Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/04—Ortho- or peri-condensed ring systems
  • C07D221/18—Ring systems of four or more rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention relates to novel bis-l,2-dihydro-3H-dibenzisoqui- noline-l,3-diones and their salts, processes for their prepara ⁇ tion, pharmaceutical compositions containing them and methods of using them to treat malignancies, mainly human solid tumor carci- nomas.
• the present invention relates to bis-l,2-dihydro-3H-dibenzisoqui- noline-l,3-diones of the formula I
• X, X', Y, and Y' are identical or different and are each H, N0 2 , NH , Ci-Ce-alkylamino, di-C ⁇ -C 6 alkylamino, NH-C ⁇ _ 6 -acyl, OH, Ci-H ⁇ -alkoxy, halogen, trihalomethyl, Ci-C ⁇ -alkyl, formyl, Ci-C ⁇ -alkylcarbonyl, ureyl, Ci-C ⁇ -alkylureyl and A is a C 4 -C ⁇ -bridge which is interrupted at one, two or three points by a secondary or tertiary amino group, where two nitrogen atoms may additionally be bonded to one another by a C ⁇ - 4 -alkylene group and the salts thereof with physiologically tolerated acids.
• One class of compounds of the present invention is bis-l,2-di- hydro-3H-dibenzisoquinoline-l,3-diones of the formula I in which at least one of X, X', Y, and Y' are not H, i.e., wherein X, X', Y, and Y' are identical or different and are selected from the group consisting of N0 2 , NH2» NH-lower acyl, Ci-e-alkylamino, di-C ⁇ - 6 -alkylamino, OH, C ⁇ _ 6 -alkoxy, halogen, trihalomethyl,
• Ci-g-alkyl, formyl, Ci-e-alkylcarbonyl, ureyl, and C ⁇ - 6 -alkylureyl It is currently preferred in various embodiments of this class for none of X, X', Y, and Y' to be N0 2 .
• One subclass of the foregoing is bis-l,2-dihydro-3H-dibenzoiso- quinoline-1,3-diones of the formula I wherein at least one of X, Y', Y and Y' is NH 2 , NH-lower acyl, C ⁇ - 6 -alkylamino or di-C ⁇ -6-alkylamino.
• This class includes, among others, compounds of the formula I in which X and Y are H; X' and Y' are NHCOCH 3 ; and -A- is -CH(CH 3 ) -CH 2 -NH-CH 2 -CH 2 -NH-CH 2 -CH(CH 3 ) - or -(CH 2 ) 2 -NH-(CH 2 ) 3 -NH- (CH 2 ) 2 -.
• Another class of compounds of the present invention is bis-l,2-dihydro-3-H-dibenzisoquinoline-l,3-diones of the for ⁇ mula I in which A is
• C n , C n' , and C n - are identical or different and are each C ⁇ - 4 -alkylene radicals and R and R'are H, C ⁇ - 4 -alkyl, benzyl, phenyl, or phenyl substituted by a halogen atom or a C ⁇ - -alkyl group or an amino group.
• R and R' are as previously defined. These compounds in- elude those in which X and X' and R and R' are all H.
• Hal means a halogen atom, preferably bromine; 3. - if A is interrupted by two nitrogen atoms - by reacting a compound of the formula IV with a diamine of the formula V:
• B plus D are alkylene residues so that 2 B plus D contain 4 to 12 carbon atoms.
• Reaction 1 is performed by reacting the compound II with a half equivalent of a polyamine of the formula III in an organic sol ⁇ vent such as alcohols (especially ethanol) , acetone, DMSO, THF, DMF, dioxane, aromatic hydrocarbons (especially toluene) , or any inert solven .
• an organic sol ⁇ vent such as alcohols (especially ethanol) , acetone, DMSO, THF, DMF, dioxane, aromatic hydrocarbons (especially toluene) , or any inert solven .
• the temperature of the reaction should be between -20°C and the boiling temperature of the solvent. Fairly high tem- peratures are preferred.
• Reactions 2 and 3 are performed under the same conditions, but in the presence of a base.
• the final product is filtered off or the reaction mixture is evaporated to dryness under reduced pressure and the residue is purified in conventional manner by crystallization or chromato- graphy.
• the starting compounds II-VI can be prepared by methods known from the literature, or they are commercial products.
• the bis-l,2-dihydro-3H-dibenzoisoquinoline-l,3-diones so obtained are used per se, or they can be acidified with the appropriate mineral or organic acid to produce a pharmaceutically acceptable salt, e.g. the methanesulfonate or the acetate salt, which can be recovered by filtration.
• Salts of the free base can also be pre ⁇ pared by acidifying a suspension of the free base in ethyl alco ⁇ hol, dichloromethane, ether, etc. with the appropriate mineral or organic acid and collecting by filtration the solid thus formed.
• Other acids for salt formation are known from the art, see e.g., Braia et al., U.S. Patent 4,874,883.
• the present invention further encompasses pharmaceutical composi- 5 tions containing a tumor-inhibiting compound according to the in ⁇ vention together with a pharmaceutically acceptable carrier. It also relates to methods for treating tumors in mammals comprising administration of a tumor-inhibiting amount of a compound accord ⁇ ing to the invention to a mammal with such a tumor.
• the compounds 0 according to the invention may be formulated into pharmaceutical compositions and administered to patients using conventional materials and methods such as are described in Brafia et al., US 4,874,883 and US 5,206,249 (the contents of both of which are hereby incorporated herein by reference) . See especially
• the compounds according to the invention have cytotoxic activity useful in the treatment of various cancers. These compounds can be evaluated for relative efficacy in in vitro and in vivo models
• the new compounds exhibit better properties than prior art compounds with regard to activity, toxicity and/or solubility.
• Cytotoxicity may be measured using standard methodology for ad ⁇ herent cell lines such as the microculture tetrazolium assay (MTT) . Details of this assay have been published Cancer Research
• the MTT dye is added (50 ⁇ l of 3 mg/ l solution of 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline). This mixture is incubated at 37°C for 5 hours, and then
• the concentration of test compound which gives a T/C of 50% growth inhibition is designated as the IC 50 .
• Compounds according to the invention may be further tested in any of the various preclinical assays for in vivo activity which are indicative of clinical utility.
• Such assays may be conducted with nude mice into which tumor tissue, preferably of human origin, has been transplanted ("xenografted") , as is well known in this field.
• Test compounds are evaluated for their antitumor efficacy following administration to the xenograft-bearing mice.
• mice which have been grown in athymic nude mice are transplanted into new recipient animals, using tu ⁇ mor fragments which are about 50 mg in size.
• the day of trans- plantation is designated as day 0.
• mice are injected intravenously or intraperitoneally with the test compounds, in groups of 5-10 mice per dose.
• the compounds are ad ⁇ ministered daily for 5 days, 10 days or 15 days, at doses from 10-100 mg/kg body weight.
• Tumor volumes are calculated using the diameters measured twice weekly. Tumor volumes whose diameters are measured with Vernier calipers are calculated by the formula:
• Mean tumor volumes are calculated for each treatment group, and T/C values determined for each group relative to the untreated control tumors.
• the data may be evaluated as follows. A T/C value of 1.0 or greater indicates that the compound had no effect on tumor growth, while values ⁇ 1.0 indicate some reduction in tumor mass. Values of 0.15-0.49 may be considered to reflect moderate activity, ⁇ 0.01-0.14 good to excellent activity. Outstanding ac ⁇ tivity indicates a compound which provides complete regression of tumor material (no visible tumor mass following therapy) . Compounds yielding T/C values > 0.50 are considered inactive.
• the invention can be further understood by referring to the fol ⁇ lowing examples, in which parts and percentages are by weight un ⁇ less otherwise specified.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Other In-Based Heterocyclic Compounds (AREA)

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Citations (5)

• 1995
  • 1995-04-12 JP JP7527954A patent/JPH09512539A/ja not_active Ceased
  • 1995-04-12 SG SG1996008471A patent/SG73418A1/en unknown
  • 1995-04-12 AU AU23065/95A patent/AU2306595A/en not_active Abandoned
  • 1995-04-12 WO PCT/EP1995/001347 patent/WO1995029895A1/en not_active Ceased
  • 1995-04-12 CA CA002188833A patent/CA2188833A1/en not_active Abandoned
  • 1995-04-12 CN CN95193192A patent/CN1092185C/zh not_active Expired - Fee Related
  • 1995-04-12 EP EP95916636A patent/EP0757676A1/en not_active Withdrawn
  • 1995-04-18 TW TW084103805A patent/TW307764B/zh active
  • 1995-04-18 IL IL11341595A patent/IL113415A/xx not_active IP Right Cessation
  • 1995-04-25 HR HR08/233,998A patent/HRP950250A2/hr not_active Application Discontinuation
  • 1995-04-26 ZA ZA953379A patent/ZA953379B/xx unknown

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