WO2008020456A2 - Pyrrolo[2,1-c][1,4]benzodiazepine hybrids and a process for the preparation thereof - Google Patents
Pyrrolo[2,1-c][1,4]benzodiazepine hybrids and a process for the preparation thereof Download PDFInfo
- Publication number
- WO2008020456A2 WO2008020456A2 PCT/IN2007/000337 IN2007000337W WO2008020456A2 WO 2008020456 A2 WO2008020456 A2 WO 2008020456A2 IN 2007000337 W IN2007000337 W IN 2007000337W WO 2008020456 A2 WO2008020456 A2 WO 2008020456A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrrolo
- benzodiazepine
- methoxy
- phenyl
- dihydro
- Prior art date
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- MSNVESLISHTIRS-UHFFFAOYSA-N 9h-pyrrolo[2,1-c][1,4]benzodiazepine Chemical compound N1=C2C=CC=CC2=CN2CC=CC2=C1 MSNVESLISHTIRS-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 11
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 230000001093 anti-cancer Effects 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- HCDXLUKTYFLIEM-UHFFFAOYSA-N 1,2-benzodiazepin-5-one Chemical compound O=C1C=CN=NC2=CC=CC=C12 HCDXLUKTYFLIEM-UHFFFAOYSA-N 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 28
- 230000000694 effects Effects 0.000 claims description 25
- 238000000338 in vitro Methods 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 14
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 13
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 238000001704 evaporation Methods 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 239000012267 brine Substances 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- RGWZQFXKEORKNL-NRFANRHFSA-N (6as)-3-[3-(6-chloro-2-oxo-4-phenylquinazolin-1-yl)propoxy]-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound COC1=CC(C(N2CCC[C@H]2C=N2)=O)=C2C=C1OCCCN(C(N=1)=O)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 RGWZQFXKEORKNL-NRFANRHFSA-N 0.000 claims description 6
- 210000003679 cervix uteri Anatomy 0.000 claims description 6
- 210000001072 colon Anatomy 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 210000004072 lung Anatomy 0.000 claims description 6
- 210000002307 prostate Anatomy 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
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- 239000012043 crude product Substances 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000006228 supernatant Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical compound Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- QREBSEGNEVYLHY-QHCPKHFHSA-N (6as)-2-methoxy-3-[4-(6-methyl-2-oxo-4-phenylquinazolin-1-yl)butoxy]-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound COC1=CC(C(N2CCC[C@H]2C=N2)=O)=C2C=C1OCCCCN(C(N=1)=O)C2=CC=C(C)C=C2C=1C1=CC=CC=C1 QREBSEGNEVYLHY-QHCPKHFHSA-N 0.000 claims 3
- UUAHXJYWTQHBEJ-QFIPXVFZSA-N (6as)-2-methoxy-3-[3-(6-methyl-2-oxo-4-phenylquinazolin-1-yl)propoxy]-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound COC1=CC(C(N2CCC[C@H]2C=N2)=O)=C2C=C1OCCCN(C(N=1)=O)C2=CC=C(C)C=C2C=1C1=CC=CC=C1 UUAHXJYWTQHBEJ-QFIPXVFZSA-N 0.000 claims 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 229940093499 ethyl acetate Drugs 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 230000010261 cell growth Effects 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- LQDGLTOVYOUCRG-QMMMGPOBSA-N (6as)-3-hydroxy-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical class N1=C[C@@H]2CCCN2C(=O)C2=C1C=C(O)C(OC)=C2 LQDGLTOVYOUCRG-QMMMGPOBSA-N 0.000 description 4
- 0 Cc(cc1)cc(C(c2ccccc2)=N2)c1N(C*(*(COC(C[C@@](C(C(N1CCCC1)=O)=C1)N=CC=N)=C1OC)N)=C)C2=O Chemical compound Cc(cc1)cc(C(c2ccccc2)=N2)c1N(C*(*(COC(C[C@@](C(C(N1CCCC1)=O)=C1)N=CC=N)=C1OC)N)=C)C2=O 0.000 description 4
- 230000004568 DNA-binding Effects 0.000 description 4
- 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 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical class N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 3
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- 238000000967 suction filtration Methods 0.000 description 3
- PBLUIXBNPDHLAM-QFIPXVFZSA-N (6as)-3-[4-(6-chloro-2-oxo-4-phenylquinazolin-1-yl)butoxy]-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound COC1=CC(C(N2CCC[C@H]2C=N2)=O)=C2C=C1OCCCCN(C(N=1)=O)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 PBLUIXBNPDHLAM-QFIPXVFZSA-N 0.000 description 2
- WKJBLXPYIDVHST-VIFPVBQESA-N (6as)-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=NC2=CC=CC=C2C(=O)N2CCC[C@H]21 WKJBLXPYIDVHST-VIFPVBQESA-N 0.000 description 2
- WKJBLXPYIDVHST-UHFFFAOYSA-N 6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=NC2=CC=CC=C2C(=O)N2CCCC21 WKJBLXPYIDVHST-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- -1 amino compound Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FDKZUPKJGZOIFX-DEOSSOPVSA-N (6as)-2-methoxy-3-[5-(6-methyl-2-oxo-4-phenylquinazolin-1-yl)pentoxy]-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound COC1=CC(C(N2CCC[C@H]2C=N2)=O)=C2C=C1OCCCCCN(C(N=1)=O)C2=CC=C(C)C=C2C=1C1=CC=CC=C1 FDKZUPKJGZOIFX-DEOSSOPVSA-N 0.000 description 1
- PXYUMIVMMHXGBH-OALUTQOASA-N (6as)-3-[3-[[(6as)-2-methoxy-11-oxo-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CCCN2C(=O)C(C=C2OC)=C1C=C2OCCCOC1=CC(N=C[C@H]2N(CCC2)C2=O)=C2C=C1OC PXYUMIVMMHXGBH-OALUTQOASA-N 0.000 description 1
- UQVNRKBFAXNOGA-LWTNMJDUSA-N (E)-tomaymycin Chemical compound CO[C@H]1NC2=CC(O)=C(OC)C=C2C(=O)N2C\C(=C\C)C[C@@H]12 UQVNRKBFAXNOGA-LWTNMJDUSA-N 0.000 description 1
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 1
- RHPYCGLDYNJYSV-UHFFFAOYSA-N 1-(3-bromopropyl)-6-chloro-4-phenylquinazolin-2-one Chemical compound C12=CC(Cl)=CC=C2N(CCCBr)C(=O)N=C1C1=CC=CC=C1 RHPYCGLDYNJYSV-UHFFFAOYSA-N 0.000 description 1
- HTCJPQJZMUHDKM-UHFFFAOYSA-N 1-(4-bromobutyl)-6-chloro-4-phenylquinazolin-2-one Chemical compound C12=CC(Cl)=CC=C2N(CCCCBr)C(=O)N=C1C1=CC=CC=C1 HTCJPQJZMUHDKM-UHFFFAOYSA-N 0.000 description 1
- WQZCZFGLNYTCPA-UHFFFAOYSA-N 1-(5-bromopentyl)-6-chloro-4-phenylquinazolin-2-one Chemical compound C12=CC(Cl)=CC=C2N(CCCCCBr)C(=O)N=C1C1=CC=CC=C1 WQZCZFGLNYTCPA-UHFFFAOYSA-N 0.000 description 1
- FXMOIYLVKOALHC-UHFFFAOYSA-N 3,9-dihydroxy-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=CC2CCC(O)N2C(=O)C2=C1C=C(O)C(OC)=C2 FXMOIYLVKOALHC-UHFFFAOYSA-N 0.000 description 1
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- UQVNRKBFAXNOGA-IUODEOHRSA-N Tomaymycin Natural products CO[C@H]1Nc2cc(O)c(OC)cc2C(=O)N3CC(=CC)C[C@H]13 UQVNRKBFAXNOGA-IUODEOHRSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000000039 congener Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
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- 230000002503 metabolic effect Effects 0.000 description 1
- 229930188317 neothramycin Natural products 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- RAGFPHFDFVNLCG-INYQBOQCSA-N sibiromycin Chemical compound O[C@@H]1[C@@](O)(C)[C@@H](NC)[C@H](C)O[C@H]1OC(C(=C1O)C)=CC(C2=O)=C1N[C@H](O)[C@H]1N2C=C(\C=C\C)C1 RAGFPHFDFVNLCG-INYQBOQCSA-N 0.000 description 1
- RAGFPHFDFVNLCG-UHFFFAOYSA-N sibiromycin Natural products OC1C(O)(C)C(NC)C(C)OC1OC(C(=C1O)C)=CC(C2=O)=C1NC(O)C1N2C=C(C=CC)C1 RAGFPHFDFVNLCG-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to quinazolinone linked pyrrolo[2,1-c][1 ,4] benzodiazepine hybrids of general formula 5, useful as potential anti tumour agents and a process for the preparation thereof. Particularly it relates to a process for the preparation of 7-methoxy-8-[n-(6-chloro-2-oxo-4-phenyl-1 ,2- dihydro-1 -quinazolinyl) alkyloxy]-(11 aS)-1 ,2,3,11 a-tetrahydro-5H-pyrrolo[2, 1 - c][1 ,4]benzodiazepine-5-one with aliphatic chain length variations for these compounds.
- the structural formula of these novel quinazolinone linked pyrrolo[2,1-c][1 , ⁇ benzodiazepines is given below.
- Pyrrolo[2,1-c][1 , ⁇ benzodiazepine antitumour antibiotics are commonly known as anthramycin class of compounds.
- PBDs ⁇ benzodiazepines
- antibiotics react covalently with DNA to form an N2-guanine adduct that lies within the minor groove of duplex DNA via an acid-labile aminal bond to the electrophilic imine at the N10-C11 position
- PBD dimers have been developed that comprise of two C2-exo- methylene substituted DC-81 subunits tethered through their C-8 position via an inert propanedioxy linker (Gregson, S. J.; Howard, P. W.; Hartely, J. A.; Brooks, N. A.; Adams, L. J.; Jenkins, T. C; Kelland, L. R. and Thurston, D. E. J. Med. Chem. 2001, 44, 737).
- a noncross-linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent antitumour activity " (Kamal, A.; Ramesh, G.
- Naturally occurring pyrrolo[2,1-c][1, ⁇ benzodiazepines belong to a group of antitumour antibiotics derived from Streptomyces species. Recently, there is much impetus for the PBD systems as they can recognize and bind to specific sequence of DNA. Examples of naturally occurring PBDs include anthramycin, DC-81 , tomaymycin, sibiromycin and neothramycin. However, the clinical efficacy for these antibiotics is hindered by several limitations, such as poor water solubility, cardiotoxicity, development of drug resistance and metabolic inactivation.
- the main objective of the present invention is to provide novel quinazolinone linked pyrrolo[2,1-c][1 ,4] benzodiazepine hybrids, useful as antitumour agents.
- Another objective of this invention is to provide a process for the preparation of novel quinazolinone linked pyrrolo[2,1-c] [1 ,4]benzodiazepine hybrid of formula 5.
- the present invention provides novel quinazolinone linked pyrrolo [2,1 -c][1 ,4]benzodiazepine hybrid of general formula 5,
- the quinazolinone linked pyrrolo [2, 1-c][1 , ⁇ benzodiazepine hybrid of formula 5 is represented by the group of the following compounds: 7-Methoxy-8-[3-(6-H-2-oxo-4-phenyl-1 ,2-dihydro-1 -quinazolinyl)propoxy]-(11 aS)-
- quinazolinone linked pyrrolo[2,1- c][1 , ⁇ benzodiazepine hybrid of formula 5 exhibits an in vitro anticancer/antitumour activity against human cancer cell lines selected from the group consisting of lung, cervix, breast, colon, prostate and oral cell lines.
- the concentration of quinazolinone linked pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrid of formula 5 used for in vitro activity against Colo205 for IC50 is in the range of 8 to 15 ⁇ m, at an exposure period of at least 48 hrs.
- the concentration of quinazolinone linked pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrid of formula 5 used for in vitro activity against DU 145 for IC50 is in the range of 8 to 15 ⁇ m, at an exposure period of at least 48 hrs.
- the concentration of quinazolinone linked pyrrolo[2,1-c][1 ,4]benzodiazepine hybrid of formula 5 used for in vitro activity against DWD for IC50 is in the range of 8 to 10 ⁇ m, at an exposure period of at least 48 hrs.
- the concentration of quinazolinone linked pyrrolo[2,1-c][1 ,4]benzodiazepine hybrid of formula 5 used for in vitro activity against HoP62 for IC50 is 5 ⁇ m, at an exposure period of at least 48 hrs.
- the concentration of quinazolinone linked pyrrolo[2,1-c][1 ,4]benzodiazepine hybrid of formula 5 used for in vitro activity against HT1080 for IC50 is in the range of 8 to 9 ⁇ m, at an exposure period of at least 48 hrs.
- the concentration of quinazolinone linked pyrrolo[2,1-c][1 ,4]benzodiazepine hybrid of formula 5 used for in vitro activity against MCF7 for IC50 is in the range of 8 to 12 ⁇ m, at an exposure period of at least 48 hrs.
- the concentration of quinazolinone linked pyrrolo[2,1-c][1 ,4]benzodiazepine hybrid of formula 5 used for in vitro activity against PC3 for IC50 is in the range of 7 to 11 ⁇ m, at an exposure period of at least 48 hrs.
- the concentration of quinazolinone linked pyrrolo[2,1-c][1 ,4]benzodiazepine hybrid of formula 5 used for in vitro activity against SiHa for IC50 is in the range of 8 to 15 ⁇ m, at an exposure period of at least 48 hrs. In yet another embodiment the concentration of quinazolinone linked pyrrolo[2,1-c][1 ,4]benzodiazepine hybrid of formula 5 used for in vitro activity against Zr-75-1 for IC50 is in the range of 8 to 15 ⁇ m, at an exposure period of at least 48 hrs.
- the present invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising quinazolinone linked pyrrolo[2i1-c][1 ,4] benzodiazepine hybrid of formula 5, its derivatives, analogues, salts or mixture thereof, optionally with pharmaceutically acceptable carriers, adjuvants and additives.
- the quinazolinone linked pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrid used in pharmaceutical composition is represented by a general formula 5,
- the present invention further provides a process for the preparation of quinazolinone linked pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrid of formula 5,
- the mild inorganic base used in steps (a) & (b) is potassium carbonate.
- aprotic organic solvent used in step (a) is acetone.
- organic solvent used in step (c) is acetonitrile.
- the alcohol used in step (b) is selected from methanol and ethanol.
- quinazolinone linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrid of formula 5a-l exhibits an in vitro anticancer/antitumour activity against human cancer cell lines selected from the group consisting of lung, cervix, breast, colon, prostate and oral cell lines.
- Example 2 To a solution of (2S)- ⁇ /-(4-hydroxy-3-methoxy-2-nitrobenzoyl)pyrrolidine-2- carboxaldehyde diethyl thioacetal 2 (512 mg, 1.28 mmol) in dry acetone (20 ml_) was added anhydrous potassium carbonate (880 mg, 6.40 mmol) and 1-(4- bromobutyl)-6-chloro-4-phenyl-1 ,2-dihydro-2-quinazolinone 1 (500 mg, 1.28 mmol). The reaction mixture was refluxed in an oil bath for 48 hr.
- Compounds Sd and 5f have been evaluated for their in vitro cytotoxicity in selected human cancer cell lines of colon (Colo205), lung (Hop-62), cervix (SiHa), prostate (DU 145, PC3), oral (DWD, HT1080), and breast (MCF7, Zr-75- 1) origin.
- a protocol of 48 h continuous drug exposure and an adriamycin (ADR) protein assay has been used to estimate cell viability or growth. The results are expressed as percent of cell growth determined relative to that of untreated control cells (Table 1).
- Compounds 5d and Sf shows promising cytotoxicity against some cancer cell lines.
- Compounds 5d and 5f exhibited less than 20% cell growth at ⁇ g/mL concentration in some cell lines.
- Compounds 5d and 5f suppress Colo205 cell growth by 92% and 85%, DU145 cell growth by 92% and 90%, DWD cell growth by 95%, Hop62 cell growth by 94% and 95%, HT1080 cell growth by 91% and 92%, MCF7 cell growth by 88% and 92% and PC3 cell growth by 89% and 93%. They are suppressing the SiHa cell growth by 84% and Zr-25-1 cell growth by 92%.
- the DNA binding activity for these compounds has been examined by thermal denaturation studies using calf thymus (CT) DNA.
- CT calf thymus
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Cited By (2)
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WO2009109984A1 (en) | 2008-03-05 | 2009-09-11 | Council Of Scientific & Industrial Research | Quinazoline linked pyrrolo[2,1-c][1, 4]benzodiazepine hybrids as potential anticancer agents and process for the preparation thereof' |
WO2010058416A1 (en) * | 2008-11-19 | 2010-05-27 | Council Of Scientific & Industrial Research | Quinazolinone linked pyrrolo[2,1 -c][1.4]benzodiazepine hybrids as potential anticancer agents and process forthe preparation thereof |
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AU2012395148B2 (en) | 2012-11-24 | 2016-10-27 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules |
WO2015127685A1 (en) | 2014-02-28 | 2015-09-03 | Hangzhou Dac Biotech Co., Ltd | Charged linkers and their uses for conjugation |
CA2991973C (en) | 2015-07-12 | 2021-12-07 | Suzhou M-Conj Biotech Co., Ltd. | Bridge linkers for conjugation of a cell-binding molecule |
US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
KR102459469B1 (en) | 2016-11-14 | 2022-10-26 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | Conjugation linkers, cell binding molecule-drug conjugates containing the likers, methods of making and uses such conjugates with the linkers |
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US6683073B1 (en) * | 2003-03-25 | 2004-01-27 | Council Of Scientific And Industrial Research | Pyrimidine linked pyrrolo[2,1-c][1,4]benzodiazepines as potential antitumour agents |
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Non-Patent Citations (2)
Title |
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KAMAL A ET AL: "Synthesis and biological activity of fluoroquinolone-pyrrolo[2,1-c][1 ,4]benzodiazepine conjugates" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 13, no. 6, 15 March 2005 (2005-03-15), pages 2021-2029, XP004759003 ISSN: 0968-0896 * |
KAMAL AHMED ET AL: "Design and synthesis of C-8 linked pyrrolobenzodiazepine-naphthalimide hybrids as anti-tumour agents" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 12, no. 15, 5 August 2002 (2002-08-05), pages 1933-1935, XP002316525 ISSN: 0960-894X * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009109984A1 (en) | 2008-03-05 | 2009-09-11 | Council Of Scientific & Industrial Research | Quinazoline linked pyrrolo[2,1-c][1, 4]benzodiazepine hybrids as potential anticancer agents and process for the preparation thereof' |
JP2011513389A (en) * | 2008-03-05 | 2011-04-28 | カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ | Quinazoline-binding pyrrolo [2,1-c] [1,4] benzodiazepine hybrid as an effective anticancer agent and method for producing the same |
US8153627B2 (en) | 2008-03-05 | 2012-04-10 | Council Of Scientific & Industrial Research | Quinazoline linked pyrrolo[2,1-C][1, 4]benzodiazepine hybrids as potential anticancer agents and process for the preparation thereof |
WO2010058416A1 (en) * | 2008-11-19 | 2010-05-27 | Council Of Scientific & Industrial Research | Quinazolinone linked pyrrolo[2,1 -c][1.4]benzodiazepine hybrids as potential anticancer agents and process forthe preparation thereof |
US8691811B2 (en) | 2008-11-19 | 2014-04-08 | Council Of Scientific & Industrial Research | Quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine hybrids as potential anticancer agents and process for the preparation thereof |
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GB2454629A (en) | 2009-05-20 |
US20080064685A1 (en) | 2008-03-13 |
US7608615B2 (en) | 2009-10-27 |
GB2454629B (en) | 2011-10-26 |
WO2008020456A3 (en) | 2008-04-24 |
GB0904091D0 (en) | 2009-04-22 |
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