CN1353609B - 酰胺取代的咪唑并喹啉 - Google Patents
酰胺取代的咪唑并喹啉 Download PDFInfo
- Publication number
- CN1353609B CN1353609B CN008084378A CN00808437A CN1353609B CN 1353609 B CN1353609 B CN 1353609B CN 008084378 A CN008084378 A CN 008084378A CN 00808437 A CN00808437 A CN 00808437A CN 1353609 B CN1353609 B CN 1353609B
- Authority
- CN
- China
- Prior art keywords
- quinoline
- amino
- imidazo
- butyl
- alkyl
- 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 - Fee Related
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- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 title 1
- 125000003368 amide group Chemical group 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 129
- 150000001875 compounds Chemical class 0.000 claims abstract description 112
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- -1 pyridine radicals Chemical class 0.000 claims description 177
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 175
- 239000008194 pharmaceutical composition Substances 0.000 claims description 124
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 55
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 43
- 229910052799 carbon Inorganic materials 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 20
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000001624 naphthyl group Chemical group 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 12
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 210000004102 animal cell Anatomy 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 5
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 4
- OFTVQECAQDHFAP-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)CC=CC=C2 Chemical compound NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)CC=CC=C2 OFTVQECAQDHFAP-UHFFFAOYSA-N 0.000 claims description 4
- 230000001851 biosynthetic effect Effects 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- 229960005206 pyrazinamide Drugs 0.000 claims description 4
- ZQPCDUXSQUHJNS-UHFFFAOYSA-N 1-[4-(4-aminoimidazo[4,5-c]quinolin-1-yl)butyl]-2H-naphthalene-1-carboxamide Chemical compound NC1=NC=2C=CC=CC=2C2=C1N=CN2CCCCC1(CC=CC2=CC=CC=C12)C(=O)N ZQPCDUXSQUHJNS-UHFFFAOYSA-N 0.000 claims description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 3
- PCGQSRGQQWVIBL-UHFFFAOYSA-N 2-[4-(4-aminoimidazo[4,5-c]quinolin-1-yl)butyl]-1H-naphthalene-2-carboxamide Chemical compound NC1=NC=2C=CC=CC=2C2=C1N=CN2CCCCC1(CC2=CC=CC=C2C=C1)C(=O)N PCGQSRGQQWVIBL-UHFFFAOYSA-N 0.000 claims description 3
- KSRJIXIOKVFZGW-UHFFFAOYSA-N 3-[4-(4-aminoimidazo[4,5-c]quinolin-1-yl)butyl]-6-chloro-2H-pyridine-3-carboxamide Chemical compound NC1=NC=2C=CC=CC=2C2=C1N=CN2CCCCC1(C(=O)N)CN=C(C=C1)Cl KSRJIXIOKVFZGW-UHFFFAOYSA-N 0.000 claims description 3
- SOWXSGADPSTMCX-UHFFFAOYSA-N NC1=NC=2C=CC=CC=2C2=C1N=C(N2CCCCC1(C(=O)N)CC=CC=C1)C Chemical compound NC1=NC=2C=CC=CC=2C2=C1N=C(N2CCCCC1(C(=O)N)CC=CC=C1)C SOWXSGADPSTMCX-UHFFFAOYSA-N 0.000 claims description 3
- ISESYRADWJWGQE-UHFFFAOYSA-N NC1=NC=2C=CC=CC=2C2=C1N=C(N2CCCCC1(C(=O)N)CC=CC=C1)CC Chemical compound NC1=NC=2C=CC=CC=2C2=C1N=C(N2CCCCC1(C(=O)N)CC=CC=C1)CC ISESYRADWJWGQE-UHFFFAOYSA-N 0.000 claims description 3
- GITORGFIUVTHSU-UHFFFAOYSA-N NC1=NC=2C=CC=CC=2C2=C1N=C(N2CCCCC1(C(=O)N)CC=CC=C1)CCCC Chemical compound NC1=NC=2C=CC=CC=2C2=C1N=C(N2CCCCC1(C(=O)N)CC=CC=C1)CCCC GITORGFIUVTHSU-UHFFFAOYSA-N 0.000 claims description 3
- SZZGOAMJKUPKCI-UHFFFAOYSA-N NC1=NC=2C=CC=CC=2C2=C1N=CN2CCC1(C(=O)N)CC=CC=C1 Chemical compound NC1=NC=2C=CC=CC=2C2=C1N=CN2CCC1(C(=O)N)CC=CC=C1 SZZGOAMJKUPKCI-UHFFFAOYSA-N 0.000 claims description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- LQDBBEBMHFPEOE-UHFFFAOYSA-N 1-[6-(4-aminoimidazo[4,5-c]quinolin-1-yl)hexyl]cyclohexa-2,4-diene-1-carboxamide Chemical compound NC1=NC=2C=CC=CC=2C2=C1N=CN2CCCCCCC1(C(=O)N)CC=CC=C1 LQDBBEBMHFPEOE-UHFFFAOYSA-N 0.000 claims description 2
- GQMYQEAXTITUAE-UHFFFAOYSA-N 1H-indole-5-carboxamide Chemical class NC(=O)C1=CC=C2NC=CC2=C1 GQMYQEAXTITUAE-UHFFFAOYSA-N 0.000 claims description 2
- LSGKMZLPZFPAIN-UHFFFAOYSA-N 1h-indole-3-carboxamide Chemical class C1=CC=C2C(C(=O)N)=CNC2=C1 LSGKMZLPZFPAIN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 4
- 229920002554 vinyl polymer Polymers 0.000 claims 4
- 125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 3
- USCLTPZQHJKYDD-UHFFFAOYSA-N 1-[4-(4-aminoimidazo[4,5-c]quinolin-1-yl)butyl]-4-(morpholin-4-ylmethyl)cyclohexa-2,4-diene-1-carboxamide Chemical compound NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)CC=C(C=C2)CN2CCOCC2 USCLTPZQHJKYDD-UHFFFAOYSA-N 0.000 claims 1
- ROARSHNYNHUBKC-UHFFFAOYSA-N 1-[4-(4-aminoimidazo[4,5-c]quinolin-1-yl)butyl]-4-(trifluoromethyl)cyclohexa-2,4-diene-1-carboxamide Chemical compound C1C=C(C=CC1(CCCCN2C=NC3=C2C4=CC=CC=C4N=C3N)C(=O)N)C(F)(F)F ROARSHNYNHUBKC-UHFFFAOYSA-N 0.000 claims 1
- OEVSKUMSWPTREP-UHFFFAOYSA-N 1-[4-(4-aminoimidazo[4,5-c]quinolin-1-yl)butyl]cyclohexane-1-carboxamide Chemical compound C1=NC2=C(N)N=C3C=CC=CC3=C2N1CCCCC1(C(=O)N)CCCCC1 OEVSKUMSWPTREP-UHFFFAOYSA-N 0.000 claims 1
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims 1
- XXUNIGZDNWWYED-UHFFFAOYSA-N 2-methylbenzamide Chemical compound CC1=CC=CC=C1C(N)=O XXUNIGZDNWWYED-UHFFFAOYSA-N 0.000 claims 1
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical class NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims 1
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims 1
- SASAFDJWDKBDFS-UHFFFAOYSA-N CC(=O)NCc1cc(Cl)ccc1[N+]([O-])=O Chemical compound CC(=O)NCc1cc(Cl)ccc1[N+]([O-])=O SASAFDJWDKBDFS-UHFFFAOYSA-N 0.000 claims 1
- ODASPBFJHBGCDG-UHFFFAOYSA-N CCCCOc1ccc(CNC(C)=O)cc1 Chemical compound CCCCOc1ccc(CNC(C)=O)cc1 ODASPBFJHBGCDG-UHFFFAOYSA-N 0.000 claims 1
- KWOPMAGDJVALLX-UHFFFAOYSA-N CCc1ccc(CNC(C)=O)o1 Chemical compound CCc1ccc(CNC(C)=O)o1 KWOPMAGDJVALLX-UHFFFAOYSA-N 0.000 claims 1
- ZFGOEBCTCYTSDD-UHFFFAOYSA-N COC1=CC=C(CNC(C)=O)C(OC)=C1OC Chemical compound COC1=CC=C(CNC(C)=O)C(OC)=C1OC ZFGOEBCTCYTSDD-UHFFFAOYSA-N 0.000 claims 1
- CJOJWXQKNVDNSA-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=C(N2CCCCC2(CC1=CC=CC=C1C=C2)C(=O)N)CCOC Chemical compound NC1=NC=2C=CC=CC2C2=C1N=C(N2CCCCC2(CC1=CC=CC=C1C=C2)C(=O)N)CCOC CJOJWXQKNVDNSA-UHFFFAOYSA-N 0.000 claims 1
- KARWALFPNCKHSC-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=C(N2CCCCC2(CC=CC1=CC=CC=C21)C(=O)N)CCOC Chemical compound NC1=NC=2C=CC=CC2C2=C1N=C(N2CCCCC2(CC=CC1=CC=CC=C21)C(=O)N)CCOC KARWALFPNCKHSC-UHFFFAOYSA-N 0.000 claims 1
- LXCUQUGTPRPSDO-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)C(C=CC=C2)Cl Chemical compound NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)C(C=CC=C2)Cl LXCUQUGTPRPSDO-UHFFFAOYSA-N 0.000 claims 1
- VDLRSJQKEAJDMX-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)C(N=CC=C2)Cl Chemical compound NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)C(N=CC=C2)Cl VDLRSJQKEAJDMX-UHFFFAOYSA-N 0.000 claims 1
- XTSKYYKBZZGKBZ-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)CC=C(C=C2)Cl Chemical compound NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)CC=C(C=C2)Cl XTSKYYKBZZGKBZ-UHFFFAOYSA-N 0.000 claims 1
- YLRJFCCGQOJLAT-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)CC=C(C=C2)F Chemical compound NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(C(=O)N)CC=C(C=C2)F YLRJFCCGQOJLAT-UHFFFAOYSA-N 0.000 claims 1
- VYXRCSQEKDJOLJ-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(OC(=CC2)[N+](=O)[O-])C(=O)N Chemical compound NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(OC(=CC2)[N+](=O)[O-])C(=O)N VYXRCSQEKDJOLJ-UHFFFAOYSA-N 0.000 claims 1
- SDNKEEUQLZRRNV-UHFFFAOYSA-N NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(OC=CC2)C(=O)N Chemical compound NC1=NC=2C=CC=CC2C2=C1N=CN2CCCCC2(OC=CC2)C(=O)N SDNKEEUQLZRRNV-UHFFFAOYSA-N 0.000 claims 1
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- 229940073608 benzyl chloride Drugs 0.000 claims 1
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims 1
- GOLHZPOXCLTFRB-UHFFFAOYSA-N furan-3-carboxamide Chemical compound NC(=O)C=1C=COC=1 GOLHZPOXCLTFRB-UHFFFAOYSA-N 0.000 claims 1
- YXCRHNOACQLGPS-UHFFFAOYSA-N n-(3-phenylpropyl)acetamide Chemical compound CC(=O)NCCCC1=CC=CC=C1 YXCRHNOACQLGPS-UHFFFAOYSA-N 0.000 claims 1
- VHVYFMZUBZMFIV-UHFFFAOYSA-N n-(furan-2-ylmethyl)acetamide Chemical compound CC(=O)NCC1=CC=CO1 VHVYFMZUBZMFIV-UHFFFAOYSA-N 0.000 claims 1
- QTAIOFTXBJBYDK-UHFFFAOYSA-N n-(furan-3-ylmethyl)acetamide Chemical compound CC(=O)NCC=1C=COC=1 QTAIOFTXBJBYDK-UHFFFAOYSA-N 0.000 claims 1
- SSOWOQCKTBJMET-UHFFFAOYSA-N n-(naphthalen-1-ylmethyl)acetamide Chemical compound C1=CC=C2C(CNC(=O)C)=CC=CC2=C1 SSOWOQCKTBJMET-UHFFFAOYSA-N 0.000 claims 1
- MZCVTBJXTMEQLJ-UHFFFAOYSA-N n-(pyridin-4-ylmethyl)acetamide Chemical compound CC(=O)NCC1=CC=NC=C1 MZCVTBJXTMEQLJ-UHFFFAOYSA-N 0.000 claims 1
- AVJOIUSFZVOHCZ-UHFFFAOYSA-N n-[(2-chloro-5-nitrophenyl)methyl]acetamide Chemical compound CC(=O)NCC1=CC([N+]([O-])=O)=CC=C1Cl AVJOIUSFZVOHCZ-UHFFFAOYSA-N 0.000 claims 1
- IEDUYFDGPFWNLZ-UHFFFAOYSA-N n-[(2-methylphenyl)methyl]acetamide Chemical compound CC(=O)NCC1=CC=CC=C1C IEDUYFDGPFWNLZ-UHFFFAOYSA-N 0.000 claims 1
- GFWHCUBLDBRXOQ-UHFFFAOYSA-N n-[(2-nitrophenyl)methyl]acetamide Chemical compound CC(=O)NCC1=CC=CC=C1[N+]([O-])=O GFWHCUBLDBRXOQ-UHFFFAOYSA-N 0.000 claims 1
- ZGUZLVSAOBXQNC-UHFFFAOYSA-N n-[(3,4,5-trimethoxyphenyl)methyl]acetamide Chemical compound COC1=CC(CNC(C)=O)=CC(OC)=C1OC ZGUZLVSAOBXQNC-UHFFFAOYSA-N 0.000 claims 1
- HBBBWKUVJSIFKV-UHFFFAOYSA-N n-[(4-bromophenyl)methyl]acetamide Chemical compound CC(=O)NCC1=CC=C(Br)C=C1 HBBBWKUVJSIFKV-UHFFFAOYSA-N 0.000 claims 1
- VGCSNHYGZYURJQ-UHFFFAOYSA-N n-[(4-methoxyphenyl)methyl]acetamide Chemical compound COC1=CC=C(CNC(C)=O)C=C1 VGCSNHYGZYURJQ-UHFFFAOYSA-N 0.000 claims 1
- ZMQPYUAJBGXGCB-UHFFFAOYSA-N n-[(4-nitrophenyl)methyl]acetamide Chemical compound CC(=O)NCC1=CC=C([N+]([O-])=O)C=C1 ZMQPYUAJBGXGCB-UHFFFAOYSA-N 0.000 claims 1
- QMEPYJKACOKGJW-UHFFFAOYSA-N n-[4-[4-amino-2-[(4-methoxyphenyl)methyl]imidazo[4,5-c]quinolin-1-yl]butyl]acetamide Chemical compound C1=CC(OC)=CC=C1CC1=NC2=C(N)N=C(C=CC=C3)C3=C2N1CCCCNC(C)=O QMEPYJKACOKGJW-UHFFFAOYSA-N 0.000 claims 1
- UZJLYRRDVFWSGA-UHFFFAOYSA-N n-benzylacetamide Chemical compound CC(=O)NCC1=CC=CC=C1 UZJLYRRDVFWSGA-UHFFFAOYSA-N 0.000 claims 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 102000004127 Cytokines Human genes 0.000 abstract description 18
- 108090000695 Cytokines Proteins 0.000 abstract description 18
- 150000001408 amides Chemical group 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 230000028993 immune response Effects 0.000 abstract description 9
- 239000003607 modifier Substances 0.000 abstract description 6
- 230000003612 virological effect Effects 0.000 abstract description 2
- GCGNWZMOENODOJ-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-imidazo[4,5-h]quinoline Chemical class C1C=C2C=CC=NC2=C2C1NCN2 GCGNWZMOENODOJ-UHFFFAOYSA-N 0.000 abstract 1
- SQQXRXKYTKFFSM-UHFFFAOYSA-N chembl1992147 Chemical compound OC1=C(OC)C(OC)=CC=C1C1=C(C)C(C(O)=O)=NC(C=2N=C3C4=NC(C)(C)N=C4C(OC)=C(O)C3=CC=2)=C1N SQQXRXKYTKFFSM-UHFFFAOYSA-N 0.000 abstract 1
- 229940124669 imidazoquinoline Drugs 0.000 abstract 1
- 230000001613 neoplastic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 200
- 239000007787 solid Substances 0.000 description 89
- 238000006243 chemical reaction Methods 0.000 description 81
- 238000000034 method Methods 0.000 description 69
- 239000000243 solution Substances 0.000 description 66
- 238000004364 calculation method Methods 0.000 description 64
- 238000005160 1H NMR spectroscopy Methods 0.000 description 63
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical class C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 description 61
- 239000000376 reactant Substances 0.000 description 59
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 52
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Abstract
1位含有酰胺官能团的咪唑并喹啉和四氢咪唑并喹啉化合物可用作免疫应答反应的调节剂。本发明的化合物和组合物可诱导各种细胞因子的生物合成,可用于治疗包括病毒疾病和肿瘤疾病在内的各种病情。
Description
发明领域
本发明涉及1位有含酰胺的取代基的咪唑并喹啉化合物,以及含有这些化合物的药物组合物。本发明另一方面涉及这些化合物作为免疫调节剂用于诱导动物细胞因子生物合成、治疗疾病(包括病毒和肿瘤疾病)的用途。
发明背景
Backman等人在J.Org.Chem.15,1278-1284(1950)中关于1H-咪唑并[4,5-c]喹啉环系的首次可靠报道描述了可用作抗疟药的1-(6-甲氧基-8-喹啉基)-2-甲基-1H-咪唑并[4,5-c]喹啉的合成。随后,报道了各种取代的1H-咪唑并[4,5-c]喹啉的合成。例如,Jain等人在J.Med.Chem.11,87-92页(1968)中合成了可能作为抗惊厥药和心血管药的化合物1-[2-(4-哌啶基)乙基]-1H-咪唑并[4,5-c]喹啉。另外,Baranov等人Chem.Abs.85,94362(1976)也报道了几种2-氧代咪唑并[4,5-c]喹啉,Berenyi等人J.Heterocyclic Chem.18,1537-1540(1981)报道了某些2-氧代咪唑并[4,5-c]喹啉。
后来,发现某些1H-咪唑并[4,5-c]喹啉-4-胺及其1-、2-取代的衍生物可用作抗病毒药、支气管扩张药和免疫调节剂。它们在美国专利4,689,338;4,689,348;4,929,624;5,037,986;5,268,376;5,346,905以及5,389,640中有所描述,所有这些专利均纳入本文作为参考。
人们对于咪唑并喹啉环系仍有兴趣。例如,EP 894 797描述了1位有含酰胺的取代基的咪唑并喹啉化合物。该系列的活性化合物需要可掺入杂环中的末端胺取代基。另一个例子是,WO 00/09506描述了1位有含酰胺的或脲的取代基的咪唑并吡啶和咪唑并喹啉化合物。该出版物中描述的有用的化合物含有一个1-取代基,其中酰胺或脲的氮是杂环的一部分。尽管已有对用作免疫应答反应调节剂的化合物进行鉴定的这些尝试,但仍然需要能通过诱导细胞因子生物合成或其它机理来调节免疫应答的化合物。
发明概述
我们已经发现一类新的化合物可用于诱导动物体内细胞因子的生物合成。因此,本发明提供了1位具有含酰胺的取代基的咪唑并喹啉-4-胺和四氢咪唑并喹啉-4-胺化合物。发现是有用的细胞因子生物合成诱导物的化合物如式(I)、(Ia)和(Ib)定义,这在下文有更详细的定义。这些化合物具有结构通式(I):
其中具有式(I)、(Ia)和(Ib)的每一类化合物的R1、R2和R如本文所定义。本发明还提供了新的如文中定义的式(Ic)、(Id)和(Ie)化合物,这些化合物也可作为免疫应答调节剂且具有上述相同的通式(I)。
式(I)、(Ia)、(Ib)、(Ic)、(Id)和(Ie)化合物可用作免疫应答调节剂,因为当它们给予动物时,它们能诱导细胞因子生物合成,并能以其它方式调节免疫应答。这使得这些化合物可用来治疗各种病情,例如对免疫应答中的这些变化作出响应的病毒疾病和肿瘤。
本发明还提供了含有该免疫应答调节性化合物的药物组合物,以及通过将式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)化合物给予动物来诱导动物体内细胞因子生物合成、治疗动物体内病毒性感染、和/或治疗动物体内肿瘤疾病的方法。
另外,本发明还提供了合成本发明化合物以及用于合成这些化合物的中间产物的方法。
发明详述
如前所述,我们已经发现某些化合物诱导动物体内细胞因子生物合成并调节免疫应答。这些化合物用下面的式(I)、(Ia)、(Ib)、(Ic)、(Id)和(Ie)表示。
其中
R1是-烷基-NR3-CO-R4或-链烯基-NR3-CO-R4其中R4是芳基、杂芳基、烷基或链烯基,它们每一个可以是未取代的或被选自下列的一个或多个取代基取代:
-烷基;
-链烯基;
-炔基;
-(烷基)0-1-芳基;
-(烷基)0-1-(取代的芳基);
-(烷基)0-1-杂芳基;
-(烷基)0-1-(取代的杂芳基);
-O-烷基;
-O-(烷基)0-1-芳基;
-O-(烷基)0-1-(取代的芳基);
-O-(烷基)0-1-杂芳基;
-O-(烷基)0-1-(取代的杂芳基);
-CO-芳基;
-CO-(取代的芳基);
-CO-杂芳基;
-CO-(取代的杂芳基);
-COOH;
-CO-O-烷基;
-CO-烷基;
-S(O)0-2-烷基;
-S(O)0-2(烷基)0-1-芳基;
-S(O)0-2-(烷基)0-1-(取代的芳基);
-S(O)0-2-(烷基)0-1-杂芳基;
-S(O)0-2-(烷基)0-1-(取代的杂芳基);
-P(O)(OR3)2;
-NR3-CO-O-烷基;
-N3;
-卤素;
-NO2;
-CN;
-卤烷基;
-O-卤烷基;
-CO-卤烷基;
-OH;
-SH;以及在烷基,链烯基,或杂环基的情况下,氧代;
或R4是
其中R5是芳基、(取代的芳基)、杂芳基、(取代的杂芳基)、杂环基或(取代的杂环基)基团;
R2选自下列:
-氢;
-烷基;
-链烯基;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-烷基-O-烷基;
-烷基-O-链烯基;和
-被选自下列的一个或多个取代基取代的烷基或链烯基:
-OH;
-卤素;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10烷基;
-CO-O-C1-10烷基;
-N3;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-CO-芳基;和
-CO-杂芳基;
每个R3独立选自:氢;C1-10烷基-杂芳基;C1-10烷基-(取代的杂芳基);C1-10烷基-芳基;C1-10烷基-(取代的芳基)和C1-10烷基;
n是0-4;
每个R独立选自:C1-10烷基,C1-10烷氧基,卤素和三氟甲基,或其药学上可接受的盐,以及和治疗上有效的载体组合。
本发明还提供了药物组合物,该组合物包含治疗有效量的式(Ia)化合物:
(Ia)
其中
R1是-烷基-NR3-CO-R4或-链烯基-NR3-CO-R4,其中R4是芳基、杂芳基、烷基或链烯基,它们每一个可以是未取代的或被选自下列的一个或多个取代基取代:
-杂环基;
-(取代的杂环基);
-(烷基)0-1杂环基;
-(烷基)0-1(取代的杂环基);
-O-(烷基)0-1杂环基;
-O-(烷基)0-1(取代的杂环基);
-S(O)0-2-(烷基)0-1杂环基;和
-S(O)0-2-(烷基)0-1(取代的杂环基);
R2选自下列:
-氢;
-烷基;
-链烯基;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-烷基-O-烷基;
-烷基-O-链烯基;和
-被选自下列的一个或多个取代基取代的烷基或链烯基:
-OH;
-卤素;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10烷基;
-CO-O-C1-10烷基;
-N3;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-CO-芳基;和
-CO-杂芳基;
每个R3独立选自:氢;C1-10烷基-杂芳基;C1-10烷基-(取代的杂芳基);C1-10烷基-芳基;C1-10烷基-(取代的芳基)和C1-10烷基;
n是0-4;
每个R独立选自:C1-10烷基,C1-10烷氧基,卤素和三氟甲基,或其药学上可接受的盐,以及药学上可接受的载体。
本发明还提供了一种药物组合物,该药物组合物含有治疗有效量的式(Ib)化合物:
其中
R1是-烷基-NR3-CO-R4或-链烯基-NR3-CO-R4,其中R4是杂环基,它可以是未取代的或被选自下列的一个或多个取代基取代:
-烷基;
-链烯基;
-炔基;
-(烷基)0-1-芳基;
-(烷基)0-1-(取代的芳基);
-(烷基)0-1-杂环基;
-(烷基)0-1-(取代的杂环基);
-(烷基)0-1-杂芳基;
-(烷基)0-1-(取代的杂芳基);
-O-烷基;
-O-(烷基)0-1-芳基;
-O-(烷基)0-1-(取代的芳基);
-O-(烷基)0-1-杂环基;
-O-(烷基)0-1-(取代的杂环基);
-O-(烷基)0-1-杂芳基;
-O-(烷基)0-1-(取代的杂芳基);
-CO-芳基;
-CO-(取代的芳基);
-CO-杂芳基;
-CO-(取代的杂芳基);
-COOH;
-CO-O-烷基;
-CO-烷基;
-S(O)0-2-烷基;
-S(O)0-2-(烷基)0-1-芳基;
-S(O)0-2-(烷基)0-1-(取代的芳基);
-S(O)0-2-(烷基)0-1-杂环基;
-S(O)0-2-(烷基)0-1-(取代的杂环基);
-S(O)0-2-(烷基)0-1-杂芳基;
-S(O)0-2-(烷基)0-1-(取代的杂芳基);
-P(O)(OR3)2;
-NR3-CO-O-烷基;
-N3;
-卤素;
-NO2;
-CN;
-卤烷基;
-O-卤烷基;
-CO-卤烷基;
-OH;
-SH;
或R4是
其中R5是芳基、(取代的芳基)、杂芳基、(取代的杂芳基)、杂环基或(取代的杂环基)基团;
R2选自下列:
-氢;
-烷基;
-链烯基;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-烷基-O-烷基;
-烷基-O-链烯基;和
-被选自下列的一个或多个取代基取代的烷基或链烯基:
-OH;
-卤素;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10烷基;
-CO-O-C1-10烷基;
-N3;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-CO-芳基;和
-CO-杂芳基;
每个R3独立选自:氢;C1-10烷基-杂芳基;C1-10烷基-(取代的杂芳基);C1-10烷基-芳基;C1-10烷基-(取代的芳基)和C1-10烷基;
n是0-4;
每个R独立选自:C1-10烷基,C1-10烷氧基,卤素和三氟甲基,或其药学上可接受的盐,以及与药学上可接受的载体组合。
本发明还提供了可用作免疫应答调节剂的化合物。一类这样的化合物具有结构式(Ic):
其中
R1是-烷基-NR3-CO-R4或-链烯基-NR3-CO-R4,其中R4是芳基、杂芳基、杂环基、烷基或链烯基,它们每一个可以是未取代的或被选自下列的一个或多个取代基取代:
-烷基;
-链烯基;
-炔基;
-(烷基)0-1-芳基;
-(烷基)0-1-(取代的芳基);
-(烷基)0-1-杂芳基;
-(烷基)0-1-(取代的杂芳基);
-(烷基)0-1-杂环基;
-(烷基)0-1-(取代的杂环基);
-O-烷基;
-O-(烷基)0-1-芳基;
-O-(烷基)0-1-(取代的芳基);
-O-(烷基)0-1-杂芳基;
-O-(烷基)0-1-(取代的杂芳基);
-O-(烷基)0-1-杂环基;
-O-(烷基)0-1-(取代的杂环基);
-CO-芳基;
-CO-(取代的芳基);
-CO-杂芳基;
-CO-(取代的杂芳基);
-COOH;
-CO-O-烷基;
-CO-烷基;
-S(O)0-2-烷基;
-S(O)0-2-(烷基)0-1-芳基;
-S(O)0-2-(烷基)0-1-(取代的芳基);
-S(O)0-2-(烷基)0-1-杂芳基;
-S(O)0-2-(烷基)0-1-(取代的杂芳基);
-S(O)0-2-(烷基)0-1-杂环基;
-S(O)0-2-(烷基)0-1-(取代的杂环基);
-P(O)(OR3)2;
-NR6-CO-O-烷基;
-N3;
-卤素;
-NO2;
-CN;
-卤烷基;
-O-卤烷基;
-CO-卤烷基;
-OH;
-SH;以及在烷基,链烯基,或杂环基的情况下,氧代;
或R4是
其中R5是芳基、(取代的芳基)、杂芳基、(取代的杂芳基)、杂环基或(取代的杂环基)基团;
R2选自下列:
-氢;
-烷基;
-链烯基;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-烷基-O-烷基;
-烷基-O-链烯基;和
-被选自下列的一个或多个取代基取代的烷基或链烯基:
-OH;
-卤素;
-N(R6)2;
-CO-N(R6)2;
-CO-C1-10烷基;
-CO-O-C1-10烷基;
-N3;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-CO-芳基;和
-CO-杂芳基;
R3选自下列C1-10烷基-杂芳基;C1-10烷基-(取代的杂芳基);C1-10烷基-芳基;C1-10烷基-(取代的芳基)和C1-10烷基;
每个R6独立选自:氢;C1-10烷基-杂芳基;C1-10烷基-(取代的杂芳基);C1-10烷基-芳基;C1-10烷基-(取代的芳基)和C1-10烷基;
n是0-4;
每个R独立选自:C1-10烷基,C1-10烷氧基,卤素和三氟甲基,或其药学上可接受的盐。
本发明提供的另一类化合物在式(Id)中有所描述:
其中
R1是-烷基-NR3-CO-R4或-链烯基-NR3-CO-R4,其中R4是芳基或杂芳基,它可以是未取代的或被选自下列的一个或多个取代基取代:
-烷基;
-链烯基;
-炔基;
-(烷基)0-1-芳基;
-(烷基)0-1-(取代的芳基);
-(烷基)0-1-杂芳基;
-(烷基)0-1-(取代的杂芳基);
-(烷基)0-1-杂环基;
-(烷基)0-1-(取代的杂环基);
-O-烷基;
-O-(烷基)0-1-芳基;
-O-(烷基)0-1-(取代的芳基);
-O-(烷基)0-1-杂芳基;
-O-(烷基)0-1-(取代的杂芳基);
-O-(烷基)0-1-杂环基;
-O-(烷基)0-1-(取代的杂环基);
-CO-芳基;
-CO-(取代的芳基);
-CO-杂芳基;
-CO-(取代的杂芳基);
-COOH;
-CO-O-烷基;
-CO-烷基;
-S(O)0-2-烷基;
-S(O)0-2-(烷基)0-1-芳基;
-S(O)0-2-(烷基)0-1-(取代的芳基);
-S(O)0-2-(烷基)0-1-杂芳基;
-S(O)0-2-(烷基)0-1-(取代的杂芳基);
-S(O)0-2-(烷基)0-1-杂环基;
-S(O)0-2-(烷基)0-1-(取代的杂环基);
-P(O)(OR3)2;
-NR3-CO-O-烷基;
-N3;
-卤素;
-NO2;
-CN;
-卤烷基;
-O-卤烷基;
-CO-卤烷基;
-OH;和
-SH;
R2选自下列:
-氢;
-烷基;
-链烯基;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-烷基-O-烷基;
-烷基-O-链烯基;和
-被选自下列的一个或多个取代基取代的烷基或链烯基:
-OH;
-卤素;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10烷基;
-CO-C1-10烷基;
-N3;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-CO-芳基;和
-CO-杂芳基;
每个R3独立选自:氢;C1-10烷基-杂芳基;C1-10烷基-(取代的杂芳基);C1-10烷基-芳基;C1-10烷基-(取代的芳基)和C1-10烷基;
n是0-4;
每个R独立选自:C1-10烷基,C1-10烷氧基,卤素和三氟甲基,或其药学上可接受的盐,
条件是R4不是未取代的苯环,且当R4是取代的苯环时,取代基选自下列:C1-20烷基,C2-20烷氧基,C1-20烷硫基,羟基,卤烷基,卤烷羰基,卤烷氧基,C1-20烷基羰基,C1-20链烯基羰基,芳基羰基,杂芳基羰基,芳基,芳烷基,杂芳基,杂芳烷基,杂环基,杂环烷基,腈,C1-20烷氧羰基,C1-20烷酰氧基,C1-20烷酰硫基,氧代和-(C1-10烷基)-NR3-(C1-10烷基)-R5,
其中R5是芳基、(取代的芳基)、杂芳基、(取代的杂芳基)、杂环基或(取代的杂环基)基团。
本发明提供的另一类化合物如式(Ie)所示:
其中
R1是-烷基-NR3-CO-R4或-链烯基-NR3-CO-R4,其中R4是被选自下列的一个或多个取代基取代的烷基或链烯基:
-炔基;
-(取代的芳基),其中取代基独立选自:烷基、烷氧基、烷硫基、羟基、卤烷基、卤烷羰基、卤烷氧基、烷基羰基、链烯基羰基、芳基羰基、杂芳基羰基、芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环烷基、腈、烷氧羰基、烷酰氧基、和烷酰硫基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-O-烷基;
-O-(烷基)0-1-(取代的芳基),其中取代基独立选自:烷基、烷氧基、烷硫基、羟基、卤烷基、卤烷羰基、卤烷氧基、烷基羰基、链烯基羰基、芳基羰基、杂芳基羰基、芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环烷基、腈、烷氧羰基、烷酰氧基、和烷酰硫基;
-O-(烷基)0-1-杂芳基;
-O-(烷基)0-1-(取代的杂芳基);
-CO-芳基;
-CO-(取代的芳基);
-CO-杂芳基;
-CO-(取代的杂芳基);
-COOH;
-CO-O-烷基;
-CO-烷基;
-S(O)0-2-烷基;
-S(O)0-2-(烷基)0-1-芳基;
-S(O)0-2-(烷基)0-1-(取代的芳基);
-S(O)0-2-(烷基)0-1-杂芳基;
-S(O)0-2-(烷基)0-1-(取代的杂芳基);
-P(O)(OR3)2;
-NR3-CO-O-烷基;
-N3;
-NO2;
-CN;
-O-卤烷基;
-CO-卤烷基;
-OH;
-SH;和氧代;
R2选自下列:
-氢;
-烷基;
-链烯基;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-烷基-O-烷基;
-烷基-O-链烯基;和
-被选自下列的一个或多个取代基取代的烷基或链烯基:
-OH;
-卤素;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10烷基;
-CO-O-C1-10烷基;
-N3;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-CO-芳基;和
-CO-杂芳基;
每个R3独立选自:氢;C1-10烷基-杂芳基;C1-10烷基-(取代的杂芳基);C1-10烷基-芳基;C1-10烷基-(取代的芳基)和C1-10烷基;
n是0-4;
且每个R独立选自:C1-10烷基,C1-10烷氧基,卤素和三氟甲基,或其药学上可接受的盐。
化合物的制备
本发明的咪唑并喹啉可根据反应方案I来制备,其中R、R1、R2和n如上定义。
在反应方案I的步骤(1)中,使式II的4-氯-3-硝基喹啉与式R1NH2的胺反应,得到式III的3-硝基喹啉-4-胺。该反应可通过将胺加入式II化合物在合适的溶剂(如氯仿或二氯甲烷)中的溶液并任选地加热来进行。许多式II喹啉是已知的化合物(例如参见美国专利4,689,338及其中引用的文献)。
在反应方案I的步骤(2)中,使式III的3-硝基喹啉-4-胺还原,得到式IV 的喹啉-3,4-二胺。较佳的是,还原用常规非均相加氢催化剂(如碳载铂或碳载钯)来进行。该反应可在帕尔装置中在合适的溶剂(如异丙醇或甲苯)中进行。
在反应方案I的步骤(3)中,使式IV的喹啉-3,4-二胺与羧酸或其等价物反应,得到式V的1H-咪唑并[4,5-c]喹啉。合适的羧酸等价物包括酰基卤、原酸酯和链烷酸1,1-二烷氧基烷酯。选择羧酸或其等价物,使得它能为式V化合物提供所需的R2取代基。例如,原甲酸三乙酯将提供R2是氢的化合物,原乙酸三乙酯将提供R2是甲基的化合物。反应可在没有溶剂下或在诸如甲苯等惰性溶剂中进行。反应进行时用充分加热,以除去形成的反应副产物醇或水。
在反应方案I的步骤(4)中,用能形成氮氧化物的常规氧化剂将式V的1H-咪唑并[4,5-c]喹啉氧化,得到式VI的1H-咪唑并[4,5-c]喹啉-5N-氧化物。较佳的反应条件包括在室温下使氯仿中的式V化合物溶液与3-氯过苯甲酸反应。
在反应方案I的步骤(5)中,使式VI的1H-咪唑并[4,5-c]喹啉-5N-氧化物胺化,得到式VII的1H-咪唑并[4,5-c]喹啉-4-胺,它是式I的亚属。步骤(5)包括(i)使式VI的化合物与酰化剂反应,然后(ii)使产物与胺化剂反应。步骤(5)的部分(i)涉及使式VI的N-氧化物与酰化剂反应。合适的酰化剂包括烷基或芳基磺酰氯(如苯磺酰氯、甲磺酰氯、对甲苯磺酰氯)。芳基磺酰氯是较佳的。对甲苯磺酰氯是最佳的。步骤(5)的部分(ii)涉及使部分(i)的产物与过量胺化剂反应。合适的胺化剂包括氨(例如以氢氧化铵形式)和铵盐(例如碳酸铵、碳酸氢铵、磷酸铵)。氢氧化铵是较佳的。反应宜这样进行:将式VI的N-氧化物溶解在惰性溶剂(如二氯甲烷)中,将胺化剂加入该溶液中,然后缓慢加入酰化剂。然后用常规方法可分离出产物或其药学上可接受的盐。
或者,步骤(5)可这样进行:(i)使式VI的N-氧化物与异氰酸酯反应,然后(ii)水解所得的产物。部分(i)是使N-氧化物与异氰酸酯反应,其中异氰酸基与羰基相连。较佳的异氰酸酯包括异氰酸三氯乙酰酯和异氰酸芳酰酯(如异氰酸苯甲酰酯)。异氰酸酯和N-氧化物的反应在基本上无水的条件下进行,方法是将异氰酸酯加入惰性溶剂(如氯仿或二氯甲烷)中的N-氧化物溶液中。部分(ii)是使部分(i)的产物水解。水解可用常规方法进行,例如在水或低级烷醇存在下,任选地在催化剂(如碱金属氢氧化物或低级醇盐)存在下加热。
反应方案I
本发明化合物也可根据反应方案II来制备,其中R、R2、R4和n如上定义,m是1-20。
在反应方案II中,使式VIII的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4-胺与式IX的酰基氯反应,得到式X化合物,它是式I的亚属。反应这样进行,在室温或低温下,将在合适溶剂(如吡啶或二氯甲烷)中的酰基氯溶液加入式VIII化合物的溶液中。许多式VIII的1H-咪唑并[4,5-c]喹啉-4-胺是已知的化合物,例如参见美国专利6,069,149(Nanba),其公开内容纳入本文作为参考;其它可用已知的合成方法制得。许多式IX的酰基氯可市售购得;其它易用已知的合成方法制得。产物或其药学上可接受的盐可用常规方法来分离。
反应方案II
本发明化合物也可根据反应方案III来制备,其中R、R2、R4和n如上定义,m是1-20。
在反应方案III中,使式VIII的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4- 胺与式XI的酸反应,得到式X化合物,它是式I的亚属。反应可在室温下诸如二氯甲烷或吡啶的溶剂中进行,采用标准的偶联剂如1,3-二环己基碳化二亚胺或1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺。产物或其药学上可接受的盐可用常规方法来分离。
反应方案III
本发明化合物也可根据反应方案IV来制备,其中R、R2、R4和n如上定义,m是1-20。
在反应方案IV中,使式VIII的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4-胺与式XII的酸酐反应,得到式X化合物,它是式I的亚属。反应可在室温下诸如二氯甲烷的惰性溶剂中在诸如N,N-二异丙基乙胺或吡啶的碱存在下进行。许多式XII酸酐可市售购得;其它易用已知的合成方法制得。产物或其药学上可接受的盐可用常规方法来分离。
反应方案IV
本发明的叔酰胺可根据反应方案V制得,其中R、R2、R3、R4和n如上定义,m是1-20。
在反应方案V的步骤(1)中,使式VIII的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4-胺与式XIII的醛反应,得到式XIV的仲胺。较佳的是,用三乙酰氧基氢硼化钠进行还原型氨化。反应可这样进行,将三乙酰氧基氢硼化钠加入惰性溶剂(如二氯甲烷)中的胺和醛溶液中。用常规方法分离叔胺或其盐。
在反应方案V的步骤(2)中,使式XIV的仲胺酰基化,得到式XV的化合物,它是式I的亚属。反应可这样进行,按照上述反应方案III、II和IV的方法,使式XIV的仲胺与酸、酰基氯或酸酐反应。产物或其药学上可接受的盐可用常规方法分离。
反应方案V
本发明的四氢咪唑并喹啉可根据反应方案VI制得,其中R2、R3和R4如上定义,m是1-20。
在反应方案VI的步骤(1)中,使式XVI的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4-胺还原,得到式XVII的氨基烷基取代的6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺。还原宜这样进行,将式XVI的化合物悬浮或溶解在三氟乙酸中,加入催化量的氧化铂(IV),然后给该混合物加氢气压力。该反应可方便地在帕尔装置上进行。用常规方法分离产物或其盐。
在反应方案VI的步骤(2)中,使式XVII的氨基烷基取代的6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺反应,得到式XVIII化合物,它是式I的亚属。当R3是氢时,反应可根据上述反应方案II、III和IV描述的方法用式XVII的四氢咪唑并喹啉代替式VIII的咪唑并喹啉进行反应。当R3不是氢时,反应可用反应方案V描述的方法来进行。可用常规方法分离产物或其药学上可接受的 盐。
反应方案VI
本发明的四氢咪唑并喹啉可根据反应方案VII制得,其中R、R2、R3和R4和n如上定义,m是1-20。
在反应方案VII的步骤(1)中,使式XIX的叔丁基氨基甲酸6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉酯水解,得到式XX的氨基烷基取代的6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺。反应可这样进行,将式XIX化合物溶解在三氟乙酸和乙腈的混合物中,在室温下搅拌。或者,可将式XIX化合物与稀盐酸合并,在蒸汽浴上加热。式XIX的叔丁基氨基甲酸四氢-1H-咪唑并[4,5-c]喹啉酯可用美国专利5,352,784(Nikolaides)中公开的合成途径来制得。产物或其盐可用常规方法来分离。
在反应方案VII的步骤(2)中,使式XX的氨基烷基取代的6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺反应,得到式XXI化合物,它是式I的亚属。当R3是氢时,反应可根据上述反应方案II、III和IV描述的方法用式XX的四氢咪唑并喹啉代替式VIII的咪唑并喹啉来进行反应。当R3不是氢时,反应可用反应方案V描述的方法来进行。可用常规方法分离产物或其药学上可接受的盐。
反应方案VII
式I的一些化合物可从式I的其它化合物制得。例如,R4取代基含有氯烷 基的化合物可以和胺反应,从而得到R4取代基被仲氨基或叔氨基取代的化合物;R4取代基含有硝基的化合物可以还原得到R4取代基含有伯胺的化合物。
本文所用的术语“烷基”、“链烯基”、“炔基”和前缀“烷(烯、炔)”包括直链和支链基团和环状基团,即环烷基和环链烯基。除非另有所述,这些基团含有1-20个碳原子,链烯基和炔基含有2-20个碳原子。较佳的基团总共最多有10个碳原子。环状基团可以是单环或多环,较佳的有3-10个环碳原子。典型的环状基团包括环丙基、环戊基、环己基和金刚烷基。
术语“卤烷基”包括被一个或多个卤原子取代的基团,包括其中所有可利用的氢原子都被卤原子代替的基团。对于具有前缀“卤烷(烯、炔)”的基团也是如此。合适的卤烷基例子是氯甲基、三氟甲基等。
本文所用的术语“芳基”包括碳环芳环或环体系。芳基例子包括苯基、萘基、联苯基、芴基和茚基。术语“杂芳基”包括含有至少一个环杂原子(如O、S、N)的芳环或环体系。合适的杂芳基包括呋喃基、噻吩基、吡啶基、喹啉基、异喹啉基、吲哚基、异吲哚基、吡咯基、四唑基、咪唑基(imidazo)、吡唑基(pyrazolo)、噁唑基(oxazolo)、噻唑基(thiazolo)等。
“杂环基(heterocyclyl)”包括含有至少一个环杂原子(如O、S、N)的非芳环或环体系。典型的杂环基团包括吡咯烷基、四氢呋喃基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、噻唑烷基和咪唑烷基。
除非另有特指,术语“取代的芳基”、“取代的杂芳基”和“取代的杂环基”指所述环或环体系被一个或多个取代基进一步取代,这些取代基独立选自烷基、烷氧基、烷硫基、羟基、卤素、卤烷基、卤烷基羰基、卤烷氧基(如三氟甲氧基)、硝基、烷基羰基、链烯基羰基、芳基羰基、杂芳基羰基、芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环烷基、腈、烷氧羰基、烷酰氧基、烷酰硫基以及氧代(在杂环基情况下)。
在表示本发明化合物的结构式中,某些键用虚线表示。这些线表示虚线表示的键可有可无。因此,本发明的化合物可以是咪唑并喹啉化合物或四氢咪唑并喹啉化合物。
本发明包括文中描述的所有药学上可接受的形式(包括异构体如非对映体和对映体、盐、溶剂合物、多晶型物等)的化合物。
药物组合物和生物活性
本发明的药物组合物含有治疗有效量的上述本发明化合物以及药学上可接受的载体。
术语“治疗有效量”指该化合物的用量足以诱导产生治疗效果,如诱导细胞因子、抗肿瘤活性和/或抗病毒活性。尽管本发明药物组合物中所用活性化合物的确切量将根据本领域技术人员已知的因素(如化合物的物理和化学特性以及载体的性质以及打算采用的剂量方案)而异,但是预计本发明组合物将含有足量的活性组分,为对象提供100毫微克/千克-50毫克/千克、较佳约为10微克/千克-5毫克/千克的化合物剂量。可采用任何常规剂型,如片剂、锭剂、肠胃外制剂、糖浆、软膏、油膏、气溶胶制剂、透皮贴剂、跨粘膜贴剂等。
在治疗方案中,本发明化合物可以单治疗剂的形式给药,或者,本发明化合物可以与另一本发明化合物或其它活性剂(包括其它的免疫应答调节剂、抗病毒药、抗生素等)联合给药。
在根据下述测试进行的试验中,本发明化合物已经显示能诱导产生某些细胞因子。这些结果表明这些化合物可用作免疫应答调节剂,它们能通过许多不同的方式调节免疫应答,从而使得它们能用于治疗各种疾病。
通过给予本发明化合物诱导产生的细胞因子通常包括干扰素-α(IFN-α)和/或肿瘤坏死因子-α(TNF-α),以及某些白细胞介素(IL)。由本发明化合物诱导生物合成的细胞因子包括IFN-α、TNF-α、IL-1、6、10和12,其它各种细胞因子。在其它作用中,细胞因子抑制病毒的产生和肿瘤细胞的生长,使得这些化合物可用于治疗病毒疾病和肿瘤。
除了能诱导产生细胞因子外,本发明的化合物还能影响先天性免疫应答的其它方面。例如,可以刺激天然杀伤细胞的活性,该作用可能由细胞因子诱导而引起。这些化合物还能激活巨噬细胞,巨噬细胞进而刺激氧化氮的分泌和额外细胞因子的产生。另外,这些化合物还能引起B-淋巴细胞增殖和分化。
本发明化合物对获得性免疫应答也有作用。例如,尽管不认为对T细胞有直接作用或直接诱导T细胞细胞因子,但在给予化合物后,化合物却间接诱导了T辅助细胞(Th1)1型细胞因子IFN-γ的产生,抑制了T辅助细胞2型细胞因子IL-4、IL-5和IL-13的产生。这一活性表明这些化合物可用来治疗需要上调Th1应答和/或下调Th2应答的疾病。鉴于本发明化合物能抑制Th2免疫应 答,预计这些化合物可用于治疗特应性疾病,如特应性皮炎、哮喘、变态反应、变应性鼻炎;全身性红斑狼疮;还可作为细胞介导的免疫力的疫苗佐剂;并可用来治疗复发性真菌疾病和衣原体疾病。
这些化合物的免疫应答调节作用使得它们可用来治疗各种情况。由于它们能诱导诸如IFN-α和/或TNF-α等细胞因子的产生,这些化合物特别可用来治疗病毒疾病和肿瘤。该免疫调节活性暗示本发明化合物可用来治疗下列疾病,例如但不局限于,病毒疾病(包括生殖器疣;寻常疣;扁平疣;乙型肝炎;丙型肝炎;I型和II型单纯疱疹病毒;触染性软疣;HIV;CMV;VZV;上皮内肿瘤如子宫颈上皮内肿瘤;人乳头瘤(HPV)和相关的肿瘤;真菌疾病,如念珠菌、曲霉菌和隐球菌脑膜炎;肿瘤疾病,如基底细胞癌瘤、毛细胞白血病、Kaposi肉瘤、肾细胞癌、鳞状上皮细胞癌、粒细胞性白血病、多发性骨髓瘤、黑色素瘤、非Hodgkin淋巴瘤、皮肤T细胞淋巴瘤和其它癌;寄生虫疾病,例如肺炎肺囊虫、似隐胞菌病、组织胞浆菌病、弓形体病、锥体虫感染和立什曼病;和细菌感染,例如结核菌和分支杆菌。可用本发明化合物治疗的其它疾病或情况包括湿疹、嗜曙红细胞增多、原发性血小板减少症、麻风病、多发性硬化、Ommen综合征、盘状狼疮、Bowen疾病、Bowen样丘疹病;以及增强或刺激伤口(包括慢性伤口)愈合。因此,本发明提供了诱导动物体内细胞因子生物合成的方法,该方法包括将本发明的化合物或组合物给予该动物。
化合物诱导细胞因子生物合成的有效量是足以使一种或多种细胞类型(如单核细胞、巨噬细胞、树突细胞和B细胞)产生比这些细胞因子本底水平有所提高的一种或多种细胞因子(例如IFN-α、TNF-α、IL-1、6、10和12)的用量。确切的用量将根据现有技术中已知的因素而异,但是预计剂量约为100毫微克/千克-50毫克/千克,较佳的约为10微克/千克-5毫克/千克。本发明还提供了治疗动物体内病毒性感染的方法和治疗动物体内肿瘤疾病的方法,这些方法包括将有效量的本发明化合物或组合物给予该动物。治疗或抑制病毒性感染的有效量是使病毒感染的一个或多个表现(如病毒性损伤、病毒装载、病毒产生的速度以及与未处理对照动物相比的死亡率)有所减少的量。确切的用量将根据现有技术中已知的因素而异,但是预计剂量约为100毫微克/千克-50毫克/千克,较佳的约为10微克/千克-5毫克/千克。化合物治疗肿瘤病情的有效量是使肿瘤大小或肿瘤病灶数量减小的量。同样,确切的用量将根据现有技术中已 知的因素而异,但是预计剂量约为100毫微克/千克-50毫克/千克,较佳的约为10微克/千克-5毫克/千克。
通过下列实施例来进一步描述,提供这些实施例只是为了描述而没有限制作用。
实施例
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺
将含1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(2.0克,7.8毫摩尔)的吡啶(1升)悬浮液温至60℃,使原料溶解。将溶液冷却至约30℃,然后缓慢加入用吡啶(100毫升)稀释的苯甲酰氯(1.1克,7.8毫摩尔)。1小时后,高效液相色谱(HPLC)分析表明残留有一些原料。加入额外量的苯甲酰氯(0.3克),将反应物温至50℃过夜。真空浓缩反应混合物。将所得残余物与氯仿(200毫升)和1%碳酸钠(200毫升)合并。分离有机层,真空浓缩。将所得残余物与乙酸丙酯(30毫升)合并,在蒸汽浴上加热使残余物溶解。使溶液冷却。过滤分离所得沉淀,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺固体,其熔点为210-212℃。C21H21N5O的计算值:%C,70.18;%H,5.89:%N,19.48;实测值:%C,69.49;%H,5.97;%N,19.64.1H NMR(500MHz,DMSO-d6)δ8.48(t,J=6.0Hz,1H),8.22(s,1H),8.04(d,J=8.0Hz,1H),7.78(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,1H),7.50(t,J=8.0Hz,1H),7.43(m,3H),7.21(t,J=8.0Hz,1H),6.62(宽s,2H),4.64(t,J=7.0Hz,2H),3.30(q,J=6.0Hz,2H),1.92(五单元组,J=7.0Hz,2H),1.58(五单元组,J=7.0Hz,2H);MS(EI)m/e 359.1746(C21H21N5O计算值为359.1746)。
实施例2
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺盐酸水合物
将N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺(1克)溶解在异丙醇中。加入盐酸(1当量,12N)。过滤分离所得沉淀,得到1克N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺盐酸水合物固体,熔点为254-256℃。C21H21N5O·HCl·1.5 H2O的分析计算值:%C,59.63;%H,5.96;%N,16.56;实测值:%C 59.61;%H,6.04;%N,16.64.1H NMR(500MHz,DMSO-d6)δ13.80(宽s,1H),9.15(宽s,2H),8.56(s,1H),8.50(t,J=6.0Hz,1H),8.23(d,J=8.0Hz,1H),7.83(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,2H),7.71(t,J=8.0Hz,1H),7.53(t,J=8.0Hz,1H),7.50(t,J=8.0Hz,1H),7.42(t,J=8.0Hz,2H),4.72(t,J=7.0Hz,2H),3.30(q,J=7.0Hz,2H),1.93(五单元组,J=7.0Hz,2H),1.61(五单元组,J=7.0Hz,2H)。
实施例3
N1-[4-(4-氨基-2-丙基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺
用实施例1的通用方法,使1-(4-氨基丁基)-2-丙基-1H-咪唑并[4,5-c]喹啉-4-胺(0.55克,1.8毫摩尔)与苯甲酰氯(0.26克,1.8毫摩尔)反应,得到N1-[4-(4-氨基-2-丙基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺固体,熔点为173-174℃。1H NMR(500MHz,DMSO-d6)δ8.80(宽s,2H),8.46(t,J=6.0Hz,1H),8.20(d,J=8.0Hz,1H),7.81(d,J=8.4Hz,1H),7.76(d,J=7.4Hz,2H),7.67(t,J=7.4Hz,1H),7.49(m,2H),7.43(t,J=7.5Hz,2H),4.63(t,J=7.0Hz,2H),3.34(m,2H),2.97(t,J=7.0Hz,2H),1.85(m,4H),1.72(五单元组,J=7.0Hz,2H),1.01(t,J=7.0Hz,3H);MS(EI)m/e 401.2210(C24H27N5O计算值为401.2216)。
实施例4
N1-[4-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺
用实施例1的通用方法,使1-(4-氨基丁基)-2-甲基-1H-咪唑并[4,5-c]喹啉-4-胺(0.5克,1.8毫摩尔)与苯甲酰氯(0.26克,1.8毫摩尔)反应,得到N1-[4-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺固体,熔点为164-170℃. 1H NMR(500MHz,DMSO-d6)δ8.47(t,J=6.0Hz,1H),8.01(d,J=8.0Hz,1H),7.78(d,J=8.0Hz,2H),7.59(dd,J=8.0,1.2Hz,1H),7.50(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,2H),7.38(dt,J=8.0,1.2Hz,1H),7.17(dt,J=8.0,1.2Hz,1H),6.48(宽s,2H),4.53(t,J=7.0Hz,2H),3.31(q,J=6.0Hz,2H),2.60(s,3H),1.88(五单元组,J=7.0Hz,2H),1.68(五单元组,J=7.0Hz,2H);MS(EI)m/e 373.1903(C22H23N5O计算值为373.1903)。
实施例5
N1-[4-(4-氨基-2-乙基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺
用实施例1的通用方法,使1-(4-氨基丁基)-2-乙基-1H-咪唑并[4,5-c]喹啉-4-胺(0.5克,1.76毫摩尔)与苯甲酰氯(0.25克,1.76毫摩尔)反应,得到N1-[4-(4-氨基-2-乙基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺固体,熔点为203-206℃.1H NMR(500MHz,DMSO-d6)δ8.48(t,J=6.0Hz,1H),8.00(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,2H),7.60(dd,J=8.0,1.0Hz,1H),7.50(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,2H),7.38(t,J=8.0Hz,1H),7.17(t,J=8.0Hz,1H),6.47(宽s,2H),4.53(t,J=7.0Hz,2H),3.32(q,J=6.0Hz,2H),2.95(q,J=7.0Hz,2H),1.87(五单元 组,J=7.0Hz,2H),1.70(五单元组,J=7.0Hz,2H),1.35(t,J=7.0Hz,3H);MS(EI)m/e 387.2058(C23H25N5O计算值为387.2059)。
实施例6
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺
使1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(0.5克,1.6毫摩尔)与吡啶(50毫升)混合,并加热至50℃。通过移液管加入苯甲酰氯(0.22克,1.6毫摩尔)。1小时后的HPLC分析表明所有原料消失,形成几种产物。真空浓缩反应混合物。使残余物与二氯甲烷和碳酸氢钠水溶液混合。分离有机层然后真空浓缩。将残余物溶解在二氯甲烷中,并加在硅胶柱上。柱用含5%甲醇的二氯甲烷洗脱,然后用含10%甲醇的二氯甲烷洗脱。合并含10%甲醇的二氯甲烷组分,真空浓缩得到N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺固体,熔点为174-175℃.1H NMR(500MHz,DMSO-d6)δ8.48(t,J=6.0Hz,1H),8.00(d,J=8.0Hz,1H),7.78(d,J=8.0Hz,2H),7.60(d,J=8.0Hz,1H),7.50(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,2H),7.39(t,J=8.0Hz,1H),7.18(t,J=8.0Hz,1H),6.50(宽s,2H),4.54(t,J=7.0Hz,2H),3.32(m,2H),2.91(t,J=7.0Hz,2H),1.86(五单元组,J=7.0Hz,2H),1.77(五单元组,J=7.0Hz,2H),1.70(五单元组,J=7.0Hz,2H),1.41(六单元组,J=7.0Hz,2H),0.91(t,J=7.0Hz,3H);MS(CI)m/e416(M+H)。
实施例7
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-(氯甲基)苯甲酰胺
部分A
将草酰氯(4.4毫升,2M,在氯仿中,8.8毫摩尔)加入含4-(氯甲基)苯甲酸(1克,5.7毫摩尔)的二氯甲烷中。加入N,N-二甲基甲酰胺(4滴)催化该反应。1小时后的HPLC分析表明有100%完全转变。将反应混合物真空浓缩,得到4-(氯甲基)苯甲酰氯。
部分B
将含4-(氯甲基)苯甲酰氯(1.06克,5.6毫摩尔)的二氯甲烷溶液加入含1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(1.0克,3.9毫摩尔)的吡啶(250毫升)悬浮液中。1小时后HPLC分析表明反应完全。真空浓缩反应混合物。使残余物与饱和的碳酸氢钠水溶液混合。过滤分离固体,然后将该固体溶解在含少量甲醇的氯仿中。用饱和的碳酸氢钠水溶液洗涤该溶液。真空浓缩有机层。所得残余物用柱色谱纯化(硅胶,用含10%甲醇的二氯甲烷洗脱),得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-(氯甲基)苯甲酰胺固体,熔点为240-300(分解).1H NMR(500MHz,DMSO-d6)δ8.49(t,J=6.0Hz,1H),8.21(s,1H),8.03(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,2H),7.42(t,J=8.0Hz,1H),7.20(t,J=8.0Hz,1H),6.80(宽s,2H),4.78(s,2H),4.62(t,J=7.0Hz,2H),3.28(q,J=6.0Hz,2H),1.89(五单元组,J=7.0Hz,2H),1.56(五单元组,J=7.0Hz,2H);MS(CI)m/e 408(M+H)。
实施例8
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-[(2-四氢-1H-1-吡咯基-1H-苯并[d]咪唑-1-基)甲基]苯甲酰胺
部分A
将2-羟基-1H-苯并咪唑(62克,0.46摩尔)加入磷酰氯(200毫升)中,使该混合物回流4.5小时。将所得溶液倒在4升冰上,用氢氧化铵使混合物呈强碱性。过滤分离所得固体,用水洗涤,干燥得到2-氯-1H-苯并咪唑粗品。
部分B
混合2-氯-1H-苯并咪唑(10.0克,0.066摩尔)、吡咯烷(18.5克,0.26摩尔)和乙醇(100毫升)。使所得溶液在160-170℃下加热6小时,然后蒸发溶剂。所得残余物与水混合。用盐酸使混合物呈强酸性,然后用氢氧化铵调至碱性。过滤分离所得固体,用水洗涤,然后空气干燥,得到11.8克褐色粉末状粗品。从乙酸乙酯/甲醇中重结晶该物质,得到4.9克2-吡咯烷基-1H-苯并咪唑。C11H13N3的分析计算值:%C,70.56;%H,7.00;%N,22.44;实测值:%C,70.13;%H,7.05;%N,22.70。
部分C
将氢化钠(402毫克,11毫摩尔)加入含2-吡咯烷基-1H-苯并咪唑(1.9克,10.1毫摩尔)的无水N,N-二甲基甲酰胺(30毫升)悬浮液中。所有固体溶解。停止发泡后,使溶液在室温下搅拌15分钟。将溶液冷却至5℃,形成固体。将4-(溴甲基)苯甲酸甲酯(2.1克,01摩尔)加入悬浮液中,所有固体溶解。在室温下搅拌溶液,形成固体。在室温下搅拌混合物过夜,然后将其倒入冰水中。过滤分离固体,用水洗涤,然后干燥,得到3.0克灰白色固体状粗品。从甲醇中重结晶该物质,得到4-[(2-吡咯烷基-1H-苯并咪唑-1-基)甲基]苯甲酸甲酯。C20H21N3O2的分析计算值:%C,71.62;%H,6.31;%N,12.53;实测值:%C,71.44;%H,6.41;%N,12.50。
部分D
将4-[(2-吡比咯烷基-1H-苯并咪唑-1-基)甲基]苯甲酸甲酯(2.5克,7.5毫摩尔) 加入含氢氧化钠(1.8克,45毫摩尔)的水(30毫升)和甲醇(10毫升)溶液中。在蒸汽浴上加热该混合物,直至所有酯溶解。继续加热15分钟,然后用等体积的水稀释溶液,用盐酸中和。过滤分离所得沉淀,用水洗涤,并干燥,得到1.9克粗品。从N,N-二甲基甲酰胺重结晶该物质,得到4-[(2-吡咯烷基-1H-苯并咪唑-1-基)甲基]苯甲酸。C19H19N3O2的分析计算值:%C,71.01;%H,5.96;%N,13.07;实测值:%C,70.01;%H,6.14;%N,13.32。
部分E
将草酰氯(4毫升)加入含4-[(2-吡咯烷基-1H-苯并咪唑-1-基)甲基]苯甲酸(0.28克,0.872毫摩尔)的氯仿(50毫升)悬浮液中。使该混合物回流1小时,然后真空浓缩。用甲苯稀释残余物,真空浓缩,然后在室温下真空干燥过周末,得到粗制的4-[(2-吡咯烷基-1H-苯并咪唑-1-基)甲基]苯甲酰氯。
部分F
将1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.20克,0.783毫摩尔)加入部分E的酰氯与吡啶(20毫升)的混合物中。10分钟后,HPLC分析表明反应混合物含有产物,加上约10%的酰氯和胺。真空浓缩该反应混合物。将残余物与水合并,用0.1N氢氧化钠处理,然后用二氯甲烷萃取。二氯甲烷萃取物用柱色谱纯化(硅胶,用含5-10%甲醇的二氯甲烷洗脱),得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-[(2-四氢-1H-1-吡咯基-1H-苯并[d]咪唑-1-基)甲基]苯甲酰胺固体,熔点为150-153℃.MS(EI)m/e 558.2865(C33H34N8O的计算值为558.2855)。
实施例9
N1-[5-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺
部分A
在氩气下,合并1,5-二氨基戊烷(25克,0.24摩尔)和苯甲酰胺(9.9克,0.081摩尔),加热回流过夜。将反应混合物真空浓缩,除去过量二胺。使残余物在大约210℃、12乇(16X102帕斯卡)下蒸馏,得到11.8克N-(5-氨基戊基)苯甲酰胺无色油。
部分B
将三乙胺(1当量)加入含盐酸4-氯-3-硝基喹啉(13克,53毫摩尔)的氯仿悬浮液中。加入含N-(5-氨基戊基)苯甲酰胺(11克,53毫摩尔)的氯仿悬浮液,使反应混合物加热回流。用HPLC监测反应的进展。真空浓缩反应混合物。残余物用甲苯稀释,加热回流,然后趁热过滤。使滤液冷却。过滤分离所得沉淀,得到16.9克N1-{5-[(3-硝基喹啉-4-基)氨基]戊基}苯甲酰胺黄色固体,熔点为130-132℃.1H NMR(500MHz,DMSO-d6)δ9.07(s,1H),9.02(宽s,1H),8.53(d,J=8.0Hz,1H),8.43(t,J=6.0Hz,1H),7.89(dd,J=8.0,1.2Hz,1H),7.83(dt,J=8.0,1.2Hz,1H),7.80(d,J=8.0Hz,2H),7.57(dt,J=8.0,1.2Hz,1H),7.50(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,2H),3.63(q,J=6.0Hz,2H),3.25(q,J=6.0Hz,2H),1.77(五单元组,J=7.0Hz,2H),1.55(五单元组,J=7.0Hz,2H),1.39(五单元组,J=7.0Hz,2H)。
部分C
将催化量的碳载钯加入含N1-{5-[(3-硝基喹啉-4-基)氨基]戊基}苯甲酰胺(3.4克,9毫摩尔)的异丙醇(250毫升)悬浮液中。将反应混合物置于帕尔装置上50psi(3.4X104帕斯卡)的氢气气氛下。2小时后,过滤反应混合物除去催 化剂。真空浓缩滤液,得到粗制的N1-{5-[(3-氨基喹啉-4-基)氨基]戊基}苯甲酰胺。将该物质与原乙酸三乙酯(1.4克,9毫摩尔)和甲苯(200毫升)混合。用Vigreux柱在蒸汽浴上加热该反应混合物过夜。从反应混合物中倾析出甲苯,然后真空浓缩,得到油状N1-[5-(2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺。
部分D
将3-氯过苯甲酸(3克,9毫摩尔)加入含部分C的油的乙酸甲酯(50毫升)溶液中。反应混合物在室温下搅拌过夜,然后用乙醚(50毫升)稀释。过滤分离所得沉淀,然后用乙醚洗涤,得到1.6克1-(5-苯甲酰氨基戊基)-2-甲基-1H-咪唑并[4,5-c]喹啉-5N-氧化物。
部分E
将氢氧化铵(50毫升)加入含1-(5-苯甲酰氨基戊基)-2-甲基-1H-咪唑并[4,5-c]喹啉-5N-氧化物(1.6克,4.12毫摩尔)的二氯甲烷(150毫升)溶液中。缓慢加入甲苯磺酰氯(0.78克,4.12毫摩尔),并迅速搅拌该反应混合物。1小时后分离有机层,用1%碳酸钠洗涤,然后真空浓缩。将所得残余物与1N盐酸(30毫升)合并,用炭处理,然后过滤。中和滤液。沉淀出油。使该油固化过夜,得到0.63克N1-[5-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺固体,熔点为110-120℃.1H NMR(500MHz,DMSO-d6)δ8.50(t,J=5.5Hz,1H),8.12(d,J=8.0Hz,1H),7.82(d,J=8.5Hz,2H),7.71(d,J=8.5Hz,1H),7.63(宽s,2H),7.55(t,J=8.5Hz,1H),7.51(t,J=8.3Hz,1H),7.46(t,J=8.0Hz,2H),7.40(t,J=8.0Hz,1H),4.52(t,J=7.5Hz,2H),3.28(q,J=6.0Hz,2H),2.64(s,3H),1.87(五单元组,J=7.0Hz,2H),1.79(五单元组,J=7.0Hz,2H),1.48(五单元组,J=7.0Hz,2H);MS(CI)m/e 388(M+H)。
实施例10
盐酸N1-[5-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺
部分A
将催化量的碳载钯加入含N1-{5-[(3-硝基喹啉-4-基)氨基]戊基}苯甲酰胺(5克,13.2毫摩尔)的甲苯(250毫升)悬浮液中。将反应混合物置于帕尔装置上50psi(3.4X104帕斯卡)的氢气气氛下。大约2小时后,在帕尔瓶底物形成了油状球。加入硫酸镁和额外的催化剂,继续加氢过夜。过滤反应混合物,除去催化剂。将帕尔瓶中的残余物与异丙醇(150毫升)合并,在蒸汽浴上加热,然后过滤。HPLC分析表明两种滤液均含有产物,因此将它们合并,真空浓缩得到粗制的N1-{5-[(3-氨基喹啉-4-基)氨基]戊基}苯甲酰胺。将该物质与甲苯(250毫升)合并。加入原甲酸三乙酯(4克,26.4毫摩尔),用Vigreux柱使反应混合物加热回流2小时。将反应混合物冷却至室温。过滤分离所得沉淀,得到3.4克N1-[5-(1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺固体,熔点为171.5-172.5℃. 1H NMR(500MHz,DMSO-d6)δ9.22(s,1H),8.43(t,J=6.0Hz,2H),8.38(m,1H),8.18(m,1H),7.80(d,J=7.0Hz,2H),7.73(m,2H),7.51(t,J=7.0Hz,1H),7.45(t,J=7.0Hz,2H),4.72(t,J=7.5Hz,2H),3.25(q,J=6.0Hz,2H),1.94(五单元组,J=7.5Hz,2H),1.58(五单元组,J=7.5Hz,2H),1.40(五单元组,J=8.5Hz,2H)。
部分B
将3-氯过苯甲酸(1.9克,5.58毫摩尔)加入含N1-[5-(1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺(2.0克,5.58毫摩尔)的氯仿溶液中。4小时后的HPLC分析表明反应完全。用1%碳酸钠(50毫升)洗涤反应物两次,然后真空浓缩,得到1-(5-苯甲酰氨基戊基)-1H-咪唑并[4,5-c]喹啉-5N-氧化物。
部分C
将氢氧化铵加入含1-(5-苯甲酰氨基戊基)-1H-咪唑并[4,5-c]喹啉-5N-氧化物(2.1克,5.58毫摩尔)的二氯甲烷溶液中。缓慢加入甲苯磺酰氯(1.06克,5.58 毫摩尔)并迅速搅拌反应混合物。1小时后,用二氯甲烷稀释反应物。分离有机层,用1%碳酸钠洗涤,然后真空浓缩。将所得残余物溶解在异丙醇(100毫升)中,然后加入6N盐酸(0.93毫升)。将所得沉淀悬浮于水(150毫升)中,加热回流,用炭处理,然后过滤。使滤液冷却。过滤分离所得沉淀,干燥得到0.9克盐酸N1-[5-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺白色结晶固体,熔点为217-219℃。C22H23N5O·HCl·1/2H2O的分析计算值:%C,52.85;%H,6.85;%N,14.01;实测值:%C,52.62;%H,6.44%;%N,13.87.1H NMR(500MHz,DMSO-d6)δ13.84(宽s,1H),9.24(宽s,2H),8.51(s,1H),8.43(t,J=6.0Hz,1H),8.22(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,2H),7.70(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.49(t,J=8.0Hz,1H),7.42(t,J=8.0Hz,2H),4.66(t,J=7.0Hz,2H),3.23(q,J=6.0Hz,2H),1.90(五单元组,J=7.0Hz,2H),1.56(五单元组,J=7.0Hz,2H),1.38(五单元组,J=7.0Hz,2H);MS(CI)m/e 374(M+H)。
实施例11
盐酸N1-[3-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺
部分A
在帕尔容器中合并苯甲酰胺(25克,0.20摩尔)和1,3-二氨基丙烷(45.9克,0.60摩尔)并于150℃加热15小时。冷却该容器,将反应混合物真空浓缩,除去过量二胺。将残余物溶解在水(500毫升)中,加入浓盐酸,调节pH至<1。过滤除去所得沉淀(原料苯甲酰胺和二酰基化产物)。用二氯甲烷洗涤滤液。加入50%氢氧化钠使水层成强碱性,然后用二氯甲烷(4X 300毫升)萃取。合并萃取物,用盐水(300毫升)洗涤,用硫酸钠干燥,然后真空浓缩得到11.9克油状N-(3-氨基丙基)苯甲酰胺。
部分B
将三乙胺(9.3毫升,67毫摩尔)加入盐酸4-氯-3-硝基喹啉(16.4克,67毫摩 尔)和二氯甲烷(400毫升)的混合物中。一次性加入含N-(3-氨基丙基)苯甲酰胺(11.9克,67毫摩尔)的二氯甲烷(100毫升)溶液。反应混合物在室温下搅拌1小时,然后在蒸汽浴上加热1小时。过滤分离所得沉淀,得到6克N1-{3-[(3-硝基喹啉-4-基)氨基]丙基}苯甲酰胺黄色固体,熔点为209-211℃.1H NMR(500MHz,DMSO-d6)δ9.07(宽s,1H),9.05(s,1H),8.54(t,J=6.0Hz,1H),8.51(d,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H),7.82(t,J=8.0Hz,1H),7.76(d,J=8.0Hz,2H),7.55(t,J=8.0Hz,1H),7.50(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,2H),3.69(q,J=6.0Hz,2H),3.35(q,J=6.0Hz,2H),2.00(五单元组,J=7.0Hz,2H)。
部分C
将含N1-{3-[(3-硝基喹啉-4-基)氨基]丙基}苯甲酰胺(1.0克,2.8毫摩尔)的异丙醇(120毫升)悬浮液温热,使一些物质溶解。加入催化量的碳载钯,将反应混合物置于帕尔装置上50psi(3.4X104帕斯卡)的氢气气氛下。3小时后,过滤反应混合物除去催化剂。真空浓缩滤液,得到粗制的油状N1-{3-[(3-氨基喹啉-4-基)氨基]丙基}苯甲酰胺。将甲苯(100毫升)加入该油,然后加入原甲酸三乙酯(0.8克,5.6毫摩尔)。使反应混合物在蒸汽浴上加热过夜。使反应混合物在室温下冷却。过滤分离所得沉淀,得到0.53克N1-[3-(1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺灰白色固体,熔点为188-190℃.1H NMR(500MHz,DMSO-d6)δ8.67(t,J=5.5Hz,1H),8.50(s,1H),8.37(d,J=7.5Hz,1H),8.17(dd,J=8.0,1.5Hz,1H),7.87(d,J=7.0Hz,2H),7.71(dt,J=7.5,1.5Hz,1H),7.56(dt,J=7.5,1.0Hz,1H),7.54(d,J=8.0Hz,2H),7.48(t,J=7.0Hz,2H),4.78(t,J=7.0Hz,2H),3.38(q,J=6.0Hz,2H),2.18(五单元组,J=7.0Hz,2H)。
部分D
在室温下将3-氯过苯甲酸(0.55克,1.6毫摩尔)缓慢加入含N1-[3-(1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺(0.53克,1.6毫摩尔)的氯仿(50毫升)溶液中。3小时后,用1%碳酸钠(2X30毫升)洗涤反应物,然后真空浓缩,得到0.32克1-(3-苯甲酰氨基丙基)-1H-咪唑并[4,5-c]喹啉-5N-氧化物固体。
部分E
将氢氧化铵(20毫升)加入含1-(3-苯甲酰氨基丙基)-1H-咪唑并[4,5-c]喹啉-5N-氧化物(0.32克,0.92毫摩尔)的二氯甲烷(100毫升)溶液中。缓慢加入甲苯磺酰氯(0.17克,0.92毫摩尔)。在室温下搅拌该反应混合物过夜,然后真空浓 缩除去二氯甲烷。过滤分离所得沉淀,然后用水洗涤。将该物质溶解在异丙醇(20毫升/克)中。加入浓盐酸(1当量),然后使反应混合物体积减少10-20%。过滤分离所得沉淀,用异丙醇洗涤,得到0.25克盐酸N1-[3-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺固体,熔点为265-270℃。C20H19N5O·HCl·1/2H2O的分析计算值:%C,61.46;%H,5.42;%N,17.92;实测值:%C,61.79;%H,5.34;%N,17.61.1H NMR(500MHz,DMSO-d6)δ13.74(宽s,1H),9.30(宽s,2H),8.73(t,J=6.0Hz,1H),8.61(s,1H),8.22(d,J=8.0Hz,1H),7.87(d,J=8.0Hz,2H),7.84(d,J=8.0Hz,1H),7.71(t,J=8.0Hz,1H),7.54(t,J=8.0Hz,1H),7.48(t,J=8.0Hz,2H),7.43(t,J=8.0Hz,1H),4.75(t,J=7.0Hz,2H),3.39(q,J=6.0Hz,2H),2.17(t,J=7.0Hz,2H);MS(EI)m/e 345.1593(C20H19N5O的计算值为345.1590)。
实施例12
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-吗啉代烟酰胺
部分A
将羰基二咪唑(18.6克,0.115摩尔)加入含6-氯烟酸(16.6克,0.105摩尔)的二氯甲烷(250毫升)悬浮液中。所有固体溶解后,在室温下搅拌反应溶液1小时,然后加入异丙醇(100毫升)。真空除去二氯甲烷。将催化量的异丙醇钠加入溶液中,使溶液加热回流1小时。然后将溶液真空浓缩。所得残余物用水制成淤浆,然后用乙醚萃取。萃取物用硫酸镁干燥,然后真空浓缩,得到23.9克6-氯烟酸异丙酯。
部分B
使含6-氯烟酸异丙酯(6.0克,0.03摩尔)和吗啉(13毫升,0.15摩尔)的异丙醇(60毫升)溶液加热回流72小时。使溶液在室温下冷却过夜。过滤分离所得沉淀,用异丙醇洗涤,然后干燥得到6-吗啉代烟酸异丙酯。滤液用水稀释,过 滤分离所得沉淀,用水洗涤,干燥得到6-吗啉代烟酸异丙酯。合并得率为8.3克。将6-吗啉代烟酸异丙酯与1N氢氧化钠(40毫升)合并,所得悬浮液在50-60℃搅拌直至所有固体溶解。在室温下搅拌溶液过夜,此时形成沉淀。过滤分离该物质,鉴定为原料。用浓盐酸中和滤液。过滤分离所得沉淀,用水洗涤,干燥得到3.3克粗品。从甲醇/二氯甲烷重结晶该物质,得到6-吗啉代烟酸固体,熔点为259-261℃。C10H12N2O3的分析计算值:%C,57.19;%H,5.81;%N,13.48;实测值:%C,57.50;%H,5.71;%N,13.53。
部分C
将N,N-二甲基甲酰胺(1毫升)缓慢加入含草酰氯(0.13克,1毫摩尔)的氯仿(5毫升)溶液中。加入6-吗啉代烟酸(0.21克,1毫摩尔),搅拌反应混合物15分钟。真空浓缩反应混合物,用甲苯稀释,然后真空浓缩得到6-吗啉代烟酰氯。使该物质在室温下处于真空下过夜,然后用于下一步。
部分D
将部分C的酰基氯溶于吡啶(20毫升),然后一次性加入温热的含1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.25克,1毫摩尔)的吡啶(25毫升)溶液中。在40℃下真空浓缩反应混合物,除去吡啶。使所得残余物与水和1N氢氧化钠(25毫升)合并。混合物用二氯甲烷萃取。真空浓缩萃取物。所得残余物从异丙醇中重结晶,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-吗啉代烟酰胺固体,熔点为160-170℃(分解).1H NMR(500MHz,DMSO-d6)δ8.55(d,J=2.5Hz,1H),8.52(s,1H),8.28(t,J=6.0Hz,1H),8.22(d,J=8.0Hz,1H),7.90(dd,J=8.0,2.5Hz,1H),7.82(d,J=8.0Hz,1H),7.69(t,J=8.0Hz,1H),7.52(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),4.70(t,J=7.0Hz,2H),3.69(t,J=5.0Hz,4H),3.54(t,J=5.0Hz,4H),3.27(q,J=6.0Hz,2H),1.91(五单元组,J=7.0Hz,2H),1.58(t,J=6.0Hz,2H);MS(EI)m/e 445.2209(C24H27N7O2计算值为445.2226)。
实施例13
N1-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]苯甲酰胺
部分A
将三乙胺(66.8克,0.33摩尔)加入含N-(2-氨基乙基)氨基甲酸叔丁酯(55.0克,0.34摩尔)的无水二氯甲烷(500毫升)溶液中。缓慢加入4-氯-3-硝基喹啉,反应放热。使反应混合物在室温下搅拌过夜。过滤分离所得沉淀,得到黄色固体状产物。用水洗涤滤液,用硫酸镁干燥,然后真空浓缩。所得残余物用己烷制成淤浆,过滤得到另一黄色固体状产物。合并两个产物,得到101克N-[2-(3-硝基喹啉-4-基)氨基乙基]氨基甲酸叔丁酯黄色固体,熔点为157-158。
部分B
将碳载钯(1克10%)硫酸钠(2克)加入含N-[2-(3-硝基喹啉-4-基)氨基乙基]氨基甲酸叔丁酯(100克,0.30摩尔)的甲苯(500毫升)淤浆中。将该混合物置于帕尔装置上50psi(3.4X 104帕斯卡)的氢气气氛下,在室温下过夜。过滤反应混合物。浓缩滤液,得到73克深金色油状N-[2-(3-氨基喹啉-4-基)氨基乙基]氨基甲酸叔丁酯。
部分C
将原甲酸三乙酯(11.3克,73.4毫摩尔)加入含N-[2-(3-氨基喹啉-4-基)氨基乙基]氨基甲酸叔丁酯(21克,69.4毫摩尔)的无水甲苯(250毫升)溶液中。使反应混合物加热回流5小时,然后使其缓慢冷却至室温。过滤分离所得沉淀,干燥得到17.6克N-[2-(1H-咪唑并[4,5-c]喹啉-1-基)乙基]氨基甲酸叔丁酯浅褐色固体,熔点为154-155℃。
部分D
将3-氯过苯甲酸(17.4克,60.6毫摩尔)小批量加入含N-[2-(1H-咪唑并[4,5-c]喹啉-1-基)乙基]氨基甲酸叔丁酯(17.2克,55.1毫摩尔)的氯仿(250毫升)溶液中。维持反应物在室温下过夜,然后用5%碳酸钠溶液淬灭。分层。用硫酸镁干燥有机层,然后真空浓缩,得到15.0克1-[2-(叔丁基氨基甲酰基)乙基]-1H-咪唑并[4,5-c]喹啉-5N-氧化物灰白色固体,熔点为213-215℃。
部分E
将异氰酸三氯乙酰酯(9.5克,50.2毫摩尔)缓慢加入搅拌的含1-[2-(叔丁基氨基甲酰基)乙基]-1H-咪唑并[4,5-c]喹啉-5N-氧化物(15.0克,45.7毫摩尔)的氯仿(200毫升)溶液中。2小时后,用浓氢氧化铵(100毫升)淬灭反应。加入水(100毫升),分层。用氯仿萃取水层。合并有机层,用硫酸镁干燥,然后真空浓缩,得到白色固体。使该物质在温热的乙酸甲酯中成为淤浆,然后过滤得到15克N-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]氨基甲酸叔丁酯白色固体,熔点为215℃.1H NMR(500MHz,DMSO-d6)δ8.13(t,J=8.0Hz,1H),8.03(s,1H),7.61(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.23(t,J=8.0Hz,1H),7.06(t,J=6.0Hz,1H),6.56(宽s,2H),4.63(t,J=7.0Hz,2H),3.43(q,J=6.0Hz,2H),1.32(s,9H);MS(EI)m/e 327.1696(C17H21N5O2的计算值为327.1695)
部分F
将N-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]氨基甲酸叔丁酯(14.8克,45.2毫摩尔),三氟乙酸(100毫升)和乙腈(100毫升)合并,在室温下维持过夜。除去乙腈,使反应混合物加热回流2小时。真空浓缩反应混合物,得到褐色固体。将该物质溶于最少量的热水中。将溶液调至pH 14,使其冷却。使溶液真空浓缩。所得残余物用回流的乙醇萃取。真空浓缩乙醇萃取物,得到3.0克1-(2-氨基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺褐色固体,熔点为265℃.1HNMR(500MHz,DMSO-d6)δ8.14(s,1H),8.08(dd,J=8.0,1.5Hz,1H),7.62(dd,J=8.0,1.5Hz,1H),7.44(dt,J=8.0,1.5Hz,1H),7.25(dt,J=8.0,1.5Hz,1H),6.58(宽s,2H),4.54(t,J=7.0Hz,2H),3.01(t,J=7.0Hz,2H),1.60(宽s,2H);MS(EI)m/e 227.1171(C12H13N5的计算值为227.1171)。
部分G
对1-(2-氨基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.40克,1.76毫摩尔)和无水吡啶(60毫升)的混合物加热,直至获得澄清的溶液。然后用冰浴冷却溶液。加入苯甲酰氯(0.25克,1.76毫摩尔)。将反应混合物维持在室温下过夜,然后真空浓缩。残余物用水(200毫升)制成淤浆,过滤分离固体。该物质从异丙醇中重结晶,得到0.15克N1-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]苯甲酰胺白色粉末,熔点为295℃.1H NMR(500MHz,DMSO-d6)δ8.50(t,J=6.0Hz,1H),8.23(d,J=8.0Hz,1H),8.04(s,1H),7.75(d,J=8.0Hz,2H),7.64(d,J=8.0Hz, 1H),7.49(t,J=8.0Hz,1H),7.43(t,J=8.0,1H),7.41(t,J=8.0Hz,2H),7.25(t,J=8.0Hz,1H),6.28(宽s,2H),4.80(t,J=7.0Hz,2H),3.80(q,J=6.0Hz,2H);MS(EI)m/e331.1429(C19H17N5O的计算值为331.1433)。
实施例14
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯氧基苯甲酰胺
在氮气氛下,用加热枪使1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.125克,0.49毫摩尔)和无水吡啶(40毫升)的混合物温热,使固体溶解。使所得溶液冷却至室温。加入含2-苯氧基苯甲酰氯(0.11克,0.47毫摩尔)的吡啶(5毫升)溶液。反应混合物在室温下维持18小时,然后真空浓缩。所得固体残余物用快速色谱纯化(硅胶,用9∶1二氯甲烷∶甲醇洗脱),得到0.12克N1-[4.(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯氧基苯甲酰胺白色固体,熔点为93-94℃. 1H NMR(500MHz,DMSO-d6)δ8.23(t,J=6.0Hz,1H),8.14(s,1H),8.00(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),7.54(dd,J=8.0,1.5Hz,1H),7.43(dt,J=8.0,1.5Hz,1H),7.42(dt,J=8.0,1.5Hz,1H),7.30(t,J=8.0Hz,2H),7.22(t,J=8.0Hz,1H),7.18(t,J=8.0Hz,1H),7.07(t,J=8.0Hz,1H),6.89(m,3H),6.59(宽s,2H),4.55(t,J=7.0Hz,2H),3.23(q,J=6.0Hz,2H),1.81(五单元组,J=7.0Hz,2H),1.47(五单元组,J=7.0Hz,2H);MS(EI)m/e 451.2004(C27H25N5O2的计算值为451.2008)。
实施例15
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-苯甲酰基苯甲酰胺
利用实施例14的方法,使1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.2克,0.78毫摩尔)与3-苯甲酰基苯甲酰氯(0.18克,0.73毫摩尔)反应,得到0.19克N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-苯甲酰基苯甲酰胺白色结晶固体,熔点为103-105℃.1H NMR(500MHz,DMSO-d6)δ8.70(t,J=6.0Hz,1H),8.22(s,1H),8.16(宽s,1H),8.08(d,J=8.0Hz,1H),8.03(d,J=8.0Hz,1H),7.85(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,2H),7.70(t,J=8.0Hz,1H),7.64(t,J=8.0Hz,1H),7.61(d,J=8.0Hz,1H),7.57(t,J=8.0Hz,2H),7.40(t,J=8.0Hz,1H),7.19(t,J=8.0Hz,1H),6.67(宽s,2H),4.63(t,J=7.0Hz,2H),3.32(q,J=6.0Hz,2H),1.91(五单元组,J=7.0Hz,2H),1.59(五单元组,J=7.0Hz,2H);MS(EI)m/e463.2022(C28H25N5O2的计算值为463.2008)。
实施例16
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-苯基丙酰胺
利用实施例14的方法,使1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.2克,0.78毫摩尔)与苯丙酰氯(0.11毫升,0.74毫摩尔)反应,得到0.14克N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-苯基丙酰胺白色固体,熔点为148-150℃.1H NMR(500MHz,DMSO-d6)δ8.19(s,1H),8.03(d,J=8.0Hz,1H),7.82(t, J=6.0Hz,1H),7.63(d,J=8.0Hz,1H),7.45(t,J=8.0Hz,1H),7.27(t,J=8.0Hz,1H),7.22(t,J=8.0Hz,2H),7.15(m,3H),6.66(宽s,2H),4.58(t,J=7.0Hz,2H),3.06(q,J=6.0Hz,2H),2.75(t,J=7.0Hz,2H),2.31(t,J=7.0Hz,2H),1.79(五单元组,J=7.0Hz,2H),1.40(t,J=7.0Hz,2H);MS(EI)m/e 387.2067(C23H25N5O的计算值为387.2059)。
实施例17
N1-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-3-苯基丙酰胺
利用实施例14的方法,使1-(2-氨基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺(100毫克,0.44毫摩尔)与苯丙酰氯(0.065毫升,0.44毫摩尔)反应,得到0.06克N1-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-3-苯基丙酰胺白色固体,熔点为254-256℃.1H NMR(500MHz,DMSO-d6)δ8.16(d,J=8.0Hz,1H),8.07(t,J=6.0Hz,1H),7.97(s,1H),7.62(dd,J=8.0,1.0Hz,1H),7.45(dt,J=8.0,1.0Hz,1H),7.26(m,3H),7.16(m,3H),6.6(宽s,2H),4.61(t,J=7.0Hz,2H),3.54(q,J=6.0Hz,2H),2.75(t,J=7.0Hz,2H),2.31(t,J=7.0Hz,2H);MS(EI)m/e359.1745(C21H21N5O的计算值为359.1746)。
实施例18
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(4-苯甲酰基苯氧基)
乙酰胺
将1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(99.6毫克,0.39毫摩尔)和2-(4-苯甲酰基苯氧基)乙酸(100毫克,0.39毫摩尔)合并在吡啶(10毫升)中。温热该混合物至均一,然后使其冷却。加入盐酸1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺(82毫克,0.43摩尔)。使反应混合物在室温下维持过夜,然后真空浓缩。使残余物在氯仿和饱和的碳酸钾溶液之间分配。分层。水层用氯仿萃取。合并有机层,用硫酸镁干燥,然后真空浓缩得到金色油。用柱色谱纯化该油(硅胶,用含10%甲醇的二氯甲烷洗脱),得到大约70毫克N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(4-苯甲酰基苯氧基)乙酰胺白色固体,熔点为73-98℃.1H NMR(500MHz,DMSO-d6)δ8.22(t,J=6.0Hz,1H),8.18(s,1H),8.03(d,J=8.3Hz,1H),7.73(d,J=8.0Hz,2H),7.68(d,J=8.0Hz,2H),7.65(t,J=8.0Hz,1H),7.60(dd,J=8.0,1.0Hz,1H),7.55(t,J=8.0Hz,2H),7.42(dt,J=8.0,1.0Hz,1H),7.25(t,J=8.0,1.0Hz,1H),7.07(d,J=8.0Hz,2H),6.58(宽s,2H),4.61(t,J=7.0Hz,2H),4.56(s,2H),3.18(q,J=6.0Hz,2H),1.86(五单元组,J=7.0Hz,2H),1.50(五单元组,J=7.0Hz,2H);MS(EI)m/e 493.2106(C29H27N5O3的计算值为493.2114)。
实施例19
N-[4-氨基-1H-咪唑并[4,5-c]喹啉-1-基]丁基-5-[(2-氧代-2,3-二氢-1H-苯并
[d]咪唑-5-基)氧]戊酰胺
用实施例18的通用方法,使1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(100毫克,0.392毫摩尔)与5-[(2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)氧]戊酸(98.1毫克,0.392毫摩尔)相连,得到20毫克N-[4-氨基-1H-咪唑并[4,5-c]喹啉-1-基]丁基-5-[(2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)氧]戊酰胺灰白色固体,熔点为150-157℃.1H NMR(500MHz,DMSO-d6)δ10.51(s,1H),10.36(s,1H),8.23(s,1H),8.05(d,J=8.0Hz,1H),7.81(t,J=6.0Hz,1H),7.64(t,J=6.0Hz,1H),7.47(t,J=8.0Hz,1H),7.29(t,J=8.0Hz,1H),6.93(宽s,2H),6.78(d,J=8.0Hz,1H),6.48(s,1H),6.47(d,J=8.0Hz,1H),4.61(t,J=7.0Hz,2H),3.82(宽s,2H),3.08(q,J=6.0Hz,2H),2.05(t,J=7.0Hz,2H),1.84(五单元组,J=7.0Hz,2H),1.58(宽s,4H),1.44(五单元组,J=7.0Hz,2H);MS(EI)m/e 487.2329(C26H29N7O3的计算值为487.2332)。
实施例20
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉1-基)丁基]-4-苯甲酰基苯甲酰胺
用实施例14的一般方法,使1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺 (0.51克,2.0毫摩尔)与4-苯甲酰基苯甲酰氯(2.0毫摩尔)反应,得到0.15克N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-苯甲酰基苯甲酰胺白色固体,熔点为159-161℃.1H NMR(500MHz,CDCl3)δ8.06(s,1H),7.96(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.85(d,J=8.0Hz,2H),7.81(d,J=8.0Hz,2H),7.76(d,J=8.0Hz,2H),7.60(m,2H),7.49(t,J=8.0Hz,2H),7.48(t,J=8.0Hz,1H),7.24(宽s,1H),6.86(宽s,1H),6.60(t,J=6Hz,1H),4.69(t,J=7.0Hz,2H),3.62(q,J=6.0Hz,2H),2.14(五单元组,J=7.0Hz,2H),1.82(五单元组,J=7.0Hz,2H);MS(EI)m/e463.2002(C28H25N5O2的计算值为463.2008)。
实施例21
N6-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-喹啉甲酰胺
用实施例18的通用方法,使1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.5克,1.96毫摩尔)与6-喹啉甲酸(0.34克,1.96毫摩尔)相连,得到0.08克N6-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-喹啉甲酰胺褐色粉末,熔点为122-127℃(起泡).1H NMR(300MHz,DMSO-d6)δ8.98(m,1H),8.73(t,J=5.4Hz,1H),8.43(m,2H),8.23(s,1H),8.13-8.03(m,3H),7.60(m,2H),7.40(m,1H),7.20(m,1H),6.58(宽s,2H),4.66(t,J=6.7Hz,2H),3.37(m,2H),1.96(m,2H),1.64(m,2H);MS(EI)m/e 410.1847(C24H22N6O计算值为410.1855)。
实施例22
N1-[3-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺
部分A
用实施例11部分C的通用方法,将N1-{3-[(3-硝基喹啉-4-基)氨基]丙基}苯甲酰胺(2.0克,5.7毫摩尔)还原成二胺,然后与原乙酸三乙酯反应,得到0.74克N1-[3-(2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺粘稠状深黄色固体。
部分B
用实施例11部分D的通用方法,使部分A的物质氧化,得到0.35克1-(3-苯甲酰氨基丙基)-2-甲基-1H-咪唑并[4,5-c]喹啉-5N-氧化物固体。
部分C
将氢氧化铵(20毫升)加入含1-(3-苯甲酰氨基丙基)-2-甲基-1H-咪唑并[4,5-c]喹啉-5N-氧化物(0.35克,0.97毫摩尔)的二氯甲烷(100毫升)溶液中。缓慢加入甲苯磺酰氯(0.185克,0.97毫摩尔)并剧烈搅拌。在室温下搅拌反应混合物过夜,然后将其真空浓缩,除去二氯甲烷。所得固体从二氯甲烷中重结晶,得到0.1克N1-[3-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺固体,熔点为230-231.4℃。
实施例23
N1-[6-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)己基]苯甲酰胺
部分A
用实施例9部分A的通用方法,使六亚甲基二胺(348.63克,3摩尔)和苯甲酰胺(121.14克,1摩尔)反应,得到136.5克N-(6-氨基己基)苯甲酰胺。
部分B
用实施例9部分B的通用方法,使盐酸4-氯-3-硝基喹啉(10克,41毫摩尔)与N-(6-氨基己基)苯甲酰胺反应,得到12.85克N1-{6-[(3-硝基喹啉-4-基)氨基]己基}苯甲酰胺黄色结晶固体。
部分C
用实施例9部分C的通用方法,使12.3克部分B的物质还原,然后与原甲酸三乙酯(8.94克,6毫摩尔)反应,得到6.4克N1-[6-(1H-咪唑并[4,5-c]喹啉-1-基)己基]苯甲酰胺棕色油。
部分D
将3-氯过苯甲酸(5.9克,17毫摩尔)缓慢加入含部分C物质的氯仿溶液中。溶液变橙色。2小时后,用水性碳酸钠洗涤反应混合物两次,然后真空浓缩,得到6.0克1-(6-苯甲酰氨基己基)-1H-咪唑并[4,5-c]喹啉-5N-氧化物橙色油。
部分E
将氢氧化铵加入含部分D物质的二氯甲烷溶液中。缓慢加入甲苯磺酰氯(2.94克,15毫摩尔)并剧烈搅拌。使反应混合物在室温下搅拌过夜,然后将其真空浓缩。所得粗品从乙酸丙酯中重结晶,得到0.91克N1-[6-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)己基]苯甲酰胺米色结晶固体,熔点为146-155℃。
实施例24
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-(2-氧代全氢
噻吩并[3,4-d]咪唑-4-基)戊酰胺
将D-生物素基N-羟基琥珀酰亚胺(0.57克,1.67毫摩尔)加入含1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(0.52克,1.67毫摩尔)的吡啶(25毫升)溶液中。使反应物在室温下维持过夜,然后浓缩至干。使残余物在二氯甲烷和饱和碳酸钾水溶液之间分配。用硫酸镁干燥有机层,然后浓缩得到0.4克N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺固体,熔点为214-215℃。C28H39N7O2S的分析计算值:%C,62.54;%H,7.31;%N,18.23;实测值:%C,61.67;%H,7.37;%N,17.62。
实施例25
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺
将含1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.38克,1.49毫摩尔)的吡啶(20毫升)溶液加入含N-羟基琥珀酰亚胺基生物素(0.51克,1.49毫摩尔)的吡啶(20毫升)溶液中。使反应物在室温下维持过夜,然后浓缩至干。 使残余物在二氯甲烷和饱和碳酸钾水溶液之间分配。用硫酸镁干燥有机层,然后浓缩得到0.58克N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺固体,熔点为104-106℃。高分辨率质谱:理论质量=481.2260,实测质量=481.2261。
实施例26
N1-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-
5-(2-亚氨基全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺
将含N-羟基琥珀酰亚胺基亚氨基生物素(0.74克,1.76毫摩尔)的吡啶(10毫升)溶液缓慢加入含1-(2-氨基乙基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(0.50克,1.76毫摩尔)的吡啶(30毫升).溶液中。使反应物在室温下维持过夜,然后浓缩至干。使残余物在二氯甲烷和饱和碳酸钾水溶液之间分配。有机层用硫酸镁干燥,然后浓缩至干。残余物从乙醇中重结晶,得到0.5克N1-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-(2-亚氨基全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺固体,熔点为95-96℃。高分辨率质谱:理论质量=508.2733,实测质量=508.2723。
实施例27
N1-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-
5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺
用实施例24的通用方法,使N-羟基琥珀酰亚胺基生物素(0.6克,1.76毫摩尔)与1-(2-氨基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.4克,1.76毫摩尔)反应,得到0.6克N1-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺固体,熔点为169℃。
实施例28
N1-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-
5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺
用实施例25的通用方法,使1-(4-氨基乙基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(0.4克,1.47毫摩尔)与N-羟基琥珀酰亚胺基生物素(0.5克,1.47毫摩尔)反应,得到0.44克N1-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺白色固体,熔点为124-126℃.高分辨率质谱:理论质量=509.25,实测质量=509.2580。
实施例29
N1-[2-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-
5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺二三氟乙酸盐
将三乙胺(1.2克,11.4毫摩尔)一次加入含盐酸1-(2-氨基乙基)-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-4-胺(3.39克,10.53毫摩尔)的氯仿(150毫升)淤浆中。反应混合物变澄清。然后缓慢加入N-羟基琥珀酰亚胺基生物素(3.0 克,8.79毫摩尔)。2小时后,使混浊的反应混合物加热回流.反应混合物维持回流过夜,然后变澄清。将反应混合物冷却至室温,然后用水淬灭。分层。有机层用硫酸镁干燥,然后浓缩得到灰白色固体。该物质从8∶2乙醇∶水重结晶,得到白色固体。用制备性HPLC纯化一部分物质,用水/乙腈/三氟乙酸洗脱,得到0.6克N1-[2-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺的二三氟乙酸盐,熔点为171-175℃。C25H33N7O3S·2C2HF3O2的分析计算值:%C,47.09;%H,4.77;%N,13.26;实测值:%C,47.06;%H,5.17;%N,13.31。
实施例30
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
6-(5-甲基-2-氧代-4-咪唑啉基)己酰胺
合并1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(0.13克,0.47毫摩尔),D-脱硫生物素(0.10克,0.47毫摩尔)和氯仿(200毫升),在室温下搅拌直至获得澄清溶液。加入盐酸1-[3-(二甲基氨基)丙基-3-乙基碳化二亚胺(0.094克,0.49毫摩尔),使反应混合物在室温下维持过夜。将反应混合物倒在硅胶柱上。使氯仿流过,然后柱用含10%甲醇的二氯甲烷洗脱。合并纯组分,浓缩得到N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-(5-甲基-2-氧代-4-咪唑啉基)己酰胺白色固体。
实施例31
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-乙氧基-1-萘甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和2-乙氧基-1-萘酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-乙氧基-1-萘甲酰胺白色粉末,熔点为219℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.33(t,J=5.8Hz,1H),8.22(s,1H),8.09(d,J=8.0Hz,1H),7.91(d,J=8.7Hz,1H),7.87-7.84(m,1H),7.64-7.56(m,2H),7.47-7.22(m,5H),6.60(s,2H),4.69(t,J=7.2Hz,2H),4.09(q,J=7.2Hz,2H),3.37(m,2H),2.01(m,2H),1.64(m,2H),1.18(t,J=7.2Hz,3H);MS(EI)m/e 453.2157(C27H27N5O2的计算值为453.2165)。
实施例32
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氰基苯甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺4-氰基苯甲酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氰基苯甲酰胺白色粉末,熔点为222.8-225.3℃。1H NMR(300MHz,DMSO-d6)δ8.73(t,J=5.7Hz,1H),8.22(s,1H),8.03(d,J=8.1Hz,1H),7.93(s,4H),7.61(dd,J=8.4,1.2Hz,1H),7.43(dt,J=7.6,1.5Hz,1H),7.21(dt,J=7.6,1.2Hz,1H),6.61(s,2H),4.64(t,J=7.2Hz,2H),3.33(m,2H),1.96(五单元组,J=7.2Hz,2H),1.58(五单元组,J=7.2Hz,2H);IR(KBr)3441,3337,3136,2945,2228,1641,1545,1531,1481,1396,1309,1257,857,755cm-1;MS(EI)m/e 384.1699(C22H20N6O的计算 值为384.1699)。
实施例33
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-氰基苯甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和3-氰基苯甲酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-氰基苯甲酰胺白色结晶固体,熔点为200.0-201.0℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.68(t,J=5.7Hz,1H),8.22(s,1H),8.17(t,J=1.8Hz,1H),8.10-7.97(m,3H),7.69-7.60(m,2H),7.42(dt,J=7.5,1.2Hz,1H),7.20(dt,J=7.5,1.5Hz,1H),6.62(s,2H),4.63(t,J=6.9Hz,2H),3.32(m,2H),1.91(五单元组,J=7.5Hz,2H),1.59(五单元组,J=7.5Hz,2H);IR(KBr)3455,3295,3072,2941,2231,1638,1581,1527,1479,1396,1312,1251,1205cm-1;MS(EI)m/e 384.1699(C22H20N6O的计算值为384.1699)。
实施例34
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-苯基苯甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和4-联苯基碳酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-苯基苯甲酰胺白色粉末,熔点为215.4℃(分解)。1H NMR(300MHz,DMSO-d6) δ8.54(t,J=5.7Hz,1H),8.22(s,1H),8.05(d,J=7.2Hz,1H),7.88(d,J=5.4Hz,2H),7.75-7.70(m,4H),7.62(dd,J=8.4,1.5Hz,1H),7.52-7.38(m,4H),7.22(dt,J=7.5,1.2Hz,1H),6.61(s,2H),4.65(t,J=7.2Hz,2H),3.30(m,2H),1.93(五单元组,J=7.5Hz,2H),1.60(五单元组,J=7.5Hz,2H);MS(EI)m/e 435.2054(C27H25N5O的计算值为435.2059)。
实施例35
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯氧基乙酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和苯氧基乙酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯氧基乙酰胺灰白色粉末,熔点为61.5℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),8.12(t,J=6.0Hz,1H),8.03(d,J=8.4Hz,1H),7.62(dd,J=8.4,1.2Hz,1H),7.44(dt,J=7.5,1.2Hz,1H),7.29-7.21(m,3H),6.96-6.88(m,3H),6.62(s,2H),4.60(t,J=7.2Hz,2H),4.42(s,2H),3.16(q,J=6.9Hz,2H),1.83(五单元组,J=7.2Hz,2H),1.47(五单元组,J=7.2Hz,2H);IR(KBr)3311,3180,2937,1664,1618,1583,1527,1493,1480,1396,1244,755cm-1;MS(EI)m/e 389.1844(C22H23N5O2的计算值为389.1852)。
实施例36
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-乙基己酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和2-乙基己酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-乙基己酰胺褐色粉末,熔点为163.0-164.0℃。1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),8.03(d,J=8.1Hz,1H),7.79(m,1H),7.61(dd,J=8.1,1.2Hz 1H),7.44(dt,J=7.5,1.2Hz,1H),7.26(dt,J=7.5,1.2Hz,1H),6.63(s,2H),4.61(t,J=6.9Hz,2H),3.12-3.05(m,2H),1.94-1.82(m,3H),1.49-1.03(m,10H),0.76(t,J=7.2Hz,3H),0.67(t,J=7.2Hz,3H);MS(EI)m/e 381.2533(C22H31N5O的计算值为381.2529)。
实施例37
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
(反式)-2-苯基环丙烷-1-甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和反式-2-苯基-1-环丙烷碳酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-(反式)-2-苯基环丙烷-1-甲酰胺灰白色固体,熔点为77.0℃。1HNMR(300MHz,DMSO-d6)δ7.90(dd,J=8.1,1.2Hz,1H),7.81(dd,J=8.1,1.2Hz,1H),7.78(s,1H),7.50(dt,J=8.1,1.5Hz,1H),7.33-7.15(m,4H),7.05-7.02(m,2H),5.84(宽s,1H),5.51(s,2H),4.52(t,J=7.2Hz,2H),3.32(q,J=6.6Hz,2H),2.49-2.43(m,1H),2.07-1.95(m,3H),1.64-1.51(m,3H),1.25-1.18(m,1H);IR(KBr)3304,3179,2939,1640,1582,1527,1479,1396,1250,755,735,689cm-1;MS(EI)m/e399.2059(C24H25N5O的计算值为399.2059)。
实施例38
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-萘甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和1-萘酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-萘甲酰胺灰白色粉末,熔点为174.5℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.52(t,J=5.6Hz,1H),8.49(s,1H),8.24(m,3H),8.10(d,J=8.1Hz,1H),7.97(m,2H),7.80(d,J=8.2Hz,1H),7.65(t,J=7.3Hz,1H),7.57-7.41(m,5H),4.75(t,J=6.9Hz,2H),2.03-1.98(m,2H),1.69-1.64(m,2H);MS(EI)m/e 409.1903(C25H23N5O的计算值为409.1903)。
实施例39
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-苯氧基苯甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和3-苯氧基苯甲酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-苯氧基苯甲酰胺白色粉末,熔点为105.0-107.0℃。1H NMR(300MHz,DMSO-d6)δ8.54(t,J=5.4Hz,1H),8.34(s,1H),8.10(d,J=8.1Hz,1H),7.69(dd,J=8.1,1.2Hz,1H),7.58-7.29(m,9H),7.19-7.13(m,2H),7.04-6.99(m,2H),4.65(t,J=7.2Hz,2H),3.28(m,2H),1.89(五单元组,J=7.2Hz,2H),1.58(五单元组,J=7.2Hz,2H);MS(EI)m/e 451.2012(C27H25N5O2的计算值为451.2008)。
实施例40
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-喹啉甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和喹啉-3-碳酰氯,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-喹啉甲酰胺白色结晶固体,熔点为116.0-118.0℃(分解)。1H NMR(300MHz,DMSO-d6)δ9.24(d,J=2.1Hz,1H),8.86(t,J=5.1Hz,1H),8.74(d,J=2.1Hz,1H),8.25(s,1H),8.09-8.05(m,3H),7.86(dt,J=7.5,1.0Hz,1H),7.69(t,J=7.5Hz,1H),7.61(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.21(t,J=7.5Hz,1H),6.68(s,2H),4.67(t,J=6.9Hz,2H),1.97(五单元组,J=7.2Hz,2H),1.65(五单元组,J=7.2Hz,2H);MS(EI)m/e 410.1864(C24H22N6O的计算值为410.1855)。
实施例41
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯氧基丙酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和2-苯氧基丙酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯氧基丙酰胺白色粉末,熔点为85.0-87.5℃。1H NMR(300MHz,DMSO-d6)δ8.15(s,1H),8.07(t,J=6.0Hz,1H),8.00(d,J=8.4Hz,1H),7.62(dd,J=8.4,1.2Hz,1H),7.43(dt,J=7.5,1.2Hz,1H),7.28-7.16(m,3H),6.91-6.81(m,3H),6.57(s,2H),4.62-4.53(m,3H),3.10(q,J=6.9Hz,2H),1.76(五单元组,J=7.1Hz,2H),1.43(五单元组,J=7.1Hz,2H),1.33(d,J=6.6Hz,3H);MS(EI)m/e 403.2005(C23H25N5O2的 计算值为403.2008)。
实施例42
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
1-苄基-1H-3-吲哚甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和1-苄基吲哚-3-碳酰氯,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-苄基-1H-3-吲哚甲酰胺白色粉末,熔点为139.0℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.24(s,1H),8.14(t,J=7.8Hz,1H),8.04(m,2H),7.93(m,1H),7.62(d,J=8.4Hz,1H),7.51(d,J=7.8Hz,1H),7.44-7.09(m,9H),6.63(s,2H),5.44(s,2H),4.66(t,J=6.6Hz,2H),1.97-1.92(m,2H),1.62-1.57(m,2H);MS(EI)m/e488.2326(C30H28N6O的计算值为488.2325)。
实施例43
N2-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-萘甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和2-萘甲酰氯,得到N2-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-萘甲酰胺白色粉末,熔点为257.0℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.85(宽s,2H),8.69(宽s,1H),8.57(s,1H),8.38(s,1H),8.25(d,J=8.4Hz,1H),7.99- 7.80(m,5H),7.75-7.50(m,4H),4.75(t,J=6.9Hz,2H),3.39(m,2H),1.98(五单元组,J=7.2Hz,2H),1.68(五单元组,J=7.2Hz,2H);MS(EI)m/e 409.1909(C25H23N5O的计算值为409.1903)。
实施例44
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2,6-二甲氧基烟酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和2,6-二甲氧基烟酰氯,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2,6-二甲氧基烟酰胺灰白色粉末,熔点为175.0-177.0℃。1H NMR(300MHz,DMSO-d6)δ8.21(s,1H),8.11-8.02(m,3H),7.62(d,J=8.2Hz,1H),7.42(t,J=7.5Hz,1H),7.20(t,J=7.5Hz,1H),6.58(宽s,2H),6.46(d,J=8.3Hz,1H),4.63(t,J=7.0Hz,2H),3.90(s,3H),3.88(s,3H),3.30(m,2H),1.90(m,2H),1.57(m,2H);MS(EI)m/e420.1909(C22H24N6O3的计算值为420.1910)。
实施例45
N8-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-8-喹啉甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和喹啉-8-碳酰氯,得到N8-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-8-喹啉甲酰胺褐色粉末,熔点为91.0-93.0℃。1H NMR(300MHz,DMSO-d6)δ10.80(t,J=5.5Hz,1H),8.79(dd,J=4.3,1.8Hz,1H),8.55-8.49(m,2H),8.24(s,1H), 8.17(dd,J=8.1,1.5Hz,1H),8.06(d,J=7.2Hz,1H),7.73(t,J=7.8Hz,1H),7.63-7.59(m,2H),7.40(dt J=7.1,1.2Hz,1H),7.14(dt,J=7.1,1.2Hz,1H),6.57(宽s,2H),4.68(t,J=7.0Hz,2H),3.51(m,2H),2.02(m,2H),1.69(m,2H);MS(EI)m/e410.1858(C24H22N6O的计算值为410.1855)。
实施例46
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
2-(4-异丁基苯基)丙酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和4-异丁基-α-甲基苯基乙酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(4-异丁基苯基)丙酰胺白色粉末,熔点为172.0-173.0℃。1HNMR(300MHz,DMSO-d6)δ8.14(s,1H),8.01(d,J=7.6Hz,1H),7.90(t,J=5.6Hz,1H),7.63(dd,J=8.1,1.0Hz,1H),7.44(dt,J=7.0,1.0Hz,1H),7.25(dt,J=7.0Hz,1H),7.14(d,J=8.0Hz,2H),6.97(d,J=8.0Hz,2H),6.58(宽s,2H),4.55(t,J=7.0Hz,2H),3.47(q,J=7.1Hz,1H),3.06(m,2H),2.34(d,J=7.1Hz,2H),1.80-1.69(m,3H),1.44(m,2H),1.24(d,J=7.0Hz,3H),0.82(d,J=6.6Hz,6H);MS(EI)m/e443.2687(C27H33N5O的计算值为443.2685)。
实施例47
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]烟酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4- 胺和盐酸烟酰氯,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]烟酰胺白色粉末,熔点为188.6-189.5℃。1H NMR(300MHz,DMSO-d6)δ8.95(dd,J=2.2,0.7Hz,1H),8.70-8.65(m,2H),8.22(s,1H),8.11(dt,J=8.3,2.0Hz,1H),8.04(dd,J=8.2,0.9Hz,1H),7.61(dd,J=8.3,1.1Hz,1H),7.50-7.39(m,2H),7.23-7.18(m,1H),6.58(宽s,2H),4.64(t,J=7.0Hz,2H),3.30(m,2H),1.93(m,2H),1.60(m,2H);MS(EI)m/e 360.1696(C20H20N6O的计算值为360.1699)。
实施例48
N4-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]异烟酰胺
根据实施例14的通用方法,1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和盐酸异烟酰氯,得到N4-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]异烟酰胺白色结晶固体,熔点为213.0-213.7℃。1H NMR(300MHz,DMSO-d6)δ8.76(m,1H),8.69(d,J=5.6Hz,2H),8.22(s,1H),8.04(d,J=8.0Hz,1H),7.67(d,J=5.7Hz,2H),7.62(d,J=8.2Hz,1H),7.43(t,J=7.5Hz,1H),7.21(t,J=7.5Hz,1H),6.62(宽s,2H),4.64(t,J=6.8Hz,2H),3.30(m,2H),1.92(m,2H),1.58(m,2H);MS(EI)m/e360.1699(C20H20N6O的计算值为360.1699)。
实施例49
N4-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-喹啉甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4- 胺和喹啉-4-碳酰氯,得到N4-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-喹啉甲酰胺白色结晶固体,熔点为214.5-215.2℃。1H NMR(300MHz,DMSO-d6)δ8.89(d,J=4.3Hz,1H),8.76(t,J=5.6Hz,1H),8.24(s,1H),8.10-8.01(m,3H),7.78(ddd,J=8.4,6.9,1.5Hz,1H),7.64(dd,J=8.4,1.1Hz,1H),7.56(ddd,J=8.3,6.9,1.4Hz,1H),7.44(ddd,J=8.3,7.0,1.3Hz,1H),7.34(d,J=4.3Hz,1H),7.24(ddd,J=8.3,7.0,1.3Hz,1H),6.60(宽s,2H),4.68(t,J=6.9Hz,2H),3.38(q,J=7.0Hz,2H),2.00(m,2H),1.63(m,2H);MS(EI)m/e 410.1860(C24H22N6O的计算值为410.1855)。
实施例50
N4-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
2-苯基-4-喹啉甲酰胺
将盐酸1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺(0.57克,3.0毫摩尔)滴加入冷(0℃)的含2-苯基-4-喹啉甲酸(0.5克,3.7毫摩尔)、1-羟基苯并三唑(0.5克,3.7毫摩尔),吡啶(2.2毫升)和二氯甲烷(20毫升)的溶液中。维持反应物15分钟,然后滴加入含1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.8克,2.55毫摩尔)的二氯甲烷(100毫升)。在室温下维持反应物过夜。真空除去溶剂,残余物用快速柱色谱纯化(硅胶,9∶1二氯甲烷\甲醇)。合并含有产物的组分,用饱和的碳酸氢钠水溶液洗涤,干燥(MgSO4),过滤并浓缩,得到0.62克N4-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯基-4-喹啉甲酰胺黄色结晶固体,熔点为118℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.88(t,J=5.7Hz,1H),8.24-8.21(m,2H),8.13-8.01(m,4H),7.83-7.78(m,1H),7.62-7.48(m,5H),7.36(m,1H),7.20(dt,J=7.6,1.2Hz,1H),6.54(宽s,2H),4.62(t,J=7.2Hz,2H),3.83(t,J=6.7Hz,2H),3.45(m,2H),3.29-3.20(m,5H), 1.96(m,2H),1.79(m,2H);MS(EI)m/e 544.2589(C33H32N6O2的计算值为544.2587)。
实施例51
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(戊基硫烷基)烟酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和2-(n-戊硫基)吡啶-3-碳酰氯,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(戊基硫烷基)烟酰胺褐色粉末,熔点为158.0-161.0℃。1H NMR(300MHz,DMSO-d6)δ8.47-8.41(m,2H),8.21(s,1H),8.06(d,J=8.2Hz,1H),7.63(dd,J=8.3,1.1Hz,1H),7.54(dd,J=7.6,1.8Hz,1H),7.47-7.41(m,1H),7.26-7.21(m,1H),7.08(dd,J=7.5,4.8Hz,1H),6.57(宽s,2H),4.64(t,J=6.9Hz,2H),3.27(m,2H),2.98(t,J=7.3Hz,2H),1.96(m,2H),1.62-1.46(m,4H),1.35-1.20(m,4H),0.83(t,J=7.1Hz,3H);MS(EI)m/e 462.2196(C25H30N6OS的计算值为462.2202)。
实施例52
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-氰基烟酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和6-氰基吡啶-3-碳酰氯,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-氰基烟酰胺灰白色粉末,熔点为125.0-129.0℃。1H NMR(300MHz,DMSO-d6)δ9.05(dd,J=2.1,0.8Hz,1H),8.88(t,J=5.6Hz,1H),8.31(dd,J=8.1,2.1 Hz,1H),8.21(s,1H),8.14(dd,J=8.1,0.8Hz,1H),8.03(m,1H),7.62(dd,J=8.3,1.1Hz,1H),7.42(m,1H),7.20(m,1H),6.59(宽s,2H),4.64(t,J=6.9Hz,2H),3.30(m,2H),1.93(m,2H),1.59(m,2H);MS(EI)m/e 385.1648(C21H19N7O的计算值为385.1651)。
实施例53
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-氯烟酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和6-氯吡啶-3-碳酰氯,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-氯烟酰胺灰白色结晶固体,熔点为144.0-148.0℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.77(dd,J=2.5,0.6Hz,1H),8.73(t,J=5.6Hz,1H),8.22(s,1H),8.16(dd,J=8.3,2.5Hz,1H),8.03(m,1H),7.63(d,J=0.5Hz,1H),7.60(d,J=0.5Hz,1H),7.45-7.40(m,1H),7.23-7.18(m,1H),6.61(宽s,2H),4.63(t,J=6.9Hz,2H),3.30(m,2H),1.92(m,2H),1.58(m,2H).MS(EI)m/e 394.1298(C20H19N6OCl的计算值为394.1309)。
实施例54
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
6-(2,2,2-三氟乙氧基)烟酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和6-(2,2,2-三氟乙氧基)吡啶-3-碳酰氯,得到N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-(2,2,2-三氟乙氧基)烟酰胺白色结晶固体,熔点为192.0-194.0℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.62(d,J=1.9Hz,1H),8.58(t,J=5.6Hz,1H),8.25(s,1H),8.15(dd,J=8.6,2.4Hz,1H),8.06(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.45(t,J=7.1Hz,1H),7.24(t,J=7.1Hz,1H),7.04(d,J=8.6Hz,1H),6.82(宽s,2H),5.06(q,J=9.1Hz,2H),4.64(t,J=6.9Hz,2H),3.30(m,2H),1.91(m,2H),1.60(m,2H);MS(EI)m/e 458.1678(C22H21N6O2F3的计算值为458.1678)。
实施例55
N2-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
2-喹啉甲酰胺
根据实施例14的通用方法,将1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和喹啉-2-碳酰氯合并在二氯甲烷和三乙胺(3当量)中,得到N2-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-2-喹啉甲酰胺白色固体,熔点为78.1-79.9℃。1H NMR(300MHz,DMSO-d6)δ9.02(t,J=6.1Hz,1H),8.55(d,J=8.5Hz,1H),8.23(d,J=8.5Hz,1H),8.10(t,J=7.6Hz,1H),8.02(d,J=7.6Hz,1H),7.90-7.84(m,1H),7.75-7.70(m,1H),7.58(dd,J=8.3,1.0Hz,1H),7.35-7.30(m,1H),7.18-7.13(m,2H),6.48(宽s,2H),4.58(m,2H),3.79(t,J=6.7Hz,2H),3.44(m,2H),3.22(m,5H),1.91-1.78(m,4H);MS(EI)m/e468.2276(C27H28N6O2的计算值为468.2274)。
实施例56
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
2-(2-氟-4-联苯基)丙酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和2-(2-氟-4-联苯基)丙酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(2-氟-4-联苯基)丙酰胺白色粉末,熔点为76.1-79.9℃。1H NMR(300MHz,DMSO-d6)δ8.17(s,1H),8.03(m,2H),7.62(d,J=8.3Hz,1H),7.49-7.14(m,10H),6.59(宽s,2H),4.58(t,J=6.9Hz,2H),3.59(q,J=7.0Hz,1H),3.09(五单元组,J=6.7Hz,2H),1.82(m,2H),1.45(m,2H),1.30(d,J=7.0Hz,3H);MS(EI)m/e 481.2268(C29H28FN5O的计算值为481.2278)。
实施例57
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
1-异喹啉甲酰胺
根据实施例50的通用方法,合并1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和异喹啉-1-甲酸,得到N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-1-异喹啉甲酰胺黄色结晶固体,熔点为61.0-63.0℃。1H NMR(300MHz,DMSO-d6)δ8.94(t,J=5.9Hz,1H),8.87(d,J=8.5Hz,1H),8.51(d,J=5.6Hz,1H),8.05-7.96(m,3H),7.84-7.96(m,1H),7.70-7.65(m,1H),7.61(dd,J=8.3,1.1Hz,1H),7.37(dt,J=7.7,1.0Hz,1H),7.19(dt,J=7.6,1.2Hz,1H), 6.53(宽s,2H),4.60(t,J=7.2Hz,2H),3.81(t,J=6.7Hz,2H),3.41(m,2H),3.28-3.12(m,5H),1.92-1.76(m,4H);MS(EI)m/e 468.2261(C27H28N6O2的计算值为468.2274)。
实施例58
N2-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
5-丁基-2-吡啶甲酰胺
根据实施例50的通用方法,合并1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和镰孢菌酸,得到N2-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-5-丁基-2-吡啶甲酰胺褐色固体,熔点为54.9-55.2℃。1H NMR(300MHz,DMSO-d6)δ8.81(t,J=6.1Hz,1H),8.44(m,1H),7.98(d,J=7.3Hz,1H),7.94(dd,J=8.0,0.7Hz,1H),7.80(dd,J=8.0,2.2Hz,1H),7.60(dd,J=8.3,1.2Hz,1H),7.39-7.34(m,1H),7.16-7.10(m,1H),6.52(宽s,2H),4.55(t,J=6.9Hz,2H),3.79(t,J=6.7Hz,2H),3.23(s,3H),3.18(t,J=6.7Hz,2H),2.67(t,J=7.6Hz,2H),1.83-1.72(m,4H),1.63-1.53(m,2H),1.34-1.24(m,2H),0.90(t,J=7.3Hz,3H);MS(EI)m/e 474.2750(C27H34N6O2的计算值为474.2743)。
实施例59
N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
3-吲哚甲酰胺
根据实施例50的通用方法,合并1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和吲哚-3-甲酸,得到N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-3-吲哚甲酰胺白色粉末,熔点为225.5-227.4℃。 1H NMR(300MHz,DMSO-d6)δ11.50(宽s,1H),8.13(d,J=7.9Hz,1H),8.06(d,J=10.2Hz,1H),7.95-7.89(m,2H),7.61(d,J=8.3Hz,1H),7.43-7.35(m,2H),7.20-7.05(m,3H),6.48(宽s,2H),4.58(t,J=7.2Hz,2H),3.80(t,J=6.6Hz,2H),3.33(m,2H),3.24-3.18(m,5H),1.88(m,2H),1.70(m,2H);13C NMR(75MHz,DMSO-d6)δ165.0,152.0,151.0,145.1,136.4,132.6,127.8,126.8,126.6,126.4,122.1,121.5,121.4,120.6,120.3,115.1,112.1,111.0,70.5,58.4,45.1,38.2,27.7,27.5,27.0;MS(EI)m/e 456.2282(C26H28N6O2的计算值为456.2274)。
实施例60
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
4-(1-吡咯基)苯甲酰胺
根据实施例50的通用方法,合并1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和4-(1-吡咯基)苯甲酸,得到N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-4-(1-吡咯基)苯甲酰胺灰白色粉末,熔点 为173.0-174.9℃。1H NMR(300MHz,DMSO-d6)δ8.52(t,J=5.5Hz,1H),8.02(d,J=7.9Hz,1H),7.90(d,J=8.7Hz,2H),7.67(d,J=8.7Hz,2H),7.61(dd,J=8.4,1.1Hz,1H),7.48(t,J=2.2Hz,2H),7.39(m,1H),7.19(dt,J=7.6,1.1Hz,1H),6.53(宽s,2H),6.30(t,J=2.2Hz,2H),4.57(t,J=7.0Hz,2H),3.82(t,J=6.7Hz,2H),3.33(m,2H),3.26(s,3H),3.20(t,J=6.7Hz,2H),1.87(m,2H),1.71(m,2H);MS(EI)m/e482.2421(C28H30N6O2的计算值为482.2430)。
实施例61
N2-{4-[4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
2-喹啉甲酰胺
将喹啉-2-碳酰氯(0.28克,在10毫升二氯甲烷中,1.46毫摩尔)滴加入含1-(4-氨基丁基)-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.49克,1.3毫摩尔),二氯甲烷(140毫升)和三乙胺(0.5毫升)的搅拌溶液中。维持反应17小时,然后真空浓缩。使黄色残余物在二氯甲烷和饱和的碳酸氢钠水溶液之间分配。干燥(MgSO4)有机组分,过滤并浓缩。粗制的残余物用快速柱色谱纯化(硅胶,用二氯甲烷到95∶5二氯甲烷\甲醇的梯度洗脱),得到0.19克N2-{4-[4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-2-喹啉甲酰胺灰白色固体,熔点为95.1-97.4℃。1H NMR(300MHz,DMSO-d6)δ8.97(t,J=6.0Hz,1H),8.56(d,J=8.4Hz,1H),8.16-8.07(m,3H),7.96(d,J=7.7Hz,1H),7.87(m,1H),7.72(m,1H),7.58(dd,J=8.3,1.1Hz,1H),7.31(m,1H),7.23(d,J=8.7Hz,2H),7.08(m,1H),6.82(d,J=8.7Hz,2H),6.58(宽s,2H),4.50(m,2H),4.33(s,2H),3.63(s,3H),3.34(m,2H),1.65(m,4H);MS(EI)m/e 530.2431(C32H30N6O2的计算值为530.2430)。
实施例62
N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
6-(1-吡咯基)烟酰胺
根据实施例50的通用方法,合并1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和2-吡咯并吡啶-5-甲酸,得到N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-6-(1-吡咯基)烟酰胺黄色结晶固体,熔点为77.0-80.0℃。1H NMR(300MHz,CDCl3)δ8.72(d,J=2.3Hz,1H),8.07(dd,J=8.4,2.4Hz,1H),7.92(d,J=7.3Hz,1H),7.82(d,J=7.4Hz,1H),7.55(t,J=2.2Hz,2H),7.49(m,1H),7.37(m,2H),6.39(d,J=2.2Hz,2H),6.20(m,1H),5.42(宽s,2H),4.59(t,J=7.5Hz,2H),3.90(t,J=7.4Hz,2H),3.56(q,J=6.7Hz,2H),3.36(s,3H),3.20(t,J=6.4Hz,2H),2.05(m,2H),1.82(m,2H);MS(EI)m/e483.2376(C27H29N7O2的计算值为483.2383)。
实施例63
N5-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
5-吲哚甲酰胺
根据实施例50的通用方法,合并1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和吲哚-5-甲酸,得到N5-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-5-吲哚甲酰胺灰白色固体。1H NMR(300MHz, DMSO-d6)δ11.31(s,1H),8.34(t,J=5.5Hz,1H),8.06(m,2H),7.63-7.58(m,2H),7.42-7.38(m,3H),7.22(t,J=7.1Hz,1H),6.67(宽s,2H),6.50(s,1H),4.58(m,2H),3.81(t,J=6.6Hz,2H),3.34(m,2H),3.25(s,3H),3.21(t,J=6.6Hz,2H),1.89(m,2H),1.72(m,2H);MS(EI)m/e 456.2264(C26H28N6O2的计算值为456.2274)。
实施例64
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-苯氧基苯甲酰胺
根据实施例14的通用方法,合并1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺和4-苯氧基苯甲酰氯,得到N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-苯氧基苯甲酰胺白色粉末,熔点为90.5-91.5℃.1H NMR(500MHz,DMSO-d6)δ8.42(t,J=5.7Hz,1H),8.21(s,1H),8.03(d,J=7.9Hz,1H),7.81(d,J=8.9Hz,2H),7.62(d,J=7.9Hz,1H),7.45-7.40(m,3H),7.21(m,2H),7.07(d,J=7.6Hz,2H),6.99(d,J=8.9Hz,2H),6.61(宽s,2H),4.63(t,J=7.0Hz,2H),3.25(m,2H),1.92(m,2H),1.58(m,2H);MS(EI)m/e 451.2008(C27H25N5O2的计算值为451.2008)。
实施例65
N5-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-
5-(2-苯基-1-乙炔基)烟酰胺
根据实施例50的通用方法,合并1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺和5-(苯基乙炔基)吡啶-3-甲酸,得到N5-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-5-(2-苯基-1-乙炔基)烟酰胺黄色固体,熔点为76.0-78.0℃.1H NMR(300MHz,DMSO-d6)δ8.95(d,J=2.1Hz,1H),8.87(d,J=2.0Hz,1H),8.79(t,J=2.1Hz,1H),8.31(d,J=2.0Hz,1H),8.02(d,J=8.1Hz,1H),7.61(m,3H),7.48(m,3H),7.40(m,1H),7.19(m,1H),6.56(宽s,2H),4.57(t,J=7.4Hz,2H),3.82(t,J=6.7Hz,2H),3.37(m,2H),3.27(s,3H),3.21(t,J=6.7Hz,2H),1.89(m,2H),1.72(m,2H);MS(CI)m/e 519(M+H)。
实施例66
N3-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]烟酰胺
部分A
在室温下,将含苯甲酰氯(5.3克,37.7毫摩尔)的二氯甲烷(100毫升)溶液缓慢加入含N-{4-[(3-氨基喹啉-4-基)氨基]丁基}氨基甲酸叔丁酯(12.5克,37.7毫摩尔)的二氯甲烷(250毫升)溶液中。反应混合物在室温下维持过夜。过滤分离所得沉淀,干燥得到11.0克盐酸N-(4-{[3-(苯甲酰基氨基)喹啉-4-基]氨基}丁基)氨基甲酸叔丁酯白色固体。
部分B
将三乙胺(7.26克,71.7毫摩尔)加入含部分A物质的乙醇(200毫升)溶液中,加热回流2天。将反应混合物浓缩,得到橙色浆状物。HPLC质谱分析显示,该浆状物含有所需的产物和原料。将浆状物加入二氯甲烷(100毫升)中,然后在冰浴中冷却。加入三乙胺(5毫升)和苯甲酰氯(1.9毫升)。反应混合物在室温下维持2天,此时HPLC分析表明反应没有完全。真空浓缩反应混合物。将残余物加入异丙醇(150毫升)中。加入三乙胺(5毫升),使反应混合物加热回流过夜。真空浓缩反应混合物。残余物用快速色谱纯化(硅胶;用含10%甲醇的二氯甲烷洗脱)。合并含产物的组分,真空浓缩。残余物从乙腈中重结晶, 得到6.7克N-[4-(2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]氨基甲酸叔丁酯固体,熔点为158-159℃。
部分C
将3-氯过苯甲酸(1.05当量,65%)分小批量缓慢加入含N-[4-(2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]氨基甲酸叔丁酯(6.56克,15.75毫摩尔)的二氯甲烷(120毫升)溶液中。3小时后,用1%碳酸氢钠水溶液(200毫升)淬灭反应。分层。水层二氯甲烷(2X 50毫升)萃取。合并有机组分,用硫酸镁干燥,然后真空浓缩得到浅橙色浆状物。用乙醚研制浆状物,得到6.8克1-[4-(叔丁基氨基甲酰基)丁基]-2-苯基-1H-咪唑并[4,5-c]喹啉-5N-氧化物浅褐色固体,熔点为178-181℃。
部分D
在冰浴中冷却含1-[4-(叔丁基氨基甲酰基)丁基]-2-苯基-1H-咪唑并[4,5-c]喹啉-5N-氧化物(6.8克,15.75毫摩尔)的二氯甲烷(100毫升)溶液。加入浓的氢氧化铵(30毫升)。在30分钟内分小批量加入甲苯磺酰氯(3.0克,15.75毫摩尔)。将反应混合物温至室温过夜。反应物用水(350毫升)淬灭。分层。水层用二氯甲烷萃取。合并有机组分,用硫酸镁干燥,然后真空浓缩得到褐色固体。该物质用快速色谱纯化(硅胶,用含10%甲醇的二氯甲烷洗脱),得到4.8克产物。大块物质用于下一步。少部分从甲苯重结晶,得到N-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]氨基甲酸叔丁酯固体,熔点为182-183℃。
C25H29N5O2的分析计算值:%C,69.58;%H,6.77;%N,16.22;实测值:%C,69.86;%H,6.95;%N,15.80。
部分E
将部分D的物质溶于甲醇(15毫升)和1N盐酸(100毫升)中,然后加热回流2小时。真空浓缩反应混合物至体积约为50毫升。加入浓氢氧化铵至pH12,结果不产生沉淀。用1N盐酸调节pH至7。混合物用二氯甲烷萃取,然后用乙酸乙酯萃取。将水层浓缩至干。将残余物溶解在水(50毫升)中,然后用回流的氯仿连续萃取36小时。真空浓缩氯仿萃取物,得到浅褐色固体。该物质从乙腈中重结晶,得到2.5克1-(4-氨基丁基)-2-苯基-1H-咪唑并[4,5-c]喹啉-4-胺灰白色固体,熔点为175-177℃。C20H21N5的分析计算值:%C,72.48;%H,6.39;%N,21.13;实测值:%C,72.72;%H,6.32;%N,20.71。
部分F
根据实施例61的通用方法,合并1-(4-氨基丁基)-2-苯基-1H-咪唑并[4,5-c]喹啉-4-胺和盐酸烟酰氯,得到N3-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]烟酰胺白色结晶固体,熔点为84.5-86.1℃.1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.69(m,1H),8.56(m,1H),8.07(m,2H),7.75-7.41(m,8H),7.21(m,1H),6.72(宽s,2H),4.60(m,2H),3.15(t,J=6.0Hz,2H),1.86(m,2H),1.40(m,2H);MS(CI)m/e 437(M+H)。
实施例67
N2-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-
2-喹啉甲酰胺
根据实施例61的通用方法,合并1-(4-氨基丁基)-2-苯基-1H-咪唑并[4,5-c]喹啉-4-胺和喹啉-2-碳酰氯,得到N2-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-喹啉甲酰胺灰白色结晶固体,熔点为81.1-83.9℃.1H NMR(300MHz,DMSO-d6)δ8.90(t,J=6.0Hz,1H),8.55(d,J=8.5Hz,1H),8.12-8.07(m,4H),7.90-7.84(m,1H),7.75-7.54(m,7H),7.36(t,J=7.5Hz,1H),7.18(t,J=7.5Hz,1H), 6.70(宽s,2H),4.61(m,2H),3.23(m,2H),1.88(m,2H),1.49(m,2H);MS(CI)m/e487(M+H)。
实施例68-102
用上述反应方案II中描述的合成方法制备下表中显示的化合物。
将有螺旋帽的试管中含1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(36微摩尔)的10毫升二氯甲烷溶液冷却至-5℃。加入二氯甲烷中0.3M溶液形式的酰基氯(45微摩尔)。在加入期间将氩气鼓入混合物并再过15秒,然后使混合物在-5℃下静置过夜。在该混合物中加入大约90毫克氨基甲基聚苯乙烯树脂(0.62meq/g,100-200目),将该混合物温至回流,在600rpm下振荡3小时。纯化化合物,用10∶1二氯甲烷-甲醇将其洗脱通过短的硅胶垫,收集约1毫升组分,合并产物组分(组分在9∶1二氯甲烷-甲醇中用tlc(薄层色谱)来分析以鉴定产物)。化合物用500MHz 1H nmr和APCI-MS(插入注射或LC/MS程序)分析。
实施例103-107
根据下述合成方法制备下表所示化合物。
将10毫克(25微摩尔)部分的N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-(氯甲基)苯甲酰胺(实施例7)溶于有螺旋帽的管中的1毫升N,N-二甲基甲酰胺中,加入合适的胺(2当量)以及大约70毫克(270微摩尔)N,N-(二异丙基)氨基甲基聚苯乙烯珠粒(PS-DIEA,3.86meq/g,Argonaut)。将该混合物加热至50℃,500rpm下振荡过夜。另外加入1-2当量的胺,然后继续加热和振荡第二夜。将过滤的反应混合物注射到半制备性HPLC系统上(Shimadzu LC-6A泵,RaininMicrosorb C18柱,21.4x250毫米,8微米粒径,60A孔,9.9毫升/分钟,梯度洗脱,在25分钟内从2-95%B,在95%B下放置5分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,检测254nm峰,收集5毫升组分),分离产物。用反相HPLC分析半制备性HPLC组分,对合适的组分进行真空干燥,得到三氟乙酸盐形式的化合物。将该化合物溶于大约3-5毫升的2∶1二氯甲烷-甲醇中,和大约80毫克(300微摩尔)二异丙基氨基甲基-聚苯乙烯树脂(Argonaut PS-二EA,3.86毫摩尔/g)一起振摇1-2小时,以释放游离的胺,然后过滤并真空干燥,得到无定形固体状化合物。每个胺产物用LC/APCI-MS进行分析。
实施例108
N1-(4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基)-2-(2-噻吩基)乙酰胺
根据实施例68-102的方法制备本化合物。(DMSO-d6)δ8.28(s,1H),8.09(m,2H),7.70(d,J=7.9Hz,1H),7.54(t,J=7.9Hz,1H),7.36(t,J=7.3Hz,1H),7.28(dd,J=0.9Hz,J=5.2Hz,1H),6.88(dd,J=3.4Hz,J=5.2Hz,1H),6.82(d,J=3.1Hz,1H),4.63(t,J=7Hz,2H),3.56(s,2H),3.10(q,J=6.5Hz,2H),1.85(五单元组,J=7.5Hz,2H),1.46(五单元组,J=7.5Hz,2H)MS(APCI)m/e 380.22(M+H)。
实施例109-119
用反应方案III中描述的合成方法制备下表中的实施例。
将1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(10毫克,0.04毫摩尔)悬浮在螺纹试管中10毫升二氯甲烷中。加入酸(0.05毫摩尔),简单地振荡混合物。在该混合物中加入盐酸1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺(EDC,10毫克,0.05毫摩尔),使混合物在室温下振摇过夜。在该管中加入大约90毫克氨基甲基聚苯乙烯树脂(Bachem,~1meq/g,100-200目),将该混合物加热至回流并振摇过夜。然后过滤该混合物除去 树脂,用半制备性反相HPLC纯化(Rainin Microsorb C18柱,21.4x250毫米,8微米粒径,60A孔,10毫升/分钟,梯度洗脱,在25分钟内从2-95%B,在95%B下放置5分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,检测254nm峰以开始组分收集)。用LC-APCI/MS分析半制备性HPLC组分,合并合适的组分,冻干得到所需酰胺的三氟乙酸盐。用LC-MS(APCI)分析化合物。
实施例120-146
用上述反应方案V中描述的合成方法制备下表中的实施例。
部分A
将1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(25毫克,0.1毫摩尔)悬浮于螺纹试管中5毫升二氯甲烷中,加入醛(大约0.1毫摩尔)。将该混合物加热至回流,在500rpm下振荡半小时。使该混合物冷却数分钟,然后加入三乙酰氧基氢硼化钠(38毫克,0.18毫摩尔)。在室温下振摇该混合物3天,然后用0.5毫升甲醇淬灭并蒸干。混合物用半制备性反相HPLC纯化(Rainin Microsorb C18柱,21.4x250毫米,8微米粒径,60A孔,10毫升/分钟,梯度洗脱,在25分钟内从2-95%B,在95%B下放置5分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,检测254nm峰以便开始收集组分)。用LC-APCI/MS分析半制备性HPLC组分,合并合适的组分并冻干,得到所需仲胺的三氟乙酸盐。用LC-MS(APCI)分析化合物。
部分B
将部分A的仲胺(大约3-30微摩尔,二-三氟乙酸盐形式)各溶解在1毫升吡啶中加入大约10当量的0.1M乙酸酐在二氯甲烷中的溶液。使该混合物静置1小时,然后加入200微升甲醇。在真空离心机中将该混合物蒸干。然后如部分A所述,用半制备性反相HPLC纯化该混合物。用LC-MS(APCI)分析化合物。
实施例147-159
用上述反应方案II的合成方法制备下表所示的化合物。
将1-(4-氨基丁基)-2-甲氧基乙基-1H-咪唑并[4,5-c]喹啉-4-胺(50毫克)置于2打兰(7.4毫升)管中。加入二异丙基乙胺(1.2当量)和二氯甲烷(1毫升)。加入含羧 酰氯(1.1当量)的二氯甲烷(1毫升)溶液。在室温下将该管置于振摇仪上大约2小时。用LC/MS分析反应混合物,以确认形成了所需的产物。除去溶剂,残余物用半制备性HPLC纯化(Capcell PakC18柱,35x20毫米,5微米粒径,20毫升/分钟,梯度洗脱,在10分钟内从5-95%B,在95%B下放置2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,检测254nm峰以便开始收集组分)。用LC-APCI/MS分析半制备性HPLC组分,合并合适的组分并冻干,得到所需酰胺的三氟乙酸盐。
实施例160-168
用上述反应方案III的合成方法制备下表中的化合物。
将1-(4-氨基丁基)-2-甲氧基乙基-1H-咪唑并[4,5-c]喹啉-4-胺(50毫克),羧酸(1.0当量)和二氯甲烷(3毫升)置于2打兰(7.4毫升)管中。加入含有盐酸1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺(1.1当量)的二氯甲烷(1毫升)溶液。将该管置于振摇仪上在室温下放置大约2小时。用LC/MS分析反应混合物,以确认形成了所需的产物。除去溶剂,残余物用半制备性HPLC纯化(Capcell Pak C18柱,35x20毫米,5微米粒径,20毫升/分钟,梯度洗脱,在10分钟内从5-95%B,在95%B下维持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,检测254nm峰以便开始收集组分)。用LC-APCI/MS分析半制备性HPLC组分,合并合适的组分并冻干,得到所需酰胺的三氟乙酸盐。
实施例169
N1-[4-(4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]乙酰胺三氟乙酸盐
利用上述实施例147-159的方法,使1-(4-氨基丁基)-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-4-胺与乙酰基氯反应,得到N1-[4-(4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]乙酰胺三氟乙酸盐。APCI-MS m/e 418.2。
实施例170和171
用实施例160-168的方法使1-(4-氨基丁基)-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-4-胺与合适的羧酸反应,制得下表中的实施例。
实施例172-174
根据上述反应方案VI中描述的合成方法制得下表中的实施例。
部分A
将催化量的氧化铂(IV)加入含1-(4-氨基丁基)-2-甲氧基乙基-1H-咪唑并[4,5-c]喹啉-4-胺(7.7克,24.5毫摩尔)的三氟乙酸(250毫升)溶液中。使反应混合物在帕尔装置中在50psi(3.44X105帕)下氢化。用LC/MS监测反应的进展。反应开始后7、11、17天加入额外量的催化剂。25天后反应完全。使反应混合物过滤通过Celite 过滤层助剂,以除去催化剂,真空浓缩该滤液。使残余物与1N盐酸(100毫升)合并,搅拌过夜。用氢氧化铵使该混合物成碱性(pH=11),然后用二氯甲烷萃取(3X300毫升)。合并萃取物,真空浓缩,得到3.5克1-(4-氨基丁基)-6,7,8,9-四氢-2-甲氧基乙基-1H-咪唑并[4,5-c]喹啉-4-胺固体。
部分B
用上述实施例DC 147-159的方法。使部分A的物质与合适的酰氯反应,得到所需的酰胺。
实施例175-180
用实施例160-168的通用方法,根据上述反应方案III的合成方法制得下表中的实施例。
人细胞中的细胞因子诱导
用体外人血细胞系统来评价本发明化合物的细胞因子诱导作用。如Testerman等人在“免疫调节剂Imiquimod和S-27609的细胞因子诱导作用”,Journal of LeukocyteBiology,58,365-372(1995年9月)所述,根据分泌到培养基中的干扰素和肿瘤坏死因子(α)来测定活性。
制备血细胞用于培养
通过静脉穿刺到EDTA真空管(vacutainer tube)收集健康供血者的全血。用Histopaque -1077(Sigma Chemicals,St.Louis,MO)进行密度梯度离心,从全血中分离出外周血单核细胞(PBMC)。将PBMC以3-4×106细胞/毫升的密度悬浮于含有10%胎牛血清、2mM L-谷氨酰胺和1%青霉素/链霉素溶液的RPMI 1640培养基(RPMI完全)中。将PBMC悬浮液加入48孔平底无菌组织培养板(Costar,Cambridge,MA或Becton Dickinson Labware,Lincoln Park,NJ)中,培养板中含有等体积的含测试化合物的RPMI完全培养基。
化合物制备
将化合物溶解在二甲基亚砜(DMSO)中。加入培养孔中的DMSO浓度不应超过1%的最终浓度。
培育
将以60μM的浓度将测试化合物溶液加入含有RPMI完全培养基的第一个孔内,并作系列稀释(3倍或10倍)。然后将PBMC悬浮液以相同的体积加入孔内,使测试化合物的浓度达到所需范围内。PBMC悬浮液的最终浓度为1.5-2×106细胞/毫升。用无菌塑料盖盖住该平板,轻微混合,然后在5%二氧化碳气氛中37℃下培育18-24小时。
分离
培育后,使平板在4℃下1000rpm(约200xg)离心5-10分钟。用无菌聚丙烯移液管取出细胞培养上清,转移到无菌聚丙烯管中。将样品置于-30℃至-70℃,直至分析。用ELISA或生物测定分析样品中的干扰素(α),用ELISA分析肿瘤坏死因子(α)。
干扰素生物测定分析
用经脑心肌炎攻击的A549人肺癌细胞进行生物试验,测定干扰素。生物测定方法的详细情况在G.L.Brennan和L.H.Kronenberg的″微量测定板中干扰素的自动化生物测定″,Biotechniques,6月/7月,78,1983中有所描述,该文纳入本文作为参考。简言之,方法如下:使A549细胞与样品或标准干扰素的稀释液在37℃下培育24小时。然后用脑心肌炎病毒接种物感染所培育的细胞。感染的细胞于37℃再培育24小时,然后评价病毒的细胞致病效应。病毒的细胞致病效应通过用结晶紫染色然后对平板作显色评分来定量测定。结果表示成根据NIH人白细胞IFN标准品获得的数值的α参考单位/毫升。
用ELISA分析干扰素(α)肿瘤坏死因子(α)
用PBL Biomedical Laboratories,New Brunswick,NJ的Human Multi-Species试剂盒通过ELISA测定干扰素(α)的浓度。
用Genzyme,Cambridge,MA;R&D Systems,Minneapolis,MN;或Pharmingen,SanDiego,CA的ELISA试剂盒测定肿瘤坏死因子(α)(TNF)的浓度。
下表列出了发现诱导出干扰素的各化合物最低浓度和发现诱导出肿瘤坏死因子的各化合物最低浓度。“**”表明在任一测试浓度下(0.12,0.37,1.11,3.33,10和30μM)均没有诱导。“***”表示在任一测试浓度(0.0001,0.001,0.1和10μM)下均没有诱导作用。除非另有所述,干扰素的生物合成用ELISA来测定。
*干扰素用生物测定方法测定
本发明已经参照几个实施方案作了描述。前面的详细描述和实施例只是为了清楚地理解,不应理解其有不必要的限制。本领域技术人员显然能在不脱离本发明精神和范围内对所述实施方案作许多改动。因此,本发明范围不应局限于本文所述组成和结构的确切细节,而是由下文权利要求来限定。
Claims (151)
1.一种药物组合物,它包含治疗有效量的式(I)化合物:
其中
虚线表示的键存在或不存在;
R1是C1-20烷基-NR3-CO-R4,其中R4是苯基、萘基、吡啶基、吲哚基、异吲哚基、喹啉基、异喹啉基、呋喃基、噻吩基、噻唑基、C1-10烷基、C1-10卤烷基或C2-10链烯基;其中
苯基没有取代或被一个或多个选自以下的基团取代:C1-10烷基、C1-10烷氧基、C1-10卤代烷基、卤素、三氟甲氧基、-O-苯基、-CO-苯基、-CN、-NO2、-CO-O-C1-10烷基、吡咯基、杂环基C1-10烷基、杂环基、芳基、或芳基C1-10烷基、(C1-10烷基吡啶基)(C1-10烷基)氨基C1-10烷基、(吡啶基C1-10烷基)氨基C1-10烷基、[(C1-10烷氧基苯基)C1-10烷基]氨基C1-10烷基;其中所述芳基选自苯基、萘基、联苯基、芴基或茚基;所述杂环基选自吡咯烷基、四氢呋喃基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、噻唑烷基或咪唑烷基;
萘基没有被取代或被C1-10烷氧基取代;
吡啶基没有被取代或被一个或多个选自以下的基团取代:C1-10烷基、C1-10烷氧基、C1-10烷硫基、卤素、-CN、C1-10卤烷基-O-、吗啉基、吡咯基、C2-20炔基、或苯基;
呋喃基没有被取代或被-NO2取代;和
噻唑基没有被取代或被C1-10烷基取代;
C1-10烷基没有被取代或被一个或多个选自以下的基团取代:苯基、苯氧基、
C1-10烷基、芳基C1-10烷基、杂芳基C1-10烷基、卤代苯基、卤代联苯基、苯甲酰基苯氧基、-CO-OC1-10烷基、-COC1-10烷基、-CO-噻吩基、杂环基、杂芳基、氧代杂环基、C2-20链烯基、C2-20炔基、-CN、或-PO(OC1-10烷基)2、C1-10烷基苯基、C1-10烷硫基苯基;其中所述芳基选自苯基、萘基、联苯基、芴基或茚基;所述杂芳基选自呋喃基、噻吩基、吡啶基、喹啉基、异喹啉基、吲哚基、异吲哚基、吡咯基、四唑基、咪唑基、吡唑基、唑基、或噻唑基;所述杂环基选自吡咯烷基、四氢呋喃基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、噻唑烷基或咪唑烷基;
C2-10链烯基没有被取代或被苯基、呋喃基、或-CO-O-C1-10烷基取代;或
R2是氢、C1-10烷基、C1-10烷基-O-C1-10烷基;苯基或(C1-10烷氧基苯基)C1-10烷基;
R3是氢、C1-10烷基、C1-10烷基苯基、C1-10烷基萘基、C1-10烷基呋喃基或C1-10烷基吡啶基;其中苯基没有取代或被C1-10烷基、C1-10烷氧基、卤素、羟基、硝基中的一个或多个取代;呋喃基没有取代或被C1-10烷基取代;萘基没有取代或被C1-10烷氧基取代;
n是0;
每个R独立选自:C1-10烷基、C1-10烷氧基、卤素和三氟甲基,
或其药学上可接受的盐,
以及药学上可接受的载体。
2.根据权利要求1所述的组合物,其中R2是氢。
3.根据权利要求1所述的组合物,其中R4是苯基、萘基、吡啶基、吲哚基、异吲哚基、喹啉基、异喹啉基、呋喃基、噻吩基或噻唑基,其中
苯基没有取代或被一个或多个选自以下的基团取代:C1-10烷基、C1-10烷氧基、C1-10卤代烷基、卤素、三氟甲氧基、-O-苯基、-CO-苯基、-CN、-NO2、-CO-O-C1-10烷基、吡咯基、杂环基C1-10烷基、杂环基、芳基、或芳基C1-10烷基、或(C1-10烷基吡啶基)(C1-10烷基)氨基C1-10烷基;
萘基没有被取代或被C1-10烷氧基取代;
吡啶基没有被取代或被一个或多个选自以下的基团取代:C1-10烷基、C1-10烷氧基、C1-10烷硫基、卤素、-CN、C1-10卤烷基-O-、吗啉基、吡咯基、C2-20炔基、或苯基;
呋喃基没有被取代或被-NO2取代;
噻唑基没有被取代或被C1-10烷基取代。
4.根据权利要求1所述的组合物,其中R4是被(吡啶基C1-10烷基)氨基C1-10烷基、[(C1-10烷氧基苯基)C1-10烷基]氨基C1-10烷基、或(C1-10烷基吡啶基)(C1-10烷基)氨基C1-10烷基取代的苯基。
5.根据权利要求4所述的组合物,其中R4是被(C1-10烷基吡啶基)(C1-10烷基)氨基C1-10烷基取代的苯基。
6.根据权利要求1所述的组合物,其中R4是苯基、萘基、吡啶基、吲哚基、异吲哚基、喹啉基、异喹啉基、呋喃基、噻吩基、噻唑基、C1-10烷基、或C2-10链烯基;其中
苯基没有取代或被一个或多个选自以下的基团取代:吡咯基、或吗啉基C1-10烷基;
吡啶基没有被取代或被一个或多个选自以下的基团取代:吗啉基或吡咯基。
7.根据权利要求1所述的组合物,其中虚线表示的键存在。
8.根据权利要求1所述的组合物,其中虚线表示的键不存在。
9.根据权利要求1所述的组合物,其中R3是C1-10烷基苯基、C1-10烷基萘基、C1-10烷基呋喃基或C1-10烷基吡啶基;其中苯基没有取代或被C1-10烷基、C1-10烷氧基、卤素、羟基或硝基中的一个或多个取代;呋喃基没有取代或被C1-10烷基取代;萘基没有取代或被C1-10烷氧基取代。
10.根据权利要求1所述的化合物,其中R3是C1-10烷基、C1-10烷基苯基、C1-10烷基萘基、C1-10烷基呋喃基或C1-10烷基吡啶基;其中苯基没有取代或被C1-10烷基、C1-10烷氧基、卤素、羟基或硝基中的一个或多个取代;呋喃基没有取代或被C1-10烷基取代;萘基没有取代或被C1-10烷氧基取代。
11.根据权利要求1所述的组合物,其中R3是2-甲氧基苄基、2-呋喃基甲基、3-呋喃基甲基、2-硝基苄基或4-吡啶基甲基。
12.根据权利要求11所述的组合物,其中R2是氢,R4是甲基。
13.根据权利要求1所述的组合物,其中R2是氢、C1-4烷基或C1-4烷基-O-C1-4烷基。
14.根据权利要求1所述的组合物,其中R1是-C1-6烷基-NR3-CO-R4,且烷基是直链烷基。
15.根据权利要求1所述的组合物,其中R4是未取代或被C1-10烷氧基取代的萘基。
16.根据权利要求4所述的组合物,其中R2是氢,C1-4烷基或C1-4烷基-O-C1-4烷基。
17.根据权利要求16所述的组合物,其中R2是氢或甲氧基乙基。
18.根据权利要求3所述的组合物,其中R1是-C1-6烷基-NR3-CO-R4,且烷基是直链烷基。
19.根据权利要求3所述的组合物,其中R3是氢。
20.根据权利要求3所述的组合物,其中R4是萘基,喹啉基,异喹啉基或吡啶基,其中
萘基没有被取代或被C1-10烷氧基取代;
吡啶基没有被取代或被一个或多个选自以下的基团取代:C1-10烷基、C1-10烷氧基、C1-10烷硫基、卤素、-CN、吗啉基、或吡咯基。
21.根据权利要求20所述的组合物,其中R3是氢。
22.根据权利要求1所述的组合物,其中R4是C1-10烷基或C2-10链烯基,其中
C1-10烷基没有被取代或被一个或多个选自以下的基团取代:乙炔基、C1-10烷基苯基、C1-10烷硫基苯基、卤代苯基、卤代联苯基、噻吩基、苯甲酰基苯氧基、-CO-噻吩基、-CO-O-C1-10烷基、-COC1-10烷基、-PO(OC1-10烷基)2、-CN;和C2-10链烯基没有被取代或被呋喃基或-CO-O-C1-10烷基取代。
23.根据权利要求22所述的组合物,其中R2是氢、C1-10烷基或C1-4烷基-O-C1-4烷基。
24.根据权利要求22所述的组合物,其中R2是氢或甲氧基乙基。
25.根据权利要求22所述的组合物,其中R3是氢。
26.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺。
27.一种药物组合物,包含:
N1-[4-(4-氨基-2-丙基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺。
28.一种药物组合物,包含:
N1-[4-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺。
29.一种药物组合物,包含:
N1-[4-(4-氨基-2-乙基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺。
30.一种药物组合物,包含:
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]苯甲酰胺。
31.一种药物组合物,包含:
N1-[5-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺。
32.一种药物组合物,包含:
N1-[5-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)戊基]苯甲酰胺。
33.一种药物组合物,包含:
N1-[3-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺。
34.一种药物组合物,包含:
N1-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]苯甲酰胺。
35.一种药物组合物,包含:
N1-[3-(4-氨基-2-甲基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]苯甲酰胺。
36.一种药物组合物,包含:
N1-[6-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)己基]苯甲酰胺。
37.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-苯基丙酰胺。
38.一种药物组合物,包含:
N1-[2-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-3-苯基丙酰胺。
39.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯氧基乙酰胺。
40.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-乙基己酰胺。
41.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯氧基丙酰胺。
42.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-氯苯甲酰胺。
43.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3,4-二氯苯甲酰胺。
44.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2,6-二氯苯甲酰胺。
45.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氟苯甲酰胺。
46.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氯苯甲酰胺。
47.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-甲氧基苯甲酰胺。
48.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-(三氟甲基)苯甲酰胺。
49.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯基乙酰胺。
50.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-(E)-3-苯基-2-丙烯酰胺。
51.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-环戊基丙酰胺。
52.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-环戊烷甲酰胺。
53.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-环己烷甲酰胺。
54.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-2-甲基苯甲酰胺。
55.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-1-环戊烷甲酰胺。
56.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-1-环己烷甲酰胺。
57.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基]丁基}苯甲酰胺。
58.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-2-苯基乙酰胺。
59.一种药物组合物,包含:
N1-[4-(4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]乙酰胺。
60.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-(反式)-2-苯基环丙烷-1-甲酰胺。
61.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-(反式)-2-苯基环丙烷-1-甲酰胺。
62.一种药物组合物,包含:
N6-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-喹啉甲酰胺。
63.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-喹啉甲酰胺。
64.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2,6-二甲氧基烟酰胺。
65.一种药物组合物,包含:
N8-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-8-喹啉甲酰胺。
66.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]烟酰胺。
67.一种药物组合物,包含:
N4-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]异烟酰胺。
68.一种药物组合物,包含:
N4-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-喹啉甲酰胺。
69.一种药物组合物,包含:
N4-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-苯基-4-喹啉甲酰胺。
70.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(戊基硫烷基)烟酰胺。
71.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-氰基烟酰胺。
72.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-氯烟酰胺。
73.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-(2,2,2-三氟乙氧基)烟酰胺。
74.一种药物组合物,包含:
N2-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-2-喹啉甲酰胺。
75.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-1-异喹啉甲酰胺。
76.一种药物组合物,包含:
N2-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-5-丁基-2-吡啶甲酰胺。
77.一种药物组合物,包含:
N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-3-吲哚甲酰胺。
78.一种药物组合物,包含:
N2-{4-[4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-2-喹啉甲酰胺。
79.一种药物组合物,包含:
N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-6-(1-吡咯基)烟酰胺。
80.一种药物组合物,包含:
N5-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-5-吲哚甲酰胺。
81.一种药物组合物,包含:
N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-5-(2-苯基-1-乙炔基)烟酰胺。
82.一种药物组合物,包含:
N3-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]烟酰胺。
83.一种药物组合物,包含:
N2-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-喹啉甲酰胺。
84.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-氯烟酰胺。
85.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(2-噻吩基)乙酰胺。
86.一种药物组合物,包含:
N1-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-(3-噻吩基)乙酰胺。
87.一种药物组合物,包含:
N2-{4-[4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-2-吡啶甲酰胺。
88.一种药物组合物,包含:
N3-{4-[4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-烟酰胺。
89.一种药物组合物,包含:
N4-{4-[4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基]丁基}异烟酰胺。
90.一种药物组合物,包含:
N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-3-糠酰胺。
91.一种药物组合物,包含:
N3-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}烟酰胺。
92.一种药物组合物,包含:
N2-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-糠酰胺。
93.一种药物组合物,包含:
N2-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-噻吩甲酰胺。
94.一种药物组合物,包含:
N2-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-硝基-2-糠酰胺。
95.一种药物组合物,包含:
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺。
96.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺。
97.一种药物组合物,包含:
N1-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-(2-亚氨基全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺。
98.一种药物组合物,包含:
N1-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺。
99.一种药物组合物,包含:
N1-[2-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-(2-氧代全氢噻吩并[3,4-d]咪唑-4-基)戊酰胺。
100.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-(吗啉代甲基)苯甲酰胺。
101.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-{[(4-[吡啶基甲基)氨基]甲基}苯甲酰胺。
102.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-{[(2-甲氧基苯乙基)氨基]甲基}苯甲酰胺。
103.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-({甲基[2-(2-吡啶基)乙基]氨基}甲基)苯甲酰胺。
104.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-2-氧代-2-苯基乙酰胺。
105.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-[(2-四氢-1H-1-吡咯基-1H-苯并[d]咪唑-1-基)甲基]苯甲酰胺。
106.一种药物组合物,包含:
N3-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-6-吗啉代烟酰胺。
107.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-乙氧基-1-萘甲酰胺。
108.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氰基苯甲酰胺。
109.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-氰基苯甲酰胺。
110.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-萘甲酰胺。
111.一种药物组合物,包含:
N2-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-萘甲酰胺。
112.一种药物组合物,包含:
N1-{4-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]丁基}-4-(1-吡咯基)苯甲酰胺。
113.一种药物组合物,包含:
N1-{4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基}-1-萘甲酰胺。
114.一种药物组合物,包含:
N2-{4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基}-2-萘甲酰胺。
115.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(4-甲氧基苄基)乙酰胺。
116.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(4-溴苄基)乙酰胺。
117.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(5-溴-2-羟基苄基)-乙酰胺。
118.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(4-丁氧基苄基)乙酰胺。
119.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2-氯苄基)乙酰胺。
120.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2-氯-5-硝基苄基)乙酰胺。
121.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(5-氯-2-硝基苄基)乙酰胺。
122.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-2-[(4-氯苯基)硫烷基]苄基乙酰胺。
123.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(3,5-二氯苄基)乙酰胺。
124.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(3,4-二氟苄基)乙酰胺。
125.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2,5-二甲氧基苄基)乙酰胺。
126.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2,3-二甲氧基苄基)乙酰胺。
127.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2,4-二甲基苄基)乙酰胺。
128.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-[(5-乙基-2-呋喃基)甲基]乙酰胺。
129.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2-呋喃基甲基)乙酰胺。
130.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(3-呋喃基甲基)乙酰胺。
131.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(3-苯基丙基)乙酰胺。
132.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-辛基乙酰胺。
133.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(1-萘基甲基)乙酰胺。
134.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-[(2-甲氧基-1-萘基甲基]乙酰胺。
135.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(4-硝基苄基)乙酰胺。
136.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2-硝基苄基)乙酰胺。
137.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(4-吡啶基甲基)乙酰胺。
138.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2-甲基苄基)乙酰胺。
139.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(2,3,4-三甲氧基苄基)乙酰胺。
140.一种药物组合物,包含:
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N1-(3,4,5-三甲氧基苄基)乙酰胺。
141.根据权利要求1所述的组合物,其中C1-10卤代烷基是三氟甲基。
142.根据权利要求4所述的组合物,其中C1-10卤代烷基是三氟甲基。
143.根据权利要求1所述的组合物,其中C2-10链烯基是乙烯基,该乙烯基被苯基、呋喃基或-CO-O-C1-10烷基取代。
144.根据权利要求22所述的组合物,其中C2-10链烯基是乙烯基,该乙烯基被呋喃基或-CO-O-C1-10烷基取代。
145.根据权利要求1所述的组合物,其中R4是被一个或多个选自以下的基团取代的苯基:吗啉基C1-10烷基、(吡啶基C1-10烷基)氨基C1-10烷基、[(C1-10烷氧基苯基)C1-10烷基]氨基C1-10烷基、或(C1-10烷基吡啶基)(C1-10烷基)氨基C1-10烷基。
146.根据权利要求3所述的组合物,其中R4是被一个或多个选自以下的基团取代的苯基:吗啉基C1-10烷基、或(C1-10烷基吡啶基)(C1-10烷基)氨基C1-10烷基。
147.根据权利要求1所述的组合物,其中R4是没有被取代的或是被以下一种或多种基团取代的C1-10烷基:苯基、苯氧基、C1-10烷基、C1-10烷硫基苯基、卤代苯基、卤代联苯基、苯甲酰基苯氧基、-CO-O-C1-10烷基、-COC1-10烷基、-CO-噻吩基、噻吩基、环戊基、-CN、乙炔基、或-PO(OC1-10烷基)2。
148.根据权利要求1所述的组合物,其中R4是被苯基、呋喃基或-CO-O-C1-10烷基取代的C2-20链烯基。
149.权利要求1所述的组合物在制备用于诱导动物体内细胞因子生物合成的药物中的用途。
150.权利要求1所述的组合物在制备用于治疗动物体内病毒疾病的药物中的用途。
151.权利要求1所述的组合物在制备用于治疗动物体内肿瘤疾病的药物中的用途。
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US09/589,580 US6451810B1 (en) | 1999-06-10 | 2000-06-07 | Amide substituted imidazoquinolines |
PCT/US2000/015702 WO2000076505A1 (en) | 1999-06-10 | 2000-06-08 | Amide substituted imidazoquinolines |
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- 2000-06-08 AU AU63349/00A patent/AU773113B2/en not_active Ceased
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US5352784A (en) * | 1993-07-15 | 1994-10-04 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
WO1998030562A1 (fr) * | 1997-01-09 | 1998-07-16 | Terumo Kabushiki Kaisha | Nouveaux derives d'amide et intermediaires utilises pour leur synthese |
Non-Patent Citations (1)
Title |
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JP特开平9-208584A 1997.08.12 |
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