CA2211979A1 - Tricyclic derivatives and their use as anti-cancer agents - Google Patents
Tricyclic derivatives and their use as anti-cancer agentsInfo
- Publication number
- CA2211979A1 CA2211979A1 CA002211979A CA2211979A CA2211979A1 CA 2211979 A1 CA2211979 A1 CA 2211979A1 CA 002211979 A CA002211979 A CA 002211979A CA 2211979 A CA2211979 A CA 2211979A CA 2211979 A1 CA2211979 A1 CA 2211979A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- compound
- coor8
- aryl
- indole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000002246 antineoplastic agent Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 48
- 125000003118 aryl group Chemical group 0.000 claims abstract description 29
- -1 COOR8 Chemical group 0.000 claims abstract description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 9
- 235000000346 sugar Nutrition 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 101100134927 Gallus gallus COR8 gene Proteins 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims abstract description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 4
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 4
- 125000004475 heteroaralkyl group Chemical group 0.000 claims abstract description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims abstract 5
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 claims description 2
- 230000021523 carboxylation Effects 0.000 claims description 2
- 238000006473 carboxylation reaction Methods 0.000 claims description 2
- YDSCZSBMZBDYRC-UHFFFAOYSA-N dibenzyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicarboxylate Chemical compound C1=C2C(C)=C3C(C)=C(C(=O)OCC=4C=CC=CC=4)N=C3C=C2N=C1C(=O)OCC1=CC=CC=C1 YDSCZSBMZBDYRC-UHFFFAOYSA-N 0.000 claims description 2
- HFPGRVHMFSJMOL-UHFFFAOYSA-N dibromomethane Chemical compound Br[CH]Br HFPGRVHMFSJMOL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- BBOIIQXFZKKCPV-UHFFFAOYSA-N ethyl 3,4,6-trimethyl-1,7-dihydropyrrolo[3,2-f]indole-2-carboxylate Chemical compound CC1=C2C(C)=C(C(=O)OCC)NC2=CC2=C1C=C(C)N2 BBOIIQXFZKKCPV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- NVNCMRNGHDRAIM-UHFFFAOYSA-N 6-o-benzyl 2-o-ethyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicarboxylate Chemical compound C=1C2=C(C)C3=C(C)C(C(=O)OCC)=NC3=CC2=NC=1C(=O)OCC1=CC=CC=C1 NVNCMRNGHDRAIM-UHFFFAOYSA-N 0.000 claims 1
- 101100134929 Gallus gallus COR9 gene Proteins 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- MJAYWAHLFHUOCT-UHFFFAOYSA-N diethyl 3,4,6-trimethyl-1,7-dihydropyrrolo[3,2-f]indole-2,5-dicarboxylate Chemical compound CC1=C2C(C)=C(C(=O)OCC)NC2=CC2=C1C(C(=O)OCC)=C(C)N2 MJAYWAHLFHUOCT-UHFFFAOYSA-N 0.000 claims 1
- LFUPIEFGEZZIHW-UHFFFAOYSA-N ethyl 3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate Chemical compound CC=1C2=CC=NC2=CC2=NC(C(=O)OCC)=C(C)C2=1 LFUPIEFGEZZIHW-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 abstract description 4
- 238000011275 oncology therapy Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 230000000259 anti-tumor effect Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 9
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- HCUARRIEZVDMPT-UHFFFAOYSA-M 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)[O-])=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-M 0.000 description 7
- 125000005605 benzo group Chemical group 0.000 description 7
- 239000004927 clay Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000010828 elution Methods 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000005907 alkyl ester group Chemical group 0.000 description 3
- 150000007860 aryl ester derivatives Chemical class 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- XTKILPAAGBOZHY-UHFFFAOYSA-N benzyl 1h-pyrrole-2-carboxylate Chemical compound C=1C=CNC=1C(=O)OCC1=CC=CC=C1 XTKILPAAGBOZHY-UHFFFAOYSA-N 0.000 description 3
- 238000013375 chromatographic separation Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- PBTPREHATAFBEN-UHFFFAOYSA-N dipyrromethane Chemical compound C=1C=CNC=1CC1=CC=CN1 PBTPREHATAFBEN-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- RXELAUDTOWNGKR-UHFFFAOYSA-N ethyl 4-acetyl-5-(acetyloxymethyl)-3-methyl-1h-pyrrole-2-carboxylate Chemical compound CCOC(=O)C=1NC(COC(C)=O)=C(C(C)=O)C=1C RXELAUDTOWNGKR-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- UPFNDLSNGMNHKG-UHFFFAOYSA-N (3-acetyl-1h-pyrrol-2-yl)methyl acetate Chemical compound CC(=O)OCC=1NC=CC=1C(C)=O UPFNDLSNGMNHKG-UHFFFAOYSA-N 0.000 description 2
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 2
- ULUNQYODBKLBOE-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-1h-pyrrole Chemical compound C1=CNC(C=2NC=CC=2)=C1 ULUNQYODBKLBOE-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- DJDPDVJJTIGJTE-UHFFFAOYSA-N ethyl 2-methyl-1h-pyrrole-3-carboxylate Chemical compound CCOC(=O)C=1C=CNC=1C DJDPDVJJTIGJTE-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- VONGYFFEWFJHNP-UHFFFAOYSA-N methyl 1h-pyrrole-2-carboxylate Chemical compound COC(=O)C1=CC=CN1 VONGYFFEWFJHNP-UHFFFAOYSA-N 0.000 description 2
- OBRHFSNTJHVMMB-UHFFFAOYSA-N methyl 2-methyl-1h-pyrrole-3-carboxylate Chemical compound COC(=O)C=1C=CNC=1C OBRHFSNTJHVMMB-UHFFFAOYSA-N 0.000 description 2
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 2
- 229960000907 methylthioninium chloride Drugs 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- LATVFWSHQUYEAD-UHFFFAOYSA-N 2-amino-5-hydroxy-6,11-dioxonaphtho[2,3-g][1]benzofuran-3-carbonitrile Chemical compound C1=CC=C2C(=O)C3=C(O)C=C(C(=C(N)O4)C#N)C4=C3C(=O)C2=C1 LATVFWSHQUYEAD-UHFFFAOYSA-N 0.000 description 1
- WVWGISSQXIWLKJ-UHFFFAOYSA-N 2-o-ethyl 7-o-methyl 3,4-dimethyl-1h-pyrrolo[3,2-f]indole-2,7-dicarboxylate Chemical compound CC1=C2C(C)=C(C(=O)OCC)NC2=CC2=C1C=CN2C(=O)OC WVWGISSQXIWLKJ-UHFFFAOYSA-N 0.000 description 1
- RNXIRXYZZGOBQG-UHFFFAOYSA-N 2h-indeno[2,1-b]thiophene Chemical class C1=CC=C2C3=CCSC3=CC2=C1 RNXIRXYZZGOBQG-UHFFFAOYSA-N 0.000 description 1
- SOKYXNKMKJMGHO-UHFFFAOYSA-N 5h-furo[2,3-f]indole Chemical class C1=C2NC=CC2=CC2=C1C=CO2 SOKYXNKMKJMGHO-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 101100496169 Arabidopsis thaliana CLH1 gene Proteins 0.000 description 1
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
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- 229930194542 Keto Natural products 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
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- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 101100080600 Schizosaccharomyces pombe (strain 972 / ATCC 24843) nse6 gene Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- LGDAGYXJBDILKZ-UHFFFAOYSA-N [2-methyl-1,1-dioxo-3-(pyridin-2-ylcarbamoyl)-1$l^{6},2-benzothiazin-4-yl] 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 LGDAGYXJBDILKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- IZOZYPGIBDWMAW-UHFFFAOYSA-N benzyl 4-acetyl-5-(acetyloxymethyl)-3-methyl-1h-pyrrole-2-carboxylate Chemical compound CC(=O)C1=C(COC(=O)C)NC(C(=O)OCC=2C=CC=CC=2)=C1C IZOZYPGIBDWMAW-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000005242 carbamoyl alkyl group Chemical group 0.000 description 1
- HJMZMZRCABDKKV-UHFFFAOYSA-N carbonocyanidic acid Chemical compound OC(=O)C#N HJMZMZRCABDKKV-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
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- 239000012050 conventional carrier Substances 0.000 description 1
- 101150111293 cor-1 gene Proteins 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- VCBOSFMJSMEERT-UHFFFAOYSA-N cyclopenta[f]indole Chemical class C=1C2=CC=NC2=CC2=CC=CC2=1 VCBOSFMJSMEERT-UHFFFAOYSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical class C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 150000002243 furanoses Chemical class 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- MORALDOSFHZOQS-UHFFFAOYSA-N methyl pyrrole-1-carboxylate Chemical compound COC(=O)N1C=CC=C1 MORALDOSFHZOQS-UHFFFAOYSA-N 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 229910052901 montmorillonite Inorganic materials 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003215 pyranoses Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ZCOSUVZGFDGWFV-UHFFFAOYSA-N pyrrolo[2,3-e]indole Chemical compound C1=CC2=NC=CC2=C2N=CC=C21 ZCOSUVZGFDGWFV-UHFFFAOYSA-N 0.000 description 1
- 150000005592 pyrroloindoles Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 102200082890 rs33972047 Human genes 0.000 description 1
- WEMQMWWWCBYPOV-UHFFFAOYSA-N s-indacene Chemical class C=1C2=CC=CC2=CC2=CC=CC2=1 WEMQMWWWCBYPOV-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003538 tetroses Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/10—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
- C07H5/06—Aminosugars
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Abstract
A compound of formula (I) or a salt or physiologically functional derivative thereof, wherein A is (a), (b), (c) (d), X is O, S, SO, SO2, CH2, CO or NR7, wherein R7 is H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulphonyl, substituted sulphonyl, or COOMe; Y is O, S, SO, SO2, CH2, CO or NR7; R1 is COR8, CHO, CH2OH, CH2OR9, CONH2, COOR8, CONHR8, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR8, CSNR8R9, CNHOR8 wherein R8 and R9 are independently hydrogen, alkoxyalkyl, heterocycloalkyl, heteroaralkyl, or C1-10 optionally substituted hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain; or R8 and R9 are a sugar group. R2 is H, halo, cyano, COOR8, alkyl, aryl, alkenyl, alkynyl, alkoxy, (wherein alkyl, aryl, alkenyl, alkynyl and alkoxy can be substituted) or CH2CH2CO2R12 wherein R12 is alkyl or aryl; R3 is H, alkyl, halogen, cyano, amino, COOR8, CONHR8, COR8, CH2OH, CH2OR8, CONH2, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR8, CSNR8R9 or CNHOR8; R4 is H, halogen, cyano, amino, alkyl, COOR8, CONHR8, COR8, CH2OH, CH2OR8, CONH2, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR8, CSNR8R9 or CNHOR8; R5 is H, hydroxy, aryloxy, aralkyloxy, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano COOR8 or CNHOR8; R5 is H, hydroxy, CHO or COR13 wherein R13 is alkyl or aryl; wherein R8 is not H when R2 is H and R3 is not H or Me when A is (c). Processes for their preparation are described, together with their use in medicine, particularly cancer therapy and pharmaceutical formulations comprising the compounds.
Description
-CA 022ll979 l997-07-30 TRICYC~IC DERIVATIYES AND THEIR USE AS ANTI~CANCER AG~N~S
The present invention relates to heterocyclic compounds which have been found to have anti-tumour activity. More specifically, the invention concerns benzo[1,2-b:4,5-b']dipyrroles, benzo[l~2-b:s~4-b~]dipyrroles~
cyclopent[f]indoles, benzo[1,2-b:4,5-b']difurans, benzo[l,2-b:5,4-b']difurans, 2H-indeno~5,6-b]furans, benzo[1,2-b:4,5-b']dithiophenes, benzo[1,2-b:5,4-b']dithiophenes, cyclopent[f]indenes and 5H-furo[2,3-f]indoles methods for their preparation, pharmaceutical formulations cont~;~ing them and their use as anti-tumour agents.
Research in the area of cancer chemotherapy has produced a variety of anti-tumour agents, which have differing degrees of efficacy. Standard clinically used agents include adriamycin, actinomyci~ D, methotrexate, 5-fluorouracil, cis-platinum, vincristine and vinblastine.
However, these presently available anti-tumour agents are known to have various disadvantages, such as toxicity to healthy cells and resistance to certain tumour types.
There thus exists a continuing need to develop new and im~G~ed anti-tumour agents.
Khoshtariya et al, khim. Geterotsikl. Soedin (1982), (4) 304-7, disclose the synthesis of certain pyrroloindoles.
Gruenhaus H., J.Heterocyclic Chem. 13(6), 1161-3 discloses the synthesis of certain indenothiophenes There have now been discovered novel compounds which exhibit anti-tumour cell activity including a group of -novel compounds which exhibit anti-tumour cell activity with low toxicity against normal cell lines.
Thus, in a first aspect the present invention provides a compound of the general formula (1) R
R~ XJ~3 (I) or a salt or physiologically functional derivative thereof, wherein A is ~R2 ~ ~ ~R2 X is O, S, SO, SO2, CH2, CO or NR7, wherein R' is H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulphonyl, substituted sulphonyl, or COOMe;
Y is O, S, SO, SO2, CH2, CO or NR7;
Rl is COR8, CHO, CH20H, CH20R8, CONH2,COOR8, CONHR8, CoNR~R9, CSOR-, CSSR8, COSR8, CSNHR', CSNR8 R9, CNHORa wherein R8 and WO95/21171 PCT/GB9~l00203 R9 are independently hydrogen, alkoxyalkyl, heterocycloalkyl, heteroaralkyl, or C11O optionally substituted hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain;
,.
or Ra and R9 are a sugar group.
R2 is H ~ halo, cyano, COOR8, alkyl, aryl, alkenyl, alkynyl, alkoxy, (wherein alkyl, aryl, alkenyl, alkynyl and alkoxy can be substituted) or CH2CH2CO2Rl2 wherein Rl2 is alkyl or aryl;
R3 is H, alkyl, halogen, cyano, amino, COORa, CONHR, COR, CH20H, CH2OR , CONH2, CONR8R9, CSORa, CSSR8, COSRa, CSNHRa, CSNRaR9 or CNHOR-;
R~ is H ~ halogen, cyano, amino, alkyl, COOR8, CONHR8, CORa, CH20H, CH20R8, CONH2, CONRaR9, CSORa, CSSR8, COSR8, CSNHR8, CSNR8R9 or CNHOR-;
Rs is H ~ hydroxy, aryloxy, aralkyloxy, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano COOR or CHO;
R6 is H~ aryl, alkyl, aralkyl, nitro, halogen, CHO or CoRl3 wherein Rl3 is alkyl or aryl; wherein Ra is not H when R2 is H and R3 is not H or Me when A is ~Y~Rl Alkyl groups present in general formula (I) may be _ _ _ _ _ _ _ _ _ _ _ straight or branched chain alkyl groups, and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, t-butyl and the like.
Acyl groups may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable acyl groups include ethanoyl and propanoyl groups.
Alkoxy may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable alkoxy groups include methoxy, ethoxy and the like.
Aryl includes both carbocyclic aryl groups and heterocyclic aryl groups normally contAining a maximum of 10 ring atoms. Carbocyclic aryl yLou~s include, eg phenyl and naphthyl and contain at least one aromatic ring.
Heterocyclic aryl yLou~ include eg thienyl, furyl, pyridyl, indole and quinoline rings.
An aralkyl group may contain from 1 to 4 atoms in the alkyl portion and the aryl portion may be a carbocyclic or heterocyclic aryl group.
Cycloalkyl includes both cycloalkyl yLOu~S and heterocyclo alkyl groups normally contA;n;ng between 3 and 6 ring atoms. Heterocycloalkyl y~o~ include e.g.
morpholino, thiomorpholino, piperidino, imidazolino, pyrrolidino, pyrazolidino, piperazino, tetrahydrofuranyl, tetrahydropyranyl.
When R8 and R9 are independently optionally substituted Cl10 hydrocarbyl which may optionally contain one or two oxygen atoms in the chain this includes optionally substituted alkyl, hydroxyalkyl, alkenyl, alkynyl, carbamoylalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, aralkyl, aryloxyalkyl.
Substituents which may be present on the Cl~O hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain include hydroxy, azido, alkenyl, halo, nitro (NO2), amino, (optionally substituted by one or 2 alkyl groups), cyano, carboxylate, alkyl ester, aralkyl esters or aryl esters, (wherein the alkyl ester, aralkyl ester and aryl ester can be substituted) alkyl, aryl, aralkyl, aryloxy, arylalkoxy, substituted arylalkoxy, sulphinyl, sulphonyl, thio, alkylthio, alkoxy, hydroxyalkyl, halo alkyl, phosphate, phosphonate, silyl, silyloxy, (wherein silyl and silyloxy may be substituted by one or more Cl6 alkyl or aryl) keto, formyl.
Substituents which may be present on alkyl esters, aralkyl esters and aryl esters include nitro, amino, hydroxy, alkoxy, halogen, cyano and alkyl.
Where R- is a sugar this group may be present in a protected or unprotected form. Preferred sugar-protecting ~LOU~ include isopropylidene, benzylidene acetate, benzoyl, paranitrobenzyl, paranitrobenzoyl, benzyl, substituted silyl and tetrahydropyranyl.
When R- is a sugar such as a tetrose, pentose, hexose (including furanose and pyranose) or heptose, preferred sugars include glucose, fructose, mannose, ribose, arabinose.
., Substituents which may be present on the sulphonyl and - - -sulphinyl include alkyl, aryl and aralkyl.
Halogen represents fluoro, chloro, bromo or iodo.
X preferably represents NH, A is preferably ~YJ'~R2 and Y preferably represents NH.
Rl is preferably COOR8, with R8 preferably being alkyl or aralkyl.
R2 is preferably H, alkyl, or COOR8 wherein R8 is preferably alkyl, R3 is preferably alkyl R' is preferably alkyl or COOR'.
R5 is preferably hydrogen and R6 is preferably hydrogen or methyl and salts and physiologically functional derivatives thereof.
one group of preferred compounds according to the present invention includes:
Ethyl 1l7-dihydro-3t4~6-trimethylpyrrolo[3~2 f~indole-2-carboxylate;
Diethyl li7-dihydro-3~4~6-trimethylpyrrolo[3r2-f]indole 2,5-dicarboxylate; and f Ethyl6-methoxycarbonyl-3~4-dimethylpyrrolo[3l2-f]indole-2-carboxylate and physiologically functional derivatives thereof.
A second group of preferred compounds according to the invention include:
Ethyl 6-Benzyloxycarbonyl-3t4-dimethylpyrrolo[3~2-f]indole-2-carboxylate;
Dibenzyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicarboxylate;
Ethyl7-methoxycarbonyl-3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate; and Ethyl 3~4-dimethylpyrrolo~3~2-f]indole-2-carboxylate and physiologically functional derivatives thereof.
Com~o~-ds of the general formula (I) have been tested against two specially developed cell lines which are clones of the human fi~rosarcoma cell-line, HT1080. ~ne clone, H~1080scc2, retains the transformed phenotype of the parental line, whilst the other, HTlO~Olc, is a morphologically flat, non-tumourigenic, revertant.
According to a further aspect, the present invention also provides a process for preparing compounds of general formula (I), which process comprises the catalysed reaction of a compound of formula (II) with a compound of formula (III) in an inert solvent at a temperature between room temperature and the reflux temperature of the solvent, wherein X, Y, Rl, R2, R3 R', R5 and R6 are as defined herein except that R3 and R' may not be hydrogen when X is NH, and L is a leaving group:-R ~ ~ R2 (II) (III) Preferred catalysts are Montmorillonite Klo clay or p-toluenesulphonic acid. Preferred solvents are 1,2-dichloroethane or toluene. Examples of suitable leaving y~OU~-~ include -OCOCH3, OEt, -N+Me3 and halo.
Insertion of the substituent R1 onto the ring system for example:
(d) Carboxylation of a polyheterocyclic compound using (i) a carbonyl halide or (ii) carbon dioxide According to known ~ocedu~es (J. March, Advanced Organic Chemistry, 2nd ed, McGraw Hill, New York, 1977, p 497-498~.
(e) Alternatively one can produce compounds of the formula (I) wherein R2 is CHO by methods known to those PCT/GB9~/00203 skilled in the art, for example:-(i) The appropriate aromatic polyheterocycle can be reacted with a formylating agent, such as that Y generated by the reaction between SnC1~ and CI2CHOCH3 or e~uivalent reagents.
For example, according to the method of A. Reiche et al, Chem. Ber. 93, 88 (1960), or with other standard formylating reagents/procedures known in the art, for example, the Gatterman-Koch reaction (CO\HCl\AlC13\CUCl), the Gatterman reaction (HCN\HCl\ZnC12), and the Vilsmeier reaction (POC13\PhN-(Me)CHO or POCI3\Me2CHO) (J. March, Vide Supra, p 494-497); or (ii) the appropriate aromatic polyheterocycle, carrying a suitable functional group, said group being converted to an aldehyde group by methods known to those skilled in the art. Suitable functional ~LO~s include CHBr2, CH,, COR1' wherein R1' is a primary or secondary C16 alkyl group, COOH or a derivative thereof such as an ester, amide, acid chloride or CN; or (f) Compounds of the formula (I) wherein Rl is CONHR10 may also be produced by the reaction of a compound wherein is COOH or a suitable reactive acid derivative thereof as outlined in J. March, Vide supra. For example an acid halide can be reacted with a compound NH2Rl~ in an inert solvent.
(g) Conversion of one compound of formula (I) into another compound of formula (I).
CA 022ll979 l997-07-30 Compounds of the invention wherein Rl is COOR8 and Ra is, for example, aralkyl can be converted to free acids wherein R8 is H by reduction in the presence of H2 and a Pd catalyst, or where R8 is, for example, alkyl, by hydrolysis in the presence of an appropriate base e.g.
caesium carbonate.
It is thereafter possible for the skilled man to synthesise ester and amide compounds within the scope of the invention by conversion of the free acids obtained, by known procedures. ~See J. March, Vide Supra, p363-365).
Compounds of the invention produced as described herein can be converted to other compounds of the invention by electrophilic substitution at R5 and/or R6, to introduce, for example, NO2, halogen and COR 3 wherein Rl3 is as defined herein.
Compounds of formula I in which X or Y is NR, and R7 is COOMe can be converted by acid or base hydrolysis to compounds of formula I in which X or Y are NH using, for example, potassium hydroxide or Br in acetic acid.
The above processes have been described for compounds wherein A is ~Y ~ R~
The skilled man will appreciate that these are equally CA 022ll979 l997-07-30 applicable when A is / Y R2 ~ Rl ~ R2 ~ R 1 Y R2 The compounds of the present invention are useful for the treatment of tumours. They may be employed in treating various forms of cancer of mammals including carcinomas, for instance of the stomach, pancreas, breast, uterus and colon; adenocarcinomas, for instance of the lung and colon; sarcomas, for instance fibrosarcoma; leukaemias, for instance lymphocytic leukaemia and lymphomas, for instance myeloid lymphoma.
The invention thus further provides a method for the treatment of tumours in animals, including mammals, especially humans, which comprises the administration of a clinically useful amount of compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative in a pharmaceutically useful form, once or several times a day or in any other a~ op~iate schedule, orally, rectally, parenterally, or applied topically.
In addition, there is provi~ed as a further, or alternative, aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof for use in therapy, for example as an antitumour agent.
- The amount of compound of formula (I) required to be effective against the aforementioned tumours will, of CA 022ll979 l997-07-30 W O95/21171 pCT/GB95/00203 course, vary and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition being treated, the route of administration, and nature of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be a~;n;stered. A suitable effective anti-tumour dose is in the range of about 0.01 to about 100 mg/kg body weight, eg 0.1 to about 100 mg/kg body weight, preferably 1-30 mg/kg body weight. The total daily dose may be given as a single dose, multiple doses, ~., two to six times per day or by intravenous infusion for selected duration. For example, for a 75 kg mammal, the dose range would be about 8 to 900 mg per day, and a typical dose could be about 50 mg per day. If discrete multiple doses are indicated treatment might typically be 15 mg of a compound of formula (I) given up to ~ times per day.
Whilst it is possible for the active compound to be administered alone, it is preferable to present the active compound in a pharmaceutical formulation.
Formulations of the present invention, for medical use, comprise a com~oulid of formula (I) or a salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients.
The carrier(s) should ~e pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The present invention, therefore, further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof together PCTIGB95l00203 wogs/21171 with a pharmaceutically acceptable carrier thereof.
There is also provided a method for the preparation of a pharmaceutical formulation comprising bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier thereof.
Formulations according to the present invention include those suitable for oral, topical, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred formulations are those suitable for oral or parenteral administration.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both and then, if neceee~ry, shaping the product into desired formulations.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each con~; n; ~g a predetermined amount of the active compound; as a powder or granules; or a solution or suspension in an aqueous or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active compound with any suitable carrier.
A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredients. Such Acc~ssory ingredients(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredients, such as a polyhydric alcohol for example glycerol or sorbitol.
Formulations for rectal administration may be presented as a 3u~poaitory with a conventional carrier such as cocoa butter.
Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Such formulations suitably comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient.
Useful formulations also comprise concentrated solutions or solids cont~in;ng the compound of formula (I) which upon dilution with an appropriate solvent give a solution for parenteral administration as above.
In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
In a further aspect the present invention provides the use of a compound of formula (I) or a pharmaceuticallY
acceptable salt or physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumours.
The invention will now be illustrated by the following non-limiting Examples:
All temperatures are in degrees Celsius (~C) IR spectra were recorded on a Perkin-Elmer 257 grating ~e~LLo~l~otometer or a Bruker FS66 ~e~L o~hotometer.
U.V. spectra were measured in ethanol on a Unicam SP800 spe~; LL ophotometer.
lH NMR spectra were obtained on a Bruker WM 360-NMR
spectrophotometer at 360 MHz, or on a Bruker AC200 spectrophotometer at 200 MHz. J values are given in Hz.
Mass spectra were obtained on Varian CH5D(EI), Kratos Concept (EI) or Kratos Ms50(FAB) instruments.
EX~MPLE 1 Diethyl 1,5-di~y~l~ 3,4,6-trimethylpyrrolo[2,3-f]indole-2,7-di~rhQYylate A solution of ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate (O.267 g, 1.0 mmol) and 3-carbethoxy-2-methylpyrrole (0.153 g, 1.0 mmol) in 1,2-dichloroethane (10 cm3) was heated at reflux and stirred with Montmorillonite clay (lg) for 18h. After filtration from clay and washing well with 1,2-dichloroethane, evaporation of the com~ined filtrates under reduced pressure gave an oil. This oil was submitted to flash chromatography on silica eluting with (0-20%) ethyl acetate in dichloromethane to give the starting 3-carbethoxy-2-methylpyrrole (0.045 g, 29.4%) and diethyl 1,5-dihydro-3,4,6-trimethylpyrrolo[2~3-f]indole-2l7 dicarboxylate as a colourless solid (0.021g, 6.14%) m.p.
269~C (decomp); ~H ([2H6]-DMSO) 11.34 (lH, s, 5-NH), 11.00 (lH, s, l-NH), 7.80 (lH, s, 8-H), 4.33 (2H, q, 7-OC~2CH3), 4.26 (2H, q, 2-OCH.CH3), 2.85 (6H, s, 3-CH3 and 4-CH3), 2.69 (3H, s, 6-CH3), 1.39 (3H, t, 7-OCH2Ç~3), and 1.37 (3H, t, 2-OCH2CH3); saturation of the singlet 8-~ at ~ 7.80 enhanced the signal due to 1-NH at ~ 11.00 (2.3%); m/z (%) 342 (75,M~), 296 (100), 268 (6), 223 (7) and 195 (5) (Found : M' 342.1580. Cl,H22N2O4 requires M, 342.1579; A max EtOH/nm (log ~ max.dm3 mol~l cm~l 378 (3.56), 365 sh (353), 329 (3.83), 3.04 (3.99) and 259 (3.74). Further elution gave diethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2,5-dicar~oxylate as a colourless solid (0.048g, 14%) m.p. 216-216.5~C (Found: C, 66.82; H, 6.68; N, 8.17.
ClgH22N2O4 requires C, 66.65; H, 6.48, N, 8.18%); ~ ([2H6]-DMSO) 11.30 (lH, s, 7-NH), 10.91 (lH, s, lN-H), 7.12 (lH, s, 8-11), 4.35 (2H, q, 5-OC_CH3), 4.28 (2H, q, 2-OCH.CH3), 2.90 (3H, s, 4-CH3), 2.87 (3H, s, 3-CH3, 2.54 (3H, s, 6-CH3), 1.36 (3H, t, 5-OCH2CH ) and 1.34 (3H, t, 2-OCH2CH3); saturation of the 8-H proton at ~ 7.12 enhanced the signals due to 7-NH at ~ 11.30 (2.4%) and 1-NH at ~ 10.91 (1.8%); m/z (%) 342 (64, M~), 296 (100), 250(5), and 194(9); A max (EtOH)/nm (log ~ max/dm3 mol~L
cm~l) 340 (4.10), 327.5 (4.53) and 270 (4.46), and the starting 5-acetoxymethyl-4-acetylpyrrole (0.029 g, 10 . 9% ) .
~AMPLE 2 Ethyl 1,7-dil~ 3,4,6-trimethylpyrrolo~3,2-f~indole-2-c~.l~xylate The general procedure of Example 1 was followed using ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrolo-2 carboxylate (0.692g, 2.59mmol), 3-methoxycarbonyl-2-methylpyrrole (O.360g, 2.59mmol), 1,2-dichloroethane (25 cm3) and Montmorillonite clay (2g). Chromatographic separation using (0-20%) ethyl acetate in dichloromethane gave ethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2-carboxylate as a pale yellow solid (0.0124g, 1.8%) m.p. 213-216~C (decomp); ~H (~2H6]-DMSO) 10.70 (lH, s, l-NH), 10.41 (lH, s, 7-NH), 7.03 (lH, s, 8-H), 6.14 (lH, s, 5-H), 4.33 (2H, q, ~~2CH3), 2.85 (3H, s, 3-CH3), 2.78 (3H, s, 4-CH3), 2.37 (3H, s, 6-CH3), and 1.35 (3H, s, OCH CH~); saturation of the 8-H proton at ~ 7.03 enhanced the signals due to 1-NH at ~ 10.70 (3.5%) and 7-NH at ~
10.41 (2.9~) and saturation of the 5-H proton at ~ 6.14 enhanced the signals due to 4-CH3 at 2.78 (2~) and 6-CH3 at 2.37 (0.6%); m/z (%) 270 (M~, 49), 234 (100), 196 (17) W O95/21171 PCT/~b5JJ~203 (Found: M 270.1337. C16Hl8N2O2 requires M 270.368, and the starting 3-methoxycarbonyl-2-methylpyrrole (0.108 g, 30%). Further elution gave ethyl methyl 1,7-dihydro-3~4~6-trimethylpyrrolo[3~2-f]indole-2~s-dicarboxylate as a colourless solid (0.066 g, 7.8%) m.p. 247-250 ~C (Found:
C, 66.11; H, 6.37; N, 8.47. C~H2~2O~ requires C, 65.84;
H, 6.14; N, 8.53); ~H ([2H6]-DMSO) 11.33 (lH, s, 7-NH), 10.91 (lH, s, 1-NH), 7.21 (lH, s, 8-H), 4.35 (2H, q, OCH2CH3], 3.78 (3H, s, OCH3), 2.88 (3H, s, CH3), 2.87 (3H, s, CH3), 2.53 (concealed by DMSO, 6-CH3) and 1.37 (3H, t, OCH ~H~); m/z (~) 328 (64, M'), 297 (5), 282 (100), 250 (6), 221 (6) and 194 (17) and the starting 5-acetoxymethyl-4-acetylpyrrole (0.037 g, 5.4%).
EXAMPT~ 3 Ethyl 6-Benzyloxycarbonyl-3,4-dimethyl~yL ~lot3,2-f]indole-2-ca~v~ylate;
(a) React-;on of benzyl ~yrrole-2-~rhnyylate and ethYl S-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate A solution of benzyl pyrrole-2-carboxylate (0.615 g, 3.06 mmol) and ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole 2-carboxylate (0.809, 3.01 mmol) in 1,2-dichloroethane (30 cm3) was heated under reflux and stirred with Montmorillonite clay (3 g) for 7 h. The reaction was followed to completion by TLC. After the clay had been filtered off and washed well with 1,2-dichlorethane, evaporation of the combined filtrates under reduced pressure gave a yellow oil. This was submitted to column chromotagraphy eluting with (5-50% ) ethyl acetate in n-hexane to give the starting pyrrole, benzylpyrrole-2-carboxylate (0.153 g, 24.80% ) Ethyl 6-Benzyloxycar~onyl-3 4-dimethylpyrrolo r 2,3-f l indole-2-carboxylate ( isomer I ) - as a yellow solid (0.043 g, 3.67%), m.p. 218-220~C (Found:
C, 70.90; H, 5.87; N, 7.34. C23H22N2O" requires C, 70.75;
H, 5.68; N, 7.18%); ~H ( [2H6]-DMSO) 11.18 (lH, br s, 5-NH), 10.97 (lH, br s, l-NH), 7.52 (2H, d J 7, O-H's of ArH), 7.36-7.48 (3H, m, Tn and ~ H's of ArH), 7.46 (lH, s, 8-H), 7.23 (lH, d J 1.5, 7-H), 5.41 (2H, s, OCH2Ph), 4.35 (2H, q, OCH2CH3), 2.93 (3H, s, 4-CH3), 2.85 (3H, s, 3-CH3) and 1.38 (3H, t, OCH2, CH3); m/z (%) 390 (100, M~), 344 (71), 282 (59), 236 (60), 228 (27), 209 (21) and 91 (78);
V max (nujol) 3400, 3350, 1725 and 1680 cm-l; and Ethyl 6-Benzyloxycarbonyl-3.4-dLmethyl~yrrolo r 3 2-f ~ indole-2-car~oxylate r isomer II ~ as a yellow solid (0.065 g, 5.55%), m.p. 179-182~C, ~H ( ~2H6]-DMSO) 11.36 (lH, br s, 7-NH) , 10.95 (lH, br s, l-NEI), 7.52 (2H, d J 7, _-H's of ArH), 7.48-7.37 (3H, m, m and ~2 H's of ArH), 7.34 (lH, br s, 5-H), 7.19 (lH, br s, 8-H), 5.39 (2H, s, 5~2Ph), 4-35 (2H, q, O~CH3), 2.89 (3H, s, 4--CH3), 2.84 (3H, s, 3--CH3) and 1.37 (OCH2, CH~); m/z (%) 390 (4, ~), 344 (7), 306 (5), 282 (5), 236 (6), 209 (15), 154 (18), 127 (19) and 91 (100) ( Found: ~ 390.1580. C23H22N2O~ requires 390.1579) -Also obtained were 2- (3 ' -acetyl-5 ' -ethoxycarbonyl-4 ' -methylpyrrol -2 ' -ylmethyl ) -5-benzoxycarbonylpyrrole as of f white crystals after crystallisation from dichloromethane-petroleum ether (0.303 g, 24.75g6), m.p.
130-132~C, ~H ( ~2H6~-DMSO) 11.96 (lH, s, l-NH), 11.65 (lH, s, l'-NH), 7.45-2.31 (5H, m, ArH), 6.70 (lH, t J2.6, 4-H), 5.75 (lH, dd J 2.6 and 4, 3-H), 5.27 (2H, S, CH2Ph), 4.28 (2H, q, OCH.CH3), 4.20 (2H, s, CH2), 2.50 (concealed by DMSO, 4'-CH3), 2.34 (3H, s, COCH3) and 1.31 ~3H, t, OCH CH~); saturation of the 4-H at S 6.70 enhanced the signal due to 3-H double doublet at ~ 5.75 (6g6) and saturation of the singlet CH2 at ~ 4.20 enhanced the signals due to 3-H at â 5.75 (4.5%), 1-NH at ~ 11.96 (4.5%) and 1'-NH at ~ 11.65 (4.5%); m/z (%) 408 (14, ~), 317 (100), 271 (97), 91 (47) (Found: M'NH~'426.2029.
C23HZ~N2OS+NH,+ requires 426.2028) and 2 3-di~3'-acetyl-5'-ethoxycarbonyl-4 '-methyl-2 ' -ylmethyl ~ -5-benzoxycarbonylpyrrole as colourless crystals after crystallisation from benzene-petroleum ether (0.256 g, 27.75g6), m.p. 164-166~C (Found: C, 66.53; H, 6.24; N, 6.71. C3,H3,N,O, requires C, 66.33; H, 6.06; N, 6.83%); ~H
(CDCl3), 10.50 (lH, br s, 1-NH), 9.10 (2H, br s, 2X NH), 7.42-7.20 (5H, m, ArH), 6.65 (lH, d J 2.5, 4-H), 5.23 (2H, s, CH2Ph), 4.32 (2H, q, 2--OCH.CH3), 4.30 (2H, q, 3--O~CH3), 4.13 (2H, s, 2-CH2), 4.08 (2H, s, 3-CH2), 2-60 (3H, s, CH3), 2.59 (3H, s, CH3), 2.55 (3H, s, COCH3), 2.54 (3H, s, COCH,), 1.36 (3H, t, 2-OCH CH~) and 1.35 (3H, t, 3-OCH~ ).
(b) Cyclisation of 2-(3'-acetyl-5~-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl-5-benzoxycarbonylpyrrQle A solution of the 2-pyrrolylmethylpyrrole (0.083 g), 0.2 mmol) in 1,2-dichloroethane (5 ml) was heated under reflux and stirred with Montmorillonite clay (0.25 g) for 14 h. The reaction was followed by TLC. After the clay has been filtered off and washed well with 1,2-dichloroethane, evaporation of the combined filtrates under reduced pressure gave an oil. Chromotagraphic separation of an oil eluting with (5-30%) ethyl acetate in hexane yielded Ethyl 6-Benzyloxycarbonyl-3.4-dimet~ylpyrrolo r 2 3-flindole-2-carboxylate woss/21171 pcTlGBs5loo2o3 (isomer I) as a yellow solid (0.0047 g, 6%) which was identical to isomer I obtained from (a) by TLC and nmr;
r and Ethyl 6-Benzyloxvcarbonyl-3~4-dimethylpyrrolo r 3 2-f~indole-2-carboxylate (isomer II) as a yellow solid - (0.0285 g, 36%) which was identical to isomer Il obtained from (a) by TLC and NMR; and the starting 2-pyrrolylmethylpyrrole (0.0116 g, 14%).
Dibenzyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicalL~ylate A solution of benzyl pyrrole-2-carboxylate (0.201 g, 1.0 mmol) and benzyl 5-acetoxymethyl-4-acetyl-3-- methylpyrrole-2-carboxylate (O.331 g, 1.O mmol) in 1,2 -dichloroethane (10 cm3) was heated under reflux and stirred with Montmorillonite clay (1 g) for 7 h. The reaction was followed to completion by TLC. After the clay had been filtered off and washed well with 1,2-dichlorethane, evaporation of the combined filtrates under reduced pressure gave an oil. This was submitted to column chromatography eluting with (5-50%) ethyl acetate in heY~ne to give D;h~n~yl 3 4-dimethylpyrroto r 2 3-flindole-2 6-dicarboxylate(;somerI) as yellow crystals after crystallisation from ethyl acetate-petroleum ether (0.019 g, 4.20%), m.p. 210-212~C
(Found: C, 73.50; H, 5.29; N, 6.13. C2~H2,N2O, requires C, 73.62; H, 5.49; N, 6.36%); ~H ~2~-DMSO) 11.17 ~lH, s, 5-NH), 11.02 (lH, s, l-NH), 7.57-7.34 (llH, m, 2 x ArH
and 8-H), 7.23 (lH, d J 1.5, 7-H), 5.42 (2H, s, CH~Ph), 5.40 (2H, s, CH.Ph), 2.93 (3H, s, 4-CH3), 2.87 (3H, s, 3-- C~3); m/z (%) 452 (68, M+), 344 (58), 236 ~17), and 91 (100); and Dibenzyl 3 4-dimethylpyrrolo r 3.2-f~indole-2 6--dicarboxylate ~isomer II) as yellow crystals after crystallisation from dichloromethane-petroleum ether (0.036 g, 7.96%), m.p. 184-186~C (Found: C, 73.71; H, 5.59; N, 6.27. C2aH24N20~ requires C, 73.62; H, 5.49; N, 6.36~ H ([2H6]-DMSO) 11.36 (lH, s, 7-NH), 10.99 (lH, s, l-NH), 7.52 (4H, d J 7, O-ArH), 7.46-7.37 (7H, m, m and ~-ArH and 8-H), 7.23 (lH, br s, 5-H), 5.40 (4H, s, 2x CH Ph~, 2.91 (3H, s, 3-CHI) and 2.86 (3H, s, 4-CH3); m/z (%) 452 ~55, M'), 344 (S9), 236 (10), and 91 (100).
Further elution gave 2-~3'-acetyl-5'-~enzoxycarbonyl-4-methylpYrrol-2'-ylmethyl)-5-benzoxycarbonylpyrrole as pale yellow crystals after crystallisation from dichloromethane-petroleum ether (0.104 g, 22.13%), m.p.
141-143~C (Found: C, 71.60; H, 5.59; N, 5.79. C2aH26N205 requires C, 71.47; H, 5.57; N, 5.95%); ~H (CDC13) 10.22 (lH, s, l-NH), 9.25 (lH, s, l'-NH), 7.48-7.28 (lOH, m, ArH), 6.83 (lH, dd J 2.5 and 4, 4-H), 6.05 ~lH, dd J 2.5 and 4, 3-H), 5.28 (2H, s, CH Ph), 5.26 (2H, s, CH.Ph), 4.13 (2H, s, CH2), 2.58 (3H, s, CH3, 2.49 (3H, s, COCH3);
m/z (%) 470 (6, M~), 379 (45), 271 (32), 91 (100), 65 (61) and 43 (38) and ~2.3-di(3'-acetyl-5'benzoyxcarbonyl-4'-methylpyrrole-2'-ylmet~yl)-s-benzoxycarbonylpyrroleasan oil (0.0924 g, 25.01%); ~H (CDC13) 11.18 (lH, s, l-NH), 10.46 (lH, s, NH), 9.31 (lH, s, NH), 7.42-7.27 (lSH, m ArH), 6.61 (lH, d J 2, 4-H), 5.31 (2H, s, ~2Ph), 5.29 (2H, ~, CH. Ph), 5.22 (2H, s, CH.Ph), 4.13 (2H, s, 2-CH2), 4.05 (2H, s, 3-CH2), 2.57 (3H, s, CH3), 2.55 (3H, s, CH3), 2.51 (3H, s, CH3), 2.37 (3H, s, CH3); m/z (%) 739 (2, M~), 696 (20), 648 (27), 631 (20), 588 (95). (Found:
739.2890. C~,H~lN308 requires 739.2893) Ethyl6-methoxycalLollyl-3~4-dimethylpyrrolo[3~2-f]indole 2-ca L~ylate ,.
A solution of methyl pyrrole-2-carboxylate (0.222 g, 1.7 mmol) and ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-car~oxylate (0.474 g, 1.7 mmol) in 1,2-dichloroethane (20 cm3) was heated under reflux and stirred with Montmorillonite clay for 7 h. The reaction was followed to completion by TLC. After the clay had been filtered off and washed well with 1,2-dichloroethane, evaporation of the combined filtrates under reduced pressure gave an oil. Chromatographic separation of an oil eluting with (5-40%) ethylacetate in hexane gave Ethyl 6-methoxycarbonyl-3,4-dimethyl~yrrolo r 2 3-flindole-2-carboxylate (isomer I) as a yellow solid after crystallisation from dichloromethane-petroleum ether (0.030 g, 5.62%), m.p. 245-248~C; ~H ([2H6]-DMSO) 11.16 (lH, s, 5-NH), 11.00 (lH, s, 1-NH), 7.45 (lH, s, 8-H), 7.20 (lH, s 7-H), 4.37 (2H, ~, OC~2CH~), 3.91 (3H, s, OÇ~b), 2.95 (3H, s, 3-CH3), 2.88 (3H, s, 4-CH3), 1.37 (3H, t, OCH2Ç~); saturation of the l-NH at ~ 11.00 enhanced the signal due to 8-H at ~ 7.45 (3.9%), saturation of the 4-CH3 of ~ 2.88 ~nhAnr~ the signal due to 5-NH at ~ 11.16 (12.3%) and saturatoin of the 5-NH at 11.16 ~nh~nce~ the signal due to 4-CH3 at ~ 2.88 (2%); m/z (~) 314 (81, M+), 282 (55), 268 (89), 236 (100), 208 (56), 179 (50), 153 (48), 118 (56), 90 (82) and 77 (72) (Found: M~314.1267.
C17H8N2O4 requires 314.1266; Ethyl 6-methoxycarbonyl-3.4-dimethylpyrrolo r 3.2-f1indole-2-car~oxylate (isomer~I) as yellow crystals after crystallisation from dichloromethane-petroleum ether (0.0584 g, 10.94%), m.p.
242-245~C; ~H (~2H6]-DMS0) 11.36 (lH, s, 7-NH), 10.92 (lH, _ _ _ _ _ _ _ _ W O95/~1171 PCTIGB95100203 s, 1-NH), 7.33 (lH, s, 8-H), 7.24 (lH, s -H), 4.36 (2H, q, OCH~CH3), 3.89 (3H, s, OCH ), 2.92 (3H, s, 3-CH3), 2.87 (3H, s, 4-CH3), 1.37 (3H, t, OCH2CH3); m/z (%) 314 (60, M~), 282 (50), 268 (62), 236 (60), 208 (60), 179 (55), 165 (34), 152 (52), 134 (48), 127 (56) and 188 (100) (Found:
M~314.1267. C17Hl~N2O4 requires 314.1266); Further elution gave 2-~3'-acetyl-5'-ethoxycar~onyl-4'-methylpyrrol-2-ylmethyl-5-methoxycarbonylpyrrole as off white crystals after crystallisation from dichloromethane-petroleum ether (0.0912 g, 16.16%), m.p. 160-162~C; ~H (CDCl3), 10.40 (lH, s, 1-NH), 9.78 (lH, s, l'-NH), 6.79 (lH, dd J
4 and 2.5, 4-H), 6.09 (lH, dd J 4 and 2.5, 3-H), 4.30 (2H, q, OÇ~kCH,); 4.22 (2H, s, CH2), 3.80 (3H, s, OCH3), 2.58 (3H, s, CH3), 2.50 (3H, s COCH3), 1.33 (3H, t, OC~,~3; m/z (%) 332 (66, M+), 300 (55), 271 (54), 254 (66), 227 (61), 211 (55), 183 (65), 155 (59), 128 (66), 106 (85), 94 (45), 78 (66), 51 (37), 43 (100); and 2.~-dif3-acetyl-5-ethoxycarbonyl-4-methyl~yrrol-2'-ylmethyl-5-methoxycarbonyl~yrrole as off white crystals after crystallisation from benzene-petroleum ether (0.1885 g, 41.15%), m.p. 203-206~C (Found: C, 62.24; H, 6.16; N, 7.66. C2.H,3N30~ requires C, 62.32; H, 6.16; N, 7.79%); ~H
(CDCl3) 11.08 (lH, s, NH), 9.42 (lH, s, NH), 9.13 (lH, s, NH), 6.63 (lH, d J 2, 4-H), 4.33 (2H, q, OCH.CH3); 4.32 (2H, q, O~kCH3), 4.13 (2H, s, 2-CH2), 4.11 (2H, s, 3-CH2), 3-77 13H, s, OCH3), 2.61 (3H, s, CH3), 2.59 (3H, s, CH3), 2.57 (6H, s, 2 x CH3), 1.37 (3H, t, OCH2Ç~3), 1.36 (3H, t, OCH7CH~).
r Ethyl7-meth~ycaL~v~ 3,4-dimet~ylpyrrolo[3,2-f]indole-2-calL~xylate v (a) Reaction of l-methyloxycarbonylpyrrole and ethyl 5-acetoxy-methyl-4-acetyl-3-methylpyrrole-2-carboxylate A solution of 1-methoxycarbonylpyrrole (1.000 g, 8 mmol) and ethyl 5-acetoxymethyl-4-acetyle-3-methyl-2-carboxylate (2.136 g, 8 mmol) in 1,2-dichloroethane (80 cm3) was heated under reflux and stirred with Montmorillonite clay (8 g) for 18 h. After the clay had been filtered off and washed well with 1,2-dichlorethane, evaporation of the combined filtrates under reduced pressure gave an oil. This was submitted to column chromatography eluting with (20-0%) petroleum ether in dichloromethane and (0-25%) ethyl acetate in dichloromethane to give the starting 1-methoxyca~bol-ylpyrrole (0.1448 g, 14.48%); 3-chloro-5-ethoxy~-Arhn~yl-2-l1'-methoxy~-hrnylpyrrol-2~-ylmethyl)-4-me~yl~yrrole as colourless crystals after crysallisation from benzene-petroleum ether (0.0143 g, 5.51%) m.p. 144-145~C (Found: C, 55.27; H, 5.45; N, 8.43.
ClsH~N2O~Cl requires C, 55.47; H, 5.28; N, 8.63~ H
(CDCl3) 9.23 (lH, br s, NH), 7.20 (lH, t, J 2.5, 4'-H), 6.12 (2H, d J 2.5, 3'- and 5'-H), 4.29 (2H, g, OCH.CH3), 4.21 (2H, s, CH2), 3.97 (3H, s, OCH3), 2.26 (3H, s, CH3), 1.34 (3H, t, OCH7CH~); m/z (%) 326 (10, M+-2), 324 (28, M'), 297 (7), 295 (22), 289 (88), 279 (23), 277 (37); 243 (86), 221 (24), 219 (66), 185 (45), 155 (75), 142 (21), 128 (32), 101 (30), 90 (30), 80 (75), 67 (70), 59 (100).
-Ethy~-methoxycarbonyl-3 4-dimethylpyrrolo r 2 3-flindole-2-carboxylate fisomer I) as colourless crystals after crystallisation from dichlormethane-petroleum ether (0.0263 g, 1.05%) m.p. 163-165~C (Found: C, 64.73; H, 5.79; N, 8.77. Cl7H,aN204 requires C, 64.95; H, 5.77; N, 8.91%); ~H ([2H6]-DMSO) 11.33 (lH, s, NH), 7.64 (lH, d J
3.5, 6-H), 7.38 (lH, s, 8-H), 6.72 (lH, d J 3.5, 7-H), 4.35 (2H, q, OC~.CH3), 3.95 (3H, s, OCH3), 2.86 (3H, s, 3-CH3), 2.75 (3H, s, 4-C~) and 1.37 (3H, t, OCH CH~); m/z (%) 314 (57, M~), 268 (100), 240 (18), 209 (19), 195 (25), 181 (52), 154 (42), 127 (28), 77 (26) and 59 (82); and Ethyl7-methoxycarhonyl-3 4-~;methylpyrrolo r 3 2-f~indole-2-~-~rhn~ylate (iso~er II) as colourless solid (O.6027 g, 23.99%) m.p. 197-200~C (Found: C, 64.82; H, 5.55; N, 8.74.
Cl7Hl~N2O~ re~uires C, 64.92; H, 5.77; N, 8.91%) ~H (~2H6~-DMSO) 11.37 (lH, s, NH), 8.03 (lH, s, 8-H), 7.58 (lH, d J 3.5, 6-H), 6.88 (lH, d J3.5, 5-H), 4.35 (2H, q, OCH CH3), 3.99 (3H, s, OCH3), 2.86 (6H, s, 2 x CH3), 1.36 (3H, t, OCH ÇH~); m/z (%) 314 (53, M~), 268 (100), 240 (13), 209 (21), 195 (12), 181 (12), 154 (13) and 127 (16). Further elution gave 3-acetyl-5-ethoxycarhnnyl-2 (1'-methoxycarbo~yl~yrrol-2'-ylmthyl)-4-methylDYrrolç as colourless solid (0.1588 g, 5.98%) m.p. 172-175~C (FoundL
C, 61.38; H, 6.22; N, 8.40. Cl7H~N20S requires C, 61.43;
H, 6.07; N, 8.43%); ~H (CDC13) 9.53 (lH, br s, NH), 7.21 (lH, dd J 3.5 and 2, 5'-H), 6.26 (lH, m, 4'-H), 6.13 (lH, t J 3.5, 3-H), 4.56 (2H, s, CH2), 4.31 (2H, q, O~H7CH3), 3.95 (3H, s, OCH3), 2.59 (3H, s, 4-CH3), 2.47 (3H, s, COCH,), and 1.35 (3H, t, OCH ~~); m/z (%) 332 (28, M~), 289 (92), 243 (100), 227 (22), 185 (28), 155 (16), 130 (10~, 77 (24), 59 (35), 43 (90); 6-~3'-acetyl-5'-ethoxYcarbonyl-4'-methylpyrrol-2'-ylmethyl)-2-ethoxycarbonyl-7-meth~xycarbonyl-3 4-di~ethYlben~oU 2-b:
5.4-b'~dipyrrole as off white solid (0.1593 g, 7.64%) Pcrl~bssl~a203 m.p. 218-222~C (Found: C, 64.19; H, 5.89; N, 7.93.
Cz~H3lN3O7 requires C, 64.48; H, 5.99; N, 8.06%); ~H ([2H6]-r DMSO) 12.08 (lH, s, pyr-NH), 11.32 (lH, s, 1-NH), 8.01 (lH, s, 8-H), 5.87 (lH, s, 5-H), 4.59 (2H, s, CH2), 4-34 (2H, q, OCH2CH3), 4.28 (2H, q, pyr-CO2~kCH3), 4.05 (3H, s, OCH3), 2.79 (3H, s, CH3), 2.64 (3H, s, CH3), 2.59 (3H, s, CH3), 2.34 (3H, s, CH3), 1.36 (3H, t, OCH CH~), 1.33 (3H, t, pyr-OCH CH~); m/z (%) 521 (2, ~), 478 (3), 432 (2), 386 (2), 370 (2), 355 (3), 342 (2), 300 (2), 193 (2), 179 (2), 105 (2), 91 (3) and 59 (100); and 2 5-di (3'acetyl-5-ethoxycarbonyl-4-methylpyrrol-~'-ylmethyl)-1-methoxycarbonyl~yrrole as colourless crystals after recrystallisation from dichloromethane-petroleum ether (0.1292 g, 5.99%) m.p. 227-230~C (Found: C, 62.27; H, 6.03; N, 7.60. C~3~3O8 requires C, 62.32; H, 6.16; N, 7.79%); ~H ([2H~]-DMSO) 11.95 (2H, s, 2 x NH), 5.19 (2H, s, 3- and 4-H), 4.38 (4H, s, 2 x CH2), 4.24 (4H, q, 2 x OCH~CH3), 4.01 (3H, s, OCH3), 2.S0 (6H, concealed by DMSO, 2 x COCH3), 2.28 (6H, s, 2 x CH3), 1.29 (6H, t, 2 x OCH~CH~); m/z (%) 539 (34, M~), 521 (34), 507 (8), 494 (13), 464 (15), 418 (13), 370 (14), 331 (99), 285 (85), 273 (40), 227 (58), 207 (46), 162 (87) and 59 (100).
(b) Cyclisation of 3-acetyl-5-ethoxycarbonyl-2-(1'-methoxy-carbonylpyrrole-2'-ylmethyl~-4-met~ylDyrrQle Toluene-p-sulfonic acid (100 mg) was added to the solution of the 3-acetyl-5-ethoxycarbonyl-2-(1'-methoxy-carbonylpyrrol-2'-ylmethyl)-4-methlypyrrole (0.435 g, 1.31 mmol) in benzene (50 cm3), the reaction mixture was heated under reflux for 5h (using Dean-Stark apparatus).
On cooling, the product crystallised, the crystals were filtered and washed with ethanol giving Ethyl 7-methoxycarbonyl-3.4-dimethyl~yrrolo r 3.2-flindole-2-.
carboxylate risomer II) as colourless crystals (0.3264 g, 79.34%) m.p. 197-200~C which was identical to the benzo[l,2-b:5,4-b']dipyrrole (isomer II3 from the previous experiment by TLC and NMR. Chromatographic separation of the remaining filtrate eluting with (5-0%) petroleum ether in dichloromethane and (0-10%) ethyl acetate in dichloromethane yielded Ethyl 5-methoxycarbonyl-3~4-dimethylpyrrolo r 2.3-flindole-2-car~oxvlate (isomer I) as colourless solid (0.002g, 0.49%) which was identical to the pyrrolo[2,3-f~ indole (isomer I) from the previous experiment. Also obtained were the }?yrrolo r 3 2-fl;ndole (;somer TT) (O.0313 g, 7.61%) and the starting 2-pyrrolylmethylpyrrole (0.0125 g, 2.87%).
EX~MPT~ 7 Ethyl 3~4-dimethylpyrrolo~3~2-f]indole-2 ~ late 5% Potassium hydroxide (10 cm3) was added to a solution of ethyl 7-methoxy-3,4-dimethylpyrrolo r 3,2-f]indole-2-carboxylate (example 6 isomer II) (O.314 g, 1.0 mmol) in tetrahy~ofuran (100 cm3) and the reaction mixture was heated at gentle reflux and stirred for 48 h. After cooling, the reaction mixture was diluted with water (3 x 50 cm3). The combined extracts were washed with water and then evaporated under r~ pressure to give a yellow solid. This was su~mitted to column chromatography eluting with (10-25%) ethylacetate and 10%
dichloromethane in petroleum ether to give the starting pyrroloindole (0.031 g, 9.87%) and ethyl 3 4-dimethyl PYrrQlO r 3~2-flindole-2-carboxylate as a pale green solid (0.169 g, 66.02%) m.p. 233-235~C; ~H (CDC13) 8.36 (lH, br s, l-NH), 7.86 (lH, br s, 7-NH), 7.17 (lH, dd J 3.3 and 2.4, 6-H), 7.09 (lH, s, 8-H), 6.62 (lH, m, 5-H), 4.14 (2H, q, 05~kCH3), 2.96 (3H, s, 3-CH3), 2.94 (3H, s, 4-CH3) and 1.43 (3H, t, 0CH2S~); m\z (~) 256 (28, ~), 227 (5), 210 (100), 181 (99), 168 (28), 15~ (89), 140 (15), 126 ~ (63), 77 (42), 63 (32).
ASSAYS FQR COMPoUN~ A~llvllY
Assays for cell proliferation/cytotoxity were carried out in tissue culture grade 96 well microtitre plates (Costar). Cells in log growth were added to the plates at a concentration of lX103 cells per well on day 0 and serially diluted compounds were then added on day 1.
Plates were then incubated at 37~C in 5% C02 in air for a further 4 days.
For quantitation of cell growth, the methylene blue biomass st~; n; ng method was used, the test being read on a Mult;sc~n plate reader at wavelength of 620nm. The morphology of the cells was checked microscopically under phase-contrast immediately before the fixation and st~ ng with methylene blue, and by ordinary light microscopy thereafter. IC50 values for active compounds were obtained using the computer p~o~lamme, GS1 and dose-response slopes were also plotted.
When compounds were tested for activity in a colony forming assay the methods used were identical to those described earlier except that serially diluted compound was added to the sloppy agar when the test was set up, and replenished at the same concentration on day 7. The test results were read on day 14.
RESULTS:
Example Compound IC50 ( uM) (HT108ûscc2 )
The present invention relates to heterocyclic compounds which have been found to have anti-tumour activity. More specifically, the invention concerns benzo[1,2-b:4,5-b']dipyrroles, benzo[l~2-b:s~4-b~]dipyrroles~
cyclopent[f]indoles, benzo[1,2-b:4,5-b']difurans, benzo[l,2-b:5,4-b']difurans, 2H-indeno~5,6-b]furans, benzo[1,2-b:4,5-b']dithiophenes, benzo[1,2-b:5,4-b']dithiophenes, cyclopent[f]indenes and 5H-furo[2,3-f]indoles methods for their preparation, pharmaceutical formulations cont~;~ing them and their use as anti-tumour agents.
Research in the area of cancer chemotherapy has produced a variety of anti-tumour agents, which have differing degrees of efficacy. Standard clinically used agents include adriamycin, actinomyci~ D, methotrexate, 5-fluorouracil, cis-platinum, vincristine and vinblastine.
However, these presently available anti-tumour agents are known to have various disadvantages, such as toxicity to healthy cells and resistance to certain tumour types.
There thus exists a continuing need to develop new and im~G~ed anti-tumour agents.
Khoshtariya et al, khim. Geterotsikl. Soedin (1982), (4) 304-7, disclose the synthesis of certain pyrroloindoles.
Gruenhaus H., J.Heterocyclic Chem. 13(6), 1161-3 discloses the synthesis of certain indenothiophenes There have now been discovered novel compounds which exhibit anti-tumour cell activity including a group of -novel compounds which exhibit anti-tumour cell activity with low toxicity against normal cell lines.
Thus, in a first aspect the present invention provides a compound of the general formula (1) R
R~ XJ~3 (I) or a salt or physiologically functional derivative thereof, wherein A is ~R2 ~ ~ ~R2 X is O, S, SO, SO2, CH2, CO or NR7, wherein R' is H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulphonyl, substituted sulphonyl, or COOMe;
Y is O, S, SO, SO2, CH2, CO or NR7;
Rl is COR8, CHO, CH20H, CH20R8, CONH2,COOR8, CONHR8, CoNR~R9, CSOR-, CSSR8, COSR8, CSNHR', CSNR8 R9, CNHORa wherein R8 and WO95/21171 PCT/GB9~l00203 R9 are independently hydrogen, alkoxyalkyl, heterocycloalkyl, heteroaralkyl, or C11O optionally substituted hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain;
,.
or Ra and R9 are a sugar group.
R2 is H ~ halo, cyano, COOR8, alkyl, aryl, alkenyl, alkynyl, alkoxy, (wherein alkyl, aryl, alkenyl, alkynyl and alkoxy can be substituted) or CH2CH2CO2Rl2 wherein Rl2 is alkyl or aryl;
R3 is H, alkyl, halogen, cyano, amino, COORa, CONHR, COR, CH20H, CH2OR , CONH2, CONR8R9, CSORa, CSSR8, COSRa, CSNHRa, CSNRaR9 or CNHOR-;
R~ is H ~ halogen, cyano, amino, alkyl, COOR8, CONHR8, CORa, CH20H, CH20R8, CONH2, CONRaR9, CSORa, CSSR8, COSR8, CSNHR8, CSNR8R9 or CNHOR-;
Rs is H ~ hydroxy, aryloxy, aralkyloxy, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano COOR or CHO;
R6 is H~ aryl, alkyl, aralkyl, nitro, halogen, CHO or CoRl3 wherein Rl3 is alkyl or aryl; wherein Ra is not H when R2 is H and R3 is not H or Me when A is ~Y~Rl Alkyl groups present in general formula (I) may be _ _ _ _ _ _ _ _ _ _ _ straight or branched chain alkyl groups, and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, t-butyl and the like.
Acyl groups may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable acyl groups include ethanoyl and propanoyl groups.
Alkoxy may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable alkoxy groups include methoxy, ethoxy and the like.
Aryl includes both carbocyclic aryl groups and heterocyclic aryl groups normally contAining a maximum of 10 ring atoms. Carbocyclic aryl yLou~s include, eg phenyl and naphthyl and contain at least one aromatic ring.
Heterocyclic aryl yLou~ include eg thienyl, furyl, pyridyl, indole and quinoline rings.
An aralkyl group may contain from 1 to 4 atoms in the alkyl portion and the aryl portion may be a carbocyclic or heterocyclic aryl group.
Cycloalkyl includes both cycloalkyl yLOu~S and heterocyclo alkyl groups normally contA;n;ng between 3 and 6 ring atoms. Heterocycloalkyl y~o~ include e.g.
morpholino, thiomorpholino, piperidino, imidazolino, pyrrolidino, pyrazolidino, piperazino, tetrahydrofuranyl, tetrahydropyranyl.
When R8 and R9 are independently optionally substituted Cl10 hydrocarbyl which may optionally contain one or two oxygen atoms in the chain this includes optionally substituted alkyl, hydroxyalkyl, alkenyl, alkynyl, carbamoylalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, aralkyl, aryloxyalkyl.
Substituents which may be present on the Cl~O hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain include hydroxy, azido, alkenyl, halo, nitro (NO2), amino, (optionally substituted by one or 2 alkyl groups), cyano, carboxylate, alkyl ester, aralkyl esters or aryl esters, (wherein the alkyl ester, aralkyl ester and aryl ester can be substituted) alkyl, aryl, aralkyl, aryloxy, arylalkoxy, substituted arylalkoxy, sulphinyl, sulphonyl, thio, alkylthio, alkoxy, hydroxyalkyl, halo alkyl, phosphate, phosphonate, silyl, silyloxy, (wherein silyl and silyloxy may be substituted by one or more Cl6 alkyl or aryl) keto, formyl.
Substituents which may be present on alkyl esters, aralkyl esters and aryl esters include nitro, amino, hydroxy, alkoxy, halogen, cyano and alkyl.
Where R- is a sugar this group may be present in a protected or unprotected form. Preferred sugar-protecting ~LOU~ include isopropylidene, benzylidene acetate, benzoyl, paranitrobenzyl, paranitrobenzoyl, benzyl, substituted silyl and tetrahydropyranyl.
When R- is a sugar such as a tetrose, pentose, hexose (including furanose and pyranose) or heptose, preferred sugars include glucose, fructose, mannose, ribose, arabinose.
., Substituents which may be present on the sulphonyl and - - -sulphinyl include alkyl, aryl and aralkyl.
Halogen represents fluoro, chloro, bromo or iodo.
X preferably represents NH, A is preferably ~YJ'~R2 and Y preferably represents NH.
Rl is preferably COOR8, with R8 preferably being alkyl or aralkyl.
R2 is preferably H, alkyl, or COOR8 wherein R8 is preferably alkyl, R3 is preferably alkyl R' is preferably alkyl or COOR'.
R5 is preferably hydrogen and R6 is preferably hydrogen or methyl and salts and physiologically functional derivatives thereof.
one group of preferred compounds according to the present invention includes:
Ethyl 1l7-dihydro-3t4~6-trimethylpyrrolo[3~2 f~indole-2-carboxylate;
Diethyl li7-dihydro-3~4~6-trimethylpyrrolo[3r2-f]indole 2,5-dicarboxylate; and f Ethyl6-methoxycarbonyl-3~4-dimethylpyrrolo[3l2-f]indole-2-carboxylate and physiologically functional derivatives thereof.
A second group of preferred compounds according to the invention include:
Ethyl 6-Benzyloxycarbonyl-3t4-dimethylpyrrolo[3~2-f]indole-2-carboxylate;
Dibenzyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicarboxylate;
Ethyl7-methoxycarbonyl-3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate; and Ethyl 3~4-dimethylpyrrolo~3~2-f]indole-2-carboxylate and physiologically functional derivatives thereof.
Com~o~-ds of the general formula (I) have been tested against two specially developed cell lines which are clones of the human fi~rosarcoma cell-line, HT1080. ~ne clone, H~1080scc2, retains the transformed phenotype of the parental line, whilst the other, HTlO~Olc, is a morphologically flat, non-tumourigenic, revertant.
According to a further aspect, the present invention also provides a process for preparing compounds of general formula (I), which process comprises the catalysed reaction of a compound of formula (II) with a compound of formula (III) in an inert solvent at a temperature between room temperature and the reflux temperature of the solvent, wherein X, Y, Rl, R2, R3 R', R5 and R6 are as defined herein except that R3 and R' may not be hydrogen when X is NH, and L is a leaving group:-R ~ ~ R2 (II) (III) Preferred catalysts are Montmorillonite Klo clay or p-toluenesulphonic acid. Preferred solvents are 1,2-dichloroethane or toluene. Examples of suitable leaving y~OU~-~ include -OCOCH3, OEt, -N+Me3 and halo.
Insertion of the substituent R1 onto the ring system for example:
(d) Carboxylation of a polyheterocyclic compound using (i) a carbonyl halide or (ii) carbon dioxide According to known ~ocedu~es (J. March, Advanced Organic Chemistry, 2nd ed, McGraw Hill, New York, 1977, p 497-498~.
(e) Alternatively one can produce compounds of the formula (I) wherein R2 is CHO by methods known to those PCT/GB9~/00203 skilled in the art, for example:-(i) The appropriate aromatic polyheterocycle can be reacted with a formylating agent, such as that Y generated by the reaction between SnC1~ and CI2CHOCH3 or e~uivalent reagents.
For example, according to the method of A. Reiche et al, Chem. Ber. 93, 88 (1960), or with other standard formylating reagents/procedures known in the art, for example, the Gatterman-Koch reaction (CO\HCl\AlC13\CUCl), the Gatterman reaction (HCN\HCl\ZnC12), and the Vilsmeier reaction (POC13\PhN-(Me)CHO or POCI3\Me2CHO) (J. March, Vide Supra, p 494-497); or (ii) the appropriate aromatic polyheterocycle, carrying a suitable functional group, said group being converted to an aldehyde group by methods known to those skilled in the art. Suitable functional ~LO~s include CHBr2, CH,, COR1' wherein R1' is a primary or secondary C16 alkyl group, COOH or a derivative thereof such as an ester, amide, acid chloride or CN; or (f) Compounds of the formula (I) wherein Rl is CONHR10 may also be produced by the reaction of a compound wherein is COOH or a suitable reactive acid derivative thereof as outlined in J. March, Vide supra. For example an acid halide can be reacted with a compound NH2Rl~ in an inert solvent.
(g) Conversion of one compound of formula (I) into another compound of formula (I).
CA 022ll979 l997-07-30 Compounds of the invention wherein Rl is COOR8 and Ra is, for example, aralkyl can be converted to free acids wherein R8 is H by reduction in the presence of H2 and a Pd catalyst, or where R8 is, for example, alkyl, by hydrolysis in the presence of an appropriate base e.g.
caesium carbonate.
It is thereafter possible for the skilled man to synthesise ester and amide compounds within the scope of the invention by conversion of the free acids obtained, by known procedures. ~See J. March, Vide Supra, p363-365).
Compounds of the invention produced as described herein can be converted to other compounds of the invention by electrophilic substitution at R5 and/or R6, to introduce, for example, NO2, halogen and COR 3 wherein Rl3 is as defined herein.
Compounds of formula I in which X or Y is NR, and R7 is COOMe can be converted by acid or base hydrolysis to compounds of formula I in which X or Y are NH using, for example, potassium hydroxide or Br in acetic acid.
The above processes have been described for compounds wherein A is ~Y ~ R~
The skilled man will appreciate that these are equally CA 022ll979 l997-07-30 applicable when A is / Y R2 ~ Rl ~ R2 ~ R 1 Y R2 The compounds of the present invention are useful for the treatment of tumours. They may be employed in treating various forms of cancer of mammals including carcinomas, for instance of the stomach, pancreas, breast, uterus and colon; adenocarcinomas, for instance of the lung and colon; sarcomas, for instance fibrosarcoma; leukaemias, for instance lymphocytic leukaemia and lymphomas, for instance myeloid lymphoma.
The invention thus further provides a method for the treatment of tumours in animals, including mammals, especially humans, which comprises the administration of a clinically useful amount of compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative in a pharmaceutically useful form, once or several times a day or in any other a~ op~iate schedule, orally, rectally, parenterally, or applied topically.
In addition, there is provi~ed as a further, or alternative, aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof for use in therapy, for example as an antitumour agent.
- The amount of compound of formula (I) required to be effective against the aforementioned tumours will, of CA 022ll979 l997-07-30 W O95/21171 pCT/GB95/00203 course, vary and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition being treated, the route of administration, and nature of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be a~;n;stered. A suitable effective anti-tumour dose is in the range of about 0.01 to about 100 mg/kg body weight, eg 0.1 to about 100 mg/kg body weight, preferably 1-30 mg/kg body weight. The total daily dose may be given as a single dose, multiple doses, ~., two to six times per day or by intravenous infusion for selected duration. For example, for a 75 kg mammal, the dose range would be about 8 to 900 mg per day, and a typical dose could be about 50 mg per day. If discrete multiple doses are indicated treatment might typically be 15 mg of a compound of formula (I) given up to ~ times per day.
Whilst it is possible for the active compound to be administered alone, it is preferable to present the active compound in a pharmaceutical formulation.
Formulations of the present invention, for medical use, comprise a com~oulid of formula (I) or a salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients.
The carrier(s) should ~e pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The present invention, therefore, further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof together PCTIGB95l00203 wogs/21171 with a pharmaceutically acceptable carrier thereof.
There is also provided a method for the preparation of a pharmaceutical formulation comprising bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier thereof.
Formulations according to the present invention include those suitable for oral, topical, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred formulations are those suitable for oral or parenteral administration.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both and then, if neceee~ry, shaping the product into desired formulations.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each con~; n; ~g a predetermined amount of the active compound; as a powder or granules; or a solution or suspension in an aqueous or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active compound with any suitable carrier.
A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredients. Such Acc~ssory ingredients(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredients, such as a polyhydric alcohol for example glycerol or sorbitol.
Formulations for rectal administration may be presented as a 3u~poaitory with a conventional carrier such as cocoa butter.
Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Such formulations suitably comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient.
Useful formulations also comprise concentrated solutions or solids cont~in;ng the compound of formula (I) which upon dilution with an appropriate solvent give a solution for parenteral administration as above.
In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
In a further aspect the present invention provides the use of a compound of formula (I) or a pharmaceuticallY
acceptable salt or physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumours.
The invention will now be illustrated by the following non-limiting Examples:
All temperatures are in degrees Celsius (~C) IR spectra were recorded on a Perkin-Elmer 257 grating ~e~LLo~l~otometer or a Bruker FS66 ~e~L o~hotometer.
U.V. spectra were measured in ethanol on a Unicam SP800 spe~; LL ophotometer.
lH NMR spectra were obtained on a Bruker WM 360-NMR
spectrophotometer at 360 MHz, or on a Bruker AC200 spectrophotometer at 200 MHz. J values are given in Hz.
Mass spectra were obtained on Varian CH5D(EI), Kratos Concept (EI) or Kratos Ms50(FAB) instruments.
EX~MPLE 1 Diethyl 1,5-di~y~l~ 3,4,6-trimethylpyrrolo[2,3-f]indole-2,7-di~rhQYylate A solution of ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate (O.267 g, 1.0 mmol) and 3-carbethoxy-2-methylpyrrole (0.153 g, 1.0 mmol) in 1,2-dichloroethane (10 cm3) was heated at reflux and stirred with Montmorillonite clay (lg) for 18h. After filtration from clay and washing well with 1,2-dichloroethane, evaporation of the com~ined filtrates under reduced pressure gave an oil. This oil was submitted to flash chromatography on silica eluting with (0-20%) ethyl acetate in dichloromethane to give the starting 3-carbethoxy-2-methylpyrrole (0.045 g, 29.4%) and diethyl 1,5-dihydro-3,4,6-trimethylpyrrolo[2~3-f]indole-2l7 dicarboxylate as a colourless solid (0.021g, 6.14%) m.p.
269~C (decomp); ~H ([2H6]-DMSO) 11.34 (lH, s, 5-NH), 11.00 (lH, s, l-NH), 7.80 (lH, s, 8-H), 4.33 (2H, q, 7-OC~2CH3), 4.26 (2H, q, 2-OCH.CH3), 2.85 (6H, s, 3-CH3 and 4-CH3), 2.69 (3H, s, 6-CH3), 1.39 (3H, t, 7-OCH2Ç~3), and 1.37 (3H, t, 2-OCH2CH3); saturation of the singlet 8-~ at ~ 7.80 enhanced the signal due to 1-NH at ~ 11.00 (2.3%); m/z (%) 342 (75,M~), 296 (100), 268 (6), 223 (7) and 195 (5) (Found : M' 342.1580. Cl,H22N2O4 requires M, 342.1579; A max EtOH/nm (log ~ max.dm3 mol~l cm~l 378 (3.56), 365 sh (353), 329 (3.83), 3.04 (3.99) and 259 (3.74). Further elution gave diethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2,5-dicar~oxylate as a colourless solid (0.048g, 14%) m.p. 216-216.5~C (Found: C, 66.82; H, 6.68; N, 8.17.
ClgH22N2O4 requires C, 66.65; H, 6.48, N, 8.18%); ~ ([2H6]-DMSO) 11.30 (lH, s, 7-NH), 10.91 (lH, s, lN-H), 7.12 (lH, s, 8-11), 4.35 (2H, q, 5-OC_CH3), 4.28 (2H, q, 2-OCH.CH3), 2.90 (3H, s, 4-CH3), 2.87 (3H, s, 3-CH3, 2.54 (3H, s, 6-CH3), 1.36 (3H, t, 5-OCH2CH ) and 1.34 (3H, t, 2-OCH2CH3); saturation of the 8-H proton at ~ 7.12 enhanced the signals due to 7-NH at ~ 11.30 (2.4%) and 1-NH at ~ 10.91 (1.8%); m/z (%) 342 (64, M~), 296 (100), 250(5), and 194(9); A max (EtOH)/nm (log ~ max/dm3 mol~L
cm~l) 340 (4.10), 327.5 (4.53) and 270 (4.46), and the starting 5-acetoxymethyl-4-acetylpyrrole (0.029 g, 10 . 9% ) .
~AMPLE 2 Ethyl 1,7-dil~ 3,4,6-trimethylpyrrolo~3,2-f~indole-2-c~.l~xylate The general procedure of Example 1 was followed using ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrolo-2 carboxylate (0.692g, 2.59mmol), 3-methoxycarbonyl-2-methylpyrrole (O.360g, 2.59mmol), 1,2-dichloroethane (25 cm3) and Montmorillonite clay (2g). Chromatographic separation using (0-20%) ethyl acetate in dichloromethane gave ethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2-carboxylate as a pale yellow solid (0.0124g, 1.8%) m.p. 213-216~C (decomp); ~H (~2H6]-DMSO) 10.70 (lH, s, l-NH), 10.41 (lH, s, 7-NH), 7.03 (lH, s, 8-H), 6.14 (lH, s, 5-H), 4.33 (2H, q, ~~2CH3), 2.85 (3H, s, 3-CH3), 2.78 (3H, s, 4-CH3), 2.37 (3H, s, 6-CH3), and 1.35 (3H, s, OCH CH~); saturation of the 8-H proton at ~ 7.03 enhanced the signals due to 1-NH at ~ 10.70 (3.5%) and 7-NH at ~
10.41 (2.9~) and saturation of the 5-H proton at ~ 6.14 enhanced the signals due to 4-CH3 at 2.78 (2~) and 6-CH3 at 2.37 (0.6%); m/z (%) 270 (M~, 49), 234 (100), 196 (17) W O95/21171 PCT/~b5JJ~203 (Found: M 270.1337. C16Hl8N2O2 requires M 270.368, and the starting 3-methoxycarbonyl-2-methylpyrrole (0.108 g, 30%). Further elution gave ethyl methyl 1,7-dihydro-3~4~6-trimethylpyrrolo[3~2-f]indole-2~s-dicarboxylate as a colourless solid (0.066 g, 7.8%) m.p. 247-250 ~C (Found:
C, 66.11; H, 6.37; N, 8.47. C~H2~2O~ requires C, 65.84;
H, 6.14; N, 8.53); ~H ([2H6]-DMSO) 11.33 (lH, s, 7-NH), 10.91 (lH, s, 1-NH), 7.21 (lH, s, 8-H), 4.35 (2H, q, OCH2CH3], 3.78 (3H, s, OCH3), 2.88 (3H, s, CH3), 2.87 (3H, s, CH3), 2.53 (concealed by DMSO, 6-CH3) and 1.37 (3H, t, OCH ~H~); m/z (~) 328 (64, M'), 297 (5), 282 (100), 250 (6), 221 (6) and 194 (17) and the starting 5-acetoxymethyl-4-acetylpyrrole (0.037 g, 5.4%).
EXAMPT~ 3 Ethyl 6-Benzyloxycarbonyl-3,4-dimethyl~yL ~lot3,2-f]indole-2-ca~v~ylate;
(a) React-;on of benzyl ~yrrole-2-~rhnyylate and ethYl S-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate A solution of benzyl pyrrole-2-carboxylate (0.615 g, 3.06 mmol) and ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole 2-carboxylate (0.809, 3.01 mmol) in 1,2-dichloroethane (30 cm3) was heated under reflux and stirred with Montmorillonite clay (3 g) for 7 h. The reaction was followed to completion by TLC. After the clay had been filtered off and washed well with 1,2-dichlorethane, evaporation of the combined filtrates under reduced pressure gave a yellow oil. This was submitted to column chromotagraphy eluting with (5-50% ) ethyl acetate in n-hexane to give the starting pyrrole, benzylpyrrole-2-carboxylate (0.153 g, 24.80% ) Ethyl 6-Benzyloxycar~onyl-3 4-dimethylpyrrolo r 2,3-f l indole-2-carboxylate ( isomer I ) - as a yellow solid (0.043 g, 3.67%), m.p. 218-220~C (Found:
C, 70.90; H, 5.87; N, 7.34. C23H22N2O" requires C, 70.75;
H, 5.68; N, 7.18%); ~H ( [2H6]-DMSO) 11.18 (lH, br s, 5-NH), 10.97 (lH, br s, l-NH), 7.52 (2H, d J 7, O-H's of ArH), 7.36-7.48 (3H, m, Tn and ~ H's of ArH), 7.46 (lH, s, 8-H), 7.23 (lH, d J 1.5, 7-H), 5.41 (2H, s, OCH2Ph), 4.35 (2H, q, OCH2CH3), 2.93 (3H, s, 4-CH3), 2.85 (3H, s, 3-CH3) and 1.38 (3H, t, OCH2, CH3); m/z (%) 390 (100, M~), 344 (71), 282 (59), 236 (60), 228 (27), 209 (21) and 91 (78);
V max (nujol) 3400, 3350, 1725 and 1680 cm-l; and Ethyl 6-Benzyloxycarbonyl-3.4-dLmethyl~yrrolo r 3 2-f ~ indole-2-car~oxylate r isomer II ~ as a yellow solid (0.065 g, 5.55%), m.p. 179-182~C, ~H ( ~2H6]-DMSO) 11.36 (lH, br s, 7-NH) , 10.95 (lH, br s, l-NEI), 7.52 (2H, d J 7, _-H's of ArH), 7.48-7.37 (3H, m, m and ~2 H's of ArH), 7.34 (lH, br s, 5-H), 7.19 (lH, br s, 8-H), 5.39 (2H, s, 5~2Ph), 4-35 (2H, q, O~CH3), 2.89 (3H, s, 4--CH3), 2.84 (3H, s, 3--CH3) and 1.37 (OCH2, CH~); m/z (%) 390 (4, ~), 344 (7), 306 (5), 282 (5), 236 (6), 209 (15), 154 (18), 127 (19) and 91 (100) ( Found: ~ 390.1580. C23H22N2O~ requires 390.1579) -Also obtained were 2- (3 ' -acetyl-5 ' -ethoxycarbonyl-4 ' -methylpyrrol -2 ' -ylmethyl ) -5-benzoxycarbonylpyrrole as of f white crystals after crystallisation from dichloromethane-petroleum ether (0.303 g, 24.75g6), m.p.
130-132~C, ~H ( ~2H6~-DMSO) 11.96 (lH, s, l-NH), 11.65 (lH, s, l'-NH), 7.45-2.31 (5H, m, ArH), 6.70 (lH, t J2.6, 4-H), 5.75 (lH, dd J 2.6 and 4, 3-H), 5.27 (2H, S, CH2Ph), 4.28 (2H, q, OCH.CH3), 4.20 (2H, s, CH2), 2.50 (concealed by DMSO, 4'-CH3), 2.34 (3H, s, COCH3) and 1.31 ~3H, t, OCH CH~); saturation of the 4-H at S 6.70 enhanced the signal due to 3-H double doublet at ~ 5.75 (6g6) and saturation of the singlet CH2 at ~ 4.20 enhanced the signals due to 3-H at â 5.75 (4.5%), 1-NH at ~ 11.96 (4.5%) and 1'-NH at ~ 11.65 (4.5%); m/z (%) 408 (14, ~), 317 (100), 271 (97), 91 (47) (Found: M'NH~'426.2029.
C23HZ~N2OS+NH,+ requires 426.2028) and 2 3-di~3'-acetyl-5'-ethoxycarbonyl-4 '-methyl-2 ' -ylmethyl ~ -5-benzoxycarbonylpyrrole as colourless crystals after crystallisation from benzene-petroleum ether (0.256 g, 27.75g6), m.p. 164-166~C (Found: C, 66.53; H, 6.24; N, 6.71. C3,H3,N,O, requires C, 66.33; H, 6.06; N, 6.83%); ~H
(CDCl3), 10.50 (lH, br s, 1-NH), 9.10 (2H, br s, 2X NH), 7.42-7.20 (5H, m, ArH), 6.65 (lH, d J 2.5, 4-H), 5.23 (2H, s, CH2Ph), 4.32 (2H, q, 2--OCH.CH3), 4.30 (2H, q, 3--O~CH3), 4.13 (2H, s, 2-CH2), 4.08 (2H, s, 3-CH2), 2-60 (3H, s, CH3), 2.59 (3H, s, CH3), 2.55 (3H, s, COCH3), 2.54 (3H, s, COCH,), 1.36 (3H, t, 2-OCH CH~) and 1.35 (3H, t, 3-OCH~ ).
(b) Cyclisation of 2-(3'-acetyl-5~-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl-5-benzoxycarbonylpyrrQle A solution of the 2-pyrrolylmethylpyrrole (0.083 g), 0.2 mmol) in 1,2-dichloroethane (5 ml) was heated under reflux and stirred with Montmorillonite clay (0.25 g) for 14 h. The reaction was followed by TLC. After the clay has been filtered off and washed well with 1,2-dichloroethane, evaporation of the combined filtrates under reduced pressure gave an oil. Chromotagraphic separation of an oil eluting with (5-30%) ethyl acetate in hexane yielded Ethyl 6-Benzyloxycarbonyl-3.4-dimet~ylpyrrolo r 2 3-flindole-2-carboxylate woss/21171 pcTlGBs5loo2o3 (isomer I) as a yellow solid (0.0047 g, 6%) which was identical to isomer I obtained from (a) by TLC and nmr;
r and Ethyl 6-Benzyloxvcarbonyl-3~4-dimethylpyrrolo r 3 2-f~indole-2-carboxylate (isomer II) as a yellow solid - (0.0285 g, 36%) which was identical to isomer Il obtained from (a) by TLC and NMR; and the starting 2-pyrrolylmethylpyrrole (0.0116 g, 14%).
Dibenzyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicalL~ylate A solution of benzyl pyrrole-2-carboxylate (0.201 g, 1.0 mmol) and benzyl 5-acetoxymethyl-4-acetyl-3-- methylpyrrole-2-carboxylate (O.331 g, 1.O mmol) in 1,2 -dichloroethane (10 cm3) was heated under reflux and stirred with Montmorillonite clay (1 g) for 7 h. The reaction was followed to completion by TLC. After the clay had been filtered off and washed well with 1,2-dichlorethane, evaporation of the combined filtrates under reduced pressure gave an oil. This was submitted to column chromatography eluting with (5-50%) ethyl acetate in heY~ne to give D;h~n~yl 3 4-dimethylpyrroto r 2 3-flindole-2 6-dicarboxylate(;somerI) as yellow crystals after crystallisation from ethyl acetate-petroleum ether (0.019 g, 4.20%), m.p. 210-212~C
(Found: C, 73.50; H, 5.29; N, 6.13. C2~H2,N2O, requires C, 73.62; H, 5.49; N, 6.36%); ~H ~2~-DMSO) 11.17 ~lH, s, 5-NH), 11.02 (lH, s, l-NH), 7.57-7.34 (llH, m, 2 x ArH
and 8-H), 7.23 (lH, d J 1.5, 7-H), 5.42 (2H, s, CH~Ph), 5.40 (2H, s, CH.Ph), 2.93 (3H, s, 4-CH3), 2.87 (3H, s, 3-- C~3); m/z (%) 452 (68, M+), 344 (58), 236 ~17), and 91 (100); and Dibenzyl 3 4-dimethylpyrrolo r 3.2-f~indole-2 6--dicarboxylate ~isomer II) as yellow crystals after crystallisation from dichloromethane-petroleum ether (0.036 g, 7.96%), m.p. 184-186~C (Found: C, 73.71; H, 5.59; N, 6.27. C2aH24N20~ requires C, 73.62; H, 5.49; N, 6.36~ H ([2H6]-DMSO) 11.36 (lH, s, 7-NH), 10.99 (lH, s, l-NH), 7.52 (4H, d J 7, O-ArH), 7.46-7.37 (7H, m, m and ~-ArH and 8-H), 7.23 (lH, br s, 5-H), 5.40 (4H, s, 2x CH Ph~, 2.91 (3H, s, 3-CHI) and 2.86 (3H, s, 4-CH3); m/z (%) 452 ~55, M'), 344 (S9), 236 (10), and 91 (100).
Further elution gave 2-~3'-acetyl-5'-~enzoxycarbonyl-4-methylpYrrol-2'-ylmethyl)-5-benzoxycarbonylpyrrole as pale yellow crystals after crystallisation from dichloromethane-petroleum ether (0.104 g, 22.13%), m.p.
141-143~C (Found: C, 71.60; H, 5.59; N, 5.79. C2aH26N205 requires C, 71.47; H, 5.57; N, 5.95%); ~H (CDC13) 10.22 (lH, s, l-NH), 9.25 (lH, s, l'-NH), 7.48-7.28 (lOH, m, ArH), 6.83 (lH, dd J 2.5 and 4, 4-H), 6.05 ~lH, dd J 2.5 and 4, 3-H), 5.28 (2H, s, CH Ph), 5.26 (2H, s, CH.Ph), 4.13 (2H, s, CH2), 2.58 (3H, s, CH3, 2.49 (3H, s, COCH3);
m/z (%) 470 (6, M~), 379 (45), 271 (32), 91 (100), 65 (61) and 43 (38) and ~2.3-di(3'-acetyl-5'benzoyxcarbonyl-4'-methylpyrrole-2'-ylmet~yl)-s-benzoxycarbonylpyrroleasan oil (0.0924 g, 25.01%); ~H (CDC13) 11.18 (lH, s, l-NH), 10.46 (lH, s, NH), 9.31 (lH, s, NH), 7.42-7.27 (lSH, m ArH), 6.61 (lH, d J 2, 4-H), 5.31 (2H, s, ~2Ph), 5.29 (2H, ~, CH. Ph), 5.22 (2H, s, CH.Ph), 4.13 (2H, s, 2-CH2), 4.05 (2H, s, 3-CH2), 2.57 (3H, s, CH3), 2.55 (3H, s, CH3), 2.51 (3H, s, CH3), 2.37 (3H, s, CH3); m/z (%) 739 (2, M~), 696 (20), 648 (27), 631 (20), 588 (95). (Found:
739.2890. C~,H~lN308 requires 739.2893) Ethyl6-methoxycalLollyl-3~4-dimethylpyrrolo[3~2-f]indole 2-ca L~ylate ,.
A solution of methyl pyrrole-2-carboxylate (0.222 g, 1.7 mmol) and ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-car~oxylate (0.474 g, 1.7 mmol) in 1,2-dichloroethane (20 cm3) was heated under reflux and stirred with Montmorillonite clay for 7 h. The reaction was followed to completion by TLC. After the clay had been filtered off and washed well with 1,2-dichloroethane, evaporation of the combined filtrates under reduced pressure gave an oil. Chromatographic separation of an oil eluting with (5-40%) ethylacetate in hexane gave Ethyl 6-methoxycarbonyl-3,4-dimethyl~yrrolo r 2 3-flindole-2-carboxylate (isomer I) as a yellow solid after crystallisation from dichloromethane-petroleum ether (0.030 g, 5.62%), m.p. 245-248~C; ~H ([2H6]-DMSO) 11.16 (lH, s, 5-NH), 11.00 (lH, s, 1-NH), 7.45 (lH, s, 8-H), 7.20 (lH, s 7-H), 4.37 (2H, ~, OC~2CH~), 3.91 (3H, s, OÇ~b), 2.95 (3H, s, 3-CH3), 2.88 (3H, s, 4-CH3), 1.37 (3H, t, OCH2Ç~); saturation of the l-NH at ~ 11.00 enhanced the signal due to 8-H at ~ 7.45 (3.9%), saturation of the 4-CH3 of ~ 2.88 ~nhAnr~ the signal due to 5-NH at ~ 11.16 (12.3%) and saturatoin of the 5-NH at 11.16 ~nh~nce~ the signal due to 4-CH3 at ~ 2.88 (2%); m/z (~) 314 (81, M+), 282 (55), 268 (89), 236 (100), 208 (56), 179 (50), 153 (48), 118 (56), 90 (82) and 77 (72) (Found: M~314.1267.
C17H8N2O4 requires 314.1266; Ethyl 6-methoxycarbonyl-3.4-dimethylpyrrolo r 3.2-f1indole-2-car~oxylate (isomer~I) as yellow crystals after crystallisation from dichloromethane-petroleum ether (0.0584 g, 10.94%), m.p.
242-245~C; ~H (~2H6]-DMS0) 11.36 (lH, s, 7-NH), 10.92 (lH, _ _ _ _ _ _ _ _ W O95/~1171 PCTIGB95100203 s, 1-NH), 7.33 (lH, s, 8-H), 7.24 (lH, s -H), 4.36 (2H, q, OCH~CH3), 3.89 (3H, s, OCH ), 2.92 (3H, s, 3-CH3), 2.87 (3H, s, 4-CH3), 1.37 (3H, t, OCH2CH3); m/z (%) 314 (60, M~), 282 (50), 268 (62), 236 (60), 208 (60), 179 (55), 165 (34), 152 (52), 134 (48), 127 (56) and 188 (100) (Found:
M~314.1267. C17Hl~N2O4 requires 314.1266); Further elution gave 2-~3'-acetyl-5'-ethoxycar~onyl-4'-methylpyrrol-2-ylmethyl-5-methoxycarbonylpyrrole as off white crystals after crystallisation from dichloromethane-petroleum ether (0.0912 g, 16.16%), m.p. 160-162~C; ~H (CDCl3), 10.40 (lH, s, 1-NH), 9.78 (lH, s, l'-NH), 6.79 (lH, dd J
4 and 2.5, 4-H), 6.09 (lH, dd J 4 and 2.5, 3-H), 4.30 (2H, q, OÇ~kCH,); 4.22 (2H, s, CH2), 3.80 (3H, s, OCH3), 2.58 (3H, s, CH3), 2.50 (3H, s COCH3), 1.33 (3H, t, OC~,~3; m/z (%) 332 (66, M+), 300 (55), 271 (54), 254 (66), 227 (61), 211 (55), 183 (65), 155 (59), 128 (66), 106 (85), 94 (45), 78 (66), 51 (37), 43 (100); and 2.~-dif3-acetyl-5-ethoxycarbonyl-4-methyl~yrrol-2'-ylmethyl-5-methoxycarbonyl~yrrole as off white crystals after crystallisation from benzene-petroleum ether (0.1885 g, 41.15%), m.p. 203-206~C (Found: C, 62.24; H, 6.16; N, 7.66. C2.H,3N30~ requires C, 62.32; H, 6.16; N, 7.79%); ~H
(CDCl3) 11.08 (lH, s, NH), 9.42 (lH, s, NH), 9.13 (lH, s, NH), 6.63 (lH, d J 2, 4-H), 4.33 (2H, q, OCH.CH3); 4.32 (2H, q, O~kCH3), 4.13 (2H, s, 2-CH2), 4.11 (2H, s, 3-CH2), 3-77 13H, s, OCH3), 2.61 (3H, s, CH3), 2.59 (3H, s, CH3), 2.57 (6H, s, 2 x CH3), 1.37 (3H, t, OCH2Ç~3), 1.36 (3H, t, OCH7CH~).
r Ethyl7-meth~ycaL~v~ 3,4-dimet~ylpyrrolo[3,2-f]indole-2-calL~xylate v (a) Reaction of l-methyloxycarbonylpyrrole and ethyl 5-acetoxy-methyl-4-acetyl-3-methylpyrrole-2-carboxylate A solution of 1-methoxycarbonylpyrrole (1.000 g, 8 mmol) and ethyl 5-acetoxymethyl-4-acetyle-3-methyl-2-carboxylate (2.136 g, 8 mmol) in 1,2-dichloroethane (80 cm3) was heated under reflux and stirred with Montmorillonite clay (8 g) for 18 h. After the clay had been filtered off and washed well with 1,2-dichlorethane, evaporation of the combined filtrates under reduced pressure gave an oil. This was submitted to column chromatography eluting with (20-0%) petroleum ether in dichloromethane and (0-25%) ethyl acetate in dichloromethane to give the starting 1-methoxyca~bol-ylpyrrole (0.1448 g, 14.48%); 3-chloro-5-ethoxy~-Arhn~yl-2-l1'-methoxy~-hrnylpyrrol-2~-ylmethyl)-4-me~yl~yrrole as colourless crystals after crysallisation from benzene-petroleum ether (0.0143 g, 5.51%) m.p. 144-145~C (Found: C, 55.27; H, 5.45; N, 8.43.
ClsH~N2O~Cl requires C, 55.47; H, 5.28; N, 8.63~ H
(CDCl3) 9.23 (lH, br s, NH), 7.20 (lH, t, J 2.5, 4'-H), 6.12 (2H, d J 2.5, 3'- and 5'-H), 4.29 (2H, g, OCH.CH3), 4.21 (2H, s, CH2), 3.97 (3H, s, OCH3), 2.26 (3H, s, CH3), 1.34 (3H, t, OCH7CH~); m/z (%) 326 (10, M+-2), 324 (28, M'), 297 (7), 295 (22), 289 (88), 279 (23), 277 (37); 243 (86), 221 (24), 219 (66), 185 (45), 155 (75), 142 (21), 128 (32), 101 (30), 90 (30), 80 (75), 67 (70), 59 (100).
-Ethy~-methoxycarbonyl-3 4-dimethylpyrrolo r 2 3-flindole-2-carboxylate fisomer I) as colourless crystals after crystallisation from dichlormethane-petroleum ether (0.0263 g, 1.05%) m.p. 163-165~C (Found: C, 64.73; H, 5.79; N, 8.77. Cl7H,aN204 requires C, 64.95; H, 5.77; N, 8.91%); ~H ([2H6]-DMSO) 11.33 (lH, s, NH), 7.64 (lH, d J
3.5, 6-H), 7.38 (lH, s, 8-H), 6.72 (lH, d J 3.5, 7-H), 4.35 (2H, q, OC~.CH3), 3.95 (3H, s, OCH3), 2.86 (3H, s, 3-CH3), 2.75 (3H, s, 4-C~) and 1.37 (3H, t, OCH CH~); m/z (%) 314 (57, M~), 268 (100), 240 (18), 209 (19), 195 (25), 181 (52), 154 (42), 127 (28), 77 (26) and 59 (82); and Ethyl7-methoxycarhonyl-3 4-~;methylpyrrolo r 3 2-f~indole-2-~-~rhn~ylate (iso~er II) as colourless solid (O.6027 g, 23.99%) m.p. 197-200~C (Found: C, 64.82; H, 5.55; N, 8.74.
Cl7Hl~N2O~ re~uires C, 64.92; H, 5.77; N, 8.91%) ~H (~2H6~-DMSO) 11.37 (lH, s, NH), 8.03 (lH, s, 8-H), 7.58 (lH, d J 3.5, 6-H), 6.88 (lH, d J3.5, 5-H), 4.35 (2H, q, OCH CH3), 3.99 (3H, s, OCH3), 2.86 (6H, s, 2 x CH3), 1.36 (3H, t, OCH ÇH~); m/z (%) 314 (53, M~), 268 (100), 240 (13), 209 (21), 195 (12), 181 (12), 154 (13) and 127 (16). Further elution gave 3-acetyl-5-ethoxycarhnnyl-2 (1'-methoxycarbo~yl~yrrol-2'-ylmthyl)-4-methylDYrrolç as colourless solid (0.1588 g, 5.98%) m.p. 172-175~C (FoundL
C, 61.38; H, 6.22; N, 8.40. Cl7H~N20S requires C, 61.43;
H, 6.07; N, 8.43%); ~H (CDC13) 9.53 (lH, br s, NH), 7.21 (lH, dd J 3.5 and 2, 5'-H), 6.26 (lH, m, 4'-H), 6.13 (lH, t J 3.5, 3-H), 4.56 (2H, s, CH2), 4.31 (2H, q, O~H7CH3), 3.95 (3H, s, OCH3), 2.59 (3H, s, 4-CH3), 2.47 (3H, s, COCH,), and 1.35 (3H, t, OCH ~~); m/z (%) 332 (28, M~), 289 (92), 243 (100), 227 (22), 185 (28), 155 (16), 130 (10~, 77 (24), 59 (35), 43 (90); 6-~3'-acetyl-5'-ethoxYcarbonyl-4'-methylpyrrol-2'-ylmethyl)-2-ethoxycarbonyl-7-meth~xycarbonyl-3 4-di~ethYlben~oU 2-b:
5.4-b'~dipyrrole as off white solid (0.1593 g, 7.64%) Pcrl~bssl~a203 m.p. 218-222~C (Found: C, 64.19; H, 5.89; N, 7.93.
Cz~H3lN3O7 requires C, 64.48; H, 5.99; N, 8.06%); ~H ([2H6]-r DMSO) 12.08 (lH, s, pyr-NH), 11.32 (lH, s, 1-NH), 8.01 (lH, s, 8-H), 5.87 (lH, s, 5-H), 4.59 (2H, s, CH2), 4-34 (2H, q, OCH2CH3), 4.28 (2H, q, pyr-CO2~kCH3), 4.05 (3H, s, OCH3), 2.79 (3H, s, CH3), 2.64 (3H, s, CH3), 2.59 (3H, s, CH3), 2.34 (3H, s, CH3), 1.36 (3H, t, OCH CH~), 1.33 (3H, t, pyr-OCH CH~); m/z (%) 521 (2, ~), 478 (3), 432 (2), 386 (2), 370 (2), 355 (3), 342 (2), 300 (2), 193 (2), 179 (2), 105 (2), 91 (3) and 59 (100); and 2 5-di (3'acetyl-5-ethoxycarbonyl-4-methylpyrrol-~'-ylmethyl)-1-methoxycarbonyl~yrrole as colourless crystals after recrystallisation from dichloromethane-petroleum ether (0.1292 g, 5.99%) m.p. 227-230~C (Found: C, 62.27; H, 6.03; N, 7.60. C~3~3O8 requires C, 62.32; H, 6.16; N, 7.79%); ~H ([2H~]-DMSO) 11.95 (2H, s, 2 x NH), 5.19 (2H, s, 3- and 4-H), 4.38 (4H, s, 2 x CH2), 4.24 (4H, q, 2 x OCH~CH3), 4.01 (3H, s, OCH3), 2.S0 (6H, concealed by DMSO, 2 x COCH3), 2.28 (6H, s, 2 x CH3), 1.29 (6H, t, 2 x OCH~CH~); m/z (%) 539 (34, M~), 521 (34), 507 (8), 494 (13), 464 (15), 418 (13), 370 (14), 331 (99), 285 (85), 273 (40), 227 (58), 207 (46), 162 (87) and 59 (100).
(b) Cyclisation of 3-acetyl-5-ethoxycarbonyl-2-(1'-methoxy-carbonylpyrrole-2'-ylmethyl~-4-met~ylDyrrQle Toluene-p-sulfonic acid (100 mg) was added to the solution of the 3-acetyl-5-ethoxycarbonyl-2-(1'-methoxy-carbonylpyrrol-2'-ylmethyl)-4-methlypyrrole (0.435 g, 1.31 mmol) in benzene (50 cm3), the reaction mixture was heated under reflux for 5h (using Dean-Stark apparatus).
On cooling, the product crystallised, the crystals were filtered and washed with ethanol giving Ethyl 7-methoxycarbonyl-3.4-dimethyl~yrrolo r 3.2-flindole-2-.
carboxylate risomer II) as colourless crystals (0.3264 g, 79.34%) m.p. 197-200~C which was identical to the benzo[l,2-b:5,4-b']dipyrrole (isomer II3 from the previous experiment by TLC and NMR. Chromatographic separation of the remaining filtrate eluting with (5-0%) petroleum ether in dichloromethane and (0-10%) ethyl acetate in dichloromethane yielded Ethyl 5-methoxycarbonyl-3~4-dimethylpyrrolo r 2.3-flindole-2-car~oxvlate (isomer I) as colourless solid (0.002g, 0.49%) which was identical to the pyrrolo[2,3-f~ indole (isomer I) from the previous experiment. Also obtained were the }?yrrolo r 3 2-fl;ndole (;somer TT) (O.0313 g, 7.61%) and the starting 2-pyrrolylmethylpyrrole (0.0125 g, 2.87%).
EX~MPT~ 7 Ethyl 3~4-dimethylpyrrolo~3~2-f]indole-2 ~ late 5% Potassium hydroxide (10 cm3) was added to a solution of ethyl 7-methoxy-3,4-dimethylpyrrolo r 3,2-f]indole-2-carboxylate (example 6 isomer II) (O.314 g, 1.0 mmol) in tetrahy~ofuran (100 cm3) and the reaction mixture was heated at gentle reflux and stirred for 48 h. After cooling, the reaction mixture was diluted with water (3 x 50 cm3). The combined extracts were washed with water and then evaporated under r~ pressure to give a yellow solid. This was su~mitted to column chromatography eluting with (10-25%) ethylacetate and 10%
dichloromethane in petroleum ether to give the starting pyrroloindole (0.031 g, 9.87%) and ethyl 3 4-dimethyl PYrrQlO r 3~2-flindole-2-carboxylate as a pale green solid (0.169 g, 66.02%) m.p. 233-235~C; ~H (CDC13) 8.36 (lH, br s, l-NH), 7.86 (lH, br s, 7-NH), 7.17 (lH, dd J 3.3 and 2.4, 6-H), 7.09 (lH, s, 8-H), 6.62 (lH, m, 5-H), 4.14 (2H, q, 05~kCH3), 2.96 (3H, s, 3-CH3), 2.94 (3H, s, 4-CH3) and 1.43 (3H, t, 0CH2S~); m\z (~) 256 (28, ~), 227 (5), 210 (100), 181 (99), 168 (28), 15~ (89), 140 (15), 126 ~ (63), 77 (42), 63 (32).
ASSAYS FQR COMPoUN~ A~llvllY
Assays for cell proliferation/cytotoxity were carried out in tissue culture grade 96 well microtitre plates (Costar). Cells in log growth were added to the plates at a concentration of lX103 cells per well on day 0 and serially diluted compounds were then added on day 1.
Plates were then incubated at 37~C in 5% C02 in air for a further 4 days.
For quantitation of cell growth, the methylene blue biomass st~; n; ng method was used, the test being read on a Mult;sc~n plate reader at wavelength of 620nm. The morphology of the cells was checked microscopically under phase-contrast immediately before the fixation and st~ ng with methylene blue, and by ordinary light microscopy thereafter. IC50 values for active compounds were obtained using the computer p~o~lamme, GS1 and dose-response slopes were also plotted.
When compounds were tested for activity in a colony forming assay the methods used were identical to those described earlier except that serially diluted compound was added to the sloppy agar when the test was set up, and replenished at the same concentration on day 7. The test results were read on day 14.
RESULTS:
Example Compound IC50 ( uM) (HT108ûscc2 )
Claims (9)
1. A compound of the general formula (I) (I) and salts and physiologically functional derivatives thereof, wherein A is X is S, SO, SO2, CH2, CO or NR7, wherein R7 is H, alkyl, aralkyl aryl, alkenyl, acyl, alkynyl, sulphonyl, substituted sulphonyl, or COOMe;
Y is S, SO, SO2, CH2, CO or NR7, R1 i s COR9, CHO, CH2CH, CH2OR9, CONH2, COOR8, CONHR8, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR9, CSNR8R9, CNHOR8 wherein R8 and R9 are independently hydrogen, alkoxyalkyl, heterocycloalkyl, heteroaralkyl, or C1-10 optionally substituted hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain;
or R8 and R9 are a sugar group.
R2 is H, halo, cyano, COOR8, alkyl, aryl, alkenyl, alkynyl, alkoxy, (wherein alkyl, aryl, alkenyl, alkynyl and alkoxy can be substituted) or CH2CH2CO2R12 wherein R12 is alkyl or aryl;
R3 is H, alkyl, halogen, cyano, amino, COOR8, CONHR8, COR8, CH2OH, CH2OR4, CONH2, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR8, CSNR8R9 or CNHOR8;
R4 is H, halogen, cyano, amino, alkyl, COOR8, CONHR8, COR8, CH2OH, CH2OR8, CONH2, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR8, CSNR8R9 or CNHOR8;
R5 is H, hydroxy, aryloxy, aralkyloxy, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano, COOR8 or CHO;
R6 is H, aryl, alkyl, aralkyl, nitro, halogen, CHO or COR13 wherein R13 is alkyl or aryl; with the following disclaimers: wherein (i) R8 is not H when R2 is H;
(ii) R3 is not H or Me when A is (iii) when A is X and Y are both NH, R3 and R6 are both H, R5 is H or CHO, R2 is H or CHO, then R1 and R4 are not both CO2Et;
(iv) when A is X and Y are both NCH2-Ph or NMe or NH, R5 and R6 are both H, R1 and R4 are both Me, then R2 and R3 are not both CO2Et;
(v) when A is X and Y are both NH, R2, R4, R5 and R5 are all H, then R1 and R3 are not both CHO;
(vi) when A is X and Y are both S, R2, R3, R5 and R5 re all H, then R1 and R4 are not CH2H or CO2Et;
(vii) when A is X and Y are both S, or R5 is CHO and R6 is C1, R2 and R3 are both H, then R1 and R4 are not both CO2Et;
(viii) when A is X and Y are both S, R5 and R6 are both C1, R2 and R4 are both H, then R1 and R3 are not both CO2Et.
Y is S, SO, SO2, CH2, CO or NR7, R1 i s COR9, CHO, CH2CH, CH2OR9, CONH2, COOR8, CONHR8, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR9, CSNR8R9, CNHOR8 wherein R8 and R9 are independently hydrogen, alkoxyalkyl, heterocycloalkyl, heteroaralkyl, or C1-10 optionally substituted hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain;
or R8 and R9 are a sugar group.
R2 is H, halo, cyano, COOR8, alkyl, aryl, alkenyl, alkynyl, alkoxy, (wherein alkyl, aryl, alkenyl, alkynyl and alkoxy can be substituted) or CH2CH2CO2R12 wherein R12 is alkyl or aryl;
R3 is H, alkyl, halogen, cyano, amino, COOR8, CONHR8, COR8, CH2OH, CH2OR4, CONH2, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR8, CSNR8R9 or CNHOR8;
R4 is H, halogen, cyano, amino, alkyl, COOR8, CONHR8, COR8, CH2OH, CH2OR8, CONH2, CONR8R9, CSOR8, CSSR8, COSR8, CSNHR8, CSNR8R9 or CNHOR8;
R5 is H, hydroxy, aryloxy, aralkyloxy, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano, COOR8 or CHO;
R6 is H, aryl, alkyl, aralkyl, nitro, halogen, CHO or COR13 wherein R13 is alkyl or aryl; with the following disclaimers: wherein (i) R8 is not H when R2 is H;
(ii) R3 is not H or Me when A is (iii) when A is X and Y are both NH, R3 and R6 are both H, R5 is H or CHO, R2 is H or CHO, then R1 and R4 are not both CO2Et;
(iv) when A is X and Y are both NCH2-Ph or NMe or NH, R5 and R6 are both H, R1 and R4 are both Me, then R2 and R3 are not both CO2Et;
(v) when A is X and Y are both NH, R2, R4, R5 and R5 are all H, then R1 and R3 are not both CHO;
(vi) when A is X and Y are both S, R2, R3, R5 and R5 re all H, then R1 and R4 are not CH2H or CO2Et;
(vii) when A is X and Y are both S, or R5 is CHO and R6 is C1, R2 and R3 are both H, then R1 and R4 are not both CO2Et;
(viii) when A is X and Y are both S, R5 and R6 are both C1, R2 and R4 are both H, then R1 and R3 are not both CO2Et.
2. A compound as claimed in Claim 1, wherein A is:
Y is NH or NCOOMe;
R1 is COOR3, wherein R8 is alkyl or aralkyl;
R2 is H, alkyl or COOR8, wherein R8 is alkyl;
R3 is H, alkyl or COOR8, wherein R8 is alkyl;
R4 is alkyl or COOR8;
R5 is H; and R6 is H or methyl;
and salts and physiologically functional derivatives thereof.
Y is NH or NCOOMe;
R1 is COOR3, wherein R8 is alkyl or aralkyl;
R2 is H, alkyl or COOR8, wherein R8 is alkyl;
R3 is H, alkyl or COOR8, wherein R8 is alkyl;
R4 is alkyl or COOR8;
R5 is H; and R6 is H or methyl;
and salts and physiologically functional derivatives thereof.
3. A compound as claimed in Claim 1 or Claim 2 which is:
Ethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]
indole-2-carboxylate;
Diethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]
indole-2,5-dicarboxylate; and Ethyl 6-methoxycarbonyl-3,4-dimethyl pyrrolo[3,2-f]
indole-2-carboxylate.
and physiologically functional derivatives thereof.
Ethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]
indole-2-carboxylate;
Diethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]
indole-2,5-dicarboxylate; and Ethyl 6-methoxycarbonyl-3,4-dimethyl pyrrolo[3,2-f]
indole-2-carboxylate.
and physiologically functional derivatives thereof.
4. A compound as claimed in Claim 1 or Claim 2 which is:
Ethyl 6-Benzyloxycarbonyl-3,4-dimethylpyrrolo[3,2-f]
indole-2-carboxylate;
Dibenzyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicarboxylate;
Ethyl 7-methoxycarbonyl-3,4-dimethyl pyrrolo[3,2-f]
indole-2-carboxylate; and Ethyl 3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate and physiologically functional derivatives thereof.
Ethyl 6-Benzyloxycarbonyl-3,4-dimethylpyrrolo[3,2-f]
indole-2-carboxylate;
Dibenzyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicarboxylate;
Ethyl 7-methoxycarbonyl-3,4-dimethyl pyrrolo[3,2-f]
indole-2-carboxylate; and Ethyl 3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate and physiologically functional derivatives thereof.
5. A process for the preparation of a compound of formula (I) which comprises the step of:
(a) reacting a compound of formjula (II) with a compound of formula (III):
(II) (III) wherein X Y R1 R2 R3 R4 R5 and R6 are as defined in Claim 1, except that R3 and R4 are not hydrogen when X is NH, in an inert solvent;
(b) carboxylation of a polyheterocyclic compound using:
(i) a carbonyl halide; or (ii) carbon dioxide;
(c) reacting a polyheterocyclic compound with a formylating agent;
(d) reacting a polyheterocyclic compound carrying a functional group selected from CHBr2, CH3 or COR14, wherein R14 is a primary or secondary C1-6 alkyl group, COOH or a derivative thereof, to convert the functional group to an aldehyde; or (e) converting one compound of formula (I) into another compound of formula (I).
(a) reacting a compound of formjula (II) with a compound of formula (III):
(II) (III) wherein X Y R1 R2 R3 R4 R5 and R6 are as defined in Claim 1, except that R3 and R4 are not hydrogen when X is NH, in an inert solvent;
(b) carboxylation of a polyheterocyclic compound using:
(i) a carbonyl halide; or (ii) carbon dioxide;
(c) reacting a polyheterocyclic compound with a formylating agent;
(d) reacting a polyheterocyclic compound carrying a functional group selected from CHBr2, CH3 or COR14, wherein R14 is a primary or secondary C1-6 alkyl group, COOH or a derivative thereof, to convert the functional group to an aldehyde; or (e) converting one compound of formula (I) into another compound of formula (I).
6. The use of a compound as claimed in any one of Claims 1 to 4 in medicine.
7. The use as claimed in Claim 6 for treating cancer.
8. A pharmaceutical formulation comprising at least one compound of formula (I) as defined in Claim 1, or a pharmaceutically acceptable salt or physiologically functional derivative thereof, together with one or more pharmaceutically acceptable diluents, carriers or excipients.
9. The use of a compound of formula (I) as defined in Claim 1 and further including the disclaimed compounds (iii) to (viii) of Claim 1, or a pharmaceutically acceptable salt or physiologically functional derivative thereof, in the manufacture of a medicament for the treatment of cancer.
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1995
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