IE83826B1 - Intermediates for the preparation of 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines - Google Patents
Intermediates for the preparation of 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines Download PDFInfo
- Publication number
- IE83826B1 IE83826B1 IE1999/0988A IE990988A IE83826B1 IE 83826 B1 IE83826 B1 IE 83826B1 IE 1999/0988 A IE1999/0988 A IE 1999/0988A IE 990988 A IE990988 A IE 990988A IE 83826 B1 IE83826 B1 IE 83826B1
- Authority
- IE
- Ireland
- Prior art keywords
- carbon atoms
- group
- alkyl
- substituted
- imidazo
- Prior art date
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- 239000000543 intermediate Substances 0.000 title description 19
- 238000002360 preparation method Methods 0.000 title description 6
- HQBUPOAKJGJGCD-UHFFFAOYSA-N 3H-imidazo[4,5-c]quinolin-4-amine Chemical class NC1=NC2=CC=CC=C2C2=C1N=CN2 HQBUPOAKJGJGCD-UHFFFAOYSA-N 0.000 title description 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 150
- 150000001875 compounds Chemical class 0.000 claims description 107
- 125000000217 alkyl group Chemical group 0.000 claims description 73
- -1 (phenyl) ethyl Chemical group 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 13
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 9
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 8
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000005333 aroyloxy group Chemical group 0.000 claims description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000005188 oxoalkyl group Chemical group 0.000 claims description 2
- 125000004416 alkarylalkyl group Chemical group 0.000 claims 1
- 125000004946 alkenylalkyl group Chemical group 0.000 claims 1
- 125000004429 atoms Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 174
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 127
- 239000007787 solid Substances 0.000 description 122
- 239000000203 mixture Substances 0.000 description 104
- 239000000047 product Substances 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 69
- 238000004458 analytical method Methods 0.000 description 66
- 239000000243 solution Substances 0.000 description 64
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 46
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- 238000007429 general method Methods 0.000 description 38
- 102000014150 Interferons Human genes 0.000 description 31
- 108010050904 Interferons Proteins 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- 229940079322 interferon Drugs 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 30
- 235000019341 magnesium sulphate Nutrition 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000002244 precipitate Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
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- 239000000908 ammonium hydroxide Substances 0.000 description 20
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 19
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- 239000000706 filtrate Substances 0.000 description 16
- 238000007792 addition Methods 0.000 description 15
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
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- 239000011780 sodium chloride Substances 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 235000020127 ayran Nutrition 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 210000004369 Blood Anatomy 0.000 description 8
- 150000001204 N-oxides Chemical class 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 8
- 238000004166 bioassay Methods 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
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- 239000008079 hexane Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 230000037348 biosynthesis Effects 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- ITIRVXDSMXFTPW-UHFFFAOYSA-N 1H-imidazo[4,5-c]quinoline Chemical group C1=CC=CC2=C(NC=N3)C3=CN=C21 ITIRVXDSMXFTPW-UHFFFAOYSA-N 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 6
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- 241000711975 Vesicular stomatitis virus Species 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 230000000120 cytopathologic Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000010998 test method Methods 0.000 description 6
- 230000003612 virological Effects 0.000 description 6
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
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- 239000002253 acid Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 150000004985 diamines Chemical class 0.000 description 5
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- 125000000524 functional group Chemical group 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 5
- 229940113083 morpholine Drugs 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000010192 crystallographic characterization Methods 0.000 description 4
- 230000001809 detectable Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
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- 238000004809 thin layer chromatography Methods 0.000 description 4
- SNIIIYRLNGBHDQ-UHFFFAOYSA-N 2-(chloromethyl)-1-(2-methylpropyl)imidazo[4,5-c]quinolin-4-amine;hydrochloride Chemical compound Cl.C1=CC=CC2=C3N(CC(C)C)C(CCl)=NC3=C(N)N=C21 SNIIIYRLNGBHDQ-UHFFFAOYSA-N 0.000 description 3
- XCZNVUYQNZLYIN-UHFFFAOYSA-N 2-nitro-1H-quinolin-4-one Chemical class C1=CC=C2C(O)=CC([N+]([O-])=O)=NC2=C1 XCZNVUYQNZLYIN-UHFFFAOYSA-N 0.000 description 3
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- 125000004892 2-methylpropylamino group Chemical group CC(CN*)C 0.000 description 2
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BMXNRHBDQNOUJP-UHFFFAOYSA-N 1-(2-methoxyethyl)-2-(methoxymethyl)imidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C3N(CCOC)C(COC)=NC3=CN=C21 BMXNRHBDQNOUJP-UHFFFAOYSA-N 0.000 description 1
- CXYOCSTZCULCAE-UHFFFAOYSA-N 1-(2-methylpropyl)imidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=CN=C21 CXYOCSTZCULCAE-UHFFFAOYSA-N 0.000 description 1
- YJKZDGOMTKOYQK-UHFFFAOYSA-N 1-(2-piperidin-4-ylethyl)imidazo[4,5-c]quinoline Chemical compound C1=NC2=CN=C3C=CC=CC3=C2N1CCC1CCNCC1 YJKZDGOMTKOYQK-UHFFFAOYSA-N 0.000 description 1
- CPVFCCNLDDNHEQ-UHFFFAOYSA-N 1-[1-(2-methylpropyl)imidazo[4,5-c]quinolin-2-yl]ethyl acetate Chemical compound C1=CC=CC2=C3N(CC(C)C)C(C(C)OC(C)=O)=NC3=CN=C21 CPVFCCNLDDNHEQ-UHFFFAOYSA-N 0.000 description 1
- CMNBVGJQAZZTGK-UHFFFAOYSA-N 1-[1-(2-methylpropyl)imidazo[4,5-c]quinolin-2-yl]pentyl acetate Chemical compound C1=CC=CC2=C(N(C(C(OC(C)=O)CCCC)=N3)CC(C)C)C3=CN=C21 CMNBVGJQAZZTGK-UHFFFAOYSA-N 0.000 description 1
- NEEYDTRCGJQSCC-UHFFFAOYSA-N 1-[4-amino-1-(2-methylpropyl)imidazo[4,5-c]quinolin-2-yl]pentyl acetate Chemical compound C1=CC=CC2=C(N(C(C(OC(C)=O)CCCC)=N3)CC(C)C)C3=C(N)N=C21 NEEYDTRCGJQSCC-UHFFFAOYSA-N 0.000 description 1
- CYOHXZCGGOMRPN-UHFFFAOYSA-N 1-benzyl-2-(ethoxymethyl)imidazo[4,5-c]quinoline Chemical compound CCOCC1=NC2=CN=C3C=CC=CC3=C2N1CC1=CC=CC=C1 CYOHXZCGGOMRPN-UHFFFAOYSA-N 0.000 description 1
- CRHOBYSOSDJWSM-UHFFFAOYSA-N 1-benzyl-2-(methoxymethyl)imidazo[4,5-c]quinoline Chemical compound COCC1=NC2=CN=C3C=CC=CC3=C2N1CC1=CC=CC=C1 CRHOBYSOSDJWSM-UHFFFAOYSA-N 0.000 description 1
- XTIGGAHUZJWQMD-UHFFFAOYSA-N 1-chloro-2-methoxyethane Chemical compound COCCCl XTIGGAHUZJWQMD-UHFFFAOYSA-N 0.000 description 1
- WUORVMPTANXIPA-UHFFFAOYSA-N 1-oxido-1H-imidazo[4,5-c]quinolin-1-ium Chemical compound C1=CC=CC2=C3[NH+]([O-])C=NC3=CN=C21 WUORVMPTANXIPA-UHFFFAOYSA-N 0.000 description 1
- GIIWGCBLYNDKBO-UHFFFAOYSA-N 1-oxidoquinolin-1-ium Chemical class C1=CC=C2[N+]([O-])=CC=CC2=C1 GIIWGCBLYNDKBO-UHFFFAOYSA-N 0.000 description 1
- QGKFIUDEXLBEEL-UHFFFAOYSA-N 2-(2-methoxyethyl)-1-(2-methylpropyl)imidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C(N(C(CCOC)=N3)CC(C)C)C3=CN=C21 QGKFIUDEXLBEEL-UHFFFAOYSA-N 0.000 description 1
- ARULEHFBAGRITH-UHFFFAOYSA-N 2-(azidomethyl)-1-(2-methylpropyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=CC=CC2=C3N(CC(C)C)C(CN=[N+]=[N-])=NC3=C(N)N=C21 ARULEHFBAGRITH-UHFFFAOYSA-N 0.000 description 1
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 2-Aminoquinoline Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- PQZXGIIGQHCVAU-UHFFFAOYSA-N 2-chloro-3-nitroquinoline Chemical compound C1=CC=C2N=C(Cl)C([N+](=O)[O-])=CC2=C1 PQZXGIIGQHCVAU-UHFFFAOYSA-N 0.000 description 1
- ZPMWWAIBJJFPPQ-UHFFFAOYSA-N 2-ethoxyacetyl chloride Chemical compound CCOCC(Cl)=O ZPMWWAIBJJFPPQ-UHFFFAOYSA-N 0.000 description 1
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 1
- VPDAGUVEZGEHJJ-UHFFFAOYSA-N 2-quinolin-2-ylethanol Chemical compound C1=CC=CC2=NC(CCO)=CC=C21 VPDAGUVEZGEHJJ-UHFFFAOYSA-N 0.000 description 1
- 150000005014 3-aminoquinolines Chemical group 0.000 description 1
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 1
- ZXVRNZRQQRBDLX-UHFFFAOYSA-N 3-nitroquinoline Chemical compound C1=CC=CC2=CC([N+](=O)[O-])=CN=C21 ZXVRNZRQQRBDLX-UHFFFAOYSA-N 0.000 description 1
- PPDAXUPXBAMEFZ-UHFFFAOYSA-N 3H-imidazo[4,5-c]quinolin-2-amine Chemical class C1=CC=CC2=C(NC(N)=N3)C3=CN=C21 PPDAXUPXBAMEFZ-UHFFFAOYSA-N 0.000 description 1
- JFMKIQOIIMSWIM-UHFFFAOYSA-N 4-N-(2-methylpropyl)quinoline-3,4-diamine Chemical compound C1=CC=C2C(NCC(C)C)=C(N)C=NC2=C1 JFMKIQOIIMSWIM-UHFFFAOYSA-N 0.000 description 1
- HKGPTTMXHQAEBO-UHFFFAOYSA-N 4-N-benzylquinoline-3,4-diamine Chemical compound NC1=CN=C2C=CC=CC2=C1NCC1=CC=CC=C1 HKGPTTMXHQAEBO-UHFFFAOYSA-N 0.000 description 1
- ZRFUZDDJSQVQBY-UHFFFAOYSA-N 4-chloro-3-nitroquinoline Chemical compound C1=CC=CC2=C(Cl)C([N+](=O)[O-])=CN=C21 ZRFUZDDJSQVQBY-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N Benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 101700010918 CPP1 Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- 208000005679 Eczema Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 241000735552 Erythroxylum Species 0.000 description 1
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- 206010019973 Herpes virus infection Diseases 0.000 description 1
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- 241000710185 Mengo virus Species 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-Methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
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- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
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- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
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- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
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- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940095076 benzaldehyde Drugs 0.000 description 1
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- 239000000168 bronchodilator agent Substances 0.000 description 1
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- 238000004364 calculation method Methods 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- 101700052859 cdf-1 Proteins 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- 235000008957 cocaer Nutrition 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000004624 dermatitis Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100001003 eczema Toxicity 0.000 description 1
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- 239000002024 ethyl acetate extract Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000005191 hydroxyalkylamino group Chemical group 0.000 description 1
- NSHFLKZNBPJNPA-UHFFFAOYSA-N imidazo[4,5-c]quinolin-2-one Chemical class C1=CC=C2C3=NC(=O)N=C3C=NC2=C1 NSHFLKZNBPJNPA-UHFFFAOYSA-N 0.000 description 1
- 230000002458 infectious Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
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- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
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- 238000000464 low-speed centrifugation Methods 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000007392 microtiter assay Methods 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
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- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
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Description
INTERMEDIATESFOR THE PREPARATION OF
-SUBSTITUTED. 2-SUBSTITUTED
lH°IMIDAZO[4.5-CIQUINOLINAHINES
BACKGROUND OF THE INVENTION
Eield oi the Invention
This disclosure relates to lH—imidazo[4,S—c]-
quinoline compounds. This invention relates to
intermediates for the preparation of antiviral lH—
imadazo[4,S-:]quinolin—4-amines. Also disclosed are
pharmaceutical compositions containing such compounds.
Description of the Related Art
The first reliable report of the 1H-imidazo-
[4,5-c]quinoline ring system, Backman et al., J. org.
Chem. 15, 1278-1284 (1950), describes the synthesis of
-(6-methoxyquinolinyl)methyl-1H-imidazo[4,5-c]-
quinoline for possible use as an antimalarial agent.
Subsequently, syntheses of various substituted 1H-
imidazo[4,5-c]quinolines have been reported. For
example, Jain et al., J. Med. Chem. 11, pp. 87-92
(1968), has synthesized the compound
1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as
a possible anticonvulsant and cardiovascular agent.
Also, Baranov et al., Chem. Abs. 85, 94362 (1976), has
reported several 2—oxoimidazo[4,S-c]quinolines, and
Berenyi et al., J. Heterocyclic Chem. 18, 1537~154O
._2 ..
(1981), has reported certain 2-oxoimidazo[4,5—c]—
quinolines.
Certain antiviral 1H-imidazo[4,5—c]quinolin—
4-amines are described in U.S. Pat. No. 4,689,338
(Gerster). These compounds are substituted on the
1-position by alkyl, hydroxyalkyl, acyloxyalkyl,
benzyl, phenylethyl or substituted phenylethyl, and at
the 2-position with hydrogen, alkyl, benzyl, or
substituted benzyl, phenylethyl or phenyl.
Furthermore, these compounds are known to induce
interferon biosynthesis. other antiviral
1H-imidazo[4,5—c]quinolinamines, substituted on the
1-position by alkenyl substituents, are described in
U.S. Pat. No. 4,929,624 (Gerster).
U.S. Pat. No. 4,698,348 (Gerster) discloses
1H-imidazo[4,5-c]quinolines that are active as
bronchodilators, such as 4—substituted 1H—imidazo—
[4,5—c]quinolines wherein the 4-substituent is, inter
alia, hydrogen, chloro, alkylamino, or dialkylamino,
and the 2-substituent is, inter alia, hydroxyalkyl,
aminoalkyl, or alkanamidoalkyl. Said patent also
discloses 3-amino and 3-nitro quinoline intermediates
substituted at the 4-position by hydroxyalkylamino or
cyclohexylmethylamino, and 1H—imidazo[4,5—c]quinoline
N-oxide intermediates substituted at the 2~position
with, inter alia, hydroxyalkyl, aminoalkyl, or
alkanamidoalkyl.
DETAILED DESCRIPTION OF THE INVENTION
This disclosure provides compounds of Formula
wherein R, is selected from the group consisting of:
hydrogen; straight chain or branched chain alkyl
containing one to about ten carbon atoms and
substituted straight chain or branched chain alkyl
containing one to about ten carbon atoms, wherein the
substituent is selected from the group consisting of
cycloalkyl containing three to about six carbon atoms
and cycloalkyl containing three to about six carbon
atoms substituted by straight chain or branched chain
alkyl containing one to about four carbon atoms;
straight chain or branched chain alkenyl containing two
to about ten carbon atoms and substituted straight
chain or branched chain alkenyl containing two to about
ten carbon atoms, wherein the substituent is selected
from the group consisting of cycloalkyl containing
three to about six carbon atoms and cycloalkyl
containing three to about six carbon atoms substituted
by straight chain or branched chain alkyl containing
one to about four carbon atoms; hydroxyalkyl of one to
about six carbon atoms; alkoxyalkyl wherein the alkoxy
moiety contains one to about four carbon atoms and the
alkyl moiety contains one to about six carbon atoms;
-acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy
of two to about four carbon atoms or benzoyloxy, and
the alkyl moiety contains one to about six carbon
atoms; benzyl; (pheny1)ethyl; and phenyl; said benzyl,
(phenyl)ethyl, or phenyl substituent being optionally
substituted on the benzene ring by one or two moieties
independently selected from the group consisting of
-4 _.
alkyl of one to about four carbon atoms, alkoxy of one
to about four carbon atoms, and halogen, with the
proviso that if said benzene ring is substituted by two
of said moieties, then the moieties together contain no
more than six carbon atoms;
Rzand R,are independently selected from the
group consisting of hydrogen, alkyl of one to about
four carbon atoms, phenyl, and substituted phenyl
wherein the substituent is selected from the group
consisting of alkyl of one to about four carbon atoms,
alkoxy of one to about four carbon atoms, and halogen;
X is selected from the group consisting of
alkoxy containing one to about four carbon atoms,
alkoxyalkyl wherein the alkoxy moiety contains one to
about four carbon atoms and the alkyl moiety contains
one to about four carbon atoms, hydroxyalkyl of one to
about four carbon atoms, haloalkyl of one to about four
carbon atoms, alkylamido wherein the alkyl group
contains one to about four carbon atoms, amino,
substituted amino wherein the substituent is alkyl or
hydroxyalkyl of one to about four carbon atoms, azido,
chloro, hydroxy, 1~morpholino, l—pyrro1idino, and
alkylthio of one to about four carbon atoms; and
R is selected from the group consisting of
hydrogen, straight chain or branched chain alkoxy
containing one to about four carbon atoms, halogen, and
straight chain or branched chain alkyl containing one
to about four carbon atoms;
or a pharmaceutically acceptable acid
addition salt thereof.
This invention provides intermediate
compounds of Formula V(a)
V(3)
nun‘
wherein R is as defined above, Y is -NO, or —NH2, and R
is alkoxyalkyl wherein the alkoxy moiety contains one
to about four carbon atoms and the alkyl moiety
contains two to about six carbon atoms.
This invention provides intermediate
compounds of Formula VII(a)
wherein R is as defined above in connection with
N
"O>
7 V[I(a)
Formula V(a) and R,‘ is alkoxy alkyl wherein the alkoxy
moiety contains one to about four carbon atoms and the
alkyl moiety contains one to about six carbon atoms.
This invention provides intermediate
compounds of Formula IX(a)
wherein
R,is selected from the group consisting of;
straight chain or branched chain alkyl containing one
to about ten carbon atoms and substituted straight
chain or branched chain alkyl containing one to
ten carbon atoms, wherein the substituent is selected
from the group consisting of cycloalkyl containing
three to six carbon atoms and cycloalkyl containing
three to six carbon atoms substituted
by straight chain or branched chain alkyl containing
one to four carbon atoms;alkoxyalkyl wherein the alkoxy moiety
contains one to four carbon atoms and the alkyl moiety
contains one to six carbon atoms;
acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy
of two to four carbon atoms or benzoyloxy, and
the alkyl moiety contains one to six carbon
atoms; benzyl; (phenyl)ethy1; and phenyl; said benzy1,-
(phenyl)ethyl, or phenyl substituent being optionally
substituted on the benzene ring by one or two moieties
independently selected from the group consisting of
alkyl of one to four carbon atoms, alkoxy of one
to four carbon atoms, and halogen , with the
proviso that if said benzene ring is substituted by two
of said moieties, then the moieties together.contain no
more than six carbon atoms; f
R; and R3 are independently selected from the group
consisting of hydroden, alkyl of one to four carbon atoms,
phenyl, and substituted phenyl wherein the substituent is
selected fron the group consisting of alkyl of one to four
carbon atoms, alkoxy of one to four carbon atoms, and
halogen; H _y p _ W ;_
G is selected from the group consisting of
alkoxy containing one to four carbon atoms,
alkoxyalkyl wherein the alkoxy moiety contains one to
four carbon atoms and the alkyl moiety contains
one to four carbon atoms, alkylamido wherein the
alkyl group contains one to four carbon atoms,
azido, chloro, 1—morpholino, l~pyrrolidino, alkylthio
of one to four carbon atoms, alkanoyloxy,
alkanoyloxyalkyl wherein the alkyl moiety contains one
to four carbon atoms, and aroyloxy, with the
provisio that when G is alkylamido then R5 is alkenyl,
substituted alkenyl, or alkozyalkyl; and
R is selected from the group consisting of hydrogen
straight chain or branched chain alkoxy containing
one to four carbon atoms, halogen and straight chain on.
branched chain alkyl containing one to four carbons.
Further this invention provides compounds of
I(I(a)
wherein R5 is selected from the group consisting of:
straight chain or branched chain alkyl containing one to ten
carbon atoms and substituted straight chains or branched
chain alkyl containing one to ten carbons, wherein the
substituent is selected from the group consisting of
cylcoalkyl containing three to six carbon atoms and
cycloalkyl containing three to six carbon atoms substituted
by straight chain or branched chain alkyl containing one to
four carbon atoms; straight chain or branched chain alkenyl
containing two to ten carbon atoms substituted straight
chains or branched chain alkenyl containing two to ten
carbon atoms, wherein the substituent is selected from the
group consisting of cycloalkyl containing three to six
carbon atoms and cycloalkyl containing three to six carbon
atoms substituted by straight chain or branched chain alkyl
containing one to four carbon atoms;
_7a__
alkoxyalkyl wherein the alkoxy moiety contains one to four
carbon atoms and the alkyl moiety contains one to six carbon
atoms; acyloxyalkyl wherein the acyloxy moiety alkanqyloxy
of two to four carbons or benzoyloxy, and the alkyl moiety
contains one to six carbon atoms;
benzyl; (phenyl)ethyl; and phenyl; said benzyl; (phenyl)
ethyl, or phenyl substituent being optionally substutituent
being optionally substituted on the benzene ring by one or
two moieties independently selected from the group
consistingsof alkyl of one to four carbon atoms, alkoxyrof
one to four carbon atoms, and halogen, with the proviso that
when said benzene ring if substituted by two of said
moieties, then the moieties together contain no more than
six carbon atoms;
R2 and R3 are independently selected from the group
consisting of hydrogen, alkyl of one to four carbon atoms,
phenyl, and substituted phenyl wherein the substituent is
selected from the group consisting of alkyl of one to four
carbon atoms, alkoxy of one to four carbon atoms and
halogen;
Z is selected from the group consisting of alkoxy containing
one to four carbon atoms, alkoxyalkyl wherein the alkoxy
moiety contains one to four and the alkyl moiety contains
one to four carbon atoms, hydroxyalkyl containing one to for
carbon atoms, oxoalkyl of two to four carbon atoms,
alkanoyloxyalkyl wherein the alkyl moiety contains one to
four carbon atoms, alkylamido wherein the alkyl group
contains one to four carbon atoms, substituted amino wherein
the substituent is alkyl or hydroxyalkyl of one to four
carbon atoms, azido, chloro, l—morpho1ino, 1—pyrrolidino,
alkylthio of one to four carbon atoms, hydroxy, alkanoyloxy,
and aroyloxy; and
Q is selected from the group consisting of hydrogen, chloro,
and Ri—(C=O)—NH wherein Ri is selected from the group
consisting of alkyl, aklenyl, alkanyl and arylalkyl;
and with the further provisio that when Q is hydrogen or
cholo and Z is alkylamido or hydrozyalkyl, then R5 is
alkenyl, substituted alkenyl, or alkoxyalkyl; and R is
selected from the group consisting of hydrogen, straight
chain or branched chain alkoxy containing one to four carbon
atoms, halogen and straight chain or branched chain alkyl
containing or to four carbon atoms.
m of Formula I preferably contains two to
about_ten carbon atoms. More preferably R, contains two
to about eight carbon atoms; Most preferably, R, is
2-methylpropyl or benzyl.
X of Formula I is preferably azido, hydroxy,
ethoxy, methoxy, 1-morpholino, or methylthio,
particularly in embodiments wherein R, is
2-methylpropyl, 2-hydroxymethylpropyl, or benzyl.
other substituents in compounds of Formula I
that contain an alkyl radical (e.g., R when R is alkoxy
or alkyl, or X when X is alkylamido) preferably contain
two carbon atoms or, more preferably, one carbon atom
in each alkyl radical.
It is preferred that R of Formula I be
hydrogen.
Most preferred compounds of Formula I include
4-amino—a-butyl(2—methylpropy1)—1H-imidazo[4,5-c]-
quinoline-2—methanol hemihydrate, 4—amino—q,q-dimethyl-
2-ethoxymethyl-1H~imidazo[4,5-c]quinoline~1-ethanol, 2-
ethoxymethyl(2-methylpropyl)~1H-imidazo[4,5-
c]quinolin~4—amine, and 4-aminophenylmethyl-
1H-imidazo[4,5-c)quinolinemethanol.
A compound of Formula I can be prepared
as described in the Reaction Scheme below, wherein R,
R,, Ru IQ, and X are as defined above and wherein P is a
hydroxyl protecting group that can subsequently be
removed, such as alkanoyloxy (e.g., acetoxy), or
aroyloxy (e.g., benzoyloxy), and R,is as defined for R.
above absent hydroxyalkyl and hydrogen.
Many quinolines of Formula III are known
compounds (see, for example, U.S. Pat. No. 3,700,674
and references cited therein). Those that are not
known can be prepared by known methods, for example,
from 4-hydroxynitroquinolines as illustrated in step
(1) of Scheme I. step (1) can be conducted by reacting
the 4—hydroxynitroquinoline of Formula II with a
chlorinating agent such as thionyl chloride or
phosphorus oxychloride. The reaction is preferably
conducted in N,N-dimethylformamide, optionally in the
presence of methylene chloride, and is preferably
accompanied by heating. Preferably, a large molar
excess of phosphorus oxychloride is avoided. Use of
about 1-2 moles of phosphorus oxychloride per mole of
the 4-hydroxynitroquinoline of Formula II has been
found to be particularly preferable.
In step (2) a 3—nitro—4—chloroquinoline of
Formula III is reacted by heating with an amine of the
formula Rfing, wherein R, is as defined above, in a
suitable solvent such as water, dichloromethane, or
tetrahydrofuran, to provide a quinoline of Formula IV.
Steps (1) and (2) can be combined such that the
3-nitrochloroquinoline need not be isolated prior to
reaction with the compound of the formula Rfiflfi. Such a
reaction is exemplified in Example 134 and Example 188
(Step A) of U.S. Pat. No. 4,689,338, the disclosure of
which is incorporated herein by reference.
A compound of Formula IV is reduced in step
(3) preferably using a catalyst such as platinum on
carbon, to provide a compound of Formula V. This can
be carried out conveniently on a Parr apparatus in an
inert solvent such as toluene or a lower alkanol.
In step (4) an intermediate compound of
Formula V is reacted with (i) a carboxylic acid of the
(0H)(R2)(R3)C-C(0AlkY1);
_lo_
wherein "alkyl" is a straight chain or branched chain
alkyl group containing one to about four carbon atoms,
or (iii) a combination of such a carboxylic acid with
such a trialkyl ortho ester to provide a compound of
In any case, the reaction can be carried
e.g., at about 130°C,
of an acid, preferably a carboxylic acid of the formula
Formula VI.
out by heating, in the presence
(on) (12,) (R,)cco,H
An alternate method of providing the
2—substituted imidazo ring is illustrated in steps (5)
and (6).
described in connection with step (4), but involving
Step (5) involves a reaction similar to that
formic acid or a trialkylorthoformate to form an
intermediate of Formula VII. The intermediate of
Formula VII can then be deprotonated by a strong base
(e.g., an alkyllithium such as n—butyllithium) and
reacted with a compound of the formula
II
R CR
to form an intermediate of Formula VI.
Step (7) involves protecting the hydroxyl
group with a removable protecting group such as an
alkanoyloxy group (e.g., acetoxy) or an aroyloxy group
(e.g., benzoyloxy). In instances wherein a hydroxyl
group is present in the 1-substituent, it too can be
protected in step (7) and later removed as appropriate
when it will no longer interfere with subsequent
reactions. Suitable protecting groups and reactions
for their placement and removal are well known to those
skilled in the art. See,
4,689,338 (Gerster), Examples 115-123.
Step (8) provides an intermediate of Formula
for example, U.S. Pat. No.
IX, through oxidation of a compound of Formula VIII
with a conventional oxidizing agent that is capable of
_ 11 -
forming N-oxides. Preferred oxidizing agents include
peroxyacids and hydrogen peroxide. Heating is
generally employed to accelerate the rate of reaction.
In step (9) an N-oxide of Formula IX is
heated in the presence of a suitable chlorinating agent
such as phosphorus oxychloride to provide a chlorinated
intermediate of Formula X.
In step (10) the 4—chloro group is replaced
by a 4-amino group and the protecting group P is
removed to provide a compound of Formula XII (a
subgenus of Formula I). The amination reaction is
carried out in the presence of ammonium hydroxide or,
preferably, ammonia. Preferably the intermediate of
Formula X is heated at 125° to 175°C under pressure for
6-24 hours. Preferably the reaction is conducted in a
sealed reactor in the presence of either ammonium
hydroxide or a solution of ammonia in an alkanol,
(8,
methanol).
A compound of Formula XII can also be
preferably about 5% to about 15% ammonia in
prepared by way of step (9a) of the Reaction Scheme.
Step (9a)
IX with an acylating agent; (ii) reacting the product
with an aminating agent; and (iii) isolating the
compound of Formula XII. Part (i) of step (9a)
involves reacting an N—oxide with an acylating agent.
Suitable acylating agents include alkyl- or
arylsulfonyl chlorides (e.g., benzenesulfonyl chloride,
methanesulfonyl chloride, p-toluenesulfonyl chloride).
Arylsulfonyl chlorides are preferred.
p—Toluenesulfonyl chloride is most preferred. Part
(ii) of step (9a) involves reacting the product of part
(i) with an excess of an aminating agent. Suitable
aminating agents include ammonia (e.g., in the form of
ammonium hydroxide) and ammonium salts (e.g., ammonium
carbonate, ammonium bicarbonate, and ammonium
phosphate). Ammonium hydroxide is preferred. The
reaction of step (9a) is preferably carried out by
involves (i) reacting a compound of Formula
._l2-
dissolving the N-oxide of Formula IX in an inert
solvent such as methylene chloride, adding the
aminating agent to the solution, and then adding the
acylating agent. Preferred conditions involve cooling
to about WT to about S%tduring the addition of the
Heating or cooling can be used to
Step (9a) also
acylating agent.
control the rate of the reaction.
involves removal of protecting group P as discussed
above in connection with step (7). A further
alternative method of preparing a compound of Formula
XII is shown in steps (11) and (12).
Step (11) involves reacting an N-oxide with
an isocyanate wherein the isocyanato group is bonded to
a hydrolytically active functional group. The term
"hydrolytically active functional group" as used herein
designates any functional group that is capable of
being subjected to a nucleophilic displacement reaction
in step (12) of the Reaction Scheme. Exemplary
hydrolytically active functional groups include
carbonyl
N
(-c-).
isocyanates of the formula K-E-NCO, wherein R is an
organic group substantially inert to quinoline N-oxides
under the conditions of step (11) and E is a
hydrolytically active functional group. suitable R
groups are easily selected by those skilled in the art.
Preferred groups R include alkyl, aryl, alkenyl, and
Particular preferred isocyanates
A particular class of such isocyanates is
combinations thereof.
include aroyl isocyanates such as benzoylisocyanate.
The reaction of the isocyanate with the N-oxide is
carried out under substantially anhydrous conditions by
adding the isocyanate to a solution of the N-oxide in
an inert
.. ._
REACTION SCHEME
N02 N02 N02
‘I N N
_'_1>__, O (2) O
OH C1 NHRS
R R
[I III R IV
(3)
NH2
' NHR
Rs
R VII R v
(6)
(4)
N P on
N g N
N a :2
, 2 3 fizz R,
R5 R5
R VIII R VI
-14..
REACTION SCI-{ENE (ccznt1nued)
C1
0' +
\N N P N N P
N R R
I 2 3 ?R2 R3
R5 as
R IX R X
(:1)
(9a) (10)
a1~—a——xu
NH2
N N p N N on
Q >“7< (12) © >_7<
N
1 R2 R3 Y R2 R3
R5 R5
R
A///// R
XI
_.1_S-
solvent such as dichloromethane. The resulting
4-substituted compound of Formula XI can be isolated by
removal of the solvent.
Step (12) of the Reaction Scheme involves
hydrolysis of a compound of Formula XI. The term
"hydrolysis" as used herein designates not only
nucleophilic displacement with water but also
displacement with other nucleophilic compounds.
reaction can be carried out by general methods well
known to those skilled in the art, e.g., by heating in
the presence of a nucleophilic solvent such as water or
a lower alkanol optionally in the presence of a
catalyst such as an alkali metal hydroxide or lower
Such a
alkoxide.
In steps (9a), (10) or (12) a compound
comprising a protecting group such as acetoxy,
benzoyloxy, or the like, is deprotected to afford a
compound comprising a hydroxyl group. A
hydroxyl—containing compound of Formula I can be
converted or elaborated by methods well known to the
skilled in the art to afford a further compound of
Formula I. For example, reaction with thionyl chloride
will provide a compound of Formula I wherein X is
chloro. Reaction of this compound with a nucleophile
such as sodium azide, pyrrolidine, methanethiol, or
morpholine will afford a compound of Formula I wherein
X is azido, 1-pyrrolidino, thiomethyl, or 1-morpholino,
respectively. Reduction of an azido compound provides
a compound of Formula I wherein X is amino.
amino compound can be acylated to form a compound
Such an
wherein X is alkylamido.
some Compounds of Formula I can be prepared
by a similar reaction scheme wherein the group X is
introduced directly in step (4) in which case
hydroxyalkyl substituents will be tolerated at the
1-position with appropriate use of the various
protection and deprotection steps.
-16..
Substituents at the 2-position can be
introduced by reacting a compound of Formula XIII
XIII
wherein R and R, are as defined above, with a lithiating
agent such a lithium diisopropylamide or n-butyllithium
in a polar aprotic solvent to afford a compound
lithiated on the 2-methyl group. The lithiated
compound can then be reacted with an appropriate
reagent containing a leaving group capable of being
displaced by the lithiated 2-methyl group, such as,
e.g., chloromethylmethylether or N-methoxy—N—
methylacetamide, in order to elaborate the 2-methyl
group. Such compounds can then be carried on as
appropriate to compounds of Formula I.
While not all compounds of Formula I can be
prepared by the illustrated reaction scheme, known
schemes can be easily adapted by those skilled in the
art in order to prepare compounds other than those
exemplified herein. For example, compounds wherein R,
is alkenyl can be prepared using the general schemes or
adaptations thereof set forth in U.S. Pat. No.
4,929,624 (Gerster et al.) and compounds wherein R,is
hydrogen can be prepared using the general schemes or
adaptations thereof set forth in commonly assigned
copending application 07/484,761 (Gerster), both being
incorporated herein by reference. A further synthetic
scheme that can be used by those skilled in the art in
the preparation of some of the compounds of the
invention is disclosed in U.s. Pat. No. 4,988,815
(Andre' et al.) incorporated herein by reference.
Further, those skilled in the art will recognize that
-17..
alteration of reaction sequence and utilization of
conventional synthetic alternatives will allow the
preparation of the compounds of the invention not
amenable to the illustrated scheme.
The product compound of Formula I can be
isolated by the conventional means disclosed in U.S.
Pat. No. 4,689,338 (Gerster), such as, for example,
removal of the solvent and recrystallization from an
appropriate solvent (e.g., N,N-dimethylformamide) or
solvent mixture, or by dissolution in an appropriate
solvent (such as methanol) and re-precipitation by
addition of a second solvent in which the compound is
insoluble.
A compound of Formula I can be used as an
antiviral agent itself or it can be used in the form of
a*pharmaceutically acceptable acid-addition salt such
as a hydrochloride, dihydrogen sulfate, trihydrogen
phosphate, hydrogen nitrate, methanesulfonate or a salt
of another pharmaceutically acceptable acid. A
pharmaceutically acceptable acid-addition salt of a
compound of Formula I can be prepared, generally by
reaction of the compound with an equimolar amount of a
relatively strong acid, preferably an inorganic acid
such as hydrochloric, sulfuric, or phosphoric acid, or
an organic acid such as methanesulfonic acid, in a
polar solvent. Isolation of the salt is facilitated by
the addition of a solvent, such as diethyl ether, in
which the salt is insoluble.
A compound of Formula I can be formulated
for the various routes of administration in a
pharmaceutically acceptable vehicle, such as water or
polyethylene glycol, along with suitable adjuvants,
excipients, and the like. Particular formulations will
be easily selected by those skilled in the art.
Suitable formulations for topical application include
creams, ointments and like formulations known to those
skilled in the art.
less than 10% by weight of a compound of Formula I,
Formulations generally contain
-18..
preferably about 0.1% to 5% by weight of a compound of
Formula I.
The compounds of Formula I exhibit antiviral
activity in mammals. They can therefore be used to
control viral infections. For example, a compound of
Formula I can be used as an agent to control infections
in mammals caused by Type II Herpes simplex virus.
Compounds of Formula I can also be used to treat a
herpes infection by oral, topical, or intraperitoneal
administration.
A number of compounds of Formula I were
tested and found to induce biosynthesis of interferon
in human cells and in mice. Furthermore, a number of
compounds of Formula I were tested and found to inhibit
tumors in mice. The test methods and results are set
forth below. These results suggest that at least
certain compounds of the invention might be useful in
treating other diseases such as rheumatoid arthritis,
warts, eczema, Hepatitis B, psoriasis, multiple
sclerosis, essential thrombocythaemia, cancer such as
basal cell carcinoma, and other neoplastic diseases.
.RE.
when the term is used in this
specification it means Reference Example.
In the following Examples and RES, all
reactions were run with stirring under an atmosphere of
dry nitrogen unless otherwise indicated. The particular
materials and amounts thereof recited in the Example or
should not
RE, as well as other conditions and details,
be construed to unduly limit the invention.
EXAMPLE 1
1—{2-Methvlpropvl)-1H-imidazor4.5-c1-
guinolinemethanol
-Nitro—4—(2-methylpropylamino)quinoline
(36.8 g; 0.15 mol) was added to a mixture of ethyl
acetate (300mL), 5% Pt/C (about 1g), and magnesium
sulfate (30g). The mixture was hydrogenated at about
50 psi initial pressure. When hydrogenation was
complete the solids were filtered from the mixture and
the ethyl acetate was evaporated. The resulting
intermediate diamine was mixed with glycolic acid (26.9
g; 0.35 mol) and the mixture was heated at 1S0~160°C
for about 3 hr with occasional manual stirring. The
reaction mixture was then dissolved in dilute
hydrochloric acid and treated with decolorizing carbon,
The
filtrate was made basic with ammonium hydroxide to
precipitate the product as a greenish solid. The solid
was filtered and dried to give 34.3 g (89.6%) of crude
and the solids were filtered from the mixture.
product. The solid was reprecipitated a second time as
above and the product recrystallized from ethyl acetate
to give greenish crystals, m.p. 165-168°C. Analysis:
Calc'd.:C, 70.6; H, 6.7; N, 16.5. Found: C, 70.4, H,
6.7; N, 16.3.
EXAMPLE 2
1-(2-Methylgrogyl)-1H-imidazo[4,5—c]—
u' ' - - e
-(2-Methylpropyl)-1H-imidazo[4,S—c]-
quinoline—2~methanol (51.4 g; 0.2 mol, Example 1) was
dissolved in dichloromethane (500 mL) containing
triethylamine (30.9 mL; 0.22 mol). The solution was
stirred at room temperature while acetyl chloride was
added dropwise. The resulting solution was stirred at
room temperature for about 24 hr and then washed with
water and aqueous sodium bicarbonate. The organic
layer was dried over magnesium sulfate and evaporated
to yield 58.1 g (97%) of the acetate as a brownish
The product was recrystallized from ethyl
Analysis:
68.1; H,
solid.
acetate to give a tan solid m.p. 147—154°C.
Calc'd.:C, 68.7; H, 6.4; N, 14.1. Found: C,
6.4; N, 13.8.
EXAMPLE 3
1-(2-Methylpropylj-1H-imidazof4,5—c]—
quinolinemethyl Benzoate
The compound was prepared from l-(2-
methylpropyl)-1H—imidazo[4,5—c]quinoline-2—methanol
_20_
(Example 1) using benzoyl chloride in the general
method of Example 2.
EXAMPLE 4
2-AcetoxvmethY1~1-(2—methvlpropvl)~1H—
imidazo[4.5-clquinoline SN Oxide
l-(2—Methylpropyl)—1H-imidazo[4,5—c]-
quinolinemethyl acetate (63.0 g; 0.21 mol, Example
2) was suspended in ethanol (47SmL) and 32% peracetic
acid (89 mL; 0.42 mol) was added to the mixture. The
mixture was heated at 50°C with stirring for 2 hr. The
solid dissolved upon heating and after about 1 1/2 hr a
heavy precipitate formed. The precipitate was filtered
from the mixture and dried to yield 33.7 g of the
N-oxide. The filtrate was concentrated to 100 mL and
an additional 15.2 g of solid was collected. A total
crude yield of 48.9 g (74.3%) was obtained. The
material was recrystallized from ethanol to give pale
yellow crystals m.p. 233~240°C. Analysis: Calc'd.:C,
65.1; H, 6.1; N, 13.4. Found: C, 64.6; H, 6.1; N, 13.2.
EXAMPLE 5
-Benzov1oxvmethY1(2-methylpropyl)-1H-
imidazof4,5—c1quinoline SN Oxide
The compound was prepared using 1-(2-
methylpropyl)-1H-imidazo[4,5-c]quinolinemethyl
benzoate (Example 3) in the method of Example 4 and
recrystallized from ethyl acetate to give a pure
product, m.p. 192—19S°C. Analysis: Calc'd.:C, 70.4; H,
.6; N, 11.2. Found: C, 70.6; H, 5.7; N, 11.2.
EXAMPLE 6
4-Chloro{2—methv1DroDvl)—1H-imidazo-
[4,5-c]guinolinemethyl Acetate
—Acetoxymethy1—1-(2-methylpropyl)—1H—
imidazo[4,5—c]quino1ine SN oxide (48.9 g; 0.156 mol,
Example 4) was suspended in dichloromethane (500 mL)
and phosphorous oxychloride (17.5 mL; 0.187 mol) was
._ _.
added dropwise to the stirred suspension. The vigorous
reaction was controlled by adjusting the rate of
addition. when addition was complete the mixture was
stirred at reflux for 1 hr. The mixture was then
cautiously neutralized with sodium bicarbonate. All
solid dissolved in the dichloromethane. The organic
layer was separated, dried over magnesium sulfate, and
evaporated to yield 43.6 g (84.2%) of crude product. A
small amount was purified by silica gel flash
chromatography (ethyl acetate as eluent) and
recrystallized from ethyl acetate to give a pure sample
m.p. 182-188°C. Analysis: Calc'd.: C, 61.5; H, 5.5; N,
.7. Found: C, 61.5; H, 5.4; N, 12.6.
EXAMPLE 7
4-Chloro(2-methvlpropyl)-1H-imidazo-
L4,5-clauinolinemethyl Benzoate
The Compound was prepared using 2-
benzoyloxymethyl-1—(2-methylpropyl)-1H-imidazo[4,5-
cjquinoline-SN-oxide (Example 5) in the method of
Example 6 and recrystallized from ethyl acetate/hexane
for analysis and characterization. m.p. 143—1S0°C.
Analysis: Calc'd.: C, 67.1; H, 5.1; N, 10.7. Found: C,
67.2; H, 5.1; N, 10.5.
EXAMPLE 8
4—Chloro(2-methvlpropvl)-1H-imida;o-
[4.5-clquinoline—2-methanol
-Ch1oro(2-methylpropyl)-1H-imidazo-
[4,5—c]guinoline—2—methyl benzoate (14.3 g; 0.36 mol,
Example 7) was suspended in dry methanol (350 mL). The
mixture was made basic (pH 10) with 25% sodium
methoxide. The mixture was stirred at room temperature
for 5 hr after which time only a trace of starting
material was detected by silica gel TLC (ethyl acetate
eluent). The mixture was made acidic with acetic acid
and then concentrated to dryness.
The solid was filtered from the
The residue was
slurried in ether.
-22..
mixture and then suspended in aqueous sodium hydroxide.
The product was filtered from the mixture, washed with
water, and dried to yield 7.5 g (71.4%) of tan solid.
The product was recrystallized from ethanol to yield
.8 g of pure product m.p. 162-166°C. Analysis:
Calc'd.: C, 62.2; H, 5.6; N, 14.5. Found: C, 62.2; H,
.6; N, 14.3.
RE 9
-Amino—1-(2-methvlpropvl)-1H-imidazo-
L9.5-c]guinoline—2-methanol
-Chloro(2-methylpropyl)-1H-imidazo-
[4,5-cjquinolinemethyl benzoate (5.0 g; 0.13 mol,
Example 7) was added to 15% methanolic ammonia (50 mL).
The mixture was heated in a Parr bomb for 7 hr at
175°C.
the volume.
The resulting solution was evaporated to reduce
A sticky solid crystallized from the
The solid was filtered from the mixture and
slurried in aqueous sodium bicarbonate solution. The
resulting solid was filtered from the mixture, washed
with water, and dried to yield 2.1 g (61.7%) of crude
product which was recrystallized from ethanol several
solution.
times to yield pure product m.p. 226-231°C. Analysis:
Calc'd.: C, 66.6: H, 6.7; N, 20.7. Found: C, 66.4; H,
6.5; N, 20.4.
RE 10
-ChloromethYl(2-methvlpropvl)-1H-
imidazof4.5-clquinolinamine Hydrochloride
4-Amino—1-(2-methylpropyl)-1H-imidazo-
[4,5-cjquinolinemethanol (5.0 g; 0.0185 mol, RE
9) was added in small portions to vigorously stirred
thionyl chloride (25 mL).
stirred at room temperature overnight.
diluted with 100 mL of ether, and the solid was
filtered from the mixture and dried thoroughly.
product was pure enough for further reactions. A
sample was recrystallized from ethanol to give a pure
The resulting mixture was
The mixture was
product which melted with decomposition from 279—292°C.
Analysis: Calc'd.: C, 55.4; H, 5.6; N, 17.2. Found: C,
55.3; H, 5.5; N, 17.1.
RE 11
2-Azidomethyl—1-(2—methv1propyl)-1H—imidazo~
L4.5-clduinolinamine
2-Chloromethyl-1(2—methylpropyl)-1H-
imidazo[4,5-c]quinolin-4—amine hydrochloride (2.5 g;
0.0077 mol, RE 10) was suspended in
N-methylpyrrolidone (15 mL). A solution of lithium
azide (2.3 g) in water (45 mL) was added to the
suspension. The resulting mixture was heated on the
steam bath for 2 hr and then diluted with water (about
45 mL). The tan solid was washed with water and dried
to yield 1.4 g (60.9%) of crude product. The solid was
recrystallized from ethanol to give a pure product m.p.
l74—l78°C. Analysis: C, 61.0; H, 5.8; N, 33.2. Found:
C, 60.9; H, 5.6; N, 32.6.
RE 12
1-(2-Methvlpropvl)morpholinomethvl-1H-imidazo-
f4.5-clquinolin-4—amine
2—Chloromethyl(2—methylpropyl)-1H-
imidazo[4,5—c]quinolin—4-amine hydrochloride (RE
, prepared from 2.0 g of the corresponding alcohol)
was added to morpholine (5 mL). The mixture was
The resulting solution was cooled
to room temperature. The solid
was filtered from the mixture and slurried in aqueous
The product was filtered
refluxed for 4 hr.
A solid precipitated.
sodium bicarbonate solution.
from the mixture, washed with water, and dried to yield
1.7 g (68.0%) of solid, which was recrystallized from
ethanol to give a pure product m.p. 228—234°C.
Analysis: Calc'd.: C, 67.2; H, 7.4; N, 20.6. Found: C,
67.3; H, 7.9; N, 20.6. A
-24..
RE 13
-(2—Methylpropyl)-2~pvrrolidinomethv1-1H-
imidazo{4.5—c1auinolinamine
The pyrrolidinomethyl compound was prepared
from 2-chloromethyl(2-methylpropyl)-1H-imidazo[4,5-
c]quinolin-4—amine hydrochloride ( RE 10) by
substituting pyrrolidine for morpholine in the method
of RE 12. A crude yield of 1.90 g (63.3%) was
obtained. Recrystallization of the crude solid from
ethanol gave the pure product. m.p. 172-187°C.
Analysis: Calc'd.: c, 70.6; H, 7.3; N, 21.7. Found: c,
70.6; H, 7.8; N, 21.5.
RE 14
—Amino~1—(2-methvlpropvl)-1H-imidazo-
L4.5—cIauinoline-Zgmgthaggming
2-Azidomethyl—1(2-methylpropyl)—1H-
imidazo[4,5-c}quinolin-4—amine (3.2g, 0.0108 mol,
RE 11) was added to ethanol (300 mL) and 5% Pd/C
(about 1g) was added to the mixture. The mixture was
hydrogenated on a Parr apparatus until hydrogen uptake
stopped. Hydrogen was removed and the mixture was
flushed with hydrogen to regenerate the catalyst.
Hydrogenation was resumed. This procedure was repeated
until no more hydrogen was absorbed. The catalyst was
filtered from the mixture and the filtrate was
evaporated. The residue was recrystallized several
times from ethanol to give yellowish crystals m.p.
-291°C. Analysis: Calc'd.: C, 66.9; H, 7.1; N,
26.0. Found: C, 66.5; H, 7.2; N, 25.1.
RE 15
N—Acetylamino—1-(2—methvlpropv1)-1H—imidazo-
L5,5—c]quinoline~2-methanamine
-Amino(2—methylpropyl)-1H—imidazo—
[4,5-cJquinoline-2—methanamine (1.1 g; 0.004 mol,
RE 14) was added to acetic anhydride (3 mL).
mixture was stirred at room temperature for 5 hrs.
The
The
_25..
solution was then diluted with methanol (50 mL) and
refluxed for 1 hr. The solution was concentrated and
the residue made basic with aqueous sodium bicarbonate
solution. The oily residue was extracted into
dichloromethane. The extracts were dried over
The
residue was recrystallized from ethyl acetate to yield
magnesium sulfate and evaporated to dryness.
pure product m.p. 214-218°C. Analysis: Calc'd.: C,
65.6; H, 6.8; N, 22.5. Found: C, 65.1; H, 6.6; N, 22.0.
EXAMPLE 16
a-gethyl(2-methylgrgpxli-lfl-imigazo—
[4,S-c]ggino;igemethanol
3-Amino—4~(2-methylpropylamino) quinoline
(29.0 g; 0.135 mol) and lactic acid (36 mL; 0.48 mol)
were mixed and heated at 140°C for 6 hr. The mixture
was then dissolved in dilute hydrochloric acid and
treated with charcoal. The solids were filtered from
The filtrate was made basic with ammonium
the mixture.
hydroxide to precipitate the product as an oil.
oil was extracted into ethyl acetate. The ethyl
acetate solution was treated with decolorizing carbon
The
filtrate was evaporated to dryness to yield a greenish
and the solids were filtered from the mixture.
oil which was pure enough for further reactions. A
small sample was triturated with hexane to obtain a
solid which was recrystallized from ethyl acetate for
analysis. m.p. 152—166°C. Analysis: Calc'd.; C, 71.4;
H, 7.11; N, 15.6. Found: C, 71.1; H, 7.33; N, 15.4.
EXAMPLE 17
a—Methvl(2-methvlpropvl)~1H-imidazo-
J4.S-clquinolinemethyl Benzoate
a-Methyl(2-methylpropyl)-1H-imidazo-
[4,5-c]quinolinemethanol (20.0 g; 0.074 mol, Example
16) was dissolved in dichloromethane (200 mL) and
triethylamine (11.4 mL; 0.082 mol) was added to the
Benzoyl chloride (9.5 mL; 0.082 mol) was
solution.
-26..
added dropwise to the stirred solution. The mixture
was stirred at room temperature for 6 hr. The solution
was washed with water and aqueous sodium bicarbonate
solution, dried over magnesium sulfate and evaporated
to yield 26.6 g of greenish, viscous oil.
was pure enough for the following N—oxidation step but
The product
a small sample was purified by silica gel flash
chromatography (ethyl acetate eluent) for analysis and
characterization. m.p. 158-163°C. Analysis: Ca1c'd.:
C, 74.0; H, 6.2; N, 11.3. Found: C, 73.7; H, 6.2; N,
11.2.
EXAMPLE 18
a-Methv1(2-methvlpropvl)-1H-imidazo-
LA.5-c1auinoline—2-methyl Benzoate SN Oxide
a-Methyl(2-methylpropyl)-1H—imidazo-
[4,5-c]quinolinemethyl benzoate (11.7 g; 0.031 mol,
Example 17) was added to ethanol and 32% peracetic acid
(11.1 mL; 0.0092 mol) was added to the solution. The
mixture was heated at 65°C for 5 hr.
The residue was treated
The product
The solution was
then evaporated to dryness.
with aqueous sodium bicarbonate solution.
was extracted into ethyl acetate, dried over magnesium
sulfate, and evaporated to yield an oily residue
containing a trace of starting material. The crude
product was used in subsequent reactions.
EXAMPLE 19
4-Ch1oro-a-methvl(2-methvlpropvll-1H-
imidazor4,5—c1quinolinemethyl Benzoate
a—Methyl(2-methylpropyl)-1H—imidazo—
[4,5-c]quinolinemethyl benzoate SN oxide (9.2 g;
0.0236 mol, Example 18) was added to dichloromethane
(200 mL). Phosphorous oxychloride (2.6 mL; 0.0283 mol)
was added to the solution.
stirred at room temperature for 2 1/2 hr.
was evaporated and the residue was mixed with water and
The reaction mixture was
The solution
ammonium hydroxide. The oil was extracted into ethyl
-27..
acetate. The extracts were dried over magnesium
sulfate and evaporated to dryness. A yield of 7.6 g
(79.2%) of product was obtained as a glassy solid,
which was used as such for the next reaction.
RB 20
4-Amino-a-methvl(2-methylpropvl)—1H-
imidazof4.5-clquinolinemethanol
-Chloro—a-methy1(2-methylpropyl)—1H—
imidazo[4,5-cjquinoline-2—methyl benzoate (3.7 g; 0.009
mol, Example 19) was added to 15% methanolic ammonia
(50 mL). The mixture was heated in a Parr bomb at
165°C for 6 hr.
evaporated and the residue was slurried in aqueous
The product was extracted into
The resulting reaction mixture was
sodium bicarbonate.
dichloromethane, and the extracts were washed with
aqueous sodium bicarbonate and dried over magnesium
sulfate. The organic extracts were evaporated to
dryness to yield an oily solid. The solid was purified
by silica gel column chromatography to yield two
products, the intended product and the 4-(N-methyl)
derivative. The intended product (Rf: 0.36 silica gel
TLC, ethyl acetate eluent) was recrystallized from
ethanol to yield a solid m.p. 190~195°C. Analysis:
Ca1c'd.: C, 67.6; H, 7.1; N, 19.7. Found: C, 67.6; H,
7.1; N, 19.7. The 4—(N-methyl) derivative was
recrystallized from ethyl acetate to give a solid, m.p.
-149°C. Analysis: Calc'd.: C, 68.4; H, 7.4; N, 18.8.
Found: C, 68.3; H, 7.4; N, 18.7.
EXAMPLE 21
a.a—Dimethyl(2-methvlpropvl)-1H-imidazo—
L4,5-clquinolinemethanol
—Amino(2-methylpropyl amino) quinoline
(28.7 g; 0.133 mol) and 2-hydroxyisobutyric acid (27.8
g; 0.267 mol) were mixed and the mixture was heated at
160°C for 5 hrs.
and a green oil formed.
water was added to the dark mixture
The oil was extracted with
.. ..
ether to yield 8.6 g of an oil which contained two
products. The mixture was purified by silica gel
column chromatography to yield 3.2 g of the intended
product. A small amount was recrystallized from ethyl
acetate for analysis and characterization. m.p.
156-164°C. Analysis: Calc'd.: C, 72.1; H, 7.5; N,
14.8. Found: C, 71.9; H, 7.4; N, 14.6.
EXAMPLE 22
—Chloro-a.a-dimethYl(2-methvlpropvl)-
1H-imidazof4.5—c1auinoline—2-methanol
a,a-Dimethyl(2-methylpropyl)—1H—imidazo-
[4,5-cjquinolinemethanol (3.0 g; 0.0106 mol, Example
21) was dissolved in ethanol (30 mL) and 32% peracetic
acid (3.8 mL; 0.0108 mol) was added. The mixture was
heated at 65°C for 4 hr. The solution was concentrated
and the residue was slurried in aqueous sodium
bicarbonate solution. The oily product was extracted
into ethyl acetate. The extracts were dried over
magnesium sulfate and evaporated to dryness. A yield
of 2.8 g of N oxide as a yellow solid was obtained.
The intermediate N oxide was added to dichloromethane
and 1.1 eq of phosphorous oxychloride was added to the
The mixture was stirred at
The
residue was slurried in aqueous sodium bicarbonate and
The product was purified
vigorously stirred mixture.
room temperature overnight and then concentrated.
extracted into ethyl acetate.
by silica gel flash chromatography (10% ethyl acetate
in dichloromethane). A small amount was recrystallized
from ethyl acetate to give a solid, m.p. 205-210°C.
Analysis: C, 64.2; H, 6.3; N, 13.2. Found: C, 64.2; H,
.3; N, 13.1.
RE 23
-Amino-a,a-dimethvl(2-methvlpropvl)-1H-
imidazof4.5-clguinoline-2—methanol
4-Chloro-a,a-dimethyl—1—(2—methylpropyl)-1H-imidazo—
[4,5-c]quinoline—2-methanol (Example 22) was aminated
in a Parr bomb at 150°C using 15% methanolic ammonia.
The product was purified by silica gel column
chromatography (5% methanol in ethyl acetate as
eluent). The product was then recrystallized from
ethyl acetate/hexane to give a solid, m.p. 214-217°C.
Analysis: Calc'd.: C, 68.4; H, 7.4; N, 18.8. Found: C,
.2; H, 7.4; N, 18.7.
EXAMPLE 24
—Phenylmethy1-1H—imidazo[4,5-c]-
guiuolinemethanol
3-amino—4-(benzylamino) quinoline (9.5 g;
.038 mol) and glycolic acid (6.8 g; 0.089 mol) were
mixed and the mixture was heated at 150°C for about 4
hr. The dark mixture was then dissolved in dilute
hydrochloric acid with heating. Upon cooling a
precipitate formed and was filtered from the mixture.
The solid was dissolved in hot water. The solution was
then made basic with ammonium hydroxide to precipitate
the product. A second, less pure, small crop was
obtained from the original filtrate by making it basic
The solid was triturated in
Total
The product was recrystallized from
with ammonium hydroxide.
ethyl acetate to give a green colored powder.
yield was 82%.
methanol to give a pure sample m.p. 211-213°C.
Analysis: Calc'd.: C, 74.7; H, 5.2; N, 14.5. Found: C,
.4; H, 5.1; N, 14.4.
EXAMPLE 25
1-Phenvlmethvl-1H-imidazo{4.5-Cl-
quinoline—2—methvl Acetate
-Phenylmethyl-1H—imidazo[4,5-c]quinoline
methanol (7.5 g; 0.026 mol, Example 24) was added to
dichloromethane (70 mL). Acetic anhydride (5.7 mL) and
pyridine (3.1 mL) were added to the mixture. The
mixture was refluxed for about 6 hr and the solids were
then filtered from the mixture. The filtrate was
evaporated and the residue was filtered, slurried
_ ..
consecutively in water and methanol/water. The solid
was then filtered from the mixture and dried to yield
.7 g (74.4%) of product. The solid was recrystallized
from methanol. m.p. 216—218°C. Analysis: C, 72.5; H,
.2; N, 12.7. Found: C, 72.1; H, 5.1; N, 12.6.
EXAMPLE 26
-Phenvlmethvl-1H-imidazoI4.5-Cl-
guinolinemethyl Acetate SN Oxide
-Phenylmethyl-1H-imidazo[4,S-c]quinoline
methyl acetate (6.7 g; 0.019 mol, Example 25) and 32%
peracetic acid (4.6 mL; 0.0214 mol) were added to a
mixture of ethyl acetate (125 mL) and ethanol (250 mL).
The mixture was refluxed for 6 hr.
evaporated to dryness and the residue was slurried with
The solution was
aqueous sodium bicarbonate solution. The solid was
filtered from the mixture, washed with water, and dried
to yield 7.2 g of crude product. The crude product was
recrystallized from ethyl acetate. m.p. 229—232°C.
Analysis: Calc'd.: C, 69.2; H, 4.9; N, 12.1. Found: C,
69.1; H, 4.9; N, 12.0.
RE 27
-Aminophenvlmethvl-1H~imidazof4,5-c]-
guino1ine—2-methanol
-Phenylmethyl-1H-imidazo[4,5-c]quinoline
methyl acetate SN oxide (5.6 g; 0.0162 mol, Example 26)
was suspended in a mixture of dichloromethane (150 mL)
and ammonium hydroxide (55 mL). The mixture was cooled
to O-5°C. A solution of p—toluenesulfonyl chloride
(3.4 g; 0.0178 mol) in dichloromethane (25mL) was added
dropwise to the vigorously stirred mixture while
maintaining the temperature at 0-5°C. when the
addition was complete the mixture was allowed to stir
at room temperature overnight. The dichloromethane was
then evaporated from the mixture and the solid was
filtered from the mixture. The tan solid was washed
with water and dried to yield 5.5 g of product which
.. ..
was found to be the acetate of the intended product.
The acetate was added to a mixture of methanol (300 mL)
and dichloromethane (100 mL).
basic with 25% methanolic sodium methoxide.
The mixture was made
After
about 1/2 hr the product began to precipitate from
solution. The solid was filtered from the mixture,
washed sequentially with water and methanol, and dried
to yield 3.1 g (64.6%). A sample was recrystallized
from methanol/dichloromethane. m.p. >3oo°c. Analysis:
Ca1c'd.: C, 71.0; H, 5.3; N, 18.4. Found: C, 71.1, H,
.0; N, 18.1.
RE 28
-Ch;oromethyl—1-Qhenylmethyl-1H-imidazo-
r4J5—c1auinolinamine Hydrochloride
-Amino—1—phenylmethyl-1H—imidazo[4,S-c]-
quinolinemethanol (2.0 g; 0.0066 mol, RE 27)
was added in small portions to thionyl chloride (10
mL). After stirring at room temperature for 30 min the
product had crystallized from solution. The mixture
was diluted with dry ether (75 mL). The solid was
filtered from the mixture, washed with ether, and
thoroughly dried. The product was used as such without
further characterization or purification.
RE 29
2-Morgholinomethylphegy1methy;—1H-imidazo-
14.5-clquinolin-4—amine
-Chloromethylphenylmethyl—1H-imidazo-
[4,5-c]quinolin—4-amine hydrochloride ( RE 28,
prepared from 2.0 g of the alcohol) was added to
morpholine (5.0 mL) and the mixture was refluxed for 4
hr. The mixture was then cooled to room temperature
and the solid was filtered from the mixture. The solid
was slurried in aqueous sodium bicarbonate solution,
filtered from the mixture, and dried. A crude yield of
2.0 g of product as a white solid was obtained. The
crude product was recrystallized from
methanol/dichloromethane. m.p. >300°C. Analysis:
Calc'd.: C, 70.7; H, 6.2; N, 18.8. Found: C, 70.4;
H, 6.2; N, 18.6.
RE 30
-Amino-N-hvdroxvethvl-N-methvlphenvlmethv1—1H-
;midazo[4,S—c]ggino1inemethanamine flemihydrate
2-Chloromethyl-1—phenylmethyl-1H-imidazo-
[4,5-c]quinolinamine hydrochloride ( RE 28,
prepared from 1.4 g of the alcohol) was added to
N-methylethanolamine (20 mL).
in an oil bath for 3 hr at about 130°C.
was diluted with water and the mixture extracted with
diethyl ether (7x200 mL).
washed with saturated sodium chloride solution and
The mixture was heated
The solution
The combined extracts were
evaporated to dryness to yield an orange solid. The
crude product was recrystallized from
methanol/dichloromethane. m.p. 188-195°C. Analysis:
Calc'd.: C, 68.1; H, 6.5; N, 18.9. Found: C, 68.4; H,
6.5: N, 18.7.
RE 31
thiometh 1 e meth l-1 -im'dazo—
L4.S-clquinolinamine
2-Chloromethyl-1—phenylmethyl-1H-imidazo-
[4,S-c]quinolinamine hydrochloride ( RE 28,
prepared from 2.11 g of the alcohol) was added to a
solution of methanethiol (1.33 g; 0.028 mol) and sodium
methoxide (1.5g; 0.028 mol) in methanol. The solid
dissolved upon addition and a cream colored solid
After stirring at room
-Met
precipitated during addition.
temperature for several hours the mixture was diluted
with water. The solid was filtered from the mixture,
washed with water, and dried. A crude yield of 2.3 g
was obtained. The product was purified by silica gel
flash chromatography (10% methanol in ethyl acetate
eluent) and recrystallized from
methanol/dichloromethane to give a cream colored solid,
-33..
m.p. 217-219°C. Analysis: Calc'd.: C, 68.2; H, 5.4; N,
16.8. Found: C, 67.5; H, 5.3; N, 15.6.
EXAMPLE 32
-Methoxvmethvl-1*(2-methvlpropvl)-1H-
imidazor4.5-clquinoline
3-Amino—4-(2-methylpropylamino)quinoline
(5.0 g; 0.023 mol) and methoxyacetic acid (20 mL) were
mixed and heated at about 200°C until all bubbling had
stopped. Heating was continued for 5-10 min longer and
the dark solution was allowed to cool to room
temperature. The solution was diluted with water, made
strongly basic with 50% sodium hydroxide and extracted
with ether. The combined extracts were dried over
magnesium sulfate and evaporated to dryness to yield
.2 g of crude product. The crude product was used as
such for further reactions. A small sample was
recrystallized from ether to yield nearly colorless
crystals, m.p. 96—99°C. Analysis: Calc'd: C, 71.4; H,
.1; N, 15.6. Found: c, 71.1; H, 7.0; N, 15.5.
EXAMPLE 33
2—Methoxymethv1(2-methvlpropvl)-1H-
imidazor4.5—c1quinoline SN Oxide Monohydrate
-Methoxymethyl(2-methylpropyl)—1H~
imidazo[4,5—c]quinoline (5.0 g; 0.0186 mol, Example 32)
was added to ethyl acetate (100 mL) containing 32%
peracetic acid (4.9 g; 0.0206 mol). The solution was
refluxed for about 15 min. The solution was then
evaporated. The residue was slurried in aqueous sodium
bicarbonate and the solid was filtered from the
mixture. A second crop was obtained by allowing the
filtrate to stand overnight at room temperature. A
combined yield of 4.6 g (86.8%) of crude product was
obtained. A pure sample was obtained by recrystallized
from isopropyl alcohol. m.p. broad; Analysis: Calc'd.:
C, 63.5; H, 7.0; N, 13.8. Found: C, 63.5; H, 6.7; N,
.8.
-34..
RE 34
2-Methoxvmethvl(2-methvlpropvll-1H-
imidazor4.5—c1quinolin-4—amine
2-Methoxymethyl~l—(2-methylpropyl)-1H-
imidazo[4,5-c]quinoline SN oxide (4.0 g; 0.014 mol,
Example 33) was dissolved in dichloromethane (80 mL).
Concentrated ammonium hydroxide (30 mL) was added to
the solution. The mixture was cooled to 0-5°C and
vigorously stirred as a solution of p-toluenesulfonyl
chloride (2.9 g; 0.015 mol) in dichloromethane (15 mL)
was added dropwise. The temperature was maintained at
0-5°C during addition. when addition was complete the
The
dichloromethane was separated from the aqueous layer,
mixture was stirred at room temperature for 1 hr.
dried over magnesium sulfate, and evaporated to dryness
to yield 1.7 g of a tan powder. Two recrystallizations
from isopropyl alcohol gave an analytically pure
sample, m.p. 157-160°C which analyzes for a quarter
mole of water. Analysis: Calc’d.: C, 66.5; H, 7.2; N,
19.4. Found: C, 66.9; H, 6.9; N, 19.0.
EXAMPLE 35
—{2-Methoxvethyl)methoxymethv1—
1H-imidazof4,5-clquinoline
-(2-Methoxyethylamino)nitroquinoline
(16.24 g; 0.066 mol) was added to a mixture of ethyl
acetate (1500 mL), 5% platinum on carbon (1 g), and
The mixture was hydrogenated
when
magnesium sulfate (6 g).
on a Parr apparatus at 30 psi initial pressure.
the hydrogenation was complete, the solids were
filtered off and the ethyl acetate was evaporated.
resulting diamine intermediate was heated with
methoxyacetic acid (70 mL) at 150°C for 2-3 hours and
then at 120°C for 2-3 hours. The reaction mixture was
poured into water (400 mL), made strongly basic with 6N
sodium hydroxide and then extracted with ether (3 x 200
mL). The ether extracts were combined, washed with I
brine then evaporated to provide 9.9 g of an oil which
-35..
crystallized on standing.
extracted again with ether (4 x 200 mL).
The aqueous layers were
The extracts
were combined, washed with brine and evaporated. The
residue was recrystallized from ethyl acetate to
provide 1.5 g yellow needles. Analysis: Calc'd: C,
66.4; H, 6.3; N, 15.5; Found: C, 66.6; H, 6.4; N, 16.1.
EXAMPLE 36
1-(2—Methoxvethyl)methoxvmethvl-1H-
imidazor4.5-clauinoline SN Oxide
1-(2~Methoxyethyl)methoxymethyl-
1H—imidazo[4,5-c]quinoline (13.3 g, 0.044 mol, Example
) was dissolved in warm ethyl acetate (150 mL) and
32% peracetic acid (12.0 mL) was slowly added to the
solution. The mixture was heated at reflux for 2-3
hours and then allowed to stand at room temperature
overnight. The resulting precipitate was collected,
rinsed with ethyl acetate then coevaporated with
toluene to yield 2.6 g of a solid. The ethyl acetate
filtrate was evaporated. The resulting residue was
taken up in about 300 mL of water and made basic with
concentrated ammonium hydroxide. The resulting
precipitate was collected, rinsed with water,
coevaporated with toluene and dried to provide 5.6 g of
solid. A total crude yield of 8.2 g was obtained and
the material was used in subsequent reactions.
RE 37
-(2-Methoxvethvllmethoxvmethvl-1H-
imidazor4,5—c1quino1inamine
1-(2-Methoxyethyl)-2—methoxymethyl-1H-
imidazo[4,5—c]quinoline SN oxide (7.67 g; 0.027 mol,
Example 36) was dissolved in methylene chloride (100
mL) and cooled to 0-5°C. Cold concentrated ammonium
hydroxide (75 mL) was added with stirring and continued
cooling and a precipitate formed. A solution of
p-toluenesulfonyl chloride (5.59 g; 0.029 mol) in
methylene chloride (20 mL) was slowly added with
continued stirring and cooling. The mixture was
maintained at 0-5°C for about 30 minutes after the
addition and then stirred at room temperature
overnight. The methylene chloride was evaporated from
the mixture and the solid was filtered from the
mixture. The volume of the aqueous filtrate was
reduced under a stream of nitrogen and the resulting
precipitate was collected, rinsed with water and dried
to provide 5.1 g of a solid. The solid was taken up in
water, acidified with concentrated hydrochloric acid
then filtered. The filtrate was made basic with 6N
sodium hydroxide.
collected, rinsed with water and dried to provide
colorless needles, m.p. 126-127°C. Analysis: Calc'd:
C, 62.9; H, 6.3; N, 19.6; Found: C, 62.9; H, 6.05: N,
.3.
The resulting precipitate was
EXAMPLE 38
- t 0 et - - - t 1 o -
1H~imidazo-4.5-clquinoline
4-(2—Methylpropylamino)nitroquinoline
(30.5 g; 0.12 mol) was added to a mixture of ethyl
acetate (800 mL),
magnesium sulfate (10 g).
on a Parr apparatus at an intitial hydrogen pressure of
% platinum on carbon (1.5 g) and
The mixture was hydrogenated
psi. When the hydrogenation was complete, the
solids were removed and the ethyl acetate was
evaporated. The resulting intermediate diamine was
mixed with ethoxyacetic acid (80.5 mL) and heated with
stirring at 130°C for 2-3 hours. The reaction mixture
was cooled, poured into 400 mL of water and then made
basic with 6N sodium hydroxide. A green solid was
collected and dried to provide 8.8 g of the desired
The structure was confirmed by nuclear
The filtrate was
The ether extracts
product.
magnetic resonance spectroscopy.
extracted with ether (4 x 150 mL).
were combined then evaporated to provide 11.2 g of a
_37_
green solid. The solids were combined and used in
subsequent reactions.
EXAMPLE 39
2rEthoxvmethvl—1—[2-methvlpropvl)-
1H-imidazo{4.5-clauinoline SN oxide
2-Ethoxymethyl(2-methylpropyl)—1H—
imidazo[4,5-cjquinoline (17.4 g; 0.061 mol, Example 38)
was dissolved in warm ethyl acetate (150 mL) and 32%
peracetic acid (14.5 mL) was slowly added to the
solution. The mixture was refluxed for 2-3 hours and
then cooled to room temperature. The precipitate was
collected, rinsed with a small amount of ethyl acetate
The
structure was confirmed by nuclear magnetic resonance
and dried to provide 6.3 g of white solid.
spectroscopy. This material was used in subsequent
reactions.
RE 40
Z:Ethoxvmethv1-l-(2-methvlproovl)-
1H-imidazof4.5—cIauinolin—4—am;ne
-Ethoxymethyl(2-methylpropyl)-1H-
imidazo[4,5-c]quinoline SN oxide (6.0 g; 0.02 mol,
Example 39) was suspended in methylene chloride (150
mL) and cooled to 0-5°C. Concentrated ammonium
hydroxide (60 mL) was cooled to 0-5°C and added to the
suspension. A solution of p-toluenesulfonyl chloride
(4.2 g; 0.022 mol) in methylene chloride (20 mL) was
slowly added to the mixture with stirring. The mixture
was allowed to stir at room temperature overnight. The
methylene chloride was evaporated and the resulting
precipitate was collected and rinsed with water to give
6.3 g of crude material. The crude material was
triturated with ether.
with ether and dried to give an analytically pure
sample, m.p. 133-137°C that analyzed for half a mole of
Calc'd: C, 66.5; H, 7.4; N, 18.2;
7.3; N, 13.2.
The solid was collected, rinsed
water.
Found: C,
Analysis:
67.0; H,
EXAMPLE 41
-(3-Methoxypropvlamino)nitroquinoline
-Hydroxynitroquinoline (19.0 g, 0.10 mol)
was suspended in methylene chloride (250 mL). Thionyl
chloride (8.0 mL, 0.11 mol) was combined with
dimethylformamide (8.5 mL, 0.11 mol) and slowly added
to the suspension. The resulting mixture was stirred
and heated at reflux for about 2 hours.
3-Methoxypropylamine (10.25 g, 0.115 mol) was combined
with triethylamine (15 mL, 0.20 mol) and slowly added
to the mixture with stirring. A vigorous heat of
reaction was observed. The mixture was evaporated and
the residue was suspended in water. The suspension was
acidified with concentrated hydrochloric acid. A dark
solid was collected. The filtrate was made basic with
concentrated ammonium hydroxide. The precipitate was
collected, rinsed with water, and dried to provide 8.4
m.p. 93—9S°C. The dark solid was
suspended in 2 liters of water, acidified with
concentrated hydrochloric acid, heated on a steam bath
for 2-3 hours and then filtered while still hot. The
filtrate was made basic with concentrated ammonium
g of a yellow solid,
hydroxide. The precipitate was collected, rinsed with
water, and dried to provide 9.2 g of a yellow solid,
m.p. 93—95°C. Analysis: Calc'd: C, 59.8; H, 5.8; N,
16.1; Found: C, 59.6; H, 5.7; N, 16.0.
EXAMPLE 42
-Ethoxvmethvl—1—(3~methoxvnropvl)-
1H-imidazof4,5-clauinoline
-(3-methoxypropylamino)nitroquinoline
(14.6 g; 0.056 mol, Example 41) was added to a mixture
of ethyl acetate (1300 mL), 5% platinum on carbon (1.0
g), and magnesium sulfate (5.0 g). The mixture was
hydrogenated on a Parr apparatus at an initial hydrogen
pressure of 30 psi. When the hydrogenation was
complete, the solids were removed and the ethyl acetate
was evaporated. The residual intermediate diamine was
mixed with ethoxyacetic acid (60 mL) and heated at
120°C for about 8 hours. The reaction mixture was
cooled to room temperature, poured into water, made
basic with 6N sodium hydroxide and then extracted with
ether (5 x 100 mL).
dried with magnesium sulfate, then evaporated.
The ether extracts were combined,
The
residue was purified by silica gel chromatography (20%
methanol in ethyl acetate as eluent) to give 13.3 g of
a green oil. This material was used in subsequent
reactions.
EXAMPLE 43
2-Ethoxvmethvl(3-methoXvDropV1-
lg-imidazo[4,5-c]gginolige SN Oxide
2-Ethoxymethyl(3-methoxypropyl)-1H-
imidazo[4,S-c]quinoline (13.3 g; 0.044 mol, Example 42)
was dissolved in ethyl acetate (150 mL) and 32%
peracetic acid (12 mL) was slowly added to the
solution. The reaction mixture was heated at reflux
for 3-4 hours then cooled to room temperature. The
mixture was evaporated. The residue was diluted with
water (300 mL),
hydroxide, then extracted with ether (7 x 100 mL).
ether extracts were combined, dried with magnesium
made basic with concentrated ammonium
The
sulfate and evaporated to provide a small amount of a
yellow oil. The aqueous base layer was then extracted
with ethyl acetate (6 x 100 mL). The ethyl acetate
extracts were combined, washed with brine, dried over
magnesium sulfate and evaporated to provide a yellow
solid. The solid was coevaporated with toluene to
provide 3.56 g of a yellow crystalline solid. The
structure was confirmed by nuclear magnetic resonance
spectroscopy. The material was used in subsequent
reactions.
-40..
RE 44
2-Ethox eth - - 3- ethox ro -
1H-imidazof4.5—c1quinolin—4-amine
2~Ethoxymethyl—1—(3-methoxypropyl)—1H-
imidazo[4,5-c]quinolin—4—amine SN oxide (3.5 g; 0.011
mol, Example 43) was dissolved in methylene chloride
(25 mL) and cooled to 0—5°C.
hydroxide (35 mL) was cooled to 0-5°C then added to the
The resulting mixture was stirred for about
Concentrated ammonium
solution.
minutes.
(2.33 g; 0.012 mol) in methylene chloride (10 mL) was
slowly added with stirring. The reaction mixture was
stirred at 0-5°C for an additional 30 minutes and then
A solution of p—toluenesulfony1 chloride
at room temperature overnight. The methylene chloride
was evaporated. The resulting precipitate was
collected, rinsed with water then recrystallized first
from ethyl acetate and then from dichloroethane to give
a crystalline solid, m.p. 123.5-125°C. Analysis:
Ca1c'd: C, 64.95; H, 7.05: N, 17.8; Found: C, 65.0; H,
7.0; N, 17.7.
EXAMPLE 45
-(2-Methvlpropvl)-a-phenvl-1H-
imidazo[4.5-c1auinoline—2-methanol
-Amino(2-methylpropylamino)quinoline
(43.5 g; 0.20 mol) and formic acid (300 mL) were
combined and heated on a steam bath for several hours.
The reaction mixture was concentrated under vacuum,
diluted with water, basified with ammonium hydroxide
then extracted twice with ether. The ether extracts
were treated with activated charcoal then combined for
a total volume of 1200 mL.
500 mL, cooled, then filtered to provide 31.1 g of a
light green crystalline solid
1-(2-methylpropyl)-1H—imidazo[4,5-c]quinoline.
-(2-Methylpropyl)-1H-imidazo[4,5-c]quinoline
(4 g; 0.017 mol) was dissolved in tetrahydrofuran (50
mL) then cooled to —78°C. A 7.75 mL portion of n—butyl
The volume was reduced to
-41..
lithium (2.5 M in hexanes) was added dropwise to the
At 15 minutes post addition,
benzaldehyde (2.7 mL; 0.027 mol) was added and the
reaction mixture was allowed to warm slightly. The
reaction was quenched with water then diluted with
ethyl ether. The ether was separated, dried with
magnesium sulfate then concentrated under vacuum.
cooled solution.
The
resulting residue was purified by silica gel
chromatography using 5% methanol in methylene chloride
as the eluent to give an oily yellow solid. This
material was recrystallized from methylene
chloride/hexane to provide a white crystalline solid,
m.p. 160-166°C. Analysis: Calc'd: C, 76.1; H, 6.4;
N, 12.7; Found: C, 75.9; H, 6.3; N, 12.7.
EXAMPLE 46
-(2-Methylprogyl)-a-ghenyl-1H~
-(2-Methylpropyl)-a—phenyl—1H-
imidazo[4,5-cjquinoline-2—methanol (3 g; 9 mmol,
Example 45) was dissolved in methylene chloride (50 mL)
then combined with acetic anhydride (1.3 mL; 13.5 mmol)
and triethylamine (1.6 mL; 11.8 mol) and stirred at
room temperature overnight. The reaction mixture was
diluted with methylene chloride, washed sequentially
with water and saturated sodium bicarbonate solution,
dried over magnesium sulfate and concentrated under
vacuum. The resulting residue was purified by silica
gel flash chromatography (50% ethyl acetate in
methylene chloride as eluent) to provide a white solid.
The structure was confirmed by nuclear magnetic
resonance spectroscopy .
EXAMPLE 47
2—(a—Acetoxvbenzvl){2-methvlpropvl)-
1H—imidazor4.5-clquinoline SN Oxide
-(2—Methylpropyl)~a—phenyl-1H-
imidazo[4,5-c]quinolinemethyl acetate (3 g; 8 mmol,
Example 46) was dissolved in ethyl acetate (50 mL) then
combined with peracetic acid (2.2 g; 8.8 mmol) and
heated at reflux for about an hour. The reaction
mixture was allowed to cool and then was stirred at
room temperature for several days. The resulting
precipitate was collected, rinsed with ethyl acetate
and dried to provide 2.6 g of a solid. The structure
was confirmed by nuclear magnetic resonance
spectroscopy.
RE 48
—Aminor2—methvlpropvl)—a—phenyl-
1H-imidazof4.5-claUino1ine~2-methanol
2-(a—acetoxybenzyl)-l-(2-methylpropy1)-1H-
imidazo[4,5-c]quinoline SN oxide (2.6 g; 6.7 mmol,
Example 47) was dissolved in methylene chloride (40
mL), combined with benzoyl isocyanate (1.2 g; 7.3 mmol)
and heated at reflux for about one hour. The reaction
mixture was diluted with methylene chloride, washed
with water, dried over magnesium sulfate and
concentrated under vacuum. The residue was taken up in
methanol, combined with a catalytic amount of 25%
sodium methoxide in methanol, and heated at reflux for
several hours. The reaction product was purified by
silica gel chromatography using 2—5% methanol in
methylene chloride then recrystallized from ethyl
acetate-hexane. The recrystallized material was
co-evaporated twice with methylene chloride to provide
about 0.5 g of a solid, m.p. 125—140°C. Analysis:
Calc'd: C, 72.8; H, 6.4; N, 16.2; Found: C, 71.9; H,
.6; N, 15.6. Mass spectrum m/z = 347.
_43_
EXAMPLE 49
2-(a-Methoxvbenzvl)(2-methvlpropvl)-
1H-imidazof4.5-clauinoline
-(2-Methylpropyl)-a-phenyl-1H-
imidazo[4,5-c]quinolinemethanol (5.0 g; 15 mmol,
Example 45) was dissolved in N,N—dimethylformamide (25
mL) then added to a cooled (0-5°C) suspension of sodium
hydride (0.5 g; 16.6 mmol) in N,N-dimethylformamide
(100 mL). The reaction mixture was stirred at room
temperature for about one hour then combined with
methyl iodide (1.4 mL; 22.6 mmol).
continued until the reaction was complete as indicated
by thin layer chromatography. The reaction mixture was
diluted with ether then quenched with water. The ether
layer was separated, washed twice with water, dried
Stirring was
over magnesium sulfate then evaporated under vacuum.
The residue was triturated with methylene
chloride/hexane to provide 4.5 g of a solid. The
structure was confirmed by nuclear magnetic resonance
spectroscopy.
EXAMPLE SO
2-la-Methoxvbenzyl)(2-methvlpropvl)-
H-imidazo[4.5-clquinoline SN oxide
—(a-Methoxybenzyl)-l-(2-methylpropyl)-1H-
imidazo[4,5—c]quinoline (4.5 g; 13 mmol, Example 49)
was dissolved in ethyl acetate (70 mL), combined with
peracetic acid (3.4 g; 14 mmol) and heated at reflux
for several hours. The reaction mixture was diluted
with ethyl acetate, washed with water, dried over
magnesium sulfate and concentrated under vacuum. The
residue was purified by silica gel chromatography (1-5%
methanol in methylene chloride as eluent) to give 3.9 g
of an oil which solidified on standing. The structure
was confirmed by nuclear magnetic resonance
spectroscopy.
-methylene chloride (20 mL) was added.
.
RE 51
2-(a-Methoxvbenzvl)(2-methvlpropyl)-1H—
lmidazof4.5-clauinolinamine
—(a-Methoxybenzyl)(2-methylpropy1)-1H-
imidazo[4,5-c]quinoline SN oxide (3.9 g; 10.8 mmol,
Example 50) was dissolved in methylene chloride (60 mL)
then mixed with ammonium hydroxide (20 mL). The
mixture was cooled in an ice bath while a solution of
p-toluenesulfonyl chloride (2.2 g; 11.8 mmol) in
The reaction
mixture was allowed to warm to room temperature and
then was stirred for several hours. The organic phase
was separated, washed with water, dried over magnesium
sulfate and concentrated under vacuum. The residue was
recrystallized from ethyl acetate/hexane to provide 2.5
g of a solid, m.p. 183-184°C. Analysis: Calculated:
C, 73.3; H, 6.7; N, 15.5; Found: C, 73.1; H, 6.7; N,
.3.
EXAMPLE 52
a-(4—Chlorophenvl)-1—(2-methvlpropvl)-
H-imidazof4.5-clcuinolinemethanol
Using the method of Example 45,
1-(2—methylpropy1)~lH-imidazo[4,5~c]quinoline (2.5 g)
was reacted with 4-chlorobenzaldehyde to provide 3.1 g
of a yellow solid. The structure was confirmed by
nuclear magnetic resonance spectroscopy.
EXAMPLE 53
a—(4-Chlorophenvl)(2—methylpropv1)—1H-
imidazo{4.5-clauinolinemethvl Acetate
Using the method of Example 46,
a-(4-chlorophenyl-l-(2-methylpropyl)-1H—imidazo—
[4,5-c]quinolinemethanol (2.6 g, 7.1 mmol, Example
52) was reacted with acetic anhydride to provide the
desired product as a thick oil. The structure was
confirmed by nuclear magnetic resonance spectroscopy.
_ 45 _
EXAMPLE 54
2-(a-Acetoxv-4—chlorobenzv1)(2-methvlpropvl)-
lH-imidazor4.5—c1quino1ine SN oxide
Using the method of Example 47,
a-(4-chloropheny1)(2—methy1propy1)—1H-
imidazo[4,5-c]quinolinemethyl acetate (2.9 g, 7.1
mmol, Example 53) was oxidized with peracetic acid to
provide the SN oxide as an oil.
RE 55
3;Amino-a-(4-chlorophenvl)(2—methv1propv1)-
;fl-im;dazo[4,5-g]gginglinemethanol
Using the method of RE 48,
2-(a-acetoxychlorobenzyl)(2—methy1propy1)-
1H-imidazo[4,5-c]quinoline SN oxide (3.3 g, 7.8 mmol,
Example 54) was reacted with benzoyl isocyanate and
hydrolyzed to provide 0.8 g of the desired product as a
solid, m.p. 140—145°C. Analysis: Calculated: C,
66.2; H, 5.6; N, 14.7; Found: C, 65.6; H, 5.5; N,
14.4.
EXAMPLE 56
a-Butvl(2-methvlpropvl)-1H-
imidazoI4.5-cIquinoline~2—methanol
Using the method of Example 45,
1-(2-methylpropyl)-1H-imidazo[4,5-cjquinoline (20 g; 89
mmol) was reacted with valeraldehyde to provide 11.6 g
of the desired product as a solid.
EXAMPLE 57
2—(1-Acetoxypentyl)(2-methvlpropv1)-
1H-imidazo[4.5-c]guino;ine
Using the general method of Example 46,
a-butyl(2-methylpropyl)-1H—imidazo[4,5-cjquinoline-2
-methanol (11.6 g; 37 mmol, Example 56) was reacted
with acetic anhydride to provide the desired product.
-46..
EXAMPLE 58
3+(1-Acetoxvnentvl){2—methv1propVl)-
lH-imiQazor4.5-Clauinoline SN Oxide
Using the general method of Example 47,
2-(1-acetoxypentyl)(2-methylpropyl)—1H-
imidazo[4,5-c]quinoline (11.5 g; 32 mmol, Example 57)
was oxidized with peracetic acid to provide the desired
SN oxide.
RE 59
-(1—Acetoxvnentvl)-1—(2-methvloronvl)~
lH-imidazor4.5—c1auinolinamine
Using the general method of RE 51,
-(1-acetoxypentyl)(2-methylpropyl)-1H—imidazo-
[4,S-cjquinoline SN oxide (12 g; 32 mmol, Example 58)
was reacted with tosyl chloride and ammonium hydroxide
to provide the desired amine.
RE 60
&-Amino-a—butvl-l-I2-methylpropvl)-
1H-imidazof4.5-clquinolinemethanol Hemihvdrate
Several drops of 25% sodium methoxide in
methanol were added to a solution of
2—(l—acetoxypentyl)(2-methylpropyl)-1H—imidazo-
[4,5-c]quinolin—4—amine (12 g; 32 mmol, RE 59) in
methanol and the resulting mixture was heated at reflux
The reaction was concentrated
A portion of this
for about one hour.
under vacuum to provide a solid.
solid was taken up in a large volume of methylene
chloride, washed with water, dried over magnesium
sulfate and reduced to a volume of about 50 mL. The
resulting precipitate was collected and dried to
provide 2.6 g of a white crystalline solid, m.p.
208-211°C. Analysis: Calculated: C, 68.0; H, 8.1; N,
16.7; Found: C, 67.8; H, 7.7; N, 16.6.
RE 61
- 1- ethox e t - - -meth o —
-imidazor4.5-clauinolinamine
Sodium hydride (0.32 g; 10.1 mmol) was added
to a suspension of 4-amino-a—butyl(2—methylpropyl)-
1H-imidazo[4,5-c]quinolinemethanol (3 g; 9.2 mmol,
RE 60) and the resulting mixture was stirred for
about 2 hours. Methyl iodide (0.82 mL; 13.8 mmol) was
added to the mixture and stirring was continued
overnight. Thin layer chromatography indicated that
the reaction was incomplete so sodium hydride (0.25 g)
was added followed two hours later by methyl iodide (1
mL). The reaction was stirred for several additional
hours then quenched with water and diluted with ethyl
acetate. The organic layer was separated, washed with
water, dried over magnesium sulfate and concentrated
under vacuum to provide an oil. The oil was purified
by silica gel chromatography (1—3% methanol in
methylene chloride as eluent) to provide 0.5 g of a
solid, m.p. 125-128°C. Analysis: Calculated: C,
70.55; H, 8.3; %N, 16.5; Found: C, 70.2; H, 8.3; N,
16.0.
RE 62
2-f1-(1-Morpholino}pentvl1(2-methvlpropvl)-
1H-imidazof4.5-clquinolinamine
Thionyl chloride (1 mL; 13.8 mmol) was added
to a chilled (0-5°C) suspension of 4-amino-a-butyl
(2—methy1propy1)-1H-imidazo[4,5-c]quinolinemethanol
(3 g; 9.2 mmol, RE 60) in methylene chloride (30
mL). The resulting mixture was stirred for several
hours. Morpholine (8 mL; 90 mmol) was added and the
reaction mixture was heated at reflux until thin layer
chromatography indicated that the reaction was
complete. The reaction mixture was diluted with
additional methylene chloride, then water and ammonium
hydroxide were added. The organic layer was separated,
washed with water, dried over magnesium sulfate and
concentrated under vacuum. The residue was purified by
sequential silica gel chromatography using ethyl
acetate as the eluent in the first column and 1—4%
methanol in methylene chloride as the eluent in the
second column to give about 1 g of the desired product
as a solid m.p. 95-100°C which analyzes for a third of
Calculated: C, 68.8, H,
.1; N, 17.4.
a mole of water. Analysis:
8.45; N, 17.4; Found: C, 68.7; H,
EXAMPLE 63
a-Methvl-1~(2-methvlpropvl)-1H-
imidazo[4,5-c]ggino;inemethanol
Using the general method of Example 45,
1-(2-methylpropyl)-1H-imidazo[4,5-cjquinoline (20 g; 89
mmol) was reacted with acetaldehyde to provide the
desired product. The structure was confirmed by
nuclear magnetic resonance spectroscopy.
EXAMPLE 64
2-(1-Methoxvethvl)(2—methvlpropvl)-
1H—imidazof4.5-cluuinoline
Using the general method of Example 49,
a-methyl(2-methylpropyl)—1H-imidazo[4,5-c]quinoline—
2-methanol (3 g; 11 mmol, Example 63) was reacted with
methyl iodide to provide 2.4 g of the desired product.
The structure was confirmed by nuclear magnetic
resonance spectroscopy.
EXAMPLE 65
2-(1-Methoxvethvl)(2-methylpropvl)—
lH-imidazor4.5-clauinoline 5N Oxide
Using the general method of Example 50,
2—(1-Methoxyethyl)(2-methylpropyl)-1H-
imidazo[4,5—c]quino1ine (2.4 g; 8.5 mmol, Example 64)
was oxidized using peracetic acid to provide the
desired SN oxide.
RE 56
-(L-uethoxyethyl)-;-(2-methylp;opyll-
1H-imidazo[4,5-c]gginolin—4-amine
Using the general method of RE 51,
2-(1-methoxyethyl)—1~(2-methylpropyl)-1H-imidazo-
[4,S-cjquinoline SN oxide (2.4 g; 8 mmol, Example 65)
was aminated to provide 1 g of the desired product as a
crystalline solid, m.p. 185-189°C which analyzes for
one fourth of a mole of water. Analysis: Calculated:
C, 67.4; H, 7.5; N, 18.5; Found: C, 67.7; H, 7.4; N,
18.1.
EXAMPLE 67
a-Methvl(2—methv1nropvl)-1H-imidazo-
LA.5—c1quinoline—2—methY1 Acetate
Using the general method of Example 46, a-
methyl—1-(2-methylpropyl)~lH-imidazo[4,5-c]-
quinoline—2—methano1 (5.89, 0.02 mol, Example 16) was
reacted with acetic anhydride to provide the desired
product.
EXAMPLE 68
2-[1-Acetoxvethvl)(2-methvlproDvl)-
1H—imidazo[4,5-c]guino1ine SN Oxide
Using the general method of Example 47 a-
methyl—l-(2—methy1propyl)—1H-imidazo[4,5-c]—
quinolinemethyl acetate, (6.3 g 0.02 mol, Example
67) was oxidized with peracetic acid to provide the
desired SN oxide as a solid. The structure was
confirmed by nuclear magnetic resonance spectroscopy.
Using the general method of RE 51, 2-(1-
acetoxyethyl)(2—methylpropyl)-1H—imidazo[4,5-
c]quinoline SN oxide (4.1 g 2.5 mmol, Example 68) was
aminated to provide the desired product as a solid,
m.p. 152—155°C which analyzes as containing one fourth
of a mole of water. Analysis: Calculated %C 65.3; %H,
6.8; %N, 16.9; Found: %C, 65.5; %H, 6.8; %N, 16.9.
EXAMPLE 70
-(2-Methoxyethyl)—1-(2-methylpropyl)-
1H-imidazof4,5—c|guinoline
Using the general method of Example 45, 2-
methyl(2-methylpropyl)~1H—imidazo[4,S-c]-
quinoline (2 g 8.4 mmol,) was reacted with 2-
chloroethyl methyl ether (0.76 mL, 10 mmol) to provide
the desired product. The structure was confirmed by
nuclear magnetic resonance spectroscopy.
EXAMPLE 71
2-(2~Methoxvethv1)—1—{2—methvlnropyl)-
1H—imidazor4,5-c]quinoline SN Oxide
Using the general method of Example 47, 2-(2-
methoxyethyl)—1—(2-methylpropyl)-1H—imidazo—
[4,S-c]quinoline (1 g, 3.5 mmol, Example 70) was
oxidized with peracetic acid to provide 0.75 g of the
desired SN oxide as a yellow solid. The structure was
confirmed by nuclear magnetic resonance spectroscopy.
RE 72
2-(2-Methoxvethvl)(2-methv1propv1)-
1H-imidazof4;5—cJquino1inyming
Using the general method of RE 51, 2—(2-
methoxyethyl)(2-methylpropyl)-1H-imidazo[4,5—
c]quinoline 5N oxide (0.75 g, Example 71) was aminated
to provide 0.4 g of the desired product as a solid,
m.p. 168—170°C. Analysis: Calculated: %C, 68.4; %H,
7.4; %N, 18.8; Found: %C, 68.4; %H, 7.4; %N, 18.6.
_5l_.
EXAMPLE 73
lrfl-(2-Methvlpropyl)-1H-imidazof4.5-cl
quinolin—2-yllpropanone
c]guinolinyl]propan—2-one (8 g, 28.4 mmol, Example
73) was suspended in ethanol (400 mL). Sodium
borohydride (1.64 g, 43.3 mmol) was added and the
reaction mixture was stirred at room temperature for
about 2 hours. Methanol (about 20 mL) was added and
stirring was continued over night. Water was added then
the solvents were removed under vacuum. The residue was
partitioned between methylene chloride and water. The
methylene chloride layer was separated, dried over
magnesium sulfate then concentrated under vacuum to
give the desired product. The structure was confirmed
by nuclear magnetic resonance spectroscopy.
EXAMPLE 75
2-(2-Methoxvpropvl)(2-methvlpropvl)-
1H-imidazor4.5-clquinoline
a—Methyl(2—methy1propy1)—1H-imidazo[4,5-
c]quino1ineethanol (6.5 g, 23 mmol, Example 74) was
-52..
dissolved in N,N-dimethylformamide (50 mL) then cooled
to 0°C. Sodium hydride (0.8 g, 25 mmol), 80%
dispersion in mineral oil) was added and the resulting
mixture was stirred at 0°C for about 1 hour. Methyl
iodide (2.2 mL, 34 mmol) was added and the resulting
mixture was stirred at 0°C for about 1 hour and then
allowed to warm to room temperature. The reaction was
quenched with water and then diluted with ethyl
acetate. The organic layer was separated, washed
several times with water, dried over magnesium sulfate
then concentrated under vacuum. The resulting residue
was purified by silica gel chromatography using 2—5%
methanol in methylene chloride to give about 3 g of the
desired product. The structure was confirmed by nuclear
magnetic resonance spectroscopy.
EXAMPLE 76
2:(2-Methoxvpropvl)(2-methvlpropvl)-
1H-imidazor4.5-clquinoline 5N Oxide
Using the general method of Example 47, 2-(2-
methoxypropy1)(2-methylpropyl)-lH-imidazo[4,5-
cjquinoline (3 g, 10 mmol, Example 75) was oxidized
with peracetic acid to provide 2.1 g of the desired SN
oxide as a solid, m.p. 125-130°C. The structure was
confirmed by nuclear magnetic resonance spectroscopy.
RE 77
2-(2-Methoxvnropvl)(2-methylpggpyll-
1H-imidazor4.5-c1auinolin—4—gmigg
Using the general method of RE 51,
methoxypropyl)(2-methylpropyl)-1H-imidazo-
[4,5-c]quinoline SN oxide (2 g, 6.4 mmol, Example 76)
was aminated to provide 1.3 g of the desired product as
a solid, m.p. 139-141°C. Analysis: Calculated: %C,
69.2; %H, 7.7; %N, 17.9; Found: %C, 69.1; %H, 7.8; %N,
17.8.
-(2-
-53..
EXAMPLE 78
a-Methvl(2-methvlpropvl)—1H-
imidazof4.5-clquinolineethyl Acetate
Using the general method of Example 46, a-
methyl(2—methylpropy1)-1H-imidazo[4,5—c]-
quinoline-2~ethanol (9.4 g, 33 mmol, Example 74) was
reacted with acetic anhydride to provide the desired
product. The structure was confirmed by nuclear
magnetic resonance spectroscopy.
EXAMPLE 79
2-(2-Acetoxvpropvl)(2-mgthylpropyl)-
1H-imidazo[4,5-c]gQino1ine SN Oxide
Using the general method of Example 47, a-
methyl(2-methylpropyl)-1H-imidazo[4,5-c]-
quinolineethyl acetate (10.7 g, 33 mmol, Example 78)
was oxidized with peracetic acid to provide the desired
SN oxide. The structure was confirmed by nuclear
magnetic resonance spectroscopy.
Using the general method of RE 2~(2-
acetoxypropyl)(2-methylpropyl)-1H—imidazo-
[4,S—c]quinoline SN oxide (10.5 g, 30 mmol, Example 79)
was aminated to provide the desired product. The
structure was confirmed by nuclear magnetic resonance
spectroscopy.
RE 81
4-Amino-a—metgy1-;-fa-methylpropyl1-
;fi;;midazoI4.5—c]quino1ine—2-ethanol
Using the general method of R3
amino—a—methy1—1—(2-methylpropyl)—1H-imidazo-
(4.5-c]quinoline—2-ethyl acetate (10.2 g, 30 mmol,
RE 80) was hydrolyzed to provide 2 g of the
, 4-
desired product as a solid, m.p. 196-197.5°C. Analysis:
_ 54 -
%C, 68.4; %H, 7.4; %N,
18.9.
Calculated : Found: %C,
.6; %H, 7.5; %N,
.8;
EXAMPLE 82
7-Chloro(2—hvdroxvmethvlpropvlamino)-
3-nitroguinoline
Using the general method of Example 41, 7-
chloro—4-hydroxynitroquinoline (18 g, 80 mmol,) was
chlorinated using thionyl chloride. After the
chlorination was complete, as indicated by thin layer
chromatography, the reaction mixture was allowed to
cool to room temperature. Triethylamine (28 mL, 200
mmol) and 2-aminomethy1—2-propanol (10.3 g, 96 mmol)
were added and the reaction mixture was heated at
reflux for about 1 hour. The reaction mixture was
cooled in an ice bath and the resulting precipitate was
collected and dried to provide the desired product as a
solid. The structure was confirmed by nuclear magnetic
resonance spectroscopy.
RE 83
7-Chloro—a.a—dimethvl—2-ethoxvmethvl-
1H-imidazof4.5-clquinoline-1~ethanol
Using the general method of Example 42, 7-
chloro—4-(2~hydroxymethylpropylamino)—3~
nitroquinoline (18.5 g, 63 mmol, Example 82) was
reduced and the resulting diamine reacted with
ethoxyacetic acid to provide the desired product as a
thick, green oil.
RE 84
7—Ch1oroethoxymethvl(2-hvdroxvmethvlpropvl)-
1H-imidazo{4.5-clquinoline SN Oxide
Using the general method of Example 47, 7-
chloro-a,a-dimethylethoxymethyl-1H-imidazo-
[4,5-c]quinolineethanol (20.9 g, 63 mmol, RE
83) was oxidized with peracetic acid to provide 14.8 g
of the desired oxide as a solid.
-55..
RE 85
4-Aminochloro-a.a-dimethvlethoxvmethv1-
lH—imidazof4.5—c1quino1ine—1—ethanol
Using the general method of RE 51, 7-
chloro-2—ethoxymethyl(2-hydroxymethylpropyl)-1H-
imidazo[4,5-c1quinoline SN oxide (14.8 g, 42 mmol,
) was aminated to provide 8.6 g of the
desired product as a solid, m.p. 238-240°C. Analysis:
Calculated: %C, 58.5; %H, 6.1; %N, 16.1; Found: %C,
58.4; tn, 6.0; %N, 16.0.
RE 86
a,a—Dimethy1hydrogymethx;—;H-
imidazo[4.5-c]ggino1ineethanol
Using the general method of Example 24, 3-
amino(2-hydroxy—2-methylpropylamino)quinoline (45 g,
0.19 mol) was reacted with glycolic acid to provide
.7 g of the desired product as a tan solid. The
structure was confirmed by nuclear magnetic resonance
spectroscopy.
RE 87
1-(2-Hydroxy-2—methylpropyl)-
1H~imidazoI4.5—c1quinoline—2-methvl Acetate
Using the general method of Example 2, a,a-
dimethyl—2-hydroxymethyl-1H—imidazo[4,5-c]quinoline
ethanol (35.0 g, 0.13 mol, RE 86) was reacted with
acetyl chloride to provide 32.3 g of a tan solid.
Nuclear magnetic resonance spectroscopy showed that the
tan solid contained the desired product plus about 10
percent of the diester. The material was used without
additional purification.
RE 88
2-Acetoxvmethvl(2-hvdroxvmethvlpropyl)—
H-imidazo[4,5-c]guino1ine 5N Oxide
Using the general method of Example 47, 1-(2-
hydroxymethylpropyl)-1H-imidazo[4,5-c]quinoline—2-
methyl acetate (31 g, RE 87) was oxidized with
peracetic acid to provide 19.6 g of crude SN oxide.
RE 89
4-Chloro{2-hvdroxvmethylpropyl)-
1H-imidazo{4.5—c1quinolinemethyl Acetate
A 16.7 g portion of the crude SN oxide
prepared in R5 88 was suspended in methylene
chloride (1200 mL).
was added to the suspension with vigorous stirring over
a period of about 5 minutes. After about 1.5 hours, the
Phosphorous oxychloride (3.5 mL)
reaction mixture was filtered to remove 7.9 g of a
solid. The methylene chloride filtrate was combined
with phosphorous oxychloride (1.2 mL) and stirred at
room temperature for about 20 hours. Saturated sodium
bicarbonate solution (250 mL) was added with stirring
to the reaction mixture. The layers were separated. The
aqueous layer was extracted with methylene chloride.
The methylene chloride layers were combined, dried over
magnesium sulfate and concentrated under vacuum to
provide 10.2 g the desired product as a tan solid. The
structure was confirmed by nuclear magnetic resonance
spectroscopy.
RE 90
—Amino-a.a—dimethYl-2—hvdroxvmethy1-
1H-imidazof4.5-clquinolineethanol
Using the general method of RE 9, 4-
chloro—1-(2-hydroxymethylpropyl)—1H-imidazo-
[4,5-c]quinoline-2—methy1 acetate (8.3 g, 24 mmol,
RE 89) was aminated to provide 2.3 g of the
desired product as a solid, m.p. 264-271°C. Analysis:
Calculated: %C, 62.9; %H, 6.3; %N, 19.6; Found: %C,
62.9; %H, 6.3; %N, 19.3.
_ 57 -
EXAMPLE 91
-Amino(phenylmethylamino)quinoline (4 g,
16 mmol) was combined with ethoxyacetic acid (4.5 mL,
48 mmol) and heated at 120°C for about 3 hours. The
reaction mixture was cooled to room temperature,
diluted with water and then made basic with ammonium
hydroxide. The resulting precipitate was collected to
provide 5.3 g of the desired product as a solid. The
structure was confirmed by nuclear magnetic resonance
spectroscopy.
EXAMPLE 92
2-Et o eth 1 en lmeth 1-
H-imidazoL4.5-clquinoline SN Oxide
Using the general method of Example 47, 2-
ethoxymethyl-1—phenylmethyl—1H-imidazo[4,5-c]-
quinoline (4.5 g, 14 mmol, Example 91) was oxidized
with peracetic acid to provide 3.2 g of the desired SN
oxide as a solid.
RE 93
2- thox eth 1- - en lmet —
1H-imidazo[4,5-c]gyinolin—4-amine
Using the general method of RE 51, 2-
ethoxymethylphenylmethy1-1H-imidazo[4,5—c}-
quinoline SN oxide (3.2 g, 9.6 mmol, Example 92) was
aminated to provide 1.1 g of the desired product as a
solid, m.p. 204-205°C. Analysis: Calculated: %C, 72.3;
%H, 6.1; %N, 16.9; Found: %C, 72.1; %H, 5.7; %N, 16.6.
RE 94
a,a-Dimethy;methogymethy1-
1H-imidazo[4,5-c]guinolineethanol
—Amino-4—(2-hydroxy—2-
methylpropylamino)quinoline (7.5 g, 32 mmol) was
combined with methoxyacetic acid (7.5 mL, 97 mmol) and
-58..
heated at about 170°C for about 3 hours. The resulting
soid residue was dissolved in ethyl acetate (150 mL).
The ethyl acetate solution was extracted twice with 0.2
N sodium hydroxide, washed with water, dried over
magnesium sulfate, treated with activated charcoal and
then concentrated to a volume of about 50 mL. Hexane
was added to the ethyl acetate and the resulting
precipitate was collected and dried to provide 0.9 g of
the desired product as a crystalline solid, m.p. 145-
148°C. Analysis: Calculated: %C, 67.3; %H, 6.7; %N,
14.7; Found: %C, 67.2; %H, 6.6; %N, 14.6.
RE 95
- - O - - t - _ _
Using the general method of Example 47, a,a-
dimethylmethoxymethyl—1H—imidazo[4,5-c]-
quinolineethanol (6.6 g, 23 mmol, RE
oxidized with peractetic acid to provide 5.7 g of the
desired SN oxide. A small sample was recrystallized
) was
from ethyl acetate to provide an analytical sample,
m.p. 175-197°C. Analysis: Calculated: %C, 63.8; %H,
6.4; %N, 14.0; Found: %C, 63.8; %H, 6.4; %N,_13.8.
RE 96
Using the general method of RE 51, 1-(2-
hydroxymethylpropyl)-2—methoxymethyl-1H-imidazo[4,5-
c]quinoline SN oxide (4.7 g, 16 mmol, R3 95) was
aminated to provide 2.4 g of the desired product as a
solid, m.p. 204-207°C. Analysis: Calculated: %C, 64.0;
%H, 6.7; %N, 18.6; Found: %C, 64.1; %H, 6.8; %N, 18.6.
RE 97
g;a-DimethylethoxvmethYl-
H—imidazo{4_5-c1quinolineethanol
Using the general method of Example 91, 3-
amino(2—hydroxy—2—methylpropylamino)quinoline (46.2
g. 0.20 mol) was reacted with ethoxyacetic acid (62.5
g, 0.6 mol) to provide 53.6 g of crude product as a
greyish solid. A small amount was recrystallized from
toluene to provide 3.6 g of a colorless solid, m.p.
l17—120°C. Analysis: Calculated: %C 68.2; %H, 7.1; %N,
14.0; Found: %C, 68.5; %H, 7.1; %N, 14.0.
RE 98
-Et o eth l - ox meth 1 o
lH-imidazo[4.5-c]gginoline SN Oxide
Using the general method of Example 47, a,a-
dimethyl-2—ethoxymethyl-1H-imidazo[4,S-c]quinoline—1-
ethanol (59.9 g, 97) was oxidized with
peracetic acid to provide 59.9 g of crude 5N oxide as a
.2 mol, RE
solid.
RE 99
4—Amino-a;a-dimethylethoxvmethyl-
1H—imidazor4.5-clquinolineethanol
Using the general method of RE 51, 2-
ethoxymethyl(2-hydroxymethylpropyl)-1H-
imidazo[4,5-c]quinoline SN oxide (30.0 g, 0.095 mol,
RE 98) was aminated to provide 25.7 g of crude
product as an off white solid. A portion (20.3 g) of
the crude product was suspended in methanol (125 mL)
and methylene chloride (60 mL) was added to the
suspension. The resulting solution was treated with
charcoal then filtered. The filtrate was evaporated
under heat to remove the methylene chloride and reduce
the total volume to about 110 mL. The solution was then
allowed to cool to room temperature. The resulting
precipitate was collected, rinsed with methanol and
dried to provide 12.1 g of the desired product as a
-60..
colorless crystalline solid, m.p. 190—193°C. Analysis:
Calculated: %C, 65.0; %H, 7.1; %N, 17.8; Found: %C,
64.8; %H, 7.1; %N, 17.9.
RE 100
-Chloro-a.a—dimethvl—2—ethoxvmethyl-
1H-imidazo[4,5—c1quinoline—1-ethanol
3-Amino-2—chloro-4—(2—hydroxy
methylpropylamino)quinoline (2.0g, 7.5 mmol) was
combined with acetonitrile (80 mL). Ethoxyacetyl
chloride (0.92g, 7.5 mmol) was added to the reaction
mixture. After about 5 minutes a yellow precipitate
formed. p-Toluenesulfonic acid (0.1 g) was added and
the reaction mixture was heated to reflux. Refluxing
was continued for about 120 hours at which time the
reaction mixture was homogeneous. The reaction mixture
was cooled and the acetonitrile was removed under
vacuum. The resulting residue was dissolved in
methylene chloride and washed with dilute ammonium
hydroxide. The aqueous phase was extracted with
methylene chloride (3 x 25 mL). The organic phases
were combined, dried over magnesium sulfate and then
concentrated to provide 2.6 g of crude product as a
dark yellow solid. The crude product was recrystallized
from t-butylmethyl ether to provide 1.8 g of a solid.
The structure was confirmed by nuclear magnetic
resonance spectroscopy.
RE 101
4—Amino-a,a-dimethylethoxvmethvl-
1H-imidazo[4.5-c1quinoline~1—ethanol
4-Ch1oro—a,a—dimethylethoxymethy1—1H~
imidazo[4,5-cjquinoline-1—ethanol (1.0 g, 3 mmol,
RE 100) and 7% methanolic ammonia (30 mL) were
placed in a steel pressure vessel at about 150-160°C
for 6 hours. The vessel was cooled to below room
temperature and the reaction solution removed and
treated with methanolic potassium hydroxide. The
-61..
solution was then evaporated to a low volume and
diluted with water. The resulting precipitate was
collected, washed with water and dried to provide 0.7 g
of the crude product as a solid. The crude product was
recrystallized from a mixture of ethyl acetate and
methanol to provide a colorless solid.
EXAMPLE 102
EXAMPLE 103
-Met 0 eth - - en
1H-imidazo[4.5-clquinoline 5N Oxide
Using the general method of Example 47, 2-
methoxymethylphenylmethyl-1H-imidazo[4,5-c]-
quinoline (4.4 g, 14.5 mmol, Example 102) was oxidized
with peracetic acid to provide 3 g of the desired SN
e 1-
oxide as a solid.
RE 104
Using the general method of RE 51, 2-
methoxymethyl-1—phenylmethyl-1H-imidazo[4,5-c]-
quinoline SN oxide (3 g, 9 mmol, Example 103) was
aminated to provide 2.0 g of the desired product as a
solid, m.p. 202-204°C. Analysis: Calculated: %C, 71.7;
%H, 5.7; %N, 17.6; Found: %C, 71.4; %H, 5.7; %N, 17.4.
_ 52 _
ANTIVIRAL ACTIVITY AND INTERFERON INDUCTION
IN GUINEA PIGS
The test methods described below demonstrate
the ability of the
number and severity of lesions developed by guinea pigs
infected with Type II Herpes simplex virus and to
induce the biosynthesis of interferon in guinea pigs.
Female Hartley guinea pigs weighing 200 to
250 g are anesthetized with methoxyflurane (available
under the tradename METAFANE"‘from Pitman-Moore, Inc.,
Washington Crossing, NJ), after which the vaginal area
compounds to reduce
is swabbed with a dry cotton swab. The guinea pigs are
then infected intravaginally with a cotton swab
saturated with Herpes simplex virus Type II strain 333
(1 X 10’plaque forming units/mL). Guinea pigs are
assigned to groups of 7 animals; one group for each
treatment and one to serve as a control (vehicle
treated).
formulated in water containing 5% Tween 80 (a
polyoxyethylene sorbitan monooleate available from
Aldrich Chemical Company, Inc., Milwaukee, WI). The
guinea pigs are treated orally once daily for four
The compounds of the invention are
consecutive days starting 24 hours after infection.
Antiviral Activity
Antiviral activity is evaluated by comparing
lesion development in compound-treated versus vehicle-
treated guinea pigs. External lesions are scored 4, 7,
8 and 9 days after infection using the following scale:
0 - no lesion, 1 - redness and swelling, 2 - a few
small vesicles, 3 - several large vesicles, 4 - large
ulcers with necrosis and 5 - paralysis. The maximum
lesion score of each guinea pig is used to calculate
the percentage lesion inhibition. The percentage
lesion inhibition is calculated as follows:
maximum lesion scores of treatment qroup x 100'
100- 2 maximum lesion scores of control group
-63..
Interferon Induction
Twenty—four hours after the initial dose of
test compound has been administered, blood is obtained
from 3 guinea pigs from each treatment group by cardiac
puncture of methoxyflurane anesthetized animals. Blood
is pooled and allowed to clot at room temperature.
After low speed centrifugation, serum is collected and
stored at -70°C until analysis.
Interferon levels in the guinea pig serum are
determined in a standard microtiter assay using
transformed guinea pig cells (ATCC CRL 1405). The
interferon assay is done in 96 well microtiter plates.
Confluent monolayers of transformed guinea pig cells
are treated with dilutions of guinea pig serum made
with medium 199 (GIBCO, Grand Island, NY). The cell
and serum dilutions are incubated at 37°C overnight.
The following day, the medium and serum are removed and
about 10 plaque forming units of Mengovirus are added
to each well. Controls consist of wells that receive
no guinea pig serum (virus positive control) and wells
that receive no virus (virus negative control). Cells
and virus are incubated for 2 to 3 days at 37°C before
quantifying for viral cytopathic effect. The viral
cytopathic effect is quantified by staining with 0.05%
crystal violet followed by spectrophotometric
absorbance measurements. The titer of interferon in
serum is expressed as units/mL and is the reciprocal of
the highest dilution that protects cells from virus.
Results are shown in the table below.
_64...
Antiviral Activity and Interferon Induction
in Guinea Pigs
Compound of Dose % Lesion Reference
RE ma/kq lflfliflifilgfl Units[mL
9 2 37% 266
0.5 29% not run
11 1 100% >12,800
11 0.5 100% >l2,80O
11 0.1 50% not run
12 2 100% >l2,800
12 0.5 82% >12,800
13 2 67% not run
2 100% not run
These results show that the tested compounds
simplex type II
Those compounds tested were also shown
inhibit Herpes virus lesions
in guinea pigs.
to induce interferon biosyntheseis in guinea pigs.
INTERFERON-a INDUCTION IN HUMAN CELLS
The test methods described below demonstrate
the ability of to the
biosynthesis of interferon-a in human cells.
An in vitro human blood cell system was used
compounds induce
to assess interferon—a induction by compounds of the
invention. Activity is based on the measurement of
interferon secreted into culture medium. Interferon is
measured by bioassay.
Blood Cell Preparation for Culture
Whole blood is collected by venipuncture into
EDTA vacutainer tubes. Peripheral blood mononuclear
cells (PBM) are prepared by LeucoPREP”‘Brand Cell
Separation Tubes (available from Becton Dickinson) and
cultured in RPMI 1640 medium (available from GIBCO,
Grand Island, NY) containing 25 mM HEPES
4-(2—hydroxyethylpiperazine-N‘ethanesulfonic acid
and L-glutamine (1% penici11in—streptomycin solution
added) with 10% autologous serum added. Alternatively,
whole blood diluted 1:10 with RPMI 1640 medium
supplemented with 25 mM HEPES and L—glutamine with 1%
pencillin-streptomycin solution added can be used. 200
uL portions of diluted whole blood or of PBM in medium
are added to 96 well (flat bottom) MicroTestT“III tissue
culture plates.
Compound Ezgpgratiog
The compounds are solubilized in water,
ethanol, or dimethyl sulfoxide then diluted with
distilled water, 0.01N sodium hydroxide or 0.01N
hydrochloric acid. (The choice of solvent will depend
on the chemical characteristics of the compound being
tested.)
concentration range of from about 0.1 pg/mL to about 5
pg/mL.
concentration of 0.5 pg/mL are then tested in a
Compounds are initially tested in a
Compounds that show induction at a
concentration range of 0.01 pg/mL to 5.0 pg/mL.
Incubation
The solution of test compound is added (in a
volume less than or equal to 50 uL) to the wells
containing 200 pL of PBM in medium or diluted whole
blood. Solvent and/or medium is added to control wells
(i.e., wells with no test compound) and also as needed
to adjust the final volume of each well to 250 uL. The
plates are covered with plastic lids, vortexed gently
and then incubated for 24 hours at 37°C with a 5%
carbon dioxide atmosphere.
Separation
Following incubation, the plates are covered
with PARAFILM“‘and then centrifuged at 1000 rpm for 15
minutes at 4°C in a Damon IEC Model CRU-5000
centrifuge. Medium (about 175 uL) is removed from 4 to
8 wells and pooled into 2 mL sterile freezing vials. A
Samples are maintained at —70°C until analysis.
_ 55 _
Interferon Analysis/Calculation
Interferon is determined by bioassay using
A549 human lung carcinoma cells challenged with
encephalomyocarditis. The details of the bioassay
method are described by G. L. Brennan and L. H.
Kronenberg in "Automated Bioassay of Interferons in
Micro—test Plates", Biotechniques, June/July; 78,
1983., incorporated herein by reference. Briefly
stated the method is as follows: interferon dilutions
and A549 cells are incubated at 37°C for 12 to 24
hours. The incubated cells are infected with an
inoculum of encephalomyocarditis virus. The infected
cells are incubated for an additional period at 37°C
before quantifying for viral cytopathic effect. The
viral cytopathic effect is quantified by staining
followed by spectrophotometric absorbance measurements.
Results are expressed as a interferon reference
on the value obtained for NIH HU IF—L
interferon was identified as essentially
alpha by testing in checkerboard
units/mL based
The
all interferon
standard.
neutralization assays againt rabbit anti-human
interferon (beta) and goat anti-human interferon
(alpha) using A549 cell monolayers challenged with
encephalomyocarditis virus. Results are shown in the
table below wherein the absence of an entry indicates
that the compound was not tested at the particular dose
concentration. Results designated as "<" a certain
number indicate that interferon was not detectable in
amounts above the lower sensitivity level of the assay.
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_70-
These results show that the tested compounds
induce interferon biosynthesis at detectable
levels in human whole blood and/or PBM cells over a
wide range of dose concentrations.
INTERFERON INDUCTION IN MICE
The test methods described below demonstrate
the ability of to
interferon biosynthesis in mice.
For each dose level being tested, three
groups (three mice per group) of CFW male mice
compounds induce
(nonfasted; weighing 23-28 g) are dosed orally with
compound. One hour later blood samples are withdrawn
from the first group. The samples are pooled then
centrifuged. The serum is removed from the centrifuge
then placed in freezing
This
procedure is repeated at 2 hours with the second group
tube, split into two portions,
vials and maintained at —70°C until analysis.
of mice and at 4 hours with the third group of mice.
Interferon AnalYsislCalcu1ation
Samples are assayed as described above in
connection with the analysis of interferon induction in
human cells. The results are expressed in the table
below as a/E reference units/mL based on the value
obtained for a mouse MU-1—IF standard.
shown in the table below wherein results designated as
Results are
"<" a certain number indicate that interferon was not
detectable in amounts above the lower sensitivity level
of the assay.
Compound of
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11
12
12
13
13
Interferon Induction in Mice
Dose
mg[kg
Reference Units/mL
hr 2 hr 4 hr
2900 5000 4
330 740 $47
$47 547 <47
<47 <47 <47
<12O <12O 600
<12O <12O <12O
<12O <12O <12O
<12O <12O <12O
850 2500 40
1100 2500 280
490 1900 30
280 1100 71
850 5800 40
850 850 40
<18
<18
700 1200 400
230 400 130
130 530 S100
<59 $130 <59
270 3100 270
<12O 270 <12O
<12O <12O <12O
<12O <12O <12O
Compound of
RE
27
29
29
31
31
34
34
34
Dose
msi./_I$.g_1.__k;r_
3
1
duct'o '
970
140
<59
<45
<45
<45
<45
<45
<45
<120
<120
<120
<120
<61
<61
140
S61
ce - continued
Reference Units/mL
_2_m:_
1200
560
<45
<45
<45
<45
<45
<45
<120
<120
<120
140
<61
320
S61
.i_h£_
140
<47
<45
<45
<45
<45
<45
<45
<45
<45
<120
<120
<120
<120
S61
S
Compound of
RE
37
37
60
60
60
60
61
61
61
61
62
62
62
62
66
66
66
66
40
40
40
40
44
44
44
44
48
48
48
48
69
69
Interferon Induction in Mice - continued
Dose
mg[kg
1
1
1
.3
.3
.3
Rgference Units[mL
_1_Q£_
<120
<120
<120
<56
1100
<74
<56
<56
1600
1000
‘S70
2000
1600
<260
1000
$270
h;
S270
<120
<12O
<12O
3400
870
1500
870
1100
500
220
<56
1100
8<56
2600
<12O
<56
<56
1600
1100
450
200
1600
1500
<260
510
2000
1600
940
<260
1000
$150
fir
$270
<12O
<12O
<12O
1100
290
120
SS6
160
120
97
<56
380
160
<56
<56
380
<56
<56
<56
170
210
110
<29
790
<260
<260
<260
"540
‘S10
<260
<260
S340
<1
Compound of
RE
85
85
85
85
90
90
90
90
93
93
93
93
96
96
96
96
99
99
99
99
104
104
104
104
These results show that the tested compounds induce
interferon biosynthesis at detectable levels in mice.
tumor growth in mice.
_ 74 _
gnterfieron Induction in Mice - continued
Dose
.3
.3
.3
EQLKQ
.3.
1
.3
Bgfierence ggits[mL
_i_m:__2_nr___4_11z_
<15O <15O <15O
<15O <15O <15O
2200 5700 '570
1500 4300 '430
'980 3900 $330
<250
$140
$130 570 574
<74 <74 <74
<74 <74 <74
2100 2900 630
1300 1300 '26O
340
S150
2900 4700 '350
3000 10000 960
3200 5000 1100
2900 3400 620
2500 4600 ‘Z20
1600 750 "220
2200 5100 460
1600 3500 390
3400 450 5660
S660 2200 <380
"780 ’780 "380
<380 <380 <380
INHIBITION OF MC-26 TUMORS IN MICE
The test methods described below demonstrate
ability
compounds
inhibit
- 75 _
On day 0 female CDF1 mice are innoculated
i.v. with 4 X 10‘ MC-26 colon tumor cells in a volume of
.2 ml of saline per mouse.
The lungs are removed and fixed with WARP
The mice are sacrificed 14
days later.
(24% ethanol, 10% formalin, and 2% acetic acid in
water) then allowed to stand for 30 minutes. The lobes
are separated and the colonies are counted. Five mice
are in each treatment group and comparisons are made to
controls.
The mice in the treatment groups were dosed
on days 3, 4, 5, 6, 7, 10, 11, 12, 13, and 14, orally
with a suspension of compound (30 mg/kg) in water (10
mL/kg).
were dosed
4, 5, 6, and
The mice in the control groups
orally with saline (10 mL/kg) on days 3,
, and with water (10 mL/kg) on days 10, 11, 12, 13,
and 14.
Results are shown in the table below.
Inhibition of MC-26 Tumors in Mice
Compound of RE Number of Colonies
ll 204 i 28
12 149 i 21
31 221 2 37
34 196 t 20
37 123 1 31
Control 385 i 31
On day 0 female CDFl mice are innoculated
i.v. with 1 x 10‘ MC-26 colon tumor cells in a volume of
0.2 mL of saline per mouse. The mice are sacrificed 21
days later. The lungs are removed and fixed with WARP
then allowed to stand for 30 minutes. The lobes are
separated and the colonies are counted. Ten mice are in
each treatment group and in the control group.
_ 75 _
The mice in the control group were dosed
orally with water (10 mL/Kg) on days 0, 1, 2, 3 and 4.
Four mice from this group died prior to day 21.
The mice in the first treatment group were
3 and 4 orally with a
suspension of the compound of RE 99 (1 mg/Kg) in
water (10 mL/Kg). one mouse from this group died prior
to day 21.
The mice in the second treatment group were
dosed on days 0, 1, 2, 3 and 4 orally with a suspension
of the compound of RE 99 (3 mg/Kg) in water (10
mL/Kg). All of the mice in this treatment group
survived until day 21.
Results are shown in the table below.
dosed on days 0, l, 2,
Inhibition of MC-26 Tumors in Mice
Treatment 3 figmber of Colonies
3 mg/Kg 10 17 i 3
1 mg/Kg 9 29 t 4
Control 6 55 1 11
These results show that the tested compounds inhibit
MC-26 tumor formation in mice.
INDIRECT IN-VITRO ANTIVIRAL ACTIVITY
The test method described below demonstrates
the of inhibit
the progress of viral infection. _
Whole blood is collected by venipuncture into
EDTA vacutainer tubes. Peripheral blood mononuclear
cells (PBM) are isolated using Ficoll—Paque0 solution
(available from Pharmacia LKB Biotechnology Inc.,
Piscataway, NJ). The PBM are washed with phosphate
buffer saline then diluted with RPMI 1640 medium
(available form GIBCO, Grand Island, New York) to
obtain a final concentration of 2.5 x 10‘ cells/mL. one
mL portions of PBM in medium are placed in 15 mL
polypropylene tubes. A 100 pL portion of autologous
ability compounds to
serum is added to each tube. The test compound is
dissolved in dimethyl sulfoxide then diluted with RPMI
1640 medium. The solution of test compound is added to
the tubes containing the PBM to give final
concentrations ranging from 0.1 pg/mL to 10 pg/mL.
Control tubes do not receive any test compound. The
tubes are then incubated for 24 hours at 37°C with a 5%
carbon dioxide atmosphere. Following incubation the
tubes are centrifuged at 400 xg for 5 minutes. The
supernatant is removed. The PBM's are brought up in 100
pL of RPMI 1640 medium and then infected with a 100 pL
containing 10’ tissue culture 50% infectious doses of
vesicular stomatitis virus (VSV). The tubes are
incubated for 30 minutes at 37°C to allow virus
adsorption. one mL of RPMI 1640 medium is added to each
tube and the tubes are incubated for 48 hours at 37°C.
The tubes are frozen then thawed to lyse the cells. The
tubes are centrifuged at 400 xg for 5 minutes to remove
cellular debris then the supernatant is assayed by
serial tenfold dilutions on Vero cells in 96 well
microtiter plates. The infected cells are incubated for
24 hours at 37°C before quantifying for viral
cytopathic effect. The viral cytopathic effect is
quantified by staining with 0.05% crystal violet.
Results are presented as VSV inhibition, defined as the
logm (control VSV yield/experimental VSV yield).
Results are shown in the table below wherein the
absence of an entry indicates that the compound was not
tested at that particular dose concentration. Control
tubes have a value of 0.
In-vitro Antiviral Activity
VSV Yield Inhibition
Compound of o e c t'o
Claims (4)
1. A compound of the formula wherein R5 is selected from the group consisting of; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyb containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cylcoalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four Carbon atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms%and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms; benzyl; (phenyl) ethyl; and phenyl; said benzyl, (phenyl) ethyl, or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen with the provisio that when said benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms:
2. R2 and R3 are independently selected from the group consisting of hydrogen, alkyl of one to four carbon atoms,,phenyl, and substituted phenyl wherein the a substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; G is selected from the group consisting of alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, } ; alkylamino wherein the alkyl group contains one to four carbon atoms, azido, chloro, l—morpholino, 1- pyrrolidino, alkylthio of one to four carbon atoms, alkanoyloxy, alkanoylcxyalkylwherein the alkyl moiety contains one to four carbon atoms, with the proviso that when G is alkoxyalkyl then R5 is alkenyl, and aroyloxy, substituted alkenyl, or alkoxyaklyl; and R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms . A compound of the formula wherein R5 is selected from the group consisting of: straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three tozsix carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; alkoxyalkyl wherein the alkoxy moiety ' contains one to four carbbn atoms and the alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl) ethyl, or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, with the provisio that when said benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms; R; and R3 are independently selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; Z is selected from the group consisting of alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, hydroxyalkyl containing one to four carbon atoms, oxoalkyl of two to four carbon atoms, alkanoyloxyalkyl wherein the alkyl moiety contains one to four carbon atoms: alkylamido wherein the alkyl group contains’one to four carbon atoms, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, chloro, 1-morpholino, 1- pyrrolidino, alkylthio of one to four carbon atoms, hydroxy, alkanoyloxy, and/aroyloxy; Q is selected from the group consisting of hydrogen, ‘ chloro, and Ri~(C=0)—NH wherein R1 is selected from the group consisting of alkyl, alkenyl, alkaryl and arylalkyl; with the provisio that when Q is Ri—(C=O)=NH, then Z is other than hydroxy, substituted amino, or hydroxyalkyl as defined above, and with the further provisio that when Q is hydrogen or chloro and Z is alkylamido,hydrOXy OI hydroxyalkyl, then R5 is alkenyl, substituted alkenyl, or alkoxyalkyl; and R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms. ' N R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one 5 to about four carbon atoms.
3. A compound as defined in Claim 1, substantially as described herein ‘by way of example.
4- A compound as defined in Claini 2., substantially as described herein by way of example. TUMKINS & co.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
USUNITEDSTATESOFAMERICA01/03/19910 | |||
US66292691A | 1991-03-01 | 1991-03-01 | |
US68732691A | 1991-04-18 | 1991-04-18 |
Publications (3)
Publication Number | Publication Date |
---|---|
IE990988A1 IE990988A1 (en) | 2000-12-13 |
IE19990988A1 IE19990988A1 (en) | 2000-12-13 |
IE83826B1 true IE83826B1 (en) | 2005-03-09 |
Family
ID=
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