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Nitro and amino substituted topoisomerase agentsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The Cyclos, The Additional Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Additional Six-membered Hetero Ring As One Of The CyclosNitro and amino substituted topoisomerase agents description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080045538, Nitro and amino substituted topoisomerase agents. Brief Patent Description - Full Patent Description - Patent Application Claims
PRIORITY OF INVENTION [0001] This application claims priority to U.S. Provisional Patent Application No. 60/402,167, filed 9 Aug. 2002. BACKGROUND OF THE INVENTION [0003] DNA-topoisomerases are enzymes which are present in the nuclei of cells where they catalyze the breaking and rejoining of DNA strands, which control the topological state of DNA. Recent studies also suggest that topoisomerases are also involved in regulating template supercoiling during RNA transcription. There are two major classes of mammalian topoisomerases. DNA-topoisomerase-I catalyzes changes in the topological state of duplex DNA by performing transient single-strand breakage-union cycles. In contrast, mammalian topoisomerase II alters the topology of DNA by causing a transient enzyme bridged double-strand break, followed by strand passing and resealing. Mammalian topoisomerase II has been further classified as Type II .alpha. and Type II .beta.. The antitumor activity associated with agents that are topoisomerase poisons is associated with their ability to stabilize the enzyme-DNA cleavable complex. This drug-induced stabilization of the enzyme-DNA cleavable complex effectively converts the enzyme into a cellular poison. [0004] Several antitumor agents in clinical use have potent activity as mammalian topoisomerase II poisons. These include adriamycin, actinomycin D, daunomycin, VP-16, and VM-26 (teniposide or epipodophyllotoxin). In contrast to the number of clinical and experimental drugs which act as topoisomerase II poisons, there are currently only a limited number of agents which have been identified as topoisomerase I poisons. Camptothecin and its structurally-related analogs are among the most extensively studied topoisomerase I poisons. Recently, bi- and terbenzimidazoles (Chen et al., Cancer Res. 1993, 53, 1332-1335; Sun et al., J. Med. Chem. 1995, 38, 3638-3644; Kim et al., J. Med. Chem. 1996, 39, 992-998), certain benzo[c]phenanthridine and protoberberine alkaloids and their synthetic analogs (Makhey et al., Med. Chem. Res. 1995, 5, 1-12; Janin et al., J. Med. Chem. 1975, 18, 708-713; Makhey et al., Bioorg. & Med. Chem. 1996, 4, 781-791), as well as the fungal metabolites, bulgarein (Fujii et al., J. Biol. Chem. 1993, 268, 13160-13165) and saintopin (Yamashita et al., Biochemistry 1991, 30, 5838-5845) and indolocarbazoles (Yamashita et al., Biochemistry 1992, 31, 12069-12075) have been identified as topoisomerase I poisons. Other topoisomerase poisons have been identified including certain benzo[i]phenanthridine and cinnoline compounds (see LaVoie et al., U.S. Pat. No. 6,140,328 and WO 01/32631). Despite these reports there is currently a need for additional agents that are useful for treating cancer. SUMMARY OF THE INVENTION [0005] Applicant has discovered compounds that show inhibitory activity against topoisomerase I and/or topoisomerase II, and compounds that are effective cytotoxic agents against cancer cells, including drug-resistant cancer cells. Accordingly, the invention provides a compound of the invention which is a compound of formula I: wherein: [0006] one of R.sub.1, R.sub.2, R.sub.3, and R.sub.4 is nitro or NR.sub.aR.sub.b; [0007] and the remaining R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each independently hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, NR.sub.aR.sub.b, COOR.sub.c, OR.sub.d; or R.sub.1 and R.sub.2, R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4 taken together are methylenedioxy, 1,2-ethylenedioxy, or 1,3-propylenedioxy; [0008] R.sub.5 is hydrogen, hydroxy, or fluoro; [0009] each R.sub.6, R.sub.7, and R.sub.8 is independently hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, NR.sub.aR.sub.b, COOR.sub.c, OR.sub.d; or R.sub.6 and R.sub.7, or R.sub.7 and R.sub.8 taken together are methylenedioxy, 1,2-ethylenedioxy, or 1,3-propylenedioxy; [0010] R.sub.9 is (C.sub.1-C.sub.6)alkyl substituted with one or more (e.g. 1, 2, 3, or 4) solubilizing groups R.sub.z; [0011] W is N or CH; [0012] X is two hydrogens, .dbd.O, .dbd.S, or .dbd.NR.sub.c; [0013] R.sub.a and R.sub.b are each independently hydrogen or (C.sub.1-C.sub.6)alkyl, or R.sub.a and R.sub.b together with the nitrogen to which they are attached form a pyrrolidino, piperidino or morpholino ring; [0014] each R.sub.c is hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, or aryl(C.sub.1-C.sub.6)alkyl; [0015] each R.sub.d is hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkanoyl, aryl, or aryl(C.sub.1-C.sub.6)alkyl; and [0016] R.sub.e is hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, or aryl(C.sub.1-C.sub.6)alkyl; [0017] or a pharmaceutically acceptable salt thereof. [0018] The invention also provides a pharmaceutical composition comprising a effective amount of a compound of the invention in combination with a pharmaceutically acceptable diluent or carrier. [0019] The invention also provides a method of inhibiting cancer cell growth, comprising administering to a mammal afflicted with cancer, an amount of a compound of the invention, effective to inhibit the growth of said cancer cells. [0020] The invention also provides a method comprising inhibiting cancer cell growth by contacting said cancer cell in vitro or in vivo with an amount of a compound of the invention, effective to inhibit the growth of said cancer cell. [0021] The invention also provides a compound of the invention for use in medical therapy, preferably for use in treating cancer, for example, solid tumors, as well as the use of a compound of the invention for the manufacture of a medicament useful for the treatment of cancer, for example, solid tumors. [0022] The invention also provides processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. Some of the compounds of formula I are useful to prepare other compounds of formula I. BRIEF DESCRIPTION OF THE FIGURES [0023] FIG. 1 shows the structure of compounds 1 and 2. [0024] FIG. 2 shows the structure of representative compounds of formula I (3a-3d and 4a-4d) and the structure of compound 5 [0025] FIG. 3 illustrates the synthesis of representative compounds of formula I (3a-3d and 4a-4d) and compound 5. [0026] FIG. 4 illustrates the synthesis of a representative compound of formula I (12a) and compound (12b) DETAILED DESCRIPTION [0027] The following definitions are used, unless otherwise described. [0028] "(C.sub.1-C.sub.6)alkyl" denotes both straight and branched carbon chains with 1, 2, 3, 4, 5, or 6, carbon atoms, but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to. [0029] "(C.sub.3-C.sub.6)cycloalkyl" denotes a carbocyclic ring with 3, 4, 5, or 6, carbon atoms. [0030] "Aryl" denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Examples of aryl include phenyl, indenyl, and naphthyl. [0031] "Aryl(C.sub.1-C.sub.6)alkyl" refers to a group of the formula aryl-(C.sub.1-C.sub.6)alkyl-, where aryl and (C.sub.1-C.sub.6)alkyl are as defined herein. 1. "Solubilizing group (R.sub.z)" is a substituent that increases the water solubility of the compound of formula I compared to the corresponding compound lacking the R.sup.z substituent (i.e. wherein R.sub.z is hydrogen). Examples of solubilizing groups include (C.sub.1-C.sub.6)alkoxycarbonyl (e.g. --CO.sub.2Me), cyano, halo, hydroxy, mercapto, oxo (.dbd.O), carboxy (COOH), nitro, pyrrolidinyl, piperidinyl, imidazolidinyl, imidazolinyl, piperazinyl, morpholinyl, thiomorpholinyl, and --NR.sub.fR.sub.g, wherein R.sub.f and R.sub.g may be the same or different and are chosen from hydrogen, (C.sub.1-C.sub.6)alkyl, and (C.sub.3-C.sub.6)cycloalkyl. [0032] Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. [0033] A specific value for W is N. [0034] Another specific value for W is CH. [0035] A specific value for R.sub.1 is nitro. [0036] Another specific value for R.sub.1 is NR.sub.aR.sub.b. Continue reading about Nitro and amino substituted topoisomerase agents... Full patent description for Nitro and amino substituted topoisomerase agents Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Nitro and amino substituted topoisomerase agents patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Nitro and amino substituted topoisomerase agents or other areas of interest. ### Previous Patent Application: Fused bicycloheterocycle substituted azabicyclic alkane derivatives Next Patent Application: Chemical compounds Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Nitro and amino substituted topoisomerase agents patent info. 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