CN1092185C - Dihydodibenzo isoquinolines diketone - Google Patents
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Abstract
本发明涉及新的二-1，2-二氢-3H-二苯并异喹啉-1，3-二酮及其盐、它们的制备方法、包含它们的药物组合物以及它们用于治疗恶性肿瘤，主要是人类实体肿瘤癌的方法。The present invention relates to novel di-1,2-dihydro-3H-dibenzisoquinoline-1,3-diones and their salts, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of malignant Oncology, primarily human solid tumor carcinomas.
Description
The present invention relates to new two-1,2-dihydro-3H-dibenzo isoquinoline 99.9-1,3-diketone and salt thereof, their preparation method comprises their pharmaceutical composition, and they are used for the treatment of malignant tumour, mainly are the methods of human entity tumour cancer.
It is known (referring to United States Patent (USP) 4,874,883,5,986,059 and German Patent 4,232,739) that the inferior acid amides of two-naphthalene is used for the treatment of the tumour cancer.Further, the dibenzo isoquinoline 99.9 (European patent EP 536,208) with antitumour activity is disclosed.
The present invention relates to two-1 of formula I, 2-dihydro-3H-dibenzo isoquinoline 99.9-1, the 3-diketone:
Wherein
X, X ', Y and Y ' are identical or different, and respectively do for oneself H, NO
2, NH
2, C
1-6Alkylamino, two-C
1-6Alkylamino NH-C
1-6-acyl group, OH, C
1-6-alkoxyl group, halogen, trihalomethyl group, C
1-6-alkyl, formyl radical, C
1-6-alkyl-carbonyl, urea groups, C
1-6-alkyl urea groups; And
A is the C that can be interrupted by the second month in a season or uncle's amino group, two or three positions
4-12-bridge, wherein two nitrogen-atoms also can pass through C
1-4Alkylidene group interconnects; And can accept the salt that acid forms with pharmacology.
A compounds of the present invention is two-1 of formula I, 2-dihydro-3H-dibenzo isoquinoline 99.9-1, and the 3-diketone, wherein at least one among X, X ', Y and the Y ' is not H, that is to say, X, X ', Y and Y ' can be identical or different, and are selected from NO separately
2, NH
2, NH-lower acyl, C
1-6Alkylamino, two-C
1-6-alkylamino, OH, C
1-6-alkoxyl group, halogen, trihalomethyl group, C
1-6-alkyl, formyl radical, C
1-6-alkyl-carbonyl, urea groups and C
1-6-alkyl urea groups.
In the example of this compounds, at present preferred X, X ', Y and Y ' all are not NO
2
One of an above-mentioned compounds is categorized as two-1 of formula I, 2-dihydro-3H-dibenzo isoquinoline 99.9-1, and the 3-diketone, wherein at least one among X, X ', Y and the Y ' is NH
2, NH-lower acyl, C
1-6Alkylamino or two-C
1-6-alkylamino.They comprise formula I compound, and wherein X and Y are H; X ' and Y ' are NHCOCH
3And-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 kind of compound of the present invention is two-1 of formula I, 2-dihydro-3H-dibenzo isoquinoline 99.9-1, and the 3-diketone, wherein A is
C
n-NR-C
N 'Or C
n-NR-C
N "-NR '-C
N 'C wherein
n, C
N 'And C
N "Can be identical or different, and the C that respectively does for oneself
1-4Alkylidene group, and R and R ' are H, C
1-4Alkyl, benzyl, phenyl, by halogen atom or C
1-4Alkyl or the amino phenyl that replaces.
One of this compounds is categorized as two-1 of formula I, 2-dihydro-3H-dibenzo isoquinoline 99.9-1, and the 3-diketone, the bridging part A that wherein connects two ring systems is:
-CH
2-CH
2-NR-CH
2-CH
2-NR '-CH
2-CH
2-or
-CH
2-CH
2-NR-CH
2-CH
2-CH
2-NR '-CH
2-CH
2-wherein R and R ' define as mentioned.These compounds comprise that wherein X and X ' and R and R ' are the compound of H.
Formula I compound of the present invention can prepare according to following method: 1) with the anthracene-1 of formula II, the polyamines of 9-dicarboxylic acid anhydride and formula III reacts:
Can use corresponding dicarboxylic acid or dicarboxylic acid halide to substitute acid anhydrides; 2) with the anthracene-1 of formula VI, the compound of 9-dicarboxamide and formula VII reacts:
Wherein Hal represents halogen atom, preferred bromine; When 3) being inserted with two nitrogen-atoms in the middle of the A, with the diamine reactant of formula IV compound and formula V:
Wherein to add D be alkylidene residue to B, makes 2B add D and comprise 4 to 12 carbon atoms.
Reaction 1 be organic solvent as alcohol (particularly ethanol), acetone, DMSO, THF, DMF, diox, aromatic hydrocarbon (particularly toluene) or any inert solvent in, a formula II compound and a seminormal formula III polyamines are reacted.Temperature of reaction should-20 ℃ between the solvent boiling temperature, preferably under comparatively high temps, carry out.
Reaction 2 and 3 is carried out under the same conditions, just carries out in the presence of alkali.
Leach final product, perhaps the vapourisation under reduced pressure reaction mixture is to doing, by the ordinary method purifying residue of crystallization or chromatogram purification.
Initial compounds II-VI can or use commercial product by known method preparation in the document.
Thus obtained two-1,2-dihydro-3H-dibenzo isoquinoline 99.9-1, the 3-diketone can directly use, and perhaps forms the acceptable salt of medicine with suitable inorganic or organic acid, and as mesylate or acetate, these salt can pass through filtered and recycled.The salt of free alkali can also be by utilizing suitable inorganic or organic acid acidifying free alkali the suspension of ethanol, methylene dichloride, ether etc. make, and by filtering the solid of collecting gained.Salifiable other acid can learn from prior art, for example referring to people's such as Brafia United States Patent (USP) 4,874,883.
The present invention further comprises and contains the pharmaceutical composition that the present invention suppresses tumour compound and drug acceptable carrier; Also relate to the method that is used for the treatment of mammal tumor, this method comprises to the Mammals that suffers from tumour takes the The compounds of this invention that suppresses tumor dose.The compounds of this invention can be made into pharmaceutical composition, and by using the United States Patent (USP) 4,874,883 and 5,206 as people such as Brafia, conventional material and the method described in 249 (content of these two pieces of documents is hereby incorporated by reference) are taken to the patient.It is last to walk to the 23rd hurdle referring to the 22nd hurdle the 10th in the United States Patent (USP) 5,206249 especially.
Compound of the present invention has the Cytotoxic activity that helps treating various cancers.The relative effectivenes of these compounds can be measured by the external and body inner model that this area is accepted usually, and these models comprise United States Patent (USP) 5,206, the model of describing in 249 (especially referring to 22 hurdles, the 19th hurdle to the).Effectiveness in these models shows the practicality of The compounds of this invention in treatment human patients noumenal tumour, and show in the importance for the treatment of in cancer, particularly noumenal tumour cancer such as colorectal carcinoma, mammary cancer, prostate cancer and non-small-scale (non-small) lung cancer.New compound exhibits go out active, toxicity and/solvability on than compound better properties of the prior art.A. in vitro method
Use the ordinary method such as the trace cultivation tetrazolium mensuration (MTT) of bonding clone can measure cytotoxicity, the detailed description of this mensuration is disclosed among the Cancer Research 48:589-601 (1988).The exponential growth culture of tumour cell such as HT-29 colorectal carcinoma or LX-1 lung cancer is used to make little plate culture of tiring.Under 37 ℃, with cell cultures in (in the medium of 150 μ l) in the 96-orifice plate, every hole 5,000-20,000 cell, cell grow overnight.With 10
-4M to 10
-1010 times of dilutions of M add test compounds.Culturing cell 48-72 hour then.In order to determine to change in each hole the quantity of cell, add MTT dyestuff (50 μ l 3mg/ml 3-(4,5-dimethylthiazole-2-yl)-2, the salt brine solution of 5-phenylbenzene tetrazolium bromide).Mixture was cultivated 5 hours down at 37 ℃, added the SDS (pH2) of 50 μ l, 25% concentration then in each hole.After cultivating a night, utilize the ELISA reader to read the specific absorption of each hole at the 50nm place.Utilize formula %T/C (the percentage ratio % of treatment/reference cell), can calculate four holes average+/-the SD data value.
(being treated the OD of cell)/(OD of reference cell) * 100=%T/C
The concentration of test compounds is defined as IC during with the growth inhibiting T/C that provides 50%
50B. method in the body
In any activity in vivo mensuration in latent period, all can further test The compounds of this invention, described activity in vivo can show clinical practice.According to technology well known in the art, this mensuration can be carried out in the tumor tissues (preferably originating from the mankind) of (" different transplanting " (xenografted)) bare mouse of transplanting.After the mouse of different transplanting fertility is taken test compounds, measure the antitumor effectiveness of this compound.
More particularly, use 50mg size tumor segment, the people's that will grow in bare mouse tumour transplatation is in new receptor.Be appointed as the 0th day that day of transplanting, after six to ten days, give mouse with test compounds intravenously or peritoneal injection, giving 5-10 mouse with every dosage is one group.Take this compound every day, took altogether 5 days, 10 days or 15 days, medication dose is every kg body weight 10-100mg.Pass through to measure diameter weekly for twice and calculate tumor size.Gross tumor volume with Verier kind of calliper diameter can calculate by following formula:
(long * wide
2)/2=mm
3(gross tumor volume).
Calculate the mean tumour volume of each treatment group, measure every group of T/C value with respect to untreated reference tumour.Data can followingly be estimated: the T/C value shows then that more than or equal to 1.0 this compound is to not effect of tumor growth; And the T/C value is less than 1.0 o'clock, and then dose,tumor reduces; The T/C value is 0.15-0.49, then shows active medium; The T/C value then shows active good less than 0.01-0.14; Outstanding activity shows that this compound can make tumour restore (cannot see tumour after the treatment) fully; The T/C value is considered to there is not activity greater than 0.50 compound.
Can further understand the present invention by following embodiment; Except as otherwise noted, umber described in the embodiment and per-cent are all by weight.
Embodiment 1N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine
With the 0.5g N that is dissolved in the 10ml toluene, N '-two (2-amino-ethyl)-1, the 3-propylene diamine is handled 1.6g (6mmol) anthracene-1, the mixture of 9-dicarboxylic acid anhydride and 40ml toluene.Mixture was refluxed 4 hours, filter then.Cooling solution filters the solid obtain, and washing is dry and by the toluene recrystallization, obtains 0.93g (95%) N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine, M.p.191 ℃ (toluene).
1H-NMR (CDCl
3) δ=1.84 (q, 2H, J=6Hz ,-CH
2-); 2.74 (broad peak, s, 2H, NH); 2.89 (t, 4H, J=6Hz, CH
2); 3.02 (t, 4H, J=6Hz, CH
2); 4.31 (t, 4H, J=6Hz, CH
2); (7.54 m, 4H, H-5 and H-9); 7.73 (m, 2H, H-10); 7.89 (d, 2H, J=8Hz, H-8); 8.22 (d, 1H, J=8Hz, H-4); 8.51 (s, 2H, H-7); 8.57 (d, 2H, J=8Hz, H-6); 9.78 (d, 2H, J=8Hz, H-11) p.p.m..C
39H
32N
4O
4The ultimate analysis calculated value: C75.46; H5.19; N9.02. measured value: C75.14; H5.37; N8.78. acetate m.p.155 ℃. mesylate m.p.243 ℃.
Embodiment 2N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1
As embodiment 1.Productive rate 66%, M.p.203 ℃ of (DMF-H
2O).
Embodiment 3N, N '-two [3-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) propyl group]-1,4-butanediamine
As embodiment 1.Productive rate 46%, M.p.183 ℃ (toluene).
Embodiment 4[3-(1,2-dihydro-1,3-dioxo-3,4-dibenzo [de, h] isoquinoline 99.9-2-yl) propyl group] [4-(1,2-dihydro-1,3-dioxo-3,4-dibenzo [de, h] isoquinoline 99.9-2-yl) butyl] amine
As embodiment 1.Productive rate 41%, M.p.244 ℃ (DMF).
Embodiment 5N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,4-butanediamine
As embodiment 1.Productive rate 40%, M.p.179 ℃ (toluene).
Embodiment 6 two [3-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) propyl group] methylamine
As embodiment 1.Productive rate 35%, M.p.194 ℃ (toluene).
Embodiment 7 two [3-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) propyl group] amine
As embodiment 1.Productive rate 83%, M.p.184 ℃ (toluene).
Embodiment 8[2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl] [3-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) propyl group] amine
As embodiment 1.Productive rate 78%, M.p.260 ℃ (DMF).
Embodiment 9 two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl] amine
As embodiment 1.Productive rate 53%, M.p.271 ℃ of (DMF-H
2O).
Embodiment 10N, N '-two [3-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) propyl group]-1
As embodiment 1.Productive rate 61%, M.p.180 ℃ (toluene).Embodiment 11N, N '-two [3-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) propyl group]-1,3-propylene diamine
As embodiment 1.Productive rate 41%, M.p.140 ℃ (toluene).
Embodiment 12N, and N '-two [1,2-dihydro-8-nitro-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1, the 3-propylene diamine
As embodiment 1.Productive rate 52%, M.p.＞340 ℃ (toluene).
Embodiment 13N, N '-two [2-(1,2-dihydro-8-nitro-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-quadrol
As embodiment 1.Productive rate 57%, M.p.＞340 ℃ (toluene).
Embodiment 14N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-N, N '-dimethyl-1
As embodiment 1.Productive rate 77%, M.p.255 ℃ (toluene).
Embodiment 15N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,5-pentamethylene diamine
As embodiment 1.Productive rate 25%, M.p.122 ℃ (toluene).
Embodiment 16N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl] hexahydropyrimidine
With 0.5g (0.8mmol) N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine and the 1ml 36% formaldehyde mixture in 100ml ethanol refluxed 7 hours.Filter out solid, washing, dry and by the toluene recrystallization, obtain 0.3g (58%) N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl] hexahydropyrimidine, M.p.222 ℃ (toluene).
Embodiment 17N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine
With the 0.4g in the 20ml toluene (2.5mmol) N, N '-two (2-amino-ethyl)-1,3-propylene diamine
Handle 1.47g (5mmol) anthracene-1, the mixture of 9-dimethyl dicarboxylate and 50ml toluene.With this suspension returning 24 hours, be cooled to room temperature then.Filter out solid, drying by the toluene recrystallization, obtains 0.65g (42%) N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine, M.p.191 ℃.
Embodiment 18N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine
With the 0.4g in the 20ml toluene (2.5mmol) N, N '-two (2-amino-ethyl)-1,3-propylene diamine join 1.51g (5mmol) anthracene-1, in the mixture of 9-dicarboxyl acyl chlorides and 50ml toluene.Suspension returning 20 hours is cooled to room temperature then.Filter out solid, drying by the toluene recrystallization, obtains 0.54g (35%) N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine, M.p.191 ℃.
Embodiment 19N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine A. 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1,3-diketone
With 1.51g (6mmol) anthracene-1, the mixture of 9-dicarboxylic acid anhydride and 0.4g (6.5mmol) thanomin in 50ml toluene refluxed 5 hours, was cooled to room temperature then.Filter out solid, drying by the toluene recrystallization, obtains 1.5g (85%) 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1,3-diketone, M.p.211 ℃.B. 2-[2-(right-tosyloxy) ethyl]-1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1,3-diketone
Handle 1.01g (3.5mmol) 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1, the mixture of 3-diketone in the 10ml pyridine with 0.69g (3.6mmol) p-toluenesulfonyl chloride.After at room temperature stirring the mixture 24 hours, inject 50ml cold water, collect solid, wash with water, vacuum-drying and by dimethyl formamide/water recrystallization obtains 1.2g (77%) 2-[2-(right-tosyloxy) ethyl]-1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1,3-diketone, M.p.240 ℃.C. N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine
Under 0.6g (5.6mmol) sodium carbonates' presence, with 2.2g (5mmol) 2-[2-(right-tosyloxy) ethyl]-1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1,3-diketone and 0.4g (2.5mmol) 1, the 3-propylene diamine mixture in the 200ml acetonitrile refluxed 24 hours.This mixture of vacuum concentration, water (100ml) is handled residue, and uses dichloromethane extraction.Merge organic phase, use dried over mgso, filter and vacuum concentration.With methylene dichloride, methyl alcohol, acetate (80: 15: 5) wash-out, chromatogram purification residue.Merge suitable fraction, vacuum concentration and by the toluene crystallization obtains 0.3g (20%) N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine, M.p.191 ℃.
Embodiment 20N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine A. 1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1,3-diketone
Handle 1.51g (6mmol) anthracene-1,9-dicarboxylic acid anhydride with 10ml ammonium hydroxide (28%).Reflux after 16 hours, collect solid, wash with water, vacuum-drying and by dimethyl formamide-water crystallization obtains 1.3g (86%) 1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1,3-diketone, M.p.310 ℃.B. N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine
With the 280mg in the 50ml ethanol (5mmol) potassium hydroxide treatment 1.23g (5mmol) 1,2-dihydro-3H-dibenzo [de, h] isoquinoline 99.9-1,3-diketone and 100ml alcoholic acid mixture.Reflux after 3 hours, add 0.65g (2.5mmol) N in the 50ml ethanol, N '-two (2-bromotrifluoromethane)-1, the 3-propylene diamine refluxed 24 hours together.The vacuum concentration reaction mixture, water (100ml) is handled residue and is used dichloromethane extraction.Merge organic layer, use dried over mgso, filter vacuum concentration.With methylene dichloride, methyl alcohol, acetate (0: 15: 5) wash-out, chromatogram purification residue.Merge suitable fraction, vacuum concentration by the toluene crystallization, obtains 0.31g (20%) N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine, M.p.191 ℃.
Embodiment 21N, and N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine A. N-[2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-N '-(2-amino-ethyl)-1, the 3-propylene diamine
With the 1.5g in the 100ml ethanol (6mmol) anthracene-1, the 9-dicarboxylic acid anhydride is handled 5.0g (31mmol) N, N '-two (2-amino-ethyl)-1, and the solution of 3-propylene diamine in 200ml 99% ethanol, and at room temperature stirred 24 hours.On strainer, collect solid, use washing with alcohol,, obtain 0.5g (20%) N-[2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl by alcohol crystal]-N '-(2-amino-ethyl)-1,3-propylene diamine, M.p.150 ℃.B. N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine
With the 0.62g in the 10ml toluene (2.5mmol) anthracene-1, the 9-dicarboxylic acid anhydride is handled 1.0g (2.5mmol) N-[2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-N '-(2-amino-ethyl)-1, the mixture of 3-propylene diamine and 50ml toluene refluxed 6 hours, was cooled to room temperature.Collect solid, vacuum-drying by the toluene crystallization, obtains 0.8g (48%) N, N '-two [2-(1,2-dihydro-1,3-dioxo-3H-dibenzo [de, h] isoquinoline 99.9-2-yl) ethyl]-1,3-propylene diamine, M.p.191 ℃.
Claims (8)
1. following formula: compound and can accept the salt that acid forms with pharmacology
Wherein X, X ', Y and Y ' can be identical or different, and respectively do for oneself H, NO
2, NH
2, C
1-6Alkylamino, two-C
1-6Alkylamino, NH-C
1-6-acyl group, OH, C
1-6-alkoxyl group, halogen, trihalomethyl group, C
1-6-alkyl, formyl radical, C
1-6-alkyl-carbonyl, urea groups, C
1-6-alkyl urea groups; And A is
C
n-NR-C
N 'Or C
n-NR-C
N "-NR '-C
N 'Wherein: C
n, C
N 'And C
N "Can be identical or different, and the C that respectively does for oneself
1-4Alkylidene group, R and R ' are H, C
1-4Alkyl, benzyl, phenyl or by halogen atom or C
1-4Alkyl or the amino phenyl that replaces.
2. according to the compound of claim 1, wherein A is
-CH
2-CH
2-NR-CH
2-CH
2-NR '-CH
2-CH
2-or
-CH
2-CH
2-NR-CH
2-CH
2-CH
2-NR’-CH
2-CH
2-
Wherein R and R ' are as defined in claim 1.
3. according to two-1 of claim 1,2-dihydro-3H-dibenzo isoquinoline 99.9-1, the 3-diketone, wherein X, X ', Y and Y ' they are hydrogen.
According among the claim 1-3 each two-1,2-dihydro-3H-dibenzo isoquinoline 99.9-1, the 3-diketone, it exists with the salt form of acetate or methylsulfonic acid.
5. pharmaceutical composition, it comprises the effective constituent that pharmacology can be accepted carrier and treatment effective dose, and the compound that it is characterized in that among the claim 1-4 each is as described effective constituent.
6. each compound is used to prepare the purposes of the medicine for the treatment of human tumor among the claim 1-4.
7. the method for formula I compound of preparation claim 1 comprises: 1) with the anthracene-1 of formula II, and the 9-dicarboxylic acid anhydride
Or corresponding free acid or carboxylic acid halides, react with the formula III compound
H
2N-A-NH
2X in III formula II and the formula III, X ' and A are as defined in claim 1; Or 2) with anthracene-1,9-dicarboxylic acid acid amides VI
Wherein, X and X ' react with formula VII compound as defined in claim 1
Hal-A-Hal VII wherein Hal is a halogen atom.
8. the method for the formula I compound of preparation claim 1 wherein is inserted with two nitrogen-atoms in the middle of the A, and this method comprises the compound with formula IV
Diamine reactant with formula V:
H
2N-D-NH
2V wherein B to add D be alkylidene residue, make 2B add D and comprise 4 to 12 carbon atoms, and X and X ' are as defined in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23399894A | 1994-04-28 | 1994-04-28 | |
| US08/233,998 | 1994-04-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1148851A CN1148851A (en) | 1997-04-30 |
| CN1092185C true CN1092185C (en) | 2002-10-09 |
Family
ID=22879465
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95193192A Expired - Fee Related CN1092185C (en) | 1994-04-28 | 1995-04-12 | Dihydodibenzo isoquinolines diketone |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0757676A1 (en) |
| JP (1) | JPH09512539A (en) |
| CN (1) | CN1092185C (en) |
| AU (1) | AU2306595A (en) |
| CA (1) | CA2188833A1 (en) |
| HR (1) | HRP950250A2 (en) |
| IL (1) | IL113415A (en) |
| SG (1) | SG73418A1 (en) |
| TW (1) | TW307764B (en) |
| WO (1) | WO1995029895A1 (en) |
| ZA (1) | ZA953379B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6121278A (en) * | 1997-09-03 | 2000-09-19 | Guilford Pharmaceuticals, Inc. | Di-n-heterocyclic compounds, methods, and compositions for inhibiting parp activity |
| US6197785B1 (en) | 1997-09-03 | 2001-03-06 | Guilford Pharmaceuticals Inc. | Alkoxy-substituted compounds, methods, and compositions for inhibiting PARP activity |
| US6291425B1 (en) | 1999-09-01 | 2001-09-18 | Guilford Pharmaceuticals Inc. | Compounds, methods and pharmaceutical compositions for treating cellular damage, such as neural or cardiovascular tissue damage |
| US6380193B1 (en) | 1998-05-15 | 2002-04-30 | Guilford Pharmaceuticals Inc. | Fused tricyclic compounds, methods and compositions for inhibiting PARP activity |
| PT103503B (en) | 2006-06-19 | 2009-05-18 | Univ Do Porto | NEW DERIVATIVES OF BISNAFTALIMIDOPROPIL, PROCESS FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND ITS USE IN CANCERIAN AND PARASITIC DISEASES, ESPECIALLY LEISHMANIOSIS, TRYPANOSOMES AND MALARIA. |
| CN101638389B (en) * | 2008-03-03 | 2012-09-05 | 河南大学 | Polyamine derivative containing naphthalimide structure, preparation method and application thereof |
| CN117074567B (en) * | 2023-08-25 | 2025-06-27 | 四川汇宇制药股份有限公司 | Method for detecting purity of amifostine intermediate and related substances thereof by high performance liquid chromatography |
| GB202407369D0 (en) | 2024-05-23 | 2024-07-10 | Reckitt Benckiser Finish Bv | Rinse aid composition |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0281902A1 (en) * | 1987-03-10 | 1988-09-14 | Knoll Ag | Bis-naphthalimides, their preparation and use |
| WO1992000281A1 (en) * | 1990-06-26 | 1992-01-09 | Research Corporation Technologies, Inc. | 1,2-dihydro-3h-dibenzisoquinoline-1,3-dione anticancer agents |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0125439B1 (en) * | 1983-04-01 | 1990-01-24 | Warner-Lambert Company | 3,6-disubstituted-1,8-naphthalimides and methods for their production and use |
| AU5127893A (en) * | 1992-09-11 | 1994-04-12 | Research Corporation Technologies, Inc. | 1,2 dihydro-3-h-dibenz(de,h) isoquinoline 1,3 dione and their use as anticancer agents |
| DE4232739A1 (en) * | 1992-09-30 | 1994-03-31 | Knoll Ag | New asymmetrically substituted bis-naphthalimides |
-
1995
- 1995-04-12 CN CN95193192A patent/CN1092185C/en not_active Expired - Fee Related
- 1995-04-12 SG SG1996008471A patent/SG73418A1/en unknown
- 1995-04-12 JP JP7527954A patent/JPH09512539A/en not_active Ceased
- 1995-04-12 EP EP95916636A patent/EP0757676A1/en not_active Withdrawn
- 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 AU AU23065/95A patent/AU2306595A/en not_active Abandoned
- 1995-04-18 TW TW084103805A patent/TW307764B/zh active
- 1995-04-18 IL IL11341595A patent/IL113415A/en not_active IP Right Cessation
- 1995-04-25 HR HR08/233,998A patent/HRP950250A2/en not_active Application Discontinuation
- 1995-04-26 ZA ZA953379A patent/ZA953379B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0281902A1 (en) * | 1987-03-10 | 1988-09-14 | Knoll Ag | Bis-naphthalimides, their preparation and use |
| WO1992000281A1 (en) * | 1990-06-26 | 1992-01-09 | Research Corporation Technologies, Inc. | 1,2-dihydro-3h-dibenzisoquinoline-1,3-dione anticancer agents |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA953379B (en) | 1996-10-28 |
| AU2306595A (en) | 1995-11-29 |
| CN1148851A (en) | 1997-04-30 |
| HRP950250A2 (en) | 1997-10-31 |
| IL113415A (en) | 1999-11-30 |
| EP0757676A1 (en) | 1997-02-12 |
| WO1995029895A1 (en) | 1995-11-09 |
| TW307764B (en) | 1997-06-11 |
| CA2188833A1 (en) | 1995-11-09 |
| JPH09512539A (en) | 1997-12-16 |
| IL113415A0 (en) | 1995-07-31 |
| SG73418A1 (en) | 2000-06-20 |
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