℃에서 2시간동안, 20℃에서 12시간동안 교반한다. 반응물은 얼음(10 g)으로 냉각시키고 Et2O(6 x 30 ㎖)로 추출한다. 모아진 유기상은 포화된 NaHCO3(2 x 15 ㎖)과 물(2 x 10 ㎖)로 순차적으로 세척하고 진공하에 가열없이 증발시킨다. 잔류물은 건조 톨루엔(16 ㎖)에 용해시키고 2시간동안 환류로 가열한다. 생성 용액은 표제 화합물의 추가적인 분리없이 사용한다.
실시예 108.2. 1-[2-(벤질-메틸-아미노)-피리딘-4-일]-3-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-유레아
CH2Cl2(1 ㎖)에 녹인 {2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸} 카르밤산 tert-부틸 에스테르(실시예 106.1, 0.22 g, 0.5 mmol)의 교반 용액에 TFA(1 ㎖)를 첨가한다. 2시간후, 반응 혼합물은 증발시키고 CH2Cl2(20 ㎖)와 1NNaOH(15 ㎖)간에 분할한다. 유기상은 건조시키고(MgSO4) 증발시킨다. 잔류물은 CH2Cl2(2 ㎖)에 용해시키고 톨루엔(2 ㎖)에 녹인 벤질-(4-이소시아나토-피리딘-2-일)-메틸-아민(실시예 108.1, 95.7 ㎎, 0.40 mmol)의 새로이 준비된 용액에 첨가한다. 혼합물은 20℃에서 15시간동안 교반한다. 용매 증발 및 HPLC 정제로 표제 화합물을 얻는다.
LC-MS(MeCN/H2O, 1:1)tR= 0.73 min, m/z = 584.3(M+1)
실시예 109-111
다음의 표에 제시된 추가의 실시예는 실시예 108의 방법에 따라 실시예 106.1 및 실시예 C9 내지 C11을 출발 물질로 하여 얻는다.
실시예 112
1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸아미노-1-일-피리딘-4-일)-유레아
eOH(10 ㎖)에 녹인 1-[2-(벤질-메틸-아미노)-피리딘-4-일]-3-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-유레아(실시예 108, 0.12 g, 0.2 mmol)와 Pd(탄소에서 10%, 20 ㎎)의 혼합물에 HCl(1N, 0.2 ㎖)을 첨가한다. 용액에 수소 증기를 0.5시간동안 통과시키고, 용액은 수소 대기하에 15시간동안 교반한다. 용액은 여과하고 증발시켜 표제 화합물을 얻는다.
LC-MS(MeCN/H2O, 1:1)tR= 0.77 min, m/z = 534.09(M+1)
실시예 113
(퀴놀린-4-일)-카르밤산 2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸 에스테르
실시예 113.1. 2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에탄올
테트라하이드로피란(3 ㎖)에 녹인 6,7-디메톡시-1-펜에틸-1,2,3,4-테트라하이드로-이소퀴놀린(실시예 A21, 59.5 ㎎, 0.2 mmol)과 2-브로모에탄올(28.3 ㎕, 0.4 mmol)의 용액은 DIPEA(68 ㎕, 0.4 mmol)로 처리하고, 반응 혼합물은 90℃, 밀봉된 플라스크에서 5일동안 교반한다. 반응 혼합물은 증발 건조시키고, 잔류물은 예비 HPLC로 정제하여 표제 화합물을 얻는다.
실시예 113.2.(퀴놀린-4-일)-카르밤산 2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸 에스테르
THF(1 ㎖)에 녹인 2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에탄올(실시예 113.1, 29.7 ㎎, 0.087 mmol) 용액에 CDI(28.2 ㎎, 0.174 mmol, 2.0 eq.)를 첨가한다. 반응 혼합물은 실온에서 3시간동안 교반하고, 이후 4-아미노-퀴놀린(실시예 C3, 14 ㎎, 0.1 mmol)을 첨가한다. 생성 용액에 1회분 NaHMDS(2M/THF, 218 ㎕, 0.44 mmol)을 첨가한다. 반응 혼합물은 실온에서 30분동안 교반하고, 이후 H2O/AcOH(9:1, 0.4 ㎖)를 첨가한다. 반응 혼합물은 증발시키고, 잔류물은 예비 HPLC로 정제하여 표제 화합물을 얻는다.
LC-MS(MeCN/H2O, 1:1)tR= 1.17 min, m/z = 512.19(M+1)
실시예 114-120
다음의 표에 제시된 추가의 실시예는 실시예 113의 방법에 따라 실시예 A1 내지 A52 및 실시예 C1 내지 C3을 출발 물질로 하여 얻는다.
실시예 121
시험관내 생물학적 특성화
유로텐신 Ⅱ에 대한 화학식 I 화합물의 저해 활성은 하기에 밝힌 검사 과정으로 입증할 수 있다.
1) 횡문근 육종 세포주에 사람[
125
I]-유로텐신 Ⅱ 결합의 저해
사람 [125I]-유로텐신 Ⅱ의 전체 세포 결합은 전체 세포 엔도텔린 결합 분석법(Breu V et al., In Vitro characterization of Ro-46-2005, a novel synthetic non-peptide antagonist of ETAand ETBreceptors. FEBS Lett. 1993, 334, 210-214)으로부터 수정된 방법으로 사람-유래된 TE-671 횡문근 육종 세포(Deutsche Sammlung Von Mikroorganismen und Zellkulturen, cell line #ACC-263)를 이용하여 실시한다.
상기 분석은 폴리프로필렌 마이크로역가 평판(Nunc, CatNo 442587)에서 25 mM HEPES(Fluka, CatNo 05473), 1.0% DMSO(Fluka, CatNo 41644), 0.5%(w/v) BSA Fraction V(Fluka, CatNo 05473)를 함유하는 250 ㎕ 둘베코 변형 이글 배지에서 실시한다. 300'000 현탁된 세포는 20 pM 사람 [125I]유로텐신 Ⅱ(Anawa Trading SA, Wagnen, Switzerland, 2130Ci/mmol) 및 점진적으로 농도가 증가하는 표지되지 않은 길항제과 함께 20℃에서 4시간동안 부드럽게 진탕하면서 배양한다. 최소와 최대 결합은 각각 100 nM 표지되지 않은 U-Ⅱ를 함유하는 시료와 이를 함유하지 않는 시료에서 유래된다. 4시간 배양후, 세포는 GF/C 필터플레이트(Packard, CatNo 6005174)에서 여과한다. 상기 필터플레이트는 건조시키고, 이후 각 웰에 50 ㎕ 신틸레이션 칵테일(Packard, MicroScint 20, CatNo 6013621)을 첨가한다. 필터플레이트는 마이크로평판 계수기(Packard Bioscience, TopCount NXT)에서 계산한다.
모든 검사 화합물은 100% DMSO에서 용해시키고 희석한다. 분석 완충액에 10배 희석은 분석물에 첨가하기에 앞서 실시한다. 상기 분석물에서 DMSO의 최종 농도는 1.0%인데, 이는 결합을 간섭하지 않는 것으로 밝혀졌다. IC50값은 [125I]사람U-Ⅱ의 특이적인 결합을 50% 저해하는 길항제의 농도로 정의된다. 특이적 결합은 전술한 바와 같이 최대 결합과 최소 결합간 차이이다. 0.206 nM의 IC50값은 표지되지 않은 사람 U-Ⅱ에서 발견된다. 본원 발명의 화합물은 이런 분석에서 1 내지 10000 nM의 IC50값을 갖는 것으로 밝혀졌다. 특정 실시예는 다음 표에 제시된 IC50값을 갖는다.
실시예 | IC50[nM] |
20 | 67 |
22 | 63 |
29 | 125 |
58 | 550 |
2) 분리된 쥐 대동맥궁의 사람 유로텐신 Ⅱ-유도된 수축의 저해
성체 Wilstar 쥐는 마취시키고(CO2흡입) 방혈한다. 대동맥궁은 잘라내고 절개하며 3개의 3 ㎜ 고리로 절단하는데, 고리 #1은 좀더 인접하고 고리 #3은 원위한다. 각 고리는 37℃로 유지되고 95% O2와 5% CO2로 포기된 Krebs-Henseleit 용액(mM; NaCl 115, KCl 4.7, MgSO41.2, KH2PO41.5, NaHCO325, CaCl22.5, 글루코오스 10; pH 7.4)으로 채워진 10 ㎖ 분리된 장기 용액조에 현탁시킨다. 이들 고리는 힘 변환기에 연결시키고 등장력(isometric tension)을 기록한다(EMKA Technologies SA, Paris, France). 고리는 3g의 안정장력(resting tension)으로 잡아당긴다. 20분간 검사 화합물이나 이의 부형제(DMSO, 10 ㎕)와 함께 배양한 이후, 누적 용량의 사람 유로텐신 Ⅱ(10-11M 내지 10-8M)를 첨가한다. 1.09±.1 nM의 EC50값은 표지되지 않은 사람 U-Ⅱ에서 발견된다. 검사 화합물의 기능적 저해능력은 다음의 공식에 따라 pD2'를 계산하여 평가한다: pD2' = Log(CR-1)-Log[B], 여기서CR은 길항제의 유무하에 최대 효과의 비율이고 [B]는 길항제의 농도이다. 특정 실시예는 다음 표에 제시된 pD2'값을 갖는다.
실시예 | pD2' |
29 | 5.23 |
93 | 5.45 |
Claims (22)
- 화학식 Ⅰ 화합물, 광학적으로 순수한 거울상이성질체나 부분입체이성질체, 거울상이성질체나 부분입체이성질체의 혼합물, 부분입체이성질성 라셈체, 부분입체이성질성 라셈체의 혼합물, 이들의 제약학적으로 수용가능한 염, 용매 복합체, 조직학적 형태:화학식 Ⅰ여기서,X는 -CH2-, -CH2CH2-, -C(CH3)2-이고;Y는 산소, NH이고;n은 1이나 2이고;Z는2, 6 혹은 8번 위치에서 저급 알킬로 단일-치환되거나 또는 2,6 혹은 2,8번 위치에서 저급 알킬로 이중-치환될 수 있는 퀴놀린-4-일; 7번 위치에서 저급 알킬로 치환될 수 있는 [1,8]나프티리딘-4-일; 2번 위치에서 R7R8N-으로 치환되고 6번 위치에서 수소 혹은 저급 알킬로 추가로 치환될 수 있는 피리딘-4-일이고;R1은 나프탈렌-1-일; 나프탈렌-2-일; 벤조[1,3]디옥솔-5-일; 벤질, 또는 페닐 고리에서 저급 알킬, 저급 알킬옥시, 트리플루오르메틸, 할로겐, 시아노로 독립적으로 치환되는 단일-, 이중-, 혹은 삼중-치환된 벤질; 페닐, 또는 저급 알킬, 저급 알킬옥시, 트리플루오르메틸, 할로겐, 시아노로 독립적으로 치환되는 단일-, 이중-, 혹은 삼중-치환된 페닐이고;R2는 수소, 저급 알킬, 아릴, 또는 R1이 E 혹은 Z 기하학적 구조의 스트릴기인 형태이고, 상기 스트릴기에서 페닐 고리는 저급 알킬, 저급 알킬옥시, 트리플루오르메틸, 할로겐, 시아노로 독립적으로 치환되는 단일-, 이중- 혹은 삼중-치환된 페닐이며;R3, R4, R5, R6은 독립적으로 수소, 시아노, 하이드록시, 저급 알킬옥시, 아르알킬옥시, 저급 알케닐옥시이고, R5는 추가적으로 R7R8NCO이며;R4와 R5는 서로 결합하여 페닐 고리와 함께, 1개 혹은 2개의 산소 원자를 보유하는 5각형이나 6각형 고리를 형성할 수 있고;R7과 R8은 독립적으로 수소, 저급 알킬, 아릴, 아르알킬이거나 또는 N과 결합하여 피롤리딘, 피페리딘 혹은 모르폴린 고리를 형성한다.
- 화학식 Ⅱ 화합물:화학식 Ⅱ여기서, R1, R2, R3, R4, R5, R6, X, Z, n은 화학식 I에서와 동일하다.
- 화학식 Ⅲ 화합물:화학식 Ⅲ여기서, R1, R2, R3, R4, R5, R6, X, Y, Z는 화학식 I에서와 동일하다.
- 화학식 Ⅳ 화합물:화학식 Ⅳ여기서, R1, R2, R3, R4, R5, R6, Y, Z, n은 화학식 I에서와 동일하다.
- 화학식 Ⅴ 화합물:화학식 Ⅴ여기서, R1, R2, R3, R4, R5, R6, Y, Z, n은 화학식 I에서와 동일하다.
- 화학식 Ⅵ 화합물:화학식 Ⅵ여기서, R1, R2, R3, R4, R5, R6, Y, Z, n은 화학식 I에서와 동일하다.
- 화학식 Ⅶ 화합물:화학식 Ⅶ여기서, R1, R3, R4, R5, R6, X, Y, Z, n은 화학식 I에서와 동일하다.
- 화학식 Ⅷ 화합물:화학식 Ⅷ여기서, Ph는 페닐; 독립적으로 수소, 저급 알킬, 저급 알킬옥시, 트리플루오르메틸, 할로겐, 시아노로 치환되는 단일-, 이중- 혹은 삼중-치환된 페닐이고, R3, R4, R5, R6, X, Y, Z, n은 화학식 I에서와 동일하다.
- 화학식 Ⅸ 화합물:화학식 Ⅸ여기서, R1, R2, X, Y, Z, n은 화학식 I에서와 동일하다.
- 화학식 Ⅹ 화합물:화학식 Ⅹ여기서, R1, R2, X, Y, Z, n은 화학식 I에서와 동일하다.
- 화학식 11 화합물:화학식 ⅩⅠ여기서, R1, R2, X, Y, Z, n은 화학식 I에서와 동일하다.
- 화학식 12 화합물:화학식 ⅩⅡ여기서, R1, R2, R3, R4, R5, R6, X, Y, n은 화학식 I에서와 동일하다.
- 화학식 ⅩⅢ 화합물:화학식 ⅩⅢ여기서, R1, R2, R3, R4, R5, R6, X, Y, n은 화학식 I에서와 동일하다.
- 화학식 ⅩⅣ 화합물:화학식 ⅩⅣ여기서, R1, R2, R3, R4, R5, R6, R7, R8, X, Y, n은 화학식 I에서와 동일하다.
- 화학식 ⅩⅤ 화합물:화학식 ⅩⅤ여기서, 1,2,3,4-테트라하이드로이소퀴놀린 고리의 1번 위치는 R 절대 입체화학적 배열을 갖고; R1, R2, R3, R4, R5, R6, X, Z, n은 화학식 I에서와 동일하다.
- 화학식 ⅩⅥ 화합물:화학식 ⅩⅥ여기서, R3, R4, R5, R6은 독립적으로 수소 또는 저급 알킬옥시이고; R1, R2, Z는 화학식 I에서와 동일하다.
- 제 1 항 내지 16 항중 어느 한 항에 있어서, 다음에서 선택되는 것을 특징으로 하는 화합물:1-{2-[1-(4-플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(3,4-디플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(3-플루오르-4-메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(3,4-디플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(3-플루오르-4-메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(4-플루오르-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-(2-{1-[2-(4-플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(2,4-디플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(2,4-디플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-퀴놀린-4-일-유레아;1-(2-{1-[2-(3,4-디플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(3,4-디플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-퀴놀린-4-일-유레아;1-(2-{1-[2-(4-플루오르-페닐)-에틸]-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-퀴놀린-4-일-유레아;1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(3,4-디메톡시-벤질)-7,8-디메톡시-1,3,4,5-테트라하이드로-벤조[c]아제핀-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[(E)-2-(2,4-디플루오르-페닐)-비닐]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[(E)-2-(2,5-디플루오르-페닐)-비닐]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(2,3-디플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(2,4-디플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(2,5-비스-트리플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(2,5-디플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(3,4-디플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(3,4-디메톡시-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(3,5-비스-트리플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{1-[2-(4-플루오르-페닐)-에틸]-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{6,7-디메톡시-1-[2-(2-메톡시-페닐)-에틸]-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{6,7-디메톡시-1-[2-(3-메톡시-페닐)-에틸]-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{6,7-디메톡시-1-[2-(4-메톡시-페닐)-에틸]-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-(2-{6,7-디메톡시-1-[2-(4-트리플루오르메틸-페닐)-에틸]-3,4-디하이드로-1H-이소퀴놀린-2-일}-에틸)-3-(2-메틸-퀴놀린-4-일)-유레아;1-[2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-(2-메틸-퀴놀린-4-일)-유레아;1-[2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-[3-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필]-3-(2-메틸-퀴놀린-4-일)-유레아;1-[3-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필]-3-퀴놀린-4-일-유레아;1-[2-(1-벤조[1,3]디옥솔-5-일메틸-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-(2-메틸-퀴놀린-4-일)-유레아;1-[2-(1-벤조[1,3]디옥솔-5-일메틸-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[2-(1-벤조[1,3]디옥솔-5-일메틸-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-[2-(1-벤질-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[2-(1-벤질-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-[2-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-(2-메틸-퀴놀린-4-일)-유레아;1-[2-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[2-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-[2-(1-벤질-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[2-(1-벤질-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-[2-(6,7-디메톡시-1-나프탈렌-2-일메틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[2-(6,7-디메톡시-1-나프탈렌-2-일메틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-[2-(6,7-디메톡시-1-페녹시메틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[3-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필]-3-(2-메틸-퀴놀린-4-일)-유레아;1-[3-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필]-3-퀴놀린-4-일-유레아;1-{2-[1-(2,5-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[1-(2,5-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(2,6-디클로로-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(3,4-디플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[1-(3,4-디플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6,7,8-트리메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(5,6,7,8-테트라하이드로-퀴놀린-4-일)-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(3-플루오르-4-메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(3-플루오르-5-트리플루오르메틸-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(4-클로로-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[1-(4-클로로-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[6,7-디메톡시-1-(2,3,4-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[6,7-디메톡시-1-(2,3,4-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[6,7-디메톡시-1-(3,4,5-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[6,7-디메톡시-1-(3,4,5-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[6,7-디메톡시-1-(3,4,5-트리메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[6,7-디메톡시-1-(3-메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[6,7-디메톡시-1-(3-메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[6,7-디메톡시-1-(4-메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[6,7-디메톡시-1-(4-메톡시-벤질)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{3-[1-(3,4-디플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-퀴놀린-4-일-유레아;1-{3-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{3-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-퀴놀린-4-일-유레아;1-{3-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{3-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-퀴놀린-4-일-유레아;1-{3-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-프로필}-3-퀴놀린-4-일-유레아;1-{2-[5-(3,4-디메톡시-벤질)-7,8-디하이드로-5H-[1,3]디옥솔로[4,5-g]이소퀴놀린-6-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[5-(3,4-디메톡시-벤질)-7,8-디하이드로-5H-[1,3]디옥솔로[4,5-g]이소퀴놀린-6-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[6-(3,4-디메톡시-벤질)-2,3,8,9-테트라하이드로-6H-[1,4]디옥시노[2,3-g]이소퀴놀린-7-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[6-(3,4-디메톡시-벤질)-2,3,8,9-테트라하이드로-6H-[1,4]디옥시노[2,3-g]이소퀴놀린-7-일]-에틸}-3-퀴놀린-4-일-유레아;1-[2-(1-벤즈하이드릴-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-[2-(1-벤즈하이드릴-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[2-(1-벤즈하이드릴-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-[2-(1-벤질-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-피리딘-4-일-유레아;1-[2-(1-벤질-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-3-퀴놀린-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(2,5-디메톡시-벤질)-5,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[6,7-디메톡시-1-(1-페닐-프로필)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-피리딘-4-일-유레아;1-{2-[6,7-디메톡시-1-(1-페닐-프로필)-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6,7-디메톡시-4,4-디메틸-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[(R)-1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[(R)-1-(3,4-디메톡시-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-퀴놀린-4-일-유레아;1-{2-[(R)-1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[7-벤질옥시-1-(3,4-디메톡시-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-{2-[1-(3,4-디메톡시-벤질)-6-메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸-퀴놀린-4-일)-유레아;1-(3,4-디클로로-벤질)-6-메톡시-2-{2-[3-(2-메틸-퀴놀린-4-일)-우레이도]-에틸}-1,2,3,4-테트라하이드로이소퀴놀린-7-카르복실산 메틸아마이드;1-(3,4-디클로로-벤질)-6-메톡시-2-{2-[3-(2-메틸-퀴놀린-4-일)-우레이도]-에틸}-1,2,3,4-테트라하이드로이소퀴놀린-7-카르복실산 프로필아마이드;1-(3,4-디클로로-벤질)-6-메톡시-2-{2-[3-(2-메틸-퀴놀린-4-일)-우레이도]-에틸}-1,2,3,4-테트라하이드로이소퀴놀린-7-카르복실산 디메틸아마이드;1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(7-메틸-[1,8]나프티리딘-4-일)-유레아;1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(5,6,7,8-테트라하이드로-퀴놀린-4-일)-유레아;1-[2-(벤질-메틸-아미노)-피리딘-4-일]-3-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-유레아;1-[2-(벤질-메틸-아미노)-6-메틸-피리딘-4-일]-3-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-유레아;1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-[2-(메틸-페닐-아미노)-피리딘-4-일]-유레아;1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-피롤리딘-1-일-피리딘-4-일)-유레아;1-{2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸}-3-(2-메틸아미노-1-일-피리딘-4-일)-유레아;퀴놀린-4-일-카르밤산 2-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸 에스테르;퀴놀린-4-일-카르밤산 2-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸 에스테르;퀴놀린-4-일-카르밤산 2-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일]-에틸에스테르;퀴놀린-4-일-카르밤산 3-(1-벤질-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;퀴놀린-4-일-카르밤산 3-(6,7-디메톡시-1-펜에틸-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;퀴놀린-4-일-카르밤산 3-[1-(3,4-디플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;퀴놀린-4-일-카르밤산 3-[1-(3,4-디메톡시-벤질)-6,8-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;퀴놀린-4-일-카르밤산 3-[1-(4-플루오르-벤질)-6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-프로필 에스테르;이들의 제약학적으로 수용가능한 염.
- 제 1 항 내지 17 항중 어느 한 항에 따른 화합물 및 통상적인 담체 물질과 어쥬번트를 함유하는 제약학적 조성물에 있어서, 유로텐신 Ⅱ 혹은 유로텐신 Ⅱ 수용체의 조절이상과 연관된 질환, 특히 혈관이나 심근의 기능장애와 연관된 질환, 예를 들면 고혈압, 죽상경화증, 협심증이나 심근 허혈, 울혈성 심장 마비, 심부전, 심장 부정맥, 신허혈, 만성 신장 질환, 신부전, 발작, 뇌혈관 연축, 뇌 허혈, 치매, 편두통, 지주막하 출혈, 당뇨병, 당뇨성 혈관경화증, 천식, 만성 폐색성 폐 질환, 높은-고도 폐 부종, 레이노 증후군, 문맥 고혈압, 갑상선 기능장애, 폐 부종, 폐 고혈압 또는 폐 섬유증의 치료에 사용되는 것을 특징으로 하는 제약학적 조성물.
- 제 1 항 내지 17 항중 어느 한 항에 따른 화합물 및 통상적인 담체 물질과 어쥬번트를 함유하는 제약학적 조성물에 있어서, 풍선이나 스텐트 혈관성형술이후 재협착, 암, 전립선 비대, 발기 장애, 청력 상실, 흑내장, 만성 기관지염, 천식, 그람 네거티브 패혈증, 쇼크, 겸상적혈구 빈혈, 사구체신염, 신장통, 녹내장, 당뇨합병증, 혈관이나 심장 수술 또는 장기 이식후 합병증, 사이클로스포린 치료의 합병증, 통증, 중독, 정신분열증, 알츠하이머병, 불안, 강박 행동, 간질성 발작, 스트레스, 우울증, 치매, 신경근육 질환, 신경퇴행성 질환의 치료와 예방에 사용되는 것을 특징으로 하는 제약학적 조성물.
- 다른 제약학적 활성 화합물과 함께 고혈압, 죽상경화증, 협심증이나 심근 허혈, 울혈성 심장 마비, 심부전, 심장 부정맥, 신허혈, 만성 신장 질환, 신부전, 발작, 뇌혈관 연축, 뇌 허혈, 치매, 편두통, 지주막하 출혈, 당뇨병, 당뇨성 혈관경화증, 천식, 만성 폐색성 폐 질환, 높은-고도 폐 부종, 레이노 증후군, 문맥 고혈압, 갑상선 기능장애, 폐 부종, 폐 고혈압, 폐 섬유증, 풍선이나 스텐트 혈관성형술이후 재협착, 암, 전립선 비대, 발기 장애, 청력 상실, 흑내장, 만성 기관지염, 천식, 그람 네거티브 패혈증, 쇼크, 겸상적혈구 빈혈, 사구체신염, 신장통, 녹내장, 당뇨합병증, 혈관이나 심장 수술 또는 장기 이식후 합병증, 사이클로스포린 치료의 합병증, 통증, 중독, 정신분열증, 알츠하이머병, 불안, 강박 행동, 간질성 발작, 스트레스, 우울증의 치료와 예방에 사용되는 제 1 항 내지 17 항중 어느 한 항에 따른 화합물의 용도.
- 제 18 항 내지 20 항중 어느 한 항에 제시된 질환의 치료를 위하여 다른 치료요법적 활성 화합물, 예를 들면 ACE 저해물질, 안지오텐신 Ⅱ 수용체 길항제, 엔도텔린 수용체 길항제, 바소프레신 길항제, 베타-아드레날린성 길항제, 알파-아드레날린성 길항제, 바소프레신 길항제, TNF알파 길항제 또는 퍼록시솜(peroxisome) 증식제 활성화 수용체 조절물질과 병용되는 제 1 항 내지 17 항중 어느 한 항에 따른 화합물의 용도.
- 본원에서 밝힌 전체 발명.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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EP0103422 | 2001-03-27 | ||
EP0103422 | 2001-03-27 | ||
EP0109845 | 2001-08-27 | ||
EP0109845 | 2001-08-27 | ||
PCT/EP2002/003131 WO2002076979A1 (en) | 2001-03-27 | 2002-03-20 | 1,2,3,4-tetrahydroisoquinolines derivatives as urotensin ii receptor antagonists |
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KR20040016844A true KR20040016844A (ko) | 2004-02-25 |
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EP (1) | EP1379523B1 (ko) |
JP (1) | JP2004529132A (ko) |
KR (1) | KR20040016844A (ko) |
CN (1) | CN1288148C (ko) |
AT (1) | ATE300533T1 (ko) |
BR (1) | BR0207715A (ko) |
CA (1) | CA2441790A1 (ko) |
DE (1) | DE60205234T2 (ko) |
ES (1) | ES2246399T3 (ko) |
HU (1) | HUP0402508A2 (ko) |
IL (1) | IL157093A0 (ko) |
MX (1) | MXPA03008639A (ko) |
NO (1) | NO20034230D0 (ko) |
NZ (1) | NZ527276A (ko) |
WO (1) | WO2002076979A1 (ko) |
Families Citing this family (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2262567T3 (es) | 2001-03-20 | 2006-12-01 | Schwarz Pharma Ag | Nuevo uso de una clase peptidica de compuesto para tratamiento del dolor inflamatorio no neuropatico. |
PT1243263E (pt) | 2001-03-21 | 2003-03-31 | Sanol Arznei Schwarz Gmbh | Nova utilizacao de uma classe peptidica de composto para o tratamento de alodinia ou de outros tipos diferentes de dor cronica ou fantasma |
EP1483233A4 (en) * | 2002-03-13 | 2005-12-21 | Univ Tennessee Res Corp | SUBSTITUTED TETRAHYDROISOQUINOLEINE COMPOUNDS, METHODS OF PREPARATION AND USE THEREOF |
RU2005111589A (ru) * | 2002-09-17 | 2006-01-20 | Актелион Фармасьютиклз Лтд. (Ch) | Производные 1-пиридин-4-илмочевины |
JP2006519229A (ja) | 2003-02-13 | 2006-08-24 | アルバート・アインシュタイン・カレッジ・オヴ・メディシン・オヴ・イェシヴァ・ユニヴァーシティ | 視床下部内の長鎖脂肪アシルCoAレベルの変調による摂食量およびグルコース産生量の調節 |
US20060211707A1 (en) * | 2003-05-07 | 2006-09-21 | Hamed Aissaoui | Piperazine-alkyl-ureido derivatives |
CN1784394A (zh) * | 2003-05-08 | 2006-06-07 | 埃科特莱茵药品有限公司 | 新型哌啶衍生物 |
KR20070014108A (ko) * | 2003-09-26 | 2007-01-31 | 액테리온 파마슈티칼 리미티드 | 피리딘 유도체 및 이의 우로텐신 ⅱ 길항제로서의 용도 |
NZ546576A (en) | 2003-12-02 | 2009-05-31 | Sanol Arznei Schwarz Gmbh | Use of peptide compounds for treating central neuropathic pain |
EP1604655A1 (en) | 2004-06-09 | 2005-12-14 | Schwarz Pharma Ag | Novel use of peptide compounds for treating pain in trigeminal neuralgia |
JP2008510758A (ja) | 2004-08-27 | 2008-04-10 | シュヴァルツ・ファーマ・アーゲー | 骨肉腫の痛み、化学療法誘発性及びヌクレオシド誘発性の痛みを治療するためのペプチド化合物の新規使用 |
BRPI0515979A (pt) | 2004-10-12 | 2008-08-12 | Actelion Pharmaceuticals Ltd | composto, processo para a preparação do mesmo, composições, uso de um ou mais compostos, e, método de tratamento de um paciente sofrendo de um distúrbio |
WO2006126255A1 (ja) * | 2005-05-24 | 2006-11-30 | Daito Chemix Corporation | N-(2-ブロモエチル)カルバミン酸tert-ブチルの製造方法 |
TW200804347A (en) * | 2006-01-10 | 2008-01-16 | Janssen Pharmaceutica Nv | Urotensin II receptor antagonists |
US20070196510A1 (en) * | 2006-02-17 | 2007-08-23 | Gerber Michael J | Method for treating resistant hypertension |
MX2008016000A (es) | 2006-06-15 | 2009-03-05 | Sanol Arznei Schwarz Gmbh | Composicion farmaceutica con efecto anticonvulsivante sinergistico. |
CL2007002097A1 (es) * | 2006-07-20 | 2008-01-18 | Smithkline Beecham Corp | Compuestos derivados de pirrolidina o morfolina antagonistas de urotensina ii; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar insuficiencia cardiaca congestiva, insuficiencia cardiaca isquemica, angina, isquemia del miocardio, vejiga hiperactiva, asma y/o copd, entre otras. |
WO2008123582A1 (ja) * | 2007-04-04 | 2008-10-16 | Kowa Company, Ltd. | テトラヒドロイソキノリン化合物 |
ES2397764T3 (es) * | 2008-04-01 | 2013-03-11 | Abbott Gmbh & Co. Kg | Tetrahidroisoquinolinas, composiciones farmacéuticas que las contienen, y su uso en terapia |
CA2736953C (en) | 2008-10-31 | 2017-07-11 | Shionogi & Co., Ltd. | Cephalosporins having catechol group |
AR075442A1 (es) | 2009-02-16 | 2011-03-30 | Abbott Gmbh & Co Kg | Derivados de aminotetralina, composiciones farmaceuticas que las contienen y sus usos en terapia |
JP5755217B2 (ja) | 2009-03-30 | 2015-07-29 | トランステック・ファーマ,エルエルシー | 置換アゾアントラセン誘導体、その医薬組成物とその使用の方法 |
US20100312480A1 (en) * | 2009-04-24 | 2010-12-09 | Hansteen Fredrik | Method for monitoring fluid flow in a multi-layered system |
US9051280B2 (en) | 2010-08-13 | 2015-06-09 | AbbVie Deutschland GmbH & Co. KG | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9045459B2 (en) | 2010-08-13 | 2015-06-02 | AbbVie Deutschland GmbH & Co. KG | Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8846743B2 (en) | 2010-08-13 | 2014-09-30 | Abbott Laboratories | Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8877794B2 (en) | 2010-08-13 | 2014-11-04 | Abbott Laboratories | Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8883839B2 (en) | 2010-08-13 | 2014-11-11 | Abbott Laboratories | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9309200B2 (en) | 2011-05-12 | 2016-04-12 | AbbVie Deutschland GmbH & Co. KG | Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy |
MX2014001457A (es) | 2011-08-05 | 2014-08-21 | Abbvie Deutschland | Derivados de aminocromano, de aminotiocromano y de amino-1,2,3,4-tetrahidroquinolina composiciones farmaceuticas que los contienen, y su uso en terapia. |
TWI537262B (zh) * | 2011-08-17 | 2016-06-11 | 美國禮來大藥廠 | 供治療糖尿病使用之新穎1,2,3,4-四氫喹啉衍生物 |
WO2013072520A1 (en) | 2011-11-18 | 2013-05-23 | AbbVie Deutschland GmbH & Co. KG | N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9365512B2 (en) | 2012-02-13 | 2016-06-14 | AbbVie Deutschland GmbH & Co. KG | Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
JP6678455B2 (ja) * | 2012-12-21 | 2020-04-08 | エピザイム,インコーポレイティド | Prmt5阻害剤およびその使用 |
US9656955B2 (en) | 2013-03-15 | 2017-05-23 | Abbvie Inc. | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9650334B2 (en) | 2013-03-15 | 2017-05-16 | Abbvie Inc. | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
AU2014336154A1 (en) | 2013-10-17 | 2016-04-28 | AbbVie Deutschland GmbH & Co. KG | Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy |
SG11201602982YA (en) | 2013-10-17 | 2016-05-30 | Abbvie Deutschland | Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
US11833156B2 (en) | 2017-09-22 | 2023-12-05 | Jubilant Epipad LLC | Heterocyclic compounds as pad inhibitors |
FI3697785T3 (fi) | 2017-10-18 | 2023-04-03 | Jubilant Epipad LLC | Imidatsopyridiiniyhdisteitä pad:n estäjinä |
EP3707135A1 (en) | 2017-11-06 | 2020-09-16 | Jubilant Prodel LLC | Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation |
JP7368369B2 (ja) | 2017-11-24 | 2023-10-24 | ジュビラント・エピスクライブ・エルエルシー | Prmt5阻害剤としてのヘテロ環式化合物 |
US11466012B2 (en) * | 2018-01-10 | 2022-10-11 | Allinky Biopharma | Tetrahydroisoquinoline compounds |
JP7279063B6 (ja) | 2018-03-13 | 2024-02-15 | ジュビラント プローデル エルエルシー | Pd1/pd-l1相互作用/活性化の阻害剤としての二環式化合物 |
CN110755434B (zh) * | 2018-07-27 | 2022-03-15 | 中国医学科学院药物研究所 | 化合物palosuran防治骨骼肌萎缩等疾病的用途 |
CN115677579A (zh) * | 2022-11-02 | 2023-02-03 | 上海药坦药物研究开发有限公司 | 四氢罂粟碱及其中间体的制备方法 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE903957A1 (en) | 1989-11-06 | 1991-05-08 | Sanofi Sa | Aromatic amine compounds, their method of preparation and¹pharmaceutical compositions in which they are present |
CA2061260A1 (en) * | 1991-02-27 | 1992-08-28 | Kiyofumi Ishikawa | Isoquinoline derivatives |
AUPP003197A0 (en) | 1997-09-03 | 1997-11-20 | Fujisawa Pharmaceutical Co., Ltd. | New heterocyclic compounds |
ATE321751T1 (de) | 1999-07-28 | 2006-04-15 | Kirin Brewery | Harnstoffderivate als ccr-3 rezeptor-inhibitoren |
US6514970B1 (en) * | 1999-12-21 | 2003-02-04 | Smithkline Beecham Corporation | Urotensin-II receptor antagonists |
EP1248607A4 (en) * | 1999-12-21 | 2004-10-06 | Smithkline Beecham Corp | UROTENSIN II RECEPTOR ANTAGONISTS |
ATE249831T1 (de) | 1999-12-21 | 2003-10-15 | Smithkline Beecham Corp | Carboxamidderivate von pyrrolidine und piperidine als urotensin-ii rezeptorantagonisten |
US7091247B2 (en) | 2000-06-28 | 2006-08-15 | Takeda Pharmaceutical Company Limited | Biphenyl compound |
AU2001271018A1 (en) | 2000-07-04 | 2002-01-14 | Takeda Chemical Industries Ltd. | Gpr14 antagonist |
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- 2002-03-20 ES ES02730036T patent/ES2246399T3/es not_active Expired - Lifetime
- 2002-03-20 WO PCT/EP2002/003131 patent/WO2002076979A1/en active IP Right Grant
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- 2002-03-20 BR BR0207715-9A patent/BR0207715A/pt not_active IP Right Cessation
- 2002-03-20 CN CNB028059417A patent/CN1288148C/zh not_active Expired - Fee Related
- 2002-03-20 CA CA002441790A patent/CA2441790A1/en not_active Abandoned
- 2002-03-20 IL IL15709302A patent/IL157093A0/xx unknown
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- 2002-03-20 NZ NZ527276A patent/NZ527276A/en unknown
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- 2002-03-20 KR KR10-2003-7012299A patent/KR20040016844A/ko not_active Application Discontinuation
- 2002-03-20 JP JP2002576237A patent/JP2004529132A/ja not_active Abandoned
- 2002-03-20 HU HU0402508A patent/HUP0402508A2/hu unknown
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2003
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US6815451B2 (en) | 2004-11-09 |
CA2441790A1 (en) | 2002-10-03 |
NO20034230L (no) | 2003-09-23 |
WO2002076979A8 (en) | 2003-11-06 |
DE60205234T2 (de) | 2006-05-24 |
US20040242564A1 (en) | 2004-12-02 |
NO20034230D0 (no) | 2003-09-23 |
NZ527276A (en) | 2004-11-26 |
WO2002076979A1 (en) | 2002-10-03 |
ATE300533T1 (de) | 2005-08-15 |
JP2004529132A (ja) | 2004-09-24 |
BR0207715A (pt) | 2004-03-23 |
IL157093A0 (en) | 2004-02-08 |
DE60205234D1 (de) | 2005-09-01 |
MXPA03008639A (es) | 2005-03-07 |
EP1379523B1 (en) | 2005-07-27 |
ES2246399T3 (es) | 2006-02-16 |
EP1379523A1 (en) | 2004-01-14 |
CN1494542A (zh) | 2004-05-05 |
US20040110744A1 (en) | 2004-06-10 |
HUP0402508A2 (hu) | 2005-03-29 |
CN1288148C (zh) | 2006-12-06 |
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