EP0757676A1 - Dihydrodibenzo(de,h)isoquinolines derivatives and their use as anti-cancer agents - Google Patents

Dihydrodibenzo(de,h)isoquinolines derivatives and their use as anti-cancer agents

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Publication number
EP0757676A1
EP0757676A1 EP95916636A EP95916636A EP0757676A1 EP 0757676 A1 EP0757676 A1 EP 0757676A1 EP 95916636 A EP95916636 A EP 95916636A EP 95916636 A EP95916636 A EP 95916636A EP 0757676 A1 EP0757676 A1 EP 0757676A1
Authority
EP
European Patent Office
Prior art keywords
dihydro
bis
compound
formula
dibenz
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95916636A
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German (de)
French (fr)
Inventor
Miguel Fernandez Brana
Jose Maria Castellano Berlanga
Cynthia Romerdahl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
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Publication of EP0757676A1 publication Critical patent/EP0757676A1/en
Withdrawn legal-status Critical Current

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    • 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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  • Organic Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

Novel bis-1,2-dihydro-3H-dibenzisoquinoline-1,3-diones of formula (I), wherein X, X', Y and Y' are identical or different and are each H, NO2, NH2, C1-C6-alkylamino, di-C1-C6 alkylamino, NH-C1-C6-acyl, OH, C1-H6-alkoxy, halogen trihalomethyl, C1-C6-alkyl, formyl, C1-C6-alkylcarbonyl, ureyl, C1-C6-alkylureyl and A is a C4-C12-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 C1-C4-alkylene group or a salt thereof with a physiologically tolerated acid. Processes for their preparation, pharmaceutical compositions containing them and methods of using them to treat malignancies, mainly human solid tumor carcinomas.

Description

Dihydrodibenzo(de.h) isoquinolines derivatives and their use as anti-cancer agents
Description
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 use of bis-naphthalimides for the treatment of tumor carcino¬ mas is already known (see e.g. US 4,874,883, US 5,986,059 and DE 4,232,739). Further, dibenzisoquinolines have been described (EP 536,208) which have anti-cancer activity.
The present invention relates to bis-l,2-dihydro-3H-dibenzisoqui- noline-l,3-diones of the formula I
wherein X, X', Y, and Y' are identical or different and are each H, N02, NH , Ci-Ce-alkylamino, di-Cι-C6 alkylamino, NH-Cι_6-acyl, OH, Ci-Hε-alkoxy, halogen, trihalomethyl, Ci-Cε-alkyl, formyl, Ci-Cδ-alkylcarbonyl, ureyl, Ci-Cε-alkylureyl and A is a C4-Cι -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 Cι-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 N02, NH2» NH-lower acyl, Ci-e-alkylamino, di-Cι-6-alkylamino, OH, Cι_6-alkoxy, halogen, trihalomethyl,
Ci-g-alkyl, formyl, Ci-e-alkylcarbonyl, ureyl, and Cι-6-alkylureyl, It is currently preferred in various embodiments of this class for none of X, X', Y, and Y' to be N02.
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 NH2, NH-lower acyl, Cι-6-alkylamino or di-Cι-6-alkylamino. This class includes, among others, compounds of the formula I in which X and Y are H; X' and Y' are NHCOCH3; and -A- is -CH(CH3) -CH2-NH-CH2-CH2-NH-CH2-CH(CH3) - or -(CH2)2-NH-(CH2)3-NH- (CH2)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
Cn- R-Cn- or Cn-NR-Cn'- R'-Cn-
wherein Cn, Cn', and Cn- are identical or different and are each Cι-4-alkylene radicals and R and R'are H, Cι-4-alkyl, benzyl, phenyl, or phenyl substituted by a halogen atom or a Cι- -alkyl group or an amino group.
One subclass of such compounds is bis-l,2-dihydro-3H-dibenzo- isoquinoline-l,3-diones of the formula I wherein the bridging moiety A joining the two ring systems is:
-CH2-CH2---NR-CH2--CH2-NR'-CH2-CH2 or
-CH2-CH2-NR-CH2-CH2-CH2-NR'-CH2-CH2
wherein R and R' are as previously defined. These compounds in- elude those in which X and X' and R and R' are all H.
Compounds I of the present invention can be synthesized according to the following methods:
1. by reacting an anthracene-1,9-dicarboxylic anhydride of the formula II with a polyamine of the formula III:
Instead of the acid anhydride the corresponding dicarboxylic acid or dicarboxylic acid halide may be used;
2. by reacting an anthracene-1,9-dicarboxylic amide VI with a compound of the formula VII:
wherein 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:
IV
wherein 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 . 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
15 US 5,206,249 at column 22, line 10 through the end of column 23.
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
20 such as are generally accepted in this art, including those de¬ scribed in US 5,206,249 (see especially column 19 to column 22, line 9) . Efficacy in such models is indicative of utility in the treatment of solid tumors in human patients and evidences impor¬ tant therapeutic utility in the treatment of cancer, particularly
25 solid tumor carcinomas, such as colon carcinoma, breast tumors, prostate cancer, and non-small lung carcinoma. The new compounds exhibit better properties than prior art compounds with regard to activity, toxicity and/or solubility.
30 A. In vitro methodology
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
35 48:589-601, 1988). Exponentially growing cultures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor are used to make microtiter plate cultures. Cells are seeded at 5000-20,000 cells per well in 96-well plates (in 150 μl of media), and grown overnight at 37°C. Test compounds are added, in 10-fold
40 dilutions varying from 10-4 M to 19-10 M. The cells are then incu¬ bated for 48-72 hours. To determine the number of viable cells in each well, the MTT dye is added (50 μl 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
45 50 μl of 25% strength SDS (pH 2) is added to each well. After overnight incubation, the absorbance of each well at 550 nm is read using an ELISA reader. The values for the mean +/- SD of data from quadruplicate wells are calculated, using the formula % T/C (% cells treated/control) .
OP of treated cal l a x IQO = % T/C OD of control cells
The concentration of test compound which gives a T/C of 50% growth inhibition is designated as the IC50.
B. In vivo methodology
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.
More specifically, human tumors 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. Six to ten days later, 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:
(length x width2) /2 = mm3 (tumor volume).
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.
Example 1
N,N'-Bis[2- (1,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- line-2-yl)ethyl] -1,3-propanediamine
A mixture of 1.6 g (6 mmol) of anthracene-1,9-dicarboxylic anhydride in 40 ml of toluene was treated with 0.5 g (3 mmol) of N,N'-bis (2-aminoethyl) -1,3-propanediamine dissolved in 10 ml of toluene. The mixture was refluxed for 4 h and then filtered. The solution was allowed to cool and the solid formed was filtered, washed, dried and recrystallized from toluene. 0.93 g (50%) of N,N,-bis[2-(l,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1,3-propanediamine were obtained. M.p. 191°C (tol¬ uene). iH-NMR (CDC13) δ = 1.84 (q, 2H, J = 6 Hz, -CH2-); 2.74 (broad,s, 2H, NH) ; 2.89 (t, 4H, J = 6 Hz, CH2) ; 3.02 (t, 4H, J = 6Hz, CH2); 4.31 (t,4H, J = 6 Hz, CH2) ; 7.54 (m, 4H, H-5 and H-9); 7.73 (m, 2H,H-10); 7.89 (d, 2H, J = 8 Hz, H-8) ; 8.22 (d, 1H, J = 8 Hz, H-4); 8.51 (S,2H, H-7) ; 8.57 (d, 2H, J = 8 Hz, H-6) ; 9.78 (d,2H, J = 8 Hz, H-ll) p.p.m.. Anal. Calculated for C3gH32 40 : C 75.46; H 5.19; N 9.02. Found: C 75.14; H 5.37; N 8.78. Acetate m.p. 155°C. Methanesulfonate m.p. 243°C.
Example 2
N,N'-Bis [2- (1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1,2-ethylenediamine.
As example 1. Yield 66%. M.p. 203°C (DMF-H20)
Example 3
N,N'-Bis[3- (1,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)propyl] -1,4-but nediamine. As example 1. Yield 46%. M.p. 183°C (toluene).
Example 4
[3- (l,2-dihydro-l,3-dioxo-3,4-dibenz[de,h]isoquino- lin-2-yl)propyl] [4- (1,2-dihydro-1,3-dioxo-3,4-dibenz[de,h]isoqui- nolin-2-yl) utyl]amine. As example 1. Yield 41%. M.p. 244°C (DMF) . Example 5
N,N'-Bis [2-1,2-dihydro-1,3-dioxo-3H-dibenz[de,h] isoquino- lin-2-yl)ethyl]-1,4-butanediamine. As example 1. Yield 40%. M.p. 179°C (toluene).
Example 6
Bis[3- (1,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)propyl]methylamine.
As example 1. Yield 35%. M.p. 194°C (toluene).
Example 7
Bis [3- (1,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)propyl]amine. As example 1. Yield 83%. M.p. 184°C (toluene).
Example 8
[2- d,2-Dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl] [3- (l,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)propyl]amine.
As example 1. Yield 78%. M.p. 260°C (DMF) .
Example 9
Bis[2- (l,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl)amine. As example 1. Yield 53%. M.p. 271°C (DMF-H 0) .
Example 10
N,N'-Bis[3-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)propyl]-1,2-ethylenediamine.
As example 1. Yield 61%. M.p. 180°C (toluene).
Example 11
N,N'-Bis[3- (1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)propyl] -1,3-propanediamine. As example 1. Yield 41%. M.p. 140°C (toluene). Example 12
N,N'-Bis [l,2-dihydro-8-nitro-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]1,3-propanediamine. As example 1. Yield 52%. M.p. >340°C (toluene)
Example 13
N,N'-Bis-[2-(l,2-dihydro-8-nitro-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]1,3-ethylenediamine.
As example 1. Yield 57%. M.p. >340°C (toluene)
Example 14
N,N'-Bis[2- (l,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-N,N'-dimethyl-1,2-ethylenediamine.
As example 1. Yield 77%. M.p. 255°C (toluene).
Example 15
N,N'-Bis[2- (1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1,5-pentanediamine.
As example 1. Yield 25%. M.p. 122°C (toluene).
Example 16
N,N'-Bis[2- (1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-y1)ethyl]hexahydropirimidine.
A mixture of 0.5 g (0.8 mmol) of N,N'-Bis[2- (1,2-di- hydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-pro- panediamine and 1 ml of 36% formaldehyde in 100 ml of ethanol was refluxed for 7 hours. The solid was filtered, washed, dried, and recrystallized from toluene. 0.3 g (58%) of N,N'-bis[2- (1,2-di- hy ro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]hexahydro¬ pirimidine were obtained. M.p. 222°C (toluene) . Example 17
N,N'-Bis [2- (1,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl] -1,3-propanediamine
A mixture of 1.47 g (5 mmol) of anthracene-1, 9-dicarboxylic acid dimethyl ester in 50 ml of toluene is treated with 0.4 g (2.5 mmol) of N,N'-bis (2-aminoethyl) -1,3-propanediamine in 20 ml of toluene. The suspension is refluxed for 24 hours and then cooled to room temperature. The solid is filtered, dried, and crystallized from toluene to give 0.65 g (42%) of N,N'- bis[2- (1,2-dihydro-1,3-dioxo-3H-dibenz[de,h] -isoquino- lin-2-yl)ethyl]-l,3-propanediamine. M.p. 191°C.
Example 18
N,N'-Bis[2- (l,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1,3-propanediamine
0.4 g (2.5 mmol) of N,N'-bis (2-aminoethyl) -1,3-propanediamine in 20 ml of toluene are added to a mixture of 1.51 g (5 mmol) of an- thracene-1,9-dicarboxylic acid dichloride in 50 ml of toluene. The suspension is refluxed for 20 hours and then cooled to room temperature. The solid is filtered, dried and crystallized from toluene to give 0.54 g (35%) of N,N'-bis[2- (1,2-di- hydro-1,3-dioxo-3H-di-benz[de,h] isoquinolin-2-yl)ethyl]-1,3-pro- panediamine. M.p. 191°C.
Example 19
N,N'-Bis[2- (1,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- 1in-2-y1)ethyl]-1,3-propanediamine
A. 2- (2-Hydroxyethyl) -1,2-dihydro-3H-dibenz[de,h]isoquino- line-l,3-dione
A mixture of 1.51 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride and 0.4 g (6.5 mmol) of ethanolamine in 50 ml of toluene is refluxed for 5 hours and then cooled to room temperature. The solid is filtered, dried and crystallized from toluene to give 1.5 g (85%) of 2- (2-hydroxy- ethyl) -l,2-dihydro-3H-dibenz[de,h] isoquinoline-l,3-dione. M.p. 211°C. B. 2- [2- (p-Toluenesulfonyloxy)ethyl]-1,2-dihydro-3H-di- benz[de,h]isoquinoline-1,3-dione
A mixture of 1.01 g (3.5 mmol) of 2- (2-hydroxyethyl)-1,2-di- hydro-3H-dibenz[de,h] isoquinoline-1,3-dione in 10 ml of pyridine is treated with 0.69 g (3.6 mmol) of p-toluenesulfo- nyl chloride. The mixture is stirred at room temperature for 24 hours and poured into 50 ml of cold water. The solid is collected, washed with water, dried in vacuo, and crystalli- zed from dimethylformamide water to give 1.2 g (77%) of 2- [2- (p-toluenesulfonyloxy)ethyl]1,2-dihydro-3H-di- benz [de,h] isoquinoline-1,3-dione. M.p. 240°C.
C. N,N'-Bis[2- (1,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1,3-propanediamine
A mixture of 2.2 g (5 mmol) of 2-[2- (p-toluenesulfony- loxy)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquino- line-l,3-dione, 0.4 g (2.5 mmol) of 1,3-propanediamine in 200 ml of acetonitrile is refluxed in the presence of 0.6 g (5.6 mmol) of sodium carbonate for 24 hours. The reaction mixture is concentrated in vacuo. The residue is treated with water (100 ml) and extracted with dichloromethane. The organic layers are combined, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromato- graphed, eluting with dichloromethane, methanol, acetic acid (80:15:5). The appropriate fractions are combined, concentra¬ ted in vacuo and crystallized from toluene to give 0.3 g (20%) of N,N'-bis[2-(l,2-dihydro-l,3-dioxo-3H-di- benz[de,h] isoquinolin-2-yl)ethyl]-1,3-propanediamine. M.p. 191°C.
Example 20
N,N'-Bis[2-(l,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1,3-propanediamine
A. l,2-Dihydro-3H-dibenz[de,h]isoquinoline-l,3-dione
1.51 g (6 mmol) of anthracene-1, 9-dicarboxylic acid anhydride was treated with 10 ml of ammonium hydroxide (28 %) . After refluxing for 16 hours the solid was collected, washed with water, dried in vacuo, and crystallized from dimethylformami- de-water to give 1.3 g (86%) of l,2-dihydro-3H-di- benz[de,h]isoquinoline-l,3-dione. M.p. 310°C. B. N,N'-Bis [2- (1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1, 3-propanediamine
A mixture of 1.23 g (5 mmol) of l,2-dihydro-3H-di- benz[de,h] isoquinoline-1,3-dione in 100 ml of ethanol is treated with 280 mg (5 mmol) of potassium hydroxide in 50 ml of ethanol. After refluxing for 3 hours, 0.65 g (2.5 mmol) of N,N'-bis (2-bromoethyl) -1,3-propanediamine in 50 ml of ethanol are added and the whole is refluxed for 24 hours. The reaction mixture is concentrated in vacuo. The residue is treated with water (100 ml) and extracted with dichloro¬ methane. The organic layers are combined, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue is c romatographed, eluting with dichloromethane, me- thanol, acetic acid (0:15:5). The appropriate fractions are combined, concentrated in vacuo and crystallized from toluene to give 0.31 g (20%) of N,N'-bis[2- (1,2-dihydro-l,3-di- oxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl] -1,3-propanedia¬ mine. M.p. 191°C.
Example 21
N,N'-Bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1,3-propanediamine
A. N- [2- (1,2-Dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- 1in-2-y1)ethyl]-N'- (2-aminoethy1)-1,3-propanediamine
A solution of 5.0 g (31 mmol) of N,N'-bis (2-amino- ethyl) -1,3-propanediamine in 200 ml of ethanol 99% is treated with 1,5 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride in 100 ml of ethanol and stirred for 24 hours at room temperature. The solid is collected on a filter, washed with ethanol and crystallized from ethanol to give 0.5 g
(20%) of N-[2- (l,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-N'- (2-aminoethy1)-1,3-propanediamine. M.p. 150°C.
B. N,N'-Bis[2-(l,2-dihydro-l,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-1,3-propanediamine
A mixture of 1.0 g (2,5 mmol) of N-[2- (1,2-dihydro-1,3-di- oxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-N'- (2-amino- ethyl) -1,3-propanediamine in 50 ml of toluene was treated with 0.62 g (2,5 mmol) of anthracene-1,9-dicarboxylic acid anhyride in 10 ml of toluene, refluxed for 6 hours, and coo- led to room temperature. The solid was collected, dried in vacuo, and crystallized from toluene to give 0.8 g 48% of N,N'-Bis [2- (1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquino- lin-2-yl)ethyl]-l,3-propanediamine. M.p. 191°C.

Claims

Claims
1. A compound of the formula
wherein X, X', Y, and Y' are identical or different and are each H, N02, NH2, Ci-Cδ-alkylamino, di-Ci-Cε alkylamino, NH-Cι_6-acyl, OH, Cι-H6-alkoxy, halogen, trihalomethyl, Ci-Cε-alkyl, formyl, Ci-Cε-alkylcarbonyl, ureyl, Ci-Cε-alkyl- ureyl and A is a C -Cι -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 Cι- -alkylene group or a salt thereof with a physiologically tolerated acids.
2. A bis-1,2-dihydro-3H-dibenzisoquinoline-l,3-dione as claimed in claim 1 where X, X', Y and Y' are hydrogen.
3. A bis-1,2-dihydro-3H-dibenzisoquinoline-l,3-dione as claimed in claim 1 as a salt of acetic or methanesulfonic acid.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as claimed in claim 1.
A method of treating tumors in humans comprising administer¬ ing to the patient with such tumor a tumor-inhibiting amount of a compound as claimed in claim 1.
6. The method of preparing a compound of the formula I according to claim 1, where
an anthracene-1,9-dicarboxylic acid anhydride of the for¬ mula I
or the corresponding free acid or acid halide, is reacted with a compound of the formula II
H2N-A-NH2 II or
an anthracene-1, 9-dicarboxylic amide VI
is reacted with a compound of the formula VII
Hal-A-Hal VII,
wherein Hal is a halogen atom or
- if A is interrupted by two nitrogen atoms - a compound of the formula IV
is reacted with a diamine of the formula V
H2N-D-NH2 V, wherein B plus D are alkylene radicals so that 2 B plus D contain 4 to 12 carbon atoms.
EP95916636A 1994-04-28 1995-04-12 Dihydrodibenzo(de,h)isoquinolines derivatives and their use as anti-cancer agents Withdrawn EP0757676A1 (en)

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