MXPA97008822A - Tribencimidazoles useful as inhibitors of topoisomeras - Google Patents
Tribencimidazoles useful as inhibitors of topoisomerasInfo
- Publication number
- MXPA97008822A MXPA97008822A MXPA/A/1997/008822A MX9708822A MXPA97008822A MX PA97008822 A MXPA97008822 A MX PA97008822A MX 9708822 A MX9708822 A MX 9708822A MX PA97008822 A MXPA97008822 A MX PA97008822A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- compound according
- halogen
- cycloalkyl
- cycloalkylalkyl
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 16
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 8
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000011780 sodium chloride Substances 0.000 claims abstract description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 150000002978 peroxides Chemical class 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 229910003204 NH2 Inorganic materials 0.000 claims abstract 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 58
- 239000000203 mixture Substances 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 210000004881 tumor cells Anatomy 0.000 claims description 10
- 125000005605 benzo group Chemical group 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 239000003981 vehicle Substances 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 230000001225 therapeutic Effects 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 102000003915 DNA Topoisomerases Human genes 0.000 abstract description 27
- 108090000323 DNA Topoisomerases Proteins 0.000 abstract description 27
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- 125000005418 aryl aryl group Chemical group 0.000 abstract 1
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
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- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
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- ALCHVVTYAHQOFY-UHFFFAOYSA-N 3H-benzimidazole-5-carbaldehyde Chemical compound O=CC1=CC=C2NC=NC2=C1 ALCHVVTYAHQOFY-UHFFFAOYSA-N 0.000 description 6
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- MQDYZYVWFUIEQU-UHFFFAOYSA-N 2-nitro-4-phenylaniline Chemical compound C1=C([N+]([O-])=O)C(N)=CC=C1C1=CC=CC=C1 MQDYZYVWFUIEQU-UHFFFAOYSA-N 0.000 description 5
- KYZKLYLXDFILGD-UHFFFAOYSA-N 2-nitro-4-prop-2-enylaniline Chemical compound NC1=CC=C(CC=C)C=C1[N+]([O-])=O KYZKLYLXDFILGD-UHFFFAOYSA-N 0.000 description 5
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 5
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- 238000002844 melting Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
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- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-Nitroaniline Chemical class NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 3
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- NQSIKKSFBQCBSI-UHFFFAOYSA-N Tetrapropylammonium perruthenate Chemical compound [O-][Ru](=O)(=O)=O.CCC[N+](CCC)(CCC)CCC NQSIKKSFBQCBSI-UHFFFAOYSA-N 0.000 description 3
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- 125000004429 atoms Chemical group 0.000 description 3
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- GJSGGHOYGKMUPT-UHFFFAOYSA-N phenoxathiine Chemical compound C1=CC=C2OC3=CC=CC=C3SC2=C1 GJSGGHOYGKMUPT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- 150000003077 polyols Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
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- 230000002035 prolonged Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible Effects 0.000 description 1
- 101710004466 rgy Proteins 0.000 description 1
- 101710030364 rgy1 Proteins 0.000 description 1
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- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
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- 230000001954 sterilising Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 150000008163 sugars Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940026754 topical Antivirals Drugs 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- BSUNTQCMCCQSQH-UHFFFAOYSA-N triazine Chemical compound C1=CN=NN=C1.C1=CN=NN=C1 BSUNTQCMCCQSQH-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- CFQJBWKKHCMCGJ-UHFFFAOYSA-N tributyl(pyridin-3-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CN=C1 CFQJBWKKHCMCGJ-UHFFFAOYSA-N 0.000 description 1
- UNEPXPMBVGDXGH-UHFFFAOYSA-N tributyl(pyridin-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=NC=C1 UNEPXPMBVGDXGH-UHFFFAOYSA-N 0.000 description 1
- GZJNLVYEAQGOSJ-UHFFFAOYSA-N tributyl-(4-chlorophenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=C(Cl)C=C1 GZJNLVYEAQGOSJ-UHFFFAOYSA-N 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical class CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
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- 239000001993 wax Substances 0.000 description 1
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- 125000005023 xylyl group Chemical group 0.000 description 1
Abstract
The present invention provides inhibitors of anti-neoplastic topoisomerase I of the formula (I), wherein Ar is (C2-C12) aryl or heteroaryl (from 5 to 12 members) comprising 1-3 of N, S or O without peroxide wherein N is unsubstituted or substituted by (C1-C4) alkyl: X is H, CN, CHO, OH, acetyl, CF3, O-(C1-C4) alkyl, NO2, NH2, halogen or halogen-alkyl (C1 -C4), each Y is individually H. alkyl or aralkyl (C1-C4), Y'es H or (C1-C4) alkyl, n is 0 or 1, and each Z is individually H, (C1-C4) alkyl , halogen or halogen (C1-C4) alkyl, or a pharmaceutically acceptable salt thereof
Description
TRISBENC I MIDAZQL.ES USEFUL AS TOPOISOMERASE INHIBITORS I
BACKGROUND OF THE INVENTION
DNA topoisomerases are nuclear enzymes that control and modify the DNA topological states catalyzing the breakdown and the assembly of DNA chains. See, for example, D'Arpa and others, Biochem. Biophvs. Acta, 989. 163 (1989) Topoisomerase II enzymes alter the topological state of DNA through a double-strand break in DNA. Mammalian topoisomerase II represents an effective pharmacological target for the development of chemotherapeutics for cancer (A Y. Chen et al., Annu Rev. Pharmacol. Toxicol., 34 191 (1994)) Among the clinical agents in use, which They are recognized as topoisomerase II inhibitors are etoposide (VP-16), teniposide (VM-26), mitoxantrone, m-AMSA, adriamycin (Doxorubicin) ellipticine and daunomycin. Compared to topoisomerase I I inhibitors, there are relatively few known inhibitors of known topoisomerase I. Camptothecin represents the mammalian topoisomerase I inhibitor most extensively studied. See, R. C. Gallo and others, J. Nati Cancer Ins .. 46. 789 (1971) and B. C. Giovanella and others Cancer Res. 51, 3052 (1991). The broad spectrum of potent antineoplastic activity observed for camptothecin has promoted further efforts to identify other agents, which can effectively poison topoisomerase I. It has recently been shown that Hoechst 33342 (1), 2 '- (4-ethoxyphenyl) -5 - (4-methyl-1-piperazinyl) -2,5'-bi-1 H-benzimidazole, is an inhibitor of topoisomerase I.
This agent, which binds to the minor DNA groove, traps the reversible cleavage complex derived from DNA and topoisomerase I and produces a limited number of highly specific individual chain A DN breaks. For example, see A. Y. Chen et al., Cancer Res. 53. 1332 (1993) and A. Chen et al., PNSA. 90. 8131 (1993). A limitation of Hoechst 33342 as an anticancer agent is the previously reported observation that it is not active against tumor cell lines, which overexpress MDR 1. Since KB 3-1 cells are known to be absolutely sensitive to Hoechst 33342, with an IC50 of approximately 9 nM, this compound is approximately 130 times less cytotoxic to KB V-1 cells, which are known to overexpress M DR. 1 . Recently, several analogues of this bisbenzimidazole have been synthesized, to further investigate the activity ratios of the structure with its potency as inhibitors of topoisomerase I and related cytotoxicity. For example, Q. Sun and others, Biorg. and Med. Chem. Lett. 4, 2871 (1994) describe the preparation of bisbenzimidazoles of the formula (2):
where n is 0, 1, 2, or 3. However, it was found that these compounds are approximately one order of magnitude less than cytotoxic than Hoechst 33342. Therefore, there is a continuing need for new compounds that can induce cleavage the DNA in the presence of mammalian topoisomerase I.
COMPENDIUM OF THE INVENTION
The present invention provides a compound of the general formula (I):
wherein Ar is aryl or a heteroaromatic group containing nitrogen, sulfur or oxygen; X is H, CN, CHO, OH, acetyl, C F3, O- (C1-C4) alkyl, NO2, N H2, halogen or halogen alkyl (C? -C); each Y is individually H, alkyl or aralkyl (C? -C); Y 'is H or alkyl (C? -C); each Z is individually H, alkyl (C? -C4), halogen or halogen alkyl (C? -C4); and n is 0 or 1; or a pharmaceutically acceptable salt thereof. Preferably, Ar is aryl (C6-C? 2), or a 5- to 12-membered heteroaryl group comprising 1 -3 atoms of N, S, or O without peroxide in the ring, wherein each N is unsubstituted or is substituted with alkyl (C? -C4). As shown, the group Ar can occupy any position of the benzo portion, that is, positions 4-7, preferably position 5, and X can occupy any available position on Ar. The group Ar can be optionally fused to the benzo portion, preferably at positions 4, 5, or 5, 6. In a preferred embodiment, Ar is phenyl, and X is H or is a 4-substituent. According to another preferred embodiment, Ar is phenyl, and X is Cl or Br, preferably occupying the para position. As shown, Z can occupy any position on the benzo moiety. Z preferably is H, halogen CH3 or CF3.
According to another embodiment, n is 0, and X is preferably
H, CN, C HO or halogen, for example, F, BR, Cl or I, preferably Cl or Br, and preferably occupies position 5 of the benzo moiety. And it is preferably H or CH3. Y 'preferably is H or CH3. The compounds of the formula (I) are inhibitors of topoisomerase I, as demonstrated by their ability to promote DNA cleavage in the presence of topoisomerase I. In addition, the compounds of the formula (I) are also cytotoxic to mammalian tumor cells, including camptothecin-sensitive and camptothecin-resistant tumor cells and tumor cell lines that exhibit resistance to multiple drugs due to the expression of the P-glycoprotein. . Therefore, the present invention also provides a method for inhibiting the growth of mammalian tumor cells, comprising contacting a tumor cell-susceptible population with an effective amount to inhibit the growth of a compound of the formula (I) , preferably in combination with a pharmaceutically acceptable carrier. The growth of the tumor cells can be inhibited in vitro, or in vivo, by administering the compound of the formula (I) to a mammal in need of extensive treatment, such as a human patient with cancer, suffering from leukemia or tumor solid. The compounds of the formula I can also be used to evaluate the activity of the topoisomerase i obtained from different sources, and it is expected to exhibit at least some of the other bioactivities observed for the topoisomerase inhibitors, such as antibacterial activity, against fungi , against protozoa, anthelmintics and / or antivirals. For example, compound 1_4, shown in Figure 1, exhibits activity against fungi.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a schematic representation of the synthesis of compounds 10-16. Figure 2 is a schematic representation of the preparation of intermediates 4-8 used to prepare the compounds of the invention. Figure 3 is a schematic representation of the preparation of intermediate 9. Figure 4 is a schematic representation of the synthesis of compounds JSKIV-68, -37, and -47. Figure 5 is a schematic representation of the preparation of intermediary J SKIV-44. Figure 6 is a schematic representation of the preparation of the modified analogs in the central benzimidazole moiety. Figure 7 is a schematic representation of the preparation of the modified analogs in the terminal benzimidazole moiety.
DETAILED DESCRIPTION OF THE INVENTION
The aryl (Ar) groups useful in the compounds of the present invention comprise aryl (C6-C? 8), preferably aryl (C6-C?). for example, systems containing aromatic rings, said systems comprise a total of 6 to 12 carbon atoms. Thus, as used herein, the term "aryl" includes aryl substituted with mono- or bis-alkyl (d-C4), such as tolyl and xylyl; aralkyl (C? -C4), such as benzyl or phenethyl; and alcaralkyl. Preferably the aryl is phenyl, benzyl or naphthyl. Heteroaromatic rings include aromatic rings containing up to 3 heterogeneous ring atoms such as N, S, or O without peroxide, and up to 12 ring atoms. Representative aromatic rings include thiophene, benzothiophene, naphthothiophene, trianthrene, furan, benzofuran, isobenzofuran, pyran, chromene, xanthene, phenoxathine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, triazole, tetrazole, pyrazine, triazine, pyrimidine, pyridazine, indolizine. , isoindol, indole, indazole, purine, quinolizone, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, phenentridine, acridine, phenanthroline, phenazine, isothiazole, phenothiazine, oxazole, isoxazole, furazan, phenoxazine and the like, Preferred heteroaromatic rings have a 5- or 6-membered heteroaromatic ring, which may or may not be fused to an aromatic ring such as a benzo ring, for example, the preferred 2-, 3-, or 4-pyridyl substituents. The term "alkyl" includes straight or branched chain alkyl, as well as cycloalkyl and (cycloalkyl) alkyl, for example, methyl, ethyl, i-propyl, cyclopropyl or cyclopropylmethyl. Pharmaceutically acceptable salts include the acid addition salts of basic NH with organic or inorganic acids, v. g., hydrochloride, carbonate, sulfate, acetate, phosphate, tartrate, citrate, maleate, propionate, and the like.
The preparation of the substituted trisbenzimidazoles is presented in Figure 1. With the exception of phenylenediamine, which is commercially available, the appropriately substituted phenylenediamines were synthesized through catalytic hydrogenation of the respective o-nitroaniline derivatives. These phenylenediamines were then coupled with 5-formyl-2- (benzimidazo-5'-yl) benzimidazole, 9, heating in nitrobenzene at 150 ° C to provide the various trisbenzimidazoles, 1_0 - 1_6, in yields ranging from 43-96% , using the general methodologies of M. P. Singh et al., Chem, Res. Toxicol .. 5 597 (1992) and Y. Bathini et al., Svnth. Comm .. 20. 955 (1990). The nitroanilines requirement, as presented in Figure 1, with the exception of 3, which was commercially available, were synthesized from 4-bromo-2-nitroaniline, 17 .. Compound V7 was prepared from o-nitroaniline in a good yield, 94%, using 2, 4,4,6-tetrabromo-2, 5-cyclohexadienone as the bromination reagent. G. J. Fox and others, Org. Svn. , 55, 20 (1973). Since allyltributylation and phenyltributylization are commercially available, the pyridyltributyltin derivatives were prepared from tributyltin chloride and 2-, 3-, and 4-bromopyridine, respectively. See, D. Peters et al., Heterocvclic Chem. 27, 2165 (1990). These tributyltin derivatives were then coupled with 4-bromo-2-nitroaniline using PdCI2 (PPh3) 2 as the catalyst in DM F, as presented in Figure 2 to provide compounds 4, 5, 6, 7 and 8_, respectively, according to the methodology of M. Iwao and others, Heterocvcles. 36. 1483 (1993). This methodology can generally be applied to prepare 3-, 4-, 5-, or 6- aryl- and heteroaryl-substituted 2-nitroanilides from the corresponding bromonitroanilines. The preparation of 5-formyl-2- (benzimidazo-5'-yl) benzimidazole, 9, was obtained as presented in Figure 3. The reduction of 5-benzimidazolecarboxylic acid to 5-hydroxymethylbenzimidazole was achieved using LiAIH4. Oxidation of the resulting crude benzyl alcohol with tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide provided, in two steps, the desired 5-formylbenzimidazole in a total yield of 32%. See, A. Cherif et al., JL_ Med. Chem. 35, 3208 (1992). Coupling of 5-formylbenzimidazole with 4-cyano-1,2-phenylenediamine provided 5-cyano-2- (benz midazol-5'-yl) benzimidazole, 1J9, which when treated with the N i-Al catalyst in The presence of aqueous formic acid gave 5-formyl-2- (benzimidazol-5'-yl) benzimidazole, 9, in 65% yield (J. Piper et al., J. Med. Chem .. 31_, 2164 (J. 1988)). The compounds of the present invention can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient with cancer, in a variety of forms adapted to the selected route of administration, i.e., orally or parenterally, by routes intravenous, intramuscular or subcutaneous. In this way, the compounds herein can be orally administered, for example, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an edible assimilable carrier. These can be enclosed in hard or soft shell gelatin capsules, can be compressed to tablets, or can be incorporated directly with the food in the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Said compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions or preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in said therapeutically useful compositions is such that an effective dose level will be obtained. The tablets, troches, pills, capsules, and the like may also contain the following: a binder such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavor may be added. When the unit dose form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or otherwise to modify the physical form of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar, and the like. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl or propylparabens as preservatives, a colorant and flavoring such as cherry or orange flavor. Of course, any material used to prepare any unit dosage form must be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained release preparations and devices. The active compound can also be administered intravenously or intraperitoneally through infusion or injection. The solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or sterile dispersions or powders comprising the active ingredient, which are adapted for the extemporaneous preparation of injectable or infusion solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form must be sterile, fluid and stable under manufacturing and storage conditions. The liquid carrier or vehicle can be a solvent or a liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol and liquid polyethylene glycols, and the like), vegetable oils, glyceryl esters not toxics, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the transformation of liposomes, through the maintenance of the required particle size in the case of dispersion or through the use of surfactants. The prevention of the action of microorganisms can be conducted through various antibacterial and anti-fungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it may be preferable to include isotonic agents, for example, sugars, pH regulators or sodium chloride. Prolonged absorption of the injectable compositions can be conducted through the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the amount required in the appropriate solvent with several of the other ingredients listed above, followed by sterilization through a filter. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients present in the sterile solutions previously. filtered. Useful doses of compounds of I can be determined by comparing their activity in vitro, and their activity in vivo in animal models, with that equivalent dose of camptothecin (see, for example, BC Giovanella et al., Cancer Res. 51, 3052 (1991)) or Hoechst 33342 (see, AY Chen et al., Cancer Res. 53, 1332 (1993)). Methods for extrapolation of effective antitumor doses in mice, and other animals, to humans, are known in the art; for example, see patent of E. U.A. No. 4,938, 949. Analogs herein may be used to treat cancers known to be susceptible to topoisomerase I inhibitors, including, but not limited to, Burkitt's tumor, chronic lymphocytic leukemia, multiple myeloma, anaplastic carcinomas. of squamous cell and large cell, adenocarcinoma of the lung, Ewing sarcoma, non-Hodgkins lymphoma, breast tumor, colon tumor, stomach tumor, ovarian cell bronchiogenic carcinoma, squamous cell carcinoma of the cervix, ovarian tumors, tumors of the bladder, testicular tumors, endometrial tumors, malignant melanoma and acute lymphocytic leukemia, and prostatic carcinoma. The compounds of the present invention can be administered as individual agents, or in combination with other antineoplastic drugs commonly employed to treat these cancers. The invention will be further described with reference to the following detailed examples, wherein the melting points were determined with a Thomas-Hoover individual melting melting point melting apparatus. The infrared (IR) spectral data were obtained in a Perkin-Elmer 1600 Fourier transformation spectrophotometer and were reported in cm "1. Proton nuclear magnetic resonances (1 H NMR) and carbon resonance (13 C NMR) were recorded in a Fourier Transform Spectrometer Varied Gemini-200. NMR spectra (200 MHz 1 H and 50 M Hz 13C) were recorded in CDCI3 (unless otherwise noted) with chemical shifts reported in units downfield from tetramethylsilane ( TMS) Coupling constants are reported in hertz Mass spectra were obtained from the Midwest Center for Mass Spectrometry within the Department of Chemistry at the University of Nebraska-Lincoln Combustion analyzes were performed through Atlantic Microlabs, Inc. ., Norcross, GA, and were + 0.4% TH F of sodium and benzophenone were freely distilled before use Aliltributyltin and phenyltributyltin were purchased from Aldrich Chemical Co. mpany
EXAMPLE 1 General Procedure for Coupling Reaction
Catalyzed with PdCI? (PPh3)? of 4-Bromo-2-nitroaniline (13) with Tin Compounds
(A) 4-Phenyl-2-nitroaniline (5). A solution of 4-bromo-2-nitroaniline 17 (1.0 g, 4.67 mmol), tributyl phenyltin (2.2 g, 6.07 mmol), bis (triphenylphosphine) palladium (II) chloride (164 mg, 0234 mmol), and triphenylphosphine (613) mg, 2.34 mmole) in DMF (15 ml) was heated under N2 at 120 ° C overnight. After the solution was cooled to room temperature, the reaction mixture was chromatographed directly on silica gel eluting with 2-5% EtOAc / hexane to give 752 mg (75%) of 5 as a yellow solid: mp. 169-171 ° C; IR (CHCl3), 3517, 3398, 3022, 1635, 1525, 1250; 1H NMR d 8.38 (1H, d, J = 2.2), 7.66 (1H, dd, J = 8.7, 2.2), 7.59-7.54 (2H, m), 7.49-7.34 (3H, m), 6.90 (1H, d , J = 8.8), 6.13 NH, brs); 13C NMR d 144.2, 139.3, 135.0, 130.9, 129.5, 127.8, 126.8, 124.4, 119.8, 112.8; Anal. Cale, for C12H10N2O2: C, 67.28; H, 4.70; N, 13.08. was found: C, 67.38, H, 4.76; N, 13.01.
(B) 4-Allyl-2-nitroaniline (4). Prepared 4-bromo-2-nitroaniline 17 (1.70 g, 7.84 mmol) and allyltributyltin (3.38 g, 10.2 mmol) as a yellow solid in 96% yield as described above for 5: pf. 29-31 ° C; IR (KBr) 3490 3374, 1638, 1518, 1341, 1253; 1H NMR d 7.90 (1H, d, J = 2.0), 7.19 (1H, dd, J = 8.5, 2.0), 6.77 (1H, d, J = 8.5), 6.05 (NH, brs), 6.00-5.80 (1H, m), 5.11 (1H, dd, J = 1.4, 1.4), 5.04 (1H, ddd, J = 6.6, 3.0, 1.5), 3.28 (1H, d, J = 6.6); 13C NMR d 143.81, 137.13,129.34, 125.59, 119.49, 116.95, 39.18; HRMS (El) cale, for C9H10N2O2 178.0742, 178.0746 was found. (C) 4- (2'-Pyridyl) -2-nitroaniline (6). Prepared from 4-bromo-2-nitroaniline 17 (507 mg, 2.75 mmol) and 2-tributylstannyl-pyridine (1.01 g, 2.75 mmol) as a yellow solid in a yield of 52% as described above for 5: pf . 146-148 ° C; IR (CHCl3) 3516, 3397, 3020, 1634, 1524, 1341, 1250; 1H NMR d 8.74 (1H, d, J = 2.2), 8.63 (1H, dd, J = 4.9, 1.5), 8.13 (1H, dd, J = 8.8, 2.1), 7.78-7.66 (2H, m), 7.20 (1H, ddd, J = 4.8, 4.7, 1.9), 6.92 (1H, d, J = 8.8), 6.37 (NH, brs); 13C NMR d 155.6, 150.1, 145.6, 137.4, 134.5, 129.1, 124.7, 122.4, 119.8, 119.7; Anal. Cale, for CnH9N3O2: C, 61.39; H, 4.21; N, 19.53. was found: C, 61.29; H, 4.23; N, 19.43.
(D) 4- (3'-Pyridyl) -2-nitroaniline (7). Prepared from 4-bromo-2-nitroaniline 17 (1.42 g, 6.53 mmol) and 3-tributylstannyl-pyridine (3.60 g, 9.79 mmol) as a yellow solid in a yield of 32% as described above for 5: pf . 177-179 ° C; IR (CHCl3) 3515, 3399, 3052, 2983, 1638, 1524, 1341, 1259; 1H NMR d 8.68 (1H, d, J = 1.7), 8.42 (1H, dd; J = 4.8, 1.5), 8.22 (1H, d, J = 2.2), 7.74 (1H, ddd, J = 7.9, 2.4, 1.6), 7.50 (1H, dd, J = 8.7, 2.2), 7.23 (1H, ddd, J = 8.0, 4.8, 0.8), 6.92 (1H, d, J = 8.8), 6.56 (NH, brs); 13C NMR d 148.7, 147.8, 145.4, 135.0, 134.4, 133.8, 126.5, 124.4, 124.0, 120.4; Anal. Cale, for CnH9N3O2 C, 61.39; H, 4.21; N, 19.53. it was found: C, 61.28; H, 4.16; N, 1940.
(E) 4- (4'-Pyridyl) -2-nitroaniline (8). Prepared from 4-bromo-2-nitroaniline 17 (165 mg, 0.76 mmol) and 4-tributylstannyl-pyridine (289c0 mg, 0.76 mmol) as a yellow solid in a 25% yield as described for 5: pf. 230-232 ° C; IR (CHCl3) 3518, 3398, 3032, 1636, 1528, 1344; 1H NMR (CD3OD) d 8.55 (2H, d, J = 6.3), 8.52 (1H, d, J = 2.3), 7.84 (1H, dd, J = 8.9, 2.3), 7 71 (2H, d, J = 6.4), 7. 13 (1H, d, J = 8.9), 13C NMR (CD3OD) d 149.4, 133.4, 124.0, 120.7, 120.0; HRMS (El) cale. for CnH9N3O. 215.0695, 215.0698 was found.
EXAMPLE 2 5-Form i l-2- (benzimidazol-5'-yl) benz imidazole (9)
A mixture of 5-cyano-2- (benzimidazol-5'-yl) benzimidazole 19
(148 mg, 0.57 mmol), Ni-Al catalyst (500 mg), formic acid (7 ml) and water (3 ml) was heated to reflux under N2 for 4 hours. The hot reaction mixture was filtered immediately through a plug of celite, and evaporated to give a yellow solid. The yellow solid was then dissolved in hot water (5 ml), and the solution was neutralized to a pH of 9 by 2 N NaOH. The solid was precipitated by suction filtration and further purified by flash chromatography on silica gel (15% MeOH / EtOAc) to give 142 mg (95%) of 9 as a white solid: mp. >; 275 ° C; IR (KBr) 3106.2835, 1685, 1118, 1432, 1293; 1H NMR (CD3OD) d 10.01 (1H, s), 8.39 (1H, s), 8.35 (1H, s), 8.13 (1H, s), 8.06 (1H, dd, J = 8.6, 1.6), 7.83 (1H , dd, J = 8.4, 1.4), 7.77 (1H, d, J = 8.5), 7.71 (1H, d, J = 8.3); HRMS (FAB) cale, for C? SHnN4O 263.0933, 263.0932 was found.
EXAMPLE 3 General Procedures for Preparing Trisbenzimidazoles 5- Substituted
(A) 2- [2 '- (Benz imidazole-5"-i I) benz imidazol-5' -i I] benzimidazole (10) A mixture of 5-formyl-2- (benzimidazol-5'-yl) Benzimidazole 9 (121 mg, 0.46 mmol) and phenylenediamine (60 mg, 0.55 mmol) in nitrobenzene (8 ml) was heated at 150 ° C under N2 overnight.The mixture was cooled to room temperature and chromatographed on silica gel (0-20% MeOH / EtOAc) to provide 155 mg (96%) of 10 as a solid: mp> 275 ° C; IR (KBr) 3400, 3157, 1630, 1542, 1438, 1294; 1H NMR (DMSO-d6 + 3 drops of CF3COOH) d 9.71 (1H, s), 8.75 (1H, s), 8.65 (1H, d, J = 1.1), 8.48 (1H, dd, J = 8.7, 1.5), 8.21 (1H, dd, J = 8.6, 1.6), 8.'¿ (1H, d, J = 8.8), 8.08 (1H, d, J = 87), 7.90 (2H, dd, J = 6.2, 3.1), 761 (2H, dd, J = 6.1.3 1); 13C NMR (DMSO-d6 + 3 drops of CF3COOH d 154.4, 149.8, 133.2, 132.0, 31.7, 126.2, 125.5, 125.4, 123.9 123.6, 116.3, 115.9, 114.23 , 114.17,114.13; HRMS (FAB) cale, for C2? H15N6 351.1358, 351.1367 was found (B) 5-Cyano-2- [2 '- (benzimidazol-5"-yl) benzimidazole. -5'-yl] benzimidazole (11). Hydrogenation of 3 (70 mg, 0.43 mmol) was achieved at 2812 kg / cm2 of H2 at room temperature for 1 hour using 10% Pd-C (30 mg in EtOAc (10 ml) .The reaction mixture was filtered and Concentrate to vacuum to provide a solid The solution of this solid and 9 (S ~ mg, 0.33 mmol) in nitrobenzene (5 ml) was heated to 150 ° C under 2 overnight The mixture was cooled to room temperature and chromatographed directly on silica gel (0-10% MeOH / EtOAc) to give 107 mg (86%) of 11 as a solid: mp> 280CC; IR (KBr) 3416, 3148, 2222, 1626 , 1 553, 1441, 1292; 1H NMR (DMSO-d6 + 3 drops of CF3COOH) d 8.50 (1H, s), 846 (1H, s), 8.40 (1H, s 8. 18-8.11 (3H, m) , 7.81-7.75 (3H, m), 7.62 (1H, dd, J = 8.3, 1 5); HRMS (FAB) cale, for C22H13N7 376.1310, 376.130S was found
(C) 5-Propyl-2- [2 '- (benzimidazol-5"-yl) benzimidazol-5'-yl] benzimidazole (12). Prepared from 4-allyl-2-nitroaniline 4 (312 mg, 1.75 mmoles) and 5-formyl-2- (benzimidazol-5'-yl) benzidnidazole 9 (121 mg, 0.46 mmol) in a 79% yield as described above for 11: solid, mp> 270 ° C; IR (Kbr) 3421, 3068, 2957, 1434; 1H NMR (DMSO-d6 + 3 drops of CF3COOH) d 9.66 (1H, s), 8.73 (1H, s), 8.59 (1H, s), 8.48 (1H , dd, J = 8.7, 1.5), 8.13 (1H, dd, J = 8.7, 1.4), 8.11 (1H, d, J = 8.7), 8.02 (1H, d, J = 8.5), 7.79 (1H, d , J = 8.4), 7.66 (1H, s), 7.45 (1H, dd, J = 8.5, 1.3), 2.80 (2H, t, J = 7.0), 1.70 (2H, m), 0.96 (3H, t, J = 7.2); 13C NMR (DMSO-d6 + 3 drops of CF3COOH) d 153 84, 149.74, 141.64, 141.01, 139.37, 133.10, 132.26, 131.99, 130.34, 127.08, 126.26, 125.14, 141.64, 141.01, 139.37, 133.10 , 132.26, 131.99, 130.34, 127.08, 126.26, 125.14,
122. 91, 117.52, 116.32, 116.06, 115.76, 113.78, 112.99, 37.45,
24. 73, 13.74;
(D) 5-Phenyl-2- [2 '- (benzimidal-5"-yl) benzimidazol-5'-yl] benzimidazole (13) Prepared from 4-phenyl-2-nitroaniline 5 (247 mg, 1.15 mmoles) and 5-formyl-2- (benzimidazol-5'-yl) benzimidazole 9 (201 mg, 0.77 mmol) in a yield of 89% as described for 11: solid, mp 262-164 ° C dec .; IR (Kbr) 3402, 3104, 16227, 1552, 1442, 1290; 1H NMR (DMSO-d6 + 3 drops of CF3COOH) d 9.66 (1H, S), 8.74 (1H, s), 8.65 (1H, s), 8.50 (1H, dd, J = 8.8, 1.1), 8.21 (1H, dd, J = 8.7, 1.4), 8.12 (1H, d, J = 8.8), 8.06 (1H, s), 8.05 (1H, d, J = 8.4), 7.97 (1H, d, J = 8.7), 7.89 (1H, dd, J = 8.7, 1.5), 7.80 (2H, d, J = 7.0), 7.61-7.47 (3H, rn) HRMS (FAB) cale, for C27H19N6 427.1671, 427.1666 was found.
(E) 5- (2-Pyridyl) -2- [2 '- (benzimidazol-5"-yl) benzimidazol-5'-yl] benzimidazole (14). Prepared from 4- (2'-pyridyl) - 2-nitroaniline, 6 (110 mg, 0.50 mmol), and 5-formyl-2- (benzimidazol-5'-yl) benzimidazole 9 (51 mg, 0.25 mmol) in an 84% yield as described above for 11: solid; mp;> 275 ° C; IR (Kbr) 3411, 3157, 1630, 1593, 1432; 1H NMR (CD3OD) d 8.59 (1H, d, J = 4.8), 8.35 (1H, s), 8.31- 8.25 (2H, m), 8.10 (1H, s), 8.04-7.94 (2H, m), 7.85-7.77 (3H, m), 7.72 (1H, d, J = 8.6), 7.68 (1H, d, J = 8.7), 7.64 (1H, d, J = 8.7), 7.30 (1H, m); HRMS (FAB) cale, for C26H1ßN7, 428.1624, 428.1611 was found.
(F) 5- (3-Pyridyl) -2- [2 '- (benzimidazol-5"-yl) benzimidazol-5'-yl] benzimidazole (15). Prepared from 4- (3'-pyridyl) - 2-nitroaniline 7 (183 mg, 0.85 mmol) and 5-formyl-2- (benzimidazol-5-yl) benzimidazole 9 in a 46% redefinition as described above for solid, mp> 275 ° C; IR (Kbr) 3400, 3070, 2836, 1438, 1289; 1H NMR (CD3OD) d 8.83 (1H, d, J = 1.6), 8.49 (1H, dd, J = 4.9, 1.5), 8.3 (1H, d , J = 1.1), 8.31 (1H, d, J = 1.1), 8.29 (1H, s), 8.11 (1H, ddd, J = 80, 2.3, 1.6), 8.05 (1H, dd, J = 8.5, 1.6 ), 8.00 (1H, dd, J = 8.5, 1 6), 7.81 (1H, d, J = 1.1), 777-7.68 3H, m), 7.55-7.47 (2H, m); HRMS (FAB) cale, for C26H18N7428.1624, 428.1612 was found.
(G) 5- (4-Pyridyl) -2- [2 - (benzimidazol-5-yl) benzamidazol-5'-yl-3-benzimidazole (16). Prepared from 4- (4'-pyridyl) -2-nitroaniline 8 (35 mg, 0.16 mmol) and 5-formyl-2- (benzimidazol-5'-yl) benzimidazole 9 (50 mg, 0.19 mmol) in a 43% yield as described above for 11: solid; pf. > 280 ° C; IR (Kbr) 3411, 3118, 1600, 1552, 1439, 1290; 1H NMR (CD3OD) d 8.51 (2H, d, J = 6.2), 8.33 (1H, d, J = 1.1), 8 27 (1H, s), 8.25 (1H, d, J = 1. 1), 8.01 (1H, dd, J = 8.6, 1 7), 7.96 (1H, dd, J = 8.9, 2.0), 7.87 (1H, d, J = 1.0), 7.74-7.56 (6H, m); HRMS (FAB) cale. for C26H1ßN7 428.1624, 428.1625 was found.
EXAMPLE 4 4-Bromo-2-nitroaniline (17)
A solution of 2-nitroaniline (5 g, 36.2 mmol) in CH2Cl2 (100 mL) was cooled to -10 ° C, and treated through 90% of 2,4,4,6-tetrabromo-2,5- cyclohexane (19.8 g, 43.5 mmol) in 5 portions. The mixture was stirred at -10 ° C for 1 hour. After warming to room temperature, the reaction mixture was washed through 2N NaOH (60 ml) and brine (50 ml), dried over Na2SO4 and evaporated. Flash chromatography on silica gel (5% EtOAc / hexane) gave 7.40 g (94%) of 17 as a yellow solid: mp. 109-110 (see lit. 112-113 ° C); 1 H NMR d 8.27 (1 H, d, J = 2.3), 7.43 (1 H, dd, J = 8.9, 2.4), 6.73 (1 H, d, J = 8.8), 6.09 (NH, brs).
EXAMPLE 5 5-Formylbenzimidazole (18)
A suspension of 5-benzimidazolecarboxylic acid (1.57 g, 9.7 mmol) in dry THF (50 mL) was cooled to -78 ° C under N2 and treated with LiAIH4 (736 mg, 19.4 mmol). After the addition, the mixture was allowed to warm slowly to room temperature and then stirred at room temperature overnight. The mixture was cautiously quenched through MeOH and H2O, and passed through a short column of silica gel eluting with 10% MeOH / EtOAc. The eluate was concentrated to give 876 mg of crude alcohol as a solid. The crude alcohol (876 mg) was dissolved in a mixture of DMF (3 ml), THF (10 ml) and CH2Cl2 (40 ml).
Subsequently, 4-methylmorpholine N-oxide (2.25 g, 19.2 mmol), 4A molecular sieves (5 g), and TPAP (169 mg, 048 mmol) were added to the crude alcohol solution. The mixture was stirred at room temperature overnight, and filtered through a pad of silica gel eluting with 10% MeOH / EtOAc. The eluate was concentrated and further purified by chromatography on silica gel eluting with 0-10% MeOH / EtOAc to give 452 mg (32%, 2 steps) of 17 as a white solid: mp. 164-166 ° C; IR (KBr) 3087, 2818, 1690, 1292, 1H NMR (CD3OD) d 9.95 (1H, s), 8.34 (1H, s), 8.08 (1H, d, J = 1.5), 7.74 (1H, dd, J = 8.4, 1.5), 7.63 (1H, d, J = 8.4); 13C NMR (CD3OD) d 194.2, 146.0, 143.0, 139.8, 133.6, 124.9, 120.7, 1 16.6; Anal. Cale, for CßH6N2O: C, 65.75; H, 4.14; N, 19.17. was found: C, 65.60; H, 4.17; N, 19.08.
EXAMPLE 6 5-Cyano-2- (benzimidazole-5 '-i I) benzimidazole (19)
A mixture of 5-formylbenzimidazole 18 (211 mg, 1.44 mmol) and 4-cyano-1,2-phenylenediamine (230 mg, 1.73 mmol) in nitrobenzene (10 ml) was heated at 150 ° C under N2 overnight. The mixture was cooled to room temperature and chromatographed directly on silica gel eluting with 0-15% MeOH / EtOAc to give 244 mg (65%) of 18 as a solid: mp. > 270 ° C; IR (KBr) 3110, 2826, 2224, 1627, 1426, 1294; 1H NMR (CD3OD) d 8.41 (1H, s), 8.33 (1H, s), 8.07 (1H, dd, J = 8.6, 1.5), 7.98 (1H, s), 7.78 (1H, d, J = 8.4) , 7.73 (1H, d, J = 8.4), 7.56 (1H, dd, J = 8.4, 1.5); 13 C NMR (DMSO-d 6 + 3 drops of CF 3 COOH) d 1 S 3 4, 140.4, 138.3, 132 9,131.6, 127.0, 125.8, 125.3, 120.8, 119.8, 116.0, 115.8, 113.9, 105.5; HRMS (FAB) cale, for C? 5H? 0N5 260.0936, 260.095 was found.
EXAMPLE 7
(A) 5-Bromo-2- [2 '- (benzimidazol-5"-yl) benzimidazol-5'-yl] -benzimidazole (JSKIV-37) A mixture of 5-formyl-2- (benzimidazole-5') -yl) benzimidazole (118.8 mg, 0.45 mmol) and 5-bromophenylenediamine (169.6 mg, 0.90 mmol) in nitrobenzene (5 ml) was heated at 150 ° C under N2 overnight.The mixture was cooled to room temperature and chromatographed using 0-10% methanol / ethyl acetate to provide 127.3 mg (66%) of a brown-yellow solid: mp> 280 ° C; IR (KBr) 3101, 1626, 1547, 1440; 1H NMR (DMSO- d6) d 7.34 (dd, 1H, J = 7.0, 2.0), 7.57 (d, 1H, J = 9.0), 7 71-7.80 (m, 3H), 8.04-8.18 (m, 2H), 8.39 (s, 2H), 8.50 (s, 1H); 13C NMR (DMSO-d6 + 3 drops CF3COOH) d 114.1 115.8, 116.2, 116.4, 117.0, 118.6, 123.5, 125.3, 126.2, 128.7, 128.9, 131.8, 132.0, 132.3, 133.1 , 134.4, 138.3, 140.6, 151.1, 153.4.
(B) 5-Chloro-2- [2 '- (benzimidazol-5"-l) benzimidazol-5'-yl] -benzimidazole (JSKIV-68) A mixture of 5-formyl-2- (benzimidazole) -5'-yl) benzimidazole (160 mg, 0.61 mmol) and 5-chlorophenylenediamine (174 mg, 1.22 mmol) in nitrobenzene (5 ml) was heated at 150 ° C under N2 overnight.The mixture was cooled to room temperature and chromatographed using 0-10% methanol / ethyl acetate to provide 167 mg (71%) of a brown-yellow solid: mp> 280 ° C; IR (Kbr) 3103, 2826, 1427, 1293; 1H NMR (DMSO-d6) d 7.24 (dd, 1H, J = 8.5, 2.0), 7.60-7.81 (m, 4H), 8.07-8.17 (m, 2H), 8.40 (s, 2H), 8.50 (s, 1H) 13C NMR (DMS0-d6 + 3 drops CF3COOH) d 114.3, 114.4, 115.3, 115.5, 115.6, 116.2, 118.5, 123.1, 125.4, 125.5, 125.6, 129.4, 132.4, 132.9, 133.0, 135.2, 138.9, 140.9, 151.8 , 153.5.
(C) 5- (p-Chlorophenyl) -2- [2 '- (benzimidazol-5"-yl) benzimidazol-5'-yl] benzimidazole (JSKIV-47) A mixture of 5-formyl-2- (benzimidazole) -5'-yl) benzimidazole (99 mg, 0.38 mmol) and 5- (p-chlorophenyl) -phenylene-diamine (154 mg, 0.71 mmol) in nitrobenzene (5 ml) was heated at 150 ° C under N2 overnight The mixture was cooled to room temperature and chromatographed using 0-10% methanol / ethyl acetate to provide 85 mg (49%) of a brown yellow solid: mp> 280 ° C; IR (KBr) 3046, 2820, 1426, 1282; 1H NMR (DMSO-d6 + 3 drops CF3COOH) d 7.56 (d, 2H, J = 8.5), 7.82 (d, 2H, J = 8.5), 7.88-8.21 (m, 6H), 8.48 (d, 1H, J = 8.8), 8.63 (s, 1H) 8.72 (s, 1H), 9.69 (s, 1H); 13C NMR (DMSO-d6 + 3 drops CF3COOH) d 111.8, 113.8, 114.7, 115.8, 116.1, 117.7, 123.0, 124.1,125.2, 125.3, 129.2, 129.3, 131.9, 132.1, 133.0, 133.1, 137.2, 138.5, 139.3, 141.6, 150.8, 153.8.
(D) 4-Bromophenylenediamine (JSKIV-35). To 2-nitro-4-bromoaniline (240 mg, 1.57 mmol) in absolute ethanol (20 ml) was added SnCl2 (1.50 g, 7.91 mmol) and refluxed overnight. The reaction mixture was then basified to a pH of 11 with 2N NaOH and extracted with another to give 275 mg (94%) of the product. This product was used without further purification for the synthesis of JSK IV-37.
(E) 4-Chlorophenylene diamine (JSKIV-67). To 2-nitro-5-chloroaniline (304 mg, 1.76 mmol) in absolute ethanol (20 ml) was added SnCl2 (1.68, 8.86 mmol) and refluxed overnight. The reaction mixture was then basified to a pH of 1 1 with 2N NaOH and extracted with ether to give 250 mg (quantitative yield) of the product. This product was used without further purification for the synthesis of JSK IV-68.
(F) p-Chlorotributyl phenyltin (JSKIV-42). 4-Bromochlorobenzene (3.2 g, 16.62 mmol) was dissolved in dry THF (20 ml). After bringing the reaction temperature down to -78 ° C with an acetone / dry ice bath, nBuLi (15.58 ml, 1.6 M, 1.5 equiv.) Was slowly added and stirred at -78 ° C. for 30 minutes. Tributyltin chloride (6.77 ml, 1.5 eq.) Was added and stirred overnight while the reaction was carried at room temperature. The reaction mixture was quenched by stirring the reaction in an open flask in air for 1 hour, after which TH F was evaporated. The product was obtained as an oil (7.35 g, 97%) after passing the mixture through a column of rapid silica gel eluting with 100% hexanes.
(G) 2-Nitro-5- (p-chlorophenyl) aniline (JSKIV-44). To JSKIV-42
(2.02 g, 5.04 mmol) and 2-nitro-4-bromoaniline (730 mg, 3.36 mmol) in DMF (18 ml) was added Pd (PPH3) 2 (17.9 mg, 0.17 mmol) and PPh3 (440.2 mg, 1.70 mmol) and heated at 120 ° C overnight. The DMF was rotated-evaporated and the mixture was separated on a column of silica gel eluting with 5-10% ethyl acetate / hexanes to give 270 mg (32%) reddish solid.
(I) 4- (p-Chlorophenyl) phenylenediamine (JSKIV-46). It dissolved
JSKIV-44 (190 mg, 0.77 mmol) in ethyl acetate (100 ml) and after adding 10% Pd-C (40 mg) was reduced by hydrogenation (3.1635 kg / cm2). The product (quantitative yield) was used in JSKIV-47 without further purification.
EXAMPLE 8
A. Topoisomerase I-mediated DNA Excision Assays Topoisomerase I was purified from calf thymus gland DNA, as previously reported by B. D. Halligan et al., X_ Biol. Che .. 260. 2475 (1985). Plasmid YEpG was also purified through the alkaline lysis method followed by deproteination with phenol and isopycnic centrifugation of CsCI / ethidium, as described by T. Mariatis et al., Molecular Cloning. A Laboratorv Manual. Cold Spring Harbor Labs, NY (1982) on pages 149-185. Final labeling of the plasmid was accomplished as previously described by L. F. Liu and others, J. Biol. Chem. 258. 15365 (1983). The cleavage assays were performed as previously reported by A. Y. Cheng et al., Cancer Res .. 53, 1332 (1993). Human topoisomerase was isolated as a recombinant fusion protein using a T7 expression system.
B. Cytotoxicity Test The cytotoxicity was determined using, as the MTT, the microtitre plate tetrazolium cytotoxicity assay (MTA), following the procedures of F. Denizot et al., J. Immunol. Methods. 89. 271 (1986); J. Carmichael et al., Cancer Res. 47. 936 (1987) and. J. Mosmann and others, Irnmunol. Methods. 65. 55 (1983). The human lymphoblast RPMI 8402 and its camptothecin-resistant variant cell line, CPT-K5, were provided by Dr. Toshiwo Andoh (Aichi Cancer Center Research Institute, Nagoya, Japan). See, for example, T. Andoh et al., Adv. Pharmacol. , 29B, 93 (1994). The cytotoxicity analysis was performed using 96-well microtiter plates. Cells were grown in the suspension at 37 ° C in 5% CO2 and were maintained through the regular passage in the RPMI medium supplemented with 10% warm inactivated fetal bovine serum, L-glutamine (2 mM), penicillin (100 U / ml) and streptomycin (0.1 mg / ml). For determination of ICso, the cells were exposed continuously with varying concentrations of drug concentrations and MTT assays were performed at the end of the fourth day. The KB-3 cell line of human drug-sensitive squamous cell carcinoma (S. Auyama et al., Somatic Cell Mol. Genet., 11, 17 (1985)) and its KBV-1 cells of variant resistant to multiple drugs selected from vinblastine (DW Shen et al., Science, 32. 643 (1986)) were provided by Dr. Michael Gottesman (National Cancer Institute, Bethesda, ML). These cells were grown as monolayer cultures in 5% CO 2 and maintained by regular passage in an essential Dulbecco minimal medium supplemented with 10% of warm inactivated fetal bovine serum. Similarly, KBV-1 cells were maintained, except that they were grown in the presence of 1 μg / ml vinblastine.
C. Results As shown in Table 1, the comparison of compounds 10-16 with Hoechst 33342 (1) as inhibitors of topoisomerase I showed that several of these trisbenzimidazoles had similar potency.
TABLE 1 DNA cleavage mediated by Topoisomerase I and
Cytotoxicity of Bis- and Trisbenzimidazoles
IC5o of Cytotoxicity (μM) Cleavage of Cell Lines Mediated DNA Compound by Topo lb RPMI CPT-K5 KB3-1 KBV-1
Hoechst 1 0.03 0.9 0.01 1.2
1.1 14 28 N.D. N.D.
11 1 > 25c > 25c N.D. N.D.
12 100 7.6 20 N.D. N.D.
13 2 0.09 0.58 0.58 0.35
14 3.3 0.16 5.8 0.05 0.09
2 0.035 2.5 0.02 0.02
16 2 0.035 2.5 0.02 0.01
19 1000 > 25c N.D. N.D. N.D. 1 1.40 1.40 JSKIV- -37 10 0.09 0.20 JSKIV-47 1 1.04 0.65 JSKIV- -68
a) IC50 was calculated after 4 days of continuous exposure to the drug. N.D. = not determined b) Topoisomerase I cleavage values such as REC, Relative Effective Concentration, ie, relative concentrations to Hoechst 3342, whose value is arbitrarily assumed to be 1, which are capable of producing the same cleavage in the plasmid DNA in the presence of of topoisomerase I of calf thymus. Cleavage was calculated from the intensity of the strongest specific band of Hoechst. c) No indication of cytotoxicity was considered indicative of the IC 50 values substantially higher than the highest doses analyzed.
Since 10 and 11 exhibited similar potency in their inhibition of topoisomerase I as observed with Hoechst 33342, both compounds failed to exhibit cytotoxicity towards the human lymphoblast cell line, RPMI 8402. However, this is due to the inability of the compound pure to penetrate the target cells, which can be overcome by selecting a suitable vehicle, such as liposomes. Trisbenzimidazole 5-phenyl substituted, 13, was about as potent as Hoechst 33342 mitas as a topoisomerase I inhibitor. In contrast to 10 and 11, however, it had significant cytotoxicity towards the human lymphoblast cell line, RPMI 8402 cells. As observed with Hoechst 33342, 13 was also effective against camptothecin-resistant CPT-K5 cells. The relative resistance of Hoechst 3342 and 13m expressed as the ratio of IC50 values of resistance against the drug-sensitive cell line, is approximately 30 times as compared to the relative resistance of camptothecin, which is 2, 500 Sometimes, as reported by AY Chen and others, Cancer Res. 53. 1332 (1993). A similar effect was observed in another pair of cell lines; 13 has an ICS0 of 0.015 μg / ml in the human ovarian tumor cell line, A2780, relative to an IC50 of 0.03 μg / ml in CPT-2000, a variant of A2780 selected for camptothecin resistance and it is known that contains a topoisomerase I resistant to mutant camptothecin. The 5-n-propyl trisbenzimidazole derivative, 12, was much less active than either 10, 11 or 13 as a topoisomerase I inhibitor. Its weak activity as an inhibitor of topoisomerase I correlates with its weak cytotoxicity. The activity of several of these compounds was also evaluated using recombinant human topoisomerase I. Several of these analogs induced a similar DNA cleavage in the presence of human topoisomerase I as compared to that observed with topoisomerase I isolated from calf thymus. The cytotoxic activity of Hoechst 3342 and 13 was also evaluated against KB 3-1 and KB V-1 cells. The primary difference between these cell lines is in the degree to which human MDR 1 is expressed (P-glycoprotein). Recent studies have shown that antineoplastic agents, which are cationic at a physiological pH, most likely serve as substrates for M DR 1 and, therefore, are less effective against cells that overexpress P-glycoprotein. In view of the fact that Hoechst 3342 is extensively protonated at a physiological pH, it is not surprising that ICso differs by approximately 2 orders of magnitude for KB 3-1 as compared to KB V-1 cells, as reported by A. Y. Chen and others, Adv. Pharmcol .. 245. 29B (1994). In contrast to Hoechst 33342, there is a small difference between the ICso values observed for 13 in these two cell lines. Thus, 13 does not seem to be a substrate for human MDR1. These data indicate that these trisbenzimidazole derivatives may have significant chemotherapeutic advantages as compared to Hoechst 33342 or pibenzimol (Hoechst 33258), 2 '- (4-Hydrosyphenyl) -5- (4-methyl-1-piperazinyl) -2,5'-bi-1H-benzimidazole. These data indicate that the substitution of these trisbenzimidazole with a 5-Ar substituent can produce derivatives, which are active as inhibitors of topoisomerase I and cytotoxic to tumor cells. Trisbenzimidazoles substituted in the 5-position with either a 2-, 3-, or 4-pyridyl group, 14-16, were evaluated for their potency as topoisomerase I inhibitors and for cytotoxicity as summarized in Table 1. These analogs , similar to 13, have activity as inhibitors of topoisomerase I. The analogs of 3-, and 4-pyridyl, 15 and 16, are slightly more active than the 2-pyridyl derivative, 14, as inhibitors of topoisomerase I as well as agents cytotoxic As observed with 13, these substituted pyridyl bisbenzimidazoles had similar cytotoxicity to KB 3-1 cells, which overexpress MDR1. A major advantage of these substituted heteroaryl trisbenzimidazoles as compared to Hoechst 33342 is their efficacy against cell lines expressing MDR1. All publications and patents are incorporated herein by reference, although individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention.
Claims (25)
1. - A compound of the formula: wherein Ar is aryl (C6-C? 2), aryl (C6-C? 2) mono or bis-alkyl (Ci-C4) substituted, aryl (C6-C12) alkyl (C? -C), aryl (C6) -C? 2) alkyl (dC) mono or bis (C? -C) substituted alkyl, heteroaryl (from 5 to 12 members) comprising 1-3 of N, S, or O without peroxide, wherein N is not substituted or substituted with alkyl (d-C4), cycloalkyl (C? -C4), or cycloalkylalkyl (C?? C), said Ar being optionally fused to the benzo moiety; X is CN, CHO, OH, acetyl, CF3, O-alkyl (C? -C4), O-cycloalkyl (C? -C), or O-cycloalkylalkyl (d-C4), NO2, NH2, halogen, halogen- alkyl (C? -C4), halogen-cycloalkyl (C? -C4), or halogen cycloalkylalkyl (C? -C); each Y is individually H, alkyl (C? -C), cycloalkyl (C1-C), cycloalkylalkyl (C? -C4), or aralkyl; Y 'is H, alkyl (d-C4), cycloalkyl (d-C4), or cycloalkylalkyl (C? -C4); each Z is individually H, alkyl (C? -C), cycloalkyl (d-C4), cycloalkylalkyl (C? -C4), halogen or halogen alkyl (C? -C4), halogen cycloalkyl (C? -C), or halogen cycloalkylalkyl (d-C4); n is 1: or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein Ar is in the 5-position.
3. The compound according to claim 1, wherein Ar is 5-6 membered heteroaryl comprising 1-2 N atoms, S or O without peroxide.
4. The compound according to claim 2, wherein Ar is phenyl or pyridyl.
5. The compound according to claim 4, wherein pyridyl is 2-pyridyl, 3-pyridyl, or 4-pyridyl.
6 - The compound according to claim 1, wherein Y 'is H.
7. The compound according to claim 4 or 5, wherein each Y is H.
8. The compound according to claim 4 , where Ar is phenyl.
9. The compound according to claim 8, wherein X is halogen.
10 - The compound according to claim 9, wherein X is Cl.
11. The compound according to claim 10, wherein X-Ar is p-chlorophenyl.
12. The compound according to claim 11, wherein Y 'is H; every Y is H; and each Z is H.
13 - The compound according to claim 1, wherein Ar is benzo.
14. The compound according to claim 13, wherein Ar is 4,5-benzo.
15. The compound according to claim 13, wherein Ar is 5,6-benzo.
16.- A compound of the formula: wherein X is CN, CHO, OH, acetyl, CF3, O-alkyl (C? -C4), O-cycloalkyl (C? -C4), or O-cycloalkylalkium (C? -C4), NO2, NH2, halogen , halogen alkyl (C? -C4), halogen-cycloalkyl (d-C4), or halogen-cycloalkylalkyl (C? -C4); each Y is individually H, alkyl (C? -C), cycloalkyl (C? -C4), cycloalkylalkyl (C? -C), or aralkyl; Y 'is H, alkyl (C? -C), cycloalkyl (C? -C4), or cycloalkylalkyl (C? -C); each Z is individually H, alkyl (C? -C4), cycloalkyl (C? -C4), cycloalkylalkyl (C? -C4), halogen or halogen alkyl (C? -C), halogen cycloalkyl (C? -C4), or halogen cycloalkylalkyl (C? -C); n is 1; or a pharmaceutically acceptable salt.
17. The compound according to claim 16, wherein X is CHO or CN.
18. The compound according to claim 17, wherein Y 'is H.
19. The compound according to claim 16, wherein X is halogen.
The compound according to claim 19, wherein X is Cl.
21 - The compound according to claim 19, wherein X is Br.
22 - The compound according to claim 20 or 21, wherein Y ' it's H; every Y is H; and each Z is H.
23. The compound according to claim 16, wherein Z is H, F, CH3 or CF3.
24. A method for inhibiting the growth of a mammalian tumor cell comprising contacting a tumor cell susceptible thereto, with an effective inhibitory amount of a compound according to claims 1 or 13, and combination with a vehicle pharmaceutically acceptable.
25. A therapeutic composition comprising the compound of claims 1 or 13 in combination with a pharmaceutically acceptable carrier.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/442,657 US5807874A (en) | 1995-05-17 | 1995-05-17 | Trisbenzimidazoles useful as topoisomerase I inhibitors |
US08442657 | 1995-05-17 | ||
US08/618,988 US5767142A (en) | 1996-03-20 | 1996-03-20 | Trisbenzimidazoles useful as topoisomerase I inhibitors |
US08618988 | 1996-03-20 |
Publications (2)
Publication Number | Publication Date |
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MX9708822A MX9708822A (en) | 1998-06-30 |
MXPA97008822A true MXPA97008822A (en) | 1998-10-30 |
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