CN102584679A - Benzocarbazole acylamide compound and preparation method and application thereof - Google Patents
Benzocarbazole acylamide compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a 11H-benzo[a]carbazole-5-methanamide compound shown as a general formula (I), a preparation method thereof and an application thereof as an antitumor medicament.
Description
Technical field
The present invention relates to one type of 11H-benzo [a] carbazole-5-Carbox amide, its preparation method and as the purposes of antitumor drug.
Background technology
Malignant tumour is that current serious influences human health, threatens one of principal disease of human life.Topoisomerase enzyme inhibitor is to use one of five maximum big series antineoplastic medicaments at present clinically, owing to multiple solid tumor determined curative effects such as digestive system tumor, lung cancer, become a clinical line medicine of malignant tumor medicine treatment.Topoisomerase II suppressor factor commonly used comprises VP (etoposide), teniposide (teniposide), Dx (doxorubicin), epirubicin (epirubicin), mitoxantrone (mitoxantrone) etc.Secular clinical medicine is used and has been proved conclusively the validity of topoisomerase II as anticancer target spot.But the toxic side effect of existing medicine often limits its use.Dx is the topoisomerase II suppressor factor of wide clinical application, and kinds of tumors is all had good result of treatment, but it also produces hydroxyl radical free radical except the effect that suppresses topoisomerase II; Because cardiac muscle is very responsive to the damaging action of hydroxyl radical free radical, so Dx is prone to heart is produced the cumulative bad damage and fatal, seriously limited its application.The mitoxantrone anti-tumor activity is higher than endoxan, vincristine(VCR) and Fluracil, and mammary cancer is had obvious curative effects, and is also better to the malignant lymphoma curative effect.But mitoxantrone exists congestive heart failure and the leukemic danger of Secondary cases.Therefore press for more safe and effective topoisomerase enzyme inhibition antitumor drug clinically.
Amonafide (amonafide) is 1, and 8-naphthalimide DNA intercalator, this compound are effectively between the base pair of intercalation of DNA molecule; Increase the viscosity of dna molecular solution; Increase the length of dna molecular, the DNA that untwists suppresses topoisomerase II in the cell, causes the dna double splitting of chain.The research of amonafide treatment mammary cancer once got into the II clinical trial phase, but failed to get into the III clinical trial phase.One of them major reason be exactly this compound amino in vivo the effect of N-acetylize transferase I I (NAT2) generate down acetylate; Generally, the acetylize of medicine, generation acetylate have detoxification; But the acetylate of amonafide is a toxic product, can cause bone marrow depression and renal toxicity.N-acetylize transferase I I has the difference between individuals of height at the intravital content of people, and content is high more, and the amonafide acetylate of generation is many more, and toxicity maybe be big more.Therefore; Though the toxicity of most medicines is owing to slow acetylation causes, amonafide is at fast acetylizad patient's toxic big (the document FEDERICO INNOCENTI that sees reference, LALITHA IYER; AND MARK J.RATAIN.DRUG METABOLISMAND DISPOSITION; 2001,29 (4), 596-600).This characteristic of amonafide metabolic conversion makes its toxicity be difficult to prediction, has seriously hindered its further clinical development.For the toxicity that glycylization produced of eliminating amonafide; The inventor designs and has synthesized one type of 11H-benzo [a] carbazole-5-Carbox amide; Substitute the amino of amonafide with the condensed indole ring; Stop the generation of acetyl amonafide, obtained one type of novel antineoplastic compound.
Summary of the invention
The purpose of this invention is to provide acceptable salt on a kind of novel 11H-benzo [a] carbazole-5-Carbox amide and the physiology thereof, it has the structure shown in the general formula (I).
Wherein,
R
1Be following any one substituting group: H, halogen ,-NH
2And C
1-C
4The alkyl list replace or disubstituted amino; Said halogen is fluorine, chlorine or bromine;
N is 2 or 3;
X is N or O;
R
2And R
3Do not exist independently of one another or be hydrogen, C independently of one another
1-C
4The substituted C of alkyl or hydroxyl
1-C
4Alkyl perhaps forms one with the nitrogen-atoms that links to each other with them and contains other 0～2 heteroatomic 5 or 6 yuan of saturated heterocyclic that are selected from N or O, like tetramethyleneimine, piperidines, piperazine or morpholine;
Another object of the present invention provides the preparation method of acceptable salt on this compounds and the physiology thereof.
A purpose more of the present invention provides the purposes of acceptable salt in the medicine of preparation treatment tumour diseases such as (comprising innocent tumour and cancer, especially lung cancer and colorectal carcinoma) on this compounds and the physiology thereof.
Another purpose of the present invention provides a kind of pharmaceutical composition, and it contains acceptable salt and acceptable accessories on 11H-benzo [a] carbazole-5-Carbox amide shown in one or more general formulas (I) of treating significant quantity or its physiology.
Advantage of the present invention:
The amido functional group that amonafide is produced toxicity in vivo substitutes with indole ring, has thoroughly stopped the possibility that toxic metabolites acetyl amonafide produces, thereby might reduce medicine toxicity in vivo; With the open loop of naphthoyl imido, increase the solubleness of medicine with minimizing and number of rings order simultaneously.
The preparation method of acceptable salt implements through the following step on 11H-benzo of the present invention [a] carbazole-5-Carbox amide and the physiology thereof:
The preparation method of said general formula I a compound comprises the steps: that wherein R does
R
2And R
3Definition the same.
A, with compound 1 (4-bromo-acid) under p-methyl benzenesulfonic acid (TsOH) catalysis, do solvent refluxing with anhydrous methanol and get compound 2 (4-bromo-acid methyl esters);
B, compound 2 are at methylcarbonate ((MeO)
2CO) and under the effect of sodium methylate, generate compound 3;
C, compound 3 are done at sodium methylate under the condition of alkali and are got compound 4 with the methyl acrylate addition;
D, compound 4 hydrolysis in potassium hydroxide aqueous solution, and with vitriol oil decarboxylation generation compound 5;
E, compound 5 encircle into compound 6 in effect ShiShimonoseki of polyphosphoric acid (PPA);
F, compound 6 make solvent at anhydrous methanol, and p-methyl benzenesulfonic acid catalysis generates the product 7 of esterification down;
G, compound 7 are made synthesis of indole 8 under the solvent with phenylhydrazine at Glacial acetic acid min. 99.5;
H, compound 8 be 2,3-two chloro-5, and 6-dicyano-1, aromatization changes into compound 9 under the oxidation of 4-benzoquinones (DDQ);
I, compound 9 make solvent at methyl alcohol, and aqueous sodium hydroxide solution is done to be hydrolyzed into 10 under the alkali condition;
J, compound 10 add the N of catalytic amount in THF (THF) solvent, dinethylformamide (DMF) adds oxalyl chloride and is reacted into acyl chlorides 11;
K, compound 11 are dissolved among the THF, drip
substituted amine and get target compound Ia.
Wherein, general formula I a compound is preferably compound 12a-20, and its structural formula is following:
From compound 12a, the inventor has synthesized the different substituted compound 12b in 2-position, 12c and 12d:
A, compound 12a are dissolved in the methyl alcohol, and the debrominate of atmospheric pressure at room catalytic hydrogenation gets compound 12b;
B, compound 12a are in the strong aqua system, and 180 ℃ of tube sealings also get compound 12c with CuI catalysis;
C, compound 12a are in the dimethylamine agueous solution system, and 100 ℃ of tube sealings also get compound 12d with CuI catalysis.
From the tumor cell in vitro proliferation inhibition test interpretation of result (seeing table 1) of compound, the effect of compound 13 is best.Consider the solubleness of compound, the inventor all is prepared into the citrate donor build-in test with positive control amonafide and compound 13.The Citrate trianion of compound 13 is a compound 21, and its synthesis type is following:
Embodiment
Below in conjunction with embodiment the present invention is done further elaboration, but these embodiment are to any restriction of the present invention anything but.Among all embodiment, fusing point is measured with B ü chi510 type fusing point appearance, and TM is not calibrated;
1H NMR is by BrucherAM-400 type and GEMINI-300 type NMR record, and chemical shift is represented with δ (ppm); Separating uses silica gel to be the 200-300 order.
Preparation embodiment
The preparation of compound 2:
With compound 1 (40g 186mmol) is dissolved in the 300ml anhydrous methanol, add TsOH (2.5g, 13mmol), rise to 70 ℃ the reaction 4 hours complete to raw material reaction.Boil off solvent, add ETHYLE ACETATE 300ml, wash anhydrous sodium sulfate drying with saturated sodium bicarbonate solution, the aqueous solution, saturated nacl aqueous solution.The pressure reducing and steaming solvent gets water white transparency oily thing 2 (41g, yield: 96%).
1H?NMR(300MHz，CDCl
3)：δ7.45(d，J＝8.7Hz，2H)，7.16(d，J＝8.6Hz，2H)，3.7(s，3H)，3.70(s，3H)，3.58(s，2H)。
The preparation of compound 3:
Take by weighing the 40g sodium Metal 99.5 and be added in the 300ml anhydrous methanol, after question response was complete, it is subsequent use that the pressure reducing and steaming solvent gets the white solid sodium methylate.40g compound 2 is dissolved in the 400ml methylcarbonate, adds the sodium methylate of new system under the mechanical stirring, distill out newly-generated methyl alcohol.When raw material reaction is complete, be cooled to room temperature, reaction mixture is poured in the frozen water into ethyl acetate extraction (200ml * 3 time).Merge organic layer, saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying, and column chromatography (petrol ether/ethyl acetate=30: 1) gets white solid (38.2g, yield: 76%).m.p.86℃。
1H?NMR(300MHz，CDCl
3)：δ7.5-7.45(d，2H，J＝8.9Hz)，7.26-7.2(d，2H，J＝9.0Hz)，4.6(s，1H)3.75(s，6H)。
The preparation of compound 4:
Take by weighing the 1g sodium Metal 99.5 and be added in the 200ml anhydrous methanol, when no longer producing bubble, (38g 132mmol) adds in the methanol solution of sodium methylate, adds methyl acrylate 20ml then, and stirring at normal temperature is spent the night, and raw material reaction is complete with compound 3.Reaction solution is quenched to acidity with Hydrogen chloride, pressure reducing and steaming methyl alcohol, raffinate merges organic layer with ETHYLE ACETATE/water extraction, and organic layer is washed with saturated sodium-chloride, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, column chromatography (petrol ether/ethyl acetate=15: 1) gets white solid (39.5g, yield: 80%).m.p.94℃。
1H?NMR(300MHz，CDCl
3)：δ7.5-7.45(d，2H，J＝8.9Hz)，7.26-7.2(d，2H，J＝9.0Hz)，3.75(s，6H)，3.64(s，3H)，2.65-2，58(t，2H，J＝8.4Hz)，2.32-2.26(t，2H，J＝8.1Hz)。
The preparation of compound 5:
(13g 34.8mmol) is added in the 120ml aqueous solution of 8g KOH, and temperature rising reflux spends the night with compound 4.Be chilled to room temperature in second day.The 6ml vitriol oil is added in the 15ml aqueous solution, be added in the above-mentioned reaction solution after being cooled to room temperature, continue temperature rising reflux after 2 hours, use ethyl acetate extraction.Ethyl acetate layer is washed with saturated common salt, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent gets water white transparency oily thing (9.6g, yield: 96%).m.p.134℃。
1H?NMR(300MHz，CDCl
3)：δ10.0(br，2H)，7.5-7.45(d，2H，J＝8.0Hz)，7.20-7.15(d，2H，J＝8.1Hz)，3.6(m，1H)，2.4(m，3H)，2.1(m，1H)。
The preparation of compound 6:
After the 100ml polyphosphoric acid is heated to 80 ℃, with compound 5 (9g 31.3mmol) under agitation adds in the poly phosphoric acid solution of heat, 95 ℃ of reactions 6 hours down, raw material reaction is complete.Reaction solution is slowly poured in the frozen water after being cooled to room temperature, and ethyl acetate extraction 3 times merges organic layer, and water, saturated nacl aqueous solution are washed respectively, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, column chromatography (petrol ether/ethyl acetate=2: 1) gets reddish-brown solid (3.8g, yield: 45%).m.p.168-170℃。
1H?NMR(300MHz，CDCl
3)：δ8.2(d，1H，J＝2.3Hz)，7.7-7.6(dd，1H，J＝8.5Hz，2.2Hz)7.3-7.26(d，1H，J＝8.5Hz)，4.0(t，1H，J＝4.65Hz)，3.0-2.85(m，1H，J＝5.1Hz)，2.75-2.6(m，1H，J＝4.6Hz)，2.6-2.5(m，1H)，2.45-2.3(m，1H)。
The preparation of compound 7:
With compound 6 (3.1g 11.5mmol) is dissolved in the 80ml anhydrous methanol, add a hydration p-methyl benzenesulfonic acid (0.8,4.2mmol), rise to 80 ℃ down reaction spend the night.Second day TLC follows the tracks of and reacts completely.Behind the pressure reducing and steaming partial solvent, add the ETHYLE ACETATE dilution, wash anhydrous sodium sulfate drying successively with saturated sodium bicarbonate, water, saturated nacl aqueous solution.The pressure reducing and steaming solvent, column chromatography (petrol ether/ethyl acetate=20: 1) gets water white transparency jelly (2.8g, yield: 86%).
1H?NMR(300MHz，CDCl
3)：δ8.2(d，1H，J＝2.3Hz)，7.65-7.6(dd，1H，J＝7.9Hz，2.2Hz)7.25-7.2(d，1H，J＝8.4Hz)，3.95(t，1H，J＝4.65Hz)，3.75(s，3H)，2.95-2.8(m，1H，J＝5.7Hz)，2.7-2.6(m，1H，J＝5.0Hz)，2.55-2.45(m，1H，J＝5.0Hz)，2.4-2.25(m，1H)。
The preparation of compound 8:
(0.63g 2.2mmol) is dissolved in the 10ml Glacial acetic acid min. 99.5, adds phenylhydrazine 0.25ml, and temperature rising reflux spends the night, and is chilled to room temperature, leaves standstill to separate out pale brown look crystal, filters, and vacuum-drying gets compound 8 (0.41g, yield: 52%) to take by weighing compound 7.m.p.266℃。
1H?NMR(300MHz，CDCl
3)：δ8.3(s，1H)，7.55(d，1H，J＝7.1Hz)7.44(d，1H，J＝1.6Hz)，7.32-7.26(m，2H)，7.2-7.1(m，3H)，4.0(q，1H，J＝7.0Hz，4.8Hz)，3.7(s，3H)，3.60-3.50(dd，1H，J＝16.3Hz，4.8Hz)，3.2-3.1(dd，1H?J＝15.8Hz，7.3Hz)。
The preparation of compound 9:
(0.4g 1.1mmol) is dissolved in 20ml 1, and in the 2-ethylene dichloride, (0.374g 1.65mmol), reacted 3 hours down at 80 ℃, and raw material reaction is complete to add DDQ with compound 8.The pressure reducing and steaming solvent, column chromatography (petrol ether/ethyl acetate=15: 1) gets white powder solid (0.156g, yield: 39%).m.p.284℃。
1H?NMR(300MHz，d-DMSO)：δ12.7(s，1H)，9.07(s，1H)，9.07-9.03(d，1H，J＝9.9Hz)，8.9(d，1H，J＝2.0Hz)，8.3(d，1H，J＝7.8Hz)，7.85-7.8(dd，1H，J＝9.3Hz，2.1Hz)，7.7(d，1H，J＝8.2Hz)，7.5(t，1H，J＝7.7Hz)，7.3(t，1H，J＝7.4Hz)4.0(s，3H)。
The preparation of compound 10:
Take by weighing compound 9 (100mg 0.28mmol) is dissolved in the 10ml methyl alcohol, adds 2N NaOH 0.6ml, temperature rising reflux 2 hours, raw material reaction is complete.The pressure reducing and steaming partial solvent, thin up is neutralized to pH=5 with Hydrogen chloride, separates out white solid, filters, and vacuum-drying gets white solid (88mg, yield: 92%).m.p.
1H?NMR(300MHz，d-DMSO)：δ12.6(s，1H)，9.2(d，1H，J＝9.0Hz)，9.05(s，1H)，8.88(d，1H，J＝1.8Hz)，8.3(d，1H，J＝7.4Hz)，7.8(dd，1H，J＝9.6Hz，1.7Hz)，7.7(d，1H，J＝8.1Hz)，7.48(t，1H，J＝7.7Hz)，7.3(t，1H，J＝7.6Hz)。
The universal method of midbody 11 preparations:
Take by weighing compound 10 (35mg 1mmol) is dissolved among the anhydrous THF of 3ml, adds a DMF, under the ice bath to 0 ℃, adds 5 of oxalyl chlorides, rise to stirring at room 30min after, the pressure reducing and steaming solvent, faint yellow solid 11, directly carry out next step reaction without separating.
The preparation method of target compound 12a:
11 of the existing 37mg that makes is dissolved among the anhydrous THF, drip (44mg, N 5eq), the N-dimethyl-ethylenediamine, stirring at normal temperature is after 2 hours, and the pressure reducing and steaming solvent is poured in the frozen water, separates out solid, filters, the dry target compound 12a that gets.
12a white powder (39mg, yield: 95%).m.p.209℃。
1H?NMR(300MHz，d-CD
3OD)δ8.62(s，1H，J＝1.8Hz)8.45(s，1H)，8.38(d，1H，J＝9.1Hz)，8.15(d，1H，J＝7.9Hz)，7.65(dd，1H，J＝8.8，2.0Hz)，7.6(d，1H，J＝6.7Hz)，7.45(t，1H，J＝7.6Hz)，7.28(t，1H，J＝7.6Hz)，3.65(t，2H，J＝6.9Hz)，2.7(t，2H，J＝6.8Hz)2.4(s，6H)。
The preparation method of target compound 13:
Except the N with 51mg, the N-dimethylated propyl diethylenetriamine replaces the N of 44mg, outside the N-dimethyl-ethylenediamine, prepares compound 13 with the preparation method identical with compound 12a.
13 (white solid 41mg, yields: 95%).m.p.146℃。
1H?NMR?(300MHz，d-CD3OD)：δ8.65(s，1H，J＝2.1Hz)8.4(s，1H)，8.35(d，1H，J＝9.1Hz)，8.15(d，1H，J＝7.9Hz)，7.65(dd，1H，J＝9.2，2.0Hz)，7.6(d，1H，J＝6.2Hz)，7.45(t，1H，J＝7.6Hz)，7.25(t，1H，J＝7.5Hz)，3.5(t，2H，J＝6.7Hz)，2.5(t，2H，J＝7.8Hz)2.3(s，6H)1.9(m，2H，J＝7.4Hz)。
The preparation method of target compound 14:
Except replace the N of 44mg with N-(2-amino-ethyl) pyrroles's alkanamine of 57mg, outside the N-dimethyl-ethylenediamine, prepare compound 14 with the preparation method identical with compound 12a.
14 white solids (44mg, yield: 100%) m.p.138 ℃.
1H?NMR(300MHz，d-CD
3OD)：δ8.65(s，1H，J＝1.9Hz)8.45(s，1H)，8.4(d，1H，J＝9.1Hz)，8.15(d，1H，J＝7.8Hz)，7.65(dd，1H，J＝8.6，2.0Hz)，7.62(d，1H，J＝7.7Hz)，7.45(t，1H，J＝7.4Hz)，7.25(t，1H，J＝7.5Hz)，3.7(t，2H，J＝7.0Hz)，2.85(t，2H，J＝6.9Hz)2.7(m，4H)，1.85(m，4H)。
The preparation method of target compound 15:
Except replace the N of 44mg with N-(2-amino-ethyl) piperidines of 64mg, outside the N-dimethyl-ethylenediamine, prepare compound 15 with the preparation method identical with compound 12a.
15 white solids (46mg, yield: m.p.126 ℃ of decomposition 100%).
1H?NMR(300MHz，d-CD
3OD)：δ8.65(s，1H，J＝2.3Hz)，8.45(s，1H)，8.4(d，1H，J＝9.0Hz)，8.15(d，1H，J＝8.0Hz)，7.65(dd，1H，J＝9.0，2.1Hz)，7.62(d，1H，J＝7.5Hz)，7.45(t，1H，J＝7.7Hz)，7.28(t，1H，J＝7.5Hz)，3.65(t，2H，J＝7.0Hz)，2.7(t，2H，J＝6.9Hz)2.6(m，4H)1.7(m，4H)1.5(m，2H)。
The preparation method of target compound 16:
Except replace the N of 44mg with N-(2-amino-ethyl) morpholino of 65mg, outside the N-dimethyl-ethylenediamine, prepare compound 16 with the preparation method identical with compound 12a.
16 white solids (45mg, yield: m.p.292 ℃ of decomposition 100%).
1H?NMR(300MHz，d-CD
3OD)：δ8.65(s，1H，J＝1.9Hz)8.45(s，1H)，8.4(d，1H，J＝9.1Hz)，8.15(d，1H，J＝7.8Hz)，7.65(dd，1H，J＝8.6，2.0Hz)，7.62(d，1H，J＝7.7Hz)，7.45(t，1H，J＝7.4Hz)，7.25(t，1H，J＝7.5Hz)，3.75(t，4H，J＝4.6Hz)，3.67(t，2H，J＝6.3Hz)2.72(t，2H，J＝6.3Hz)2.62(t，4H，J＝5.6Hz)
The preparation method of target compound 17:
Except replace the N of 44mg with the N-methyl ethylenediamine of 37mg, outside the N-dimethyl-ethylenediamine, prepare compound 17 with the preparation method identical with compound 12a.
17 white solids (34mg, yield: 87%) m.p.220 ℃.
1H?NMR(300MHz，d-CD
3OD)：δ8.72(s，1H)，8.35(s，1H)，8.15(d，1H，J＝7.4Hz)，7.85(d，1H，J＝8.7)，7.7(dd，1H，J＝8.3，1.3Hz)，7.65(d，1H，J＝8.1Hz)，7.45(t，1H，J＝7.1Hz)，7.3(t，1H，J＝7.5Hz)，3.4(t，2H，J＝6.4Hz)，3.3(t，2H，J＝6.4Hz)，2.96(s，6H)。ES-API?(％)：396，398(100，M
++1)
The preparation method of target compound 18:
Except replace the N of 44mg with N-(2-amino-ethyl) piperazine of 65mg, outside the N-dimethyl-ethylenediamine, prepare compound 18 with the preparation method identical with compound 12a.
18 white solids (38mg, yield: 84%) m.p.200 ℃.
1H?NMR(300MHz，d-CD
3OD)：δ8.7(s，1H，J＝2.2Hz)8.2(s，1H)，8.15(d，1H，J＝7.7Hz)，7.85(d，1H，J＝9.2Hz)，7.7(dd，1H，J＝9.1，2.0Hz)，7.63(d，1H，J＝8.2Hz)，7.45(t，1H，J＝8.1Hz)，7.28(t，1H，J＝7.7Hz)，4.0(br?s，2H)3.3(br?s，2H)3.05(t，2H，J＝5.9Hz)2.72(br?s，2H)，2.65(t，2H，J＝5.9Hz)2.4(br?s，2H)。ES-API?(％)：451，453(100，M
++1)。
The preparation method of target compound 19:
Except replace the N of 44mg with the 2-monoethanolamine of 30mg, outside the N-dimethyl-ethylenediamine, prepare compound 19 with the preparation method identical with compound 12a.
19 white solids (28mg, yield: m.p.290 ℃ of decomposition 73%).
1H?NMR(300MHz，d-CD
3OD)：δ8.65(s，1H，J＝2.2Hz)8.5(s，1H)，8.4(d，1H，J＝9.1Hz)，8.25(d，1H，J＝7.7Hz)，7.66(dd，1H，J＝8.9，2.0Hz)，7.62(d，1H，J＝8.3Hz)，7.45(t，1H，J＝7.1Hz)，7.28(t，1H，J＝7.4Hz)3.83(t，2H，J＝5.8Hz)，3.63(t，2H，J＝5.7Hz)
The preparation method of target compound 20:
Except replace the N of 44mg with the AEEA of 52mg, outside the N-dimethyl-ethylenediamine, prepare compound 20 with the preparation method identical with compound 12a.
20 white solids (36mg, yield: 84%) m.p.213 ℃.
1H?NMR(300MHz，d-CD
3OD)：δ8.65(s，1H，J＝1.8Hz)8.48(s，1H)，8.4(d，1H，J＝9.1Hz)，8.15(d，1H，J＝7.9Hz)，7.65(dd，1H，J＝9.1，2.0Hz)，7.62(d，1H，J＝7.8Hz)，7.45(t，1H，J＝7.2Hz)，7.28(t，1H，J＝7.0Hz)3.72(t，2H，J＝5.5Hz)，3.67(t，2H，J＝6.5Hz)2.98(t，2H，J＝6.2Hz)2.85(t，2H，J＝5.4Hz)
The preparation method of compound 12b:
Take by weighing compound 12a (41mg 0.1mmol) is dissolved in the 5ml anhydrous methanol, adds Pd/C 10mg, replaces 3 times argon gas, logical again hydrogen, stirring at normal temperature 8 hours, raw material reaction is complete.Diatomite filtration, pressure reducing and steaming solvent, preparation of silica gel plate separate white solid (29mg, yield: 88%).m.p.174℃。
1H?NMR(300MHz，d-CD
3OD)：δ8.56(s，1H)8.53(d，1H，J＝7.9Hz)8.45(dd，1H，J＝7.8Hz，1.0Hz)8.17(d，1H，J＝7.9Hz)7.9(s，1H)7.67-7.55(m，3H)7.44(t，1H，J＝8.0Hz)7.27(t，1H，J＝7.7Hz)3.85(t，2H，J＝5.9Hz)3.42(t，2H，J＝6.1Hz)2.96(s，6H)。
The preparation method of compound 12c:
(160mg 0.4mmol) as in the tube sealing, adds ammoniacal liquor (28%) 6ml, and (38mg 0.2mmol), is warming up to 180 ℃ of reactions 7 hours to CuI, and it is complete that TLC follows the tracks of raw material reaction to take by weighing compound 12a.Stopped reaction is chilled to room temperature, the pressure reducing and steaming solvent, and column chromatography (methylene chloride=10: 1) gets brown solid (69mg, yield: 50%).m.p.170℃
1H?NMR(300MHz，d-CD
3OD)：δ8.3(d，1H，J＝8.9Hz)，8.2(s，1H)，8.1(d，1H，J＝8.0Hz)，7.6(d，1H，J＝8.3Hz)，7.5(s，1H)，7.44(t，1H，J＝7.7Hz)，7.2(t，1H，J＝7.5Hz)7.08(d，1H，J＝8.6Hz)，3.75(t，2H，J＝6.4Hz)，3.15(t，2H，J＝6.1Hz)，2.75(s，6H)。ES-API(％)：347(100，M+1)
The preparation method of compound 12d:
(41mg 0.1mmol) as in the tube sealing, adds dimethylamine agueous solution 6ml, and (19mg 0.1mmol), is warming up to 100 ℃ and reacts complete to TLC tracking raw material reaction CuI to take by weighing compound 12a.Stopped reaction is chilled to room temperature, the pressure reducing and steaming solvent, and column chromatography (methylene chloride=10: 1) gets brown solid (20mg, yield: 53%).m.p.183℃。
1H?NMR(300MHz，d-CD
3OD)：δ8.37(d，1H，J＝9.2Hz)，8.24(s，1H)，8.08(d，1H，J＝7.9Hz)，7.6(d，1H，J＝8.1Hz)，7.5(d，1H，J＝3.2Hz)，，7.38(t，1H，J＝8.2Hz)，7.24-7.18(m，2H)，3.84(t，2H，J＝6.0Hz)，3.4(t，2H，J＝6.0Hz)，3.12(s，6H)2.96(s，6H)。
The preparation of the Citrate trianion 21 of compound 13:
(60mg 0.31mmol) is dissolved in the ethanol solution of 0.5ml, and (133mg is in 0.5ml ethanol solution 0.31mmol) dropwise to be added drop-wise to compound 13 with Hydrocerol A.After dropwising, the solid of separating out is filtered rapidly, place vacuum drying oven.Mp：120℃
1H?NMR(300MHz，d-DMSO)：δ8.7(s，1H)，8.5(s，1H)，8.4(d，1H，J＝9.1Hz)，8.2(d，1H，J＝7.8Hz)，7.7(dd，1H，J＝9.7Hz，1.3Hz)，7.65(d，1H，J＝7.9Hz)，7.45(t，1H，J＝7.4Hz)，7.3(t，1H，J＝7.0Hz)，3.6(m，2H)，2.95(s，6H)，2.7(m，4H)，2.1(m，2H)。
EXPERIMENTAL EXAMPLE:
1. tumor cell in vitro proliferate suppresses active
Detect The compounds of this invention with sulphonyl rhodamine B protein staining method (srb assay) and suppressed the tumor cell proliferation effect.In 96 orifice plates by tumour cell under certain density kind, treat adherent after, add finite concentration testing compound nutrient solution effect 72h, discard nutrient solution; Add Tricholroacetic Acid and fix, distillation washing five times, drying; Add the dyeing of sulphonyl rhodamine B, wash five times drying with 1% Glacial acetic acid min. 99.5; Add tris buffer, ELIASA 560nm wavelength is surveyed the OD value down, calculates inhibiting rate.
The result shows that test-compound all has inhibition people lung cancer A549 cell and human colon carcinoma HCT-116 cell proliferation growth activity (table 1) in various degree; Wherein, compound 13 effects are the strongest, to A549 and the growth inhibiting IC of HCT-116 cell proliferation
50Be respectively 8.2 μ M and 9.5 μ M, 2 kinds of cytosis degree are not had notable difference; Overall anti tumor activity in vitro and amonafide are quite or slightly by force.The result sees table 1.
Table 1 11H-benzo [a] card azoles-5-amides
Inhibition to people's lung cancer A549 cell and human colon carcinoma HCT-116 cell proliferation growth is active.
2. anti-tumor in vivo activity research
Human colon carcinoma HCT-116 cell inoculation is formed transplanted tumor in the nude mouse oxter, treat gross tumor volume to 100～200mm
3The time, dividing the cage administration at random, vein is given Citrate trianion (being compound 21), amonafide Citrate trianion or the saline water of 15mg/kg compound 13, and is inferior on every Wendesdays.
The result shows that compound 21 can significantly suppress the growth of transplanted tumor, and action intensity is suitable with the amonafide Citrate trianion, and the result sees table 2.
The Citrate trianion of table 2. compound 13 (being compound 21) is to the restraining effect of human colon carcinoma HCT-116 cell Nude Mice growth.
Claims (8)
1. acceptable salt on 11H-benzo [a] carbazole-5-Carbox amide shown in one type of general formula (I) and the physiology thereof;
Wherein,
R
1Be following any one substituting group: H, halogen ,-NH
2And C
1-C
4The alkyl list replace or disubstituted amino; Said halogen is fluorine, chlorine or bromine;
N is 2 or 3;
X is N or O;
R
2And R
3Do not exist independently of one another or be hydrogen, C independently of one another
1-C
4The substituted C of alkyl or hydroxyl
1-C
4Alkyl perhaps forms one with the nitrogen-atoms that links to each other with them and contains other 0～2 heteroatomic 5 or 6 yuan of saturated heterocyclic that are selected from N or O.
2. acceptable salt on 11H-benzo according to claim 1 [a] carbazole-5-Carbox amide and the physiology thereof, wherein: R
2And R
3Do not exist independently of one another or be hydrogen, C independently of one another
1-C
4The substituted C of alkyl or hydroxyl
1-C
4Alkyl perhaps forms tetramethyleneimine, piperidines, piperazine or morpholine with the nitrogen-atoms that links to each other with them.
3. acceptable salt on 11H-benzo according to claim 1 and 2 [a] carbazole-5-Carbox amide and the physiology thereof is characterized in that, acceptable salt is selected from the following compound on this compound and the physiology thereof:
4. the preparation method of acceptable salt on a 11H-benzo [a] carbazole-5-Carbox amide and the physiology thereof, this method is implemented through the following step:
Wherein, R does
R
2And R
3Definition with claim 1;
A, with compound 1 under p-methyl benzenesulfonic acid TsOH catalysis, do solvent refluxing with anhydrous methanol and get compound 2;
B, compound 2 are at methylcarbonate (MeO)
2Under the effect of CO and sodium methylate, generate compound 3;
C, compound 3 are done at sodium methylate under the condition of alkali and are got compound 4 with the methyl acrylate addition;
D, compound 4 hydrolysis in potassium hydroxide aqueous solution, and with vitriol oil decarboxylation generation compound 5;
E, compound 5 encircle into compound 6 in effect ShiShimonoseki of polyphosphoric acid PPA;
F, compound 6 make solvent at anhydrous methanol, and p-methyl benzenesulfonic acid catalysis generates the product 7 of esterification down;
G, compound 7 are made synthesis of indole 8 under the solvent with phenylhydrazine at Glacial acetic acid min. 99.5;
H, compound 8 be 2,3-two chloro-5, and 6-dicyano-1, aromatization changes into compound 9 under the oxidation of 4-benzoquinones DDQ;
I, compound 9 make solvent at methyl alcohol, and aqueous sodium hydroxide solution is done to be hydrolyzed into 10 under the alkali condition;
J, compound 10 add the N of catalytic amount in the tetrahydrofuran THF solvent, dinethylformamide DMF adds oxalyl chloride and is reacted into acyl chlorides 11;
K, compound 11 are dissolved among the THF, drip
substituted amine and get target compound Ia.
5. the preparation method of acceptable salt on a 11H-benzo [a] carbazole-5-Carbox amide and the physiology thereof, this method is implemented through the following step:
A, compound 12a are dissolved in the methyl alcohol, and the debrominate of atmospheric pressure at room catalytic hydrogenation gets compound 12b;
B, compound 12a are in the strong aqua system, and 180 ℃ of tube sealings also get compound 12c with CuI catalysis;
C, compound 12a are in the dimethylamine agueous solution system, and 100 ℃ of tube sealings also get compound 12d with CuI catalysis.
6. the purposes of acceptable salt in the medicine of preparation treatment tumor disease on the described 11H-benzo of claim 1 [a] carbazole-5-Carbox amide and the physiology thereof.
7. purposes according to claim 6 is characterized in that described tumour comprises lung cancer and colorectal carcinoma.
8. pharmaceutical composition, it contains acceptable salt and acceptable accessories on 11H-benzo [a] carbazole-5-Carbox amide or its physiology of one or more claims 1 of treating significant quantity.
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| CN104098506A (en) * | 2014-07-15 | 2014-10-15 | 华东理工大学 | Preparation method and application of benzo[c] carbazole amide compound |
| CN108997223A (en) * | 2018-08-09 | 2018-12-14 | 浙江先锋科技股份有限公司 | 5-(4- bromophenyl) -4,6- dichloro pyrimidine preparation method |
| CN111961048A (en) * | 2020-08-26 | 2020-11-20 | 南通大学 | Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof |
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| CN1087018C (en) * | 1997-08-06 | 2002-07-03 | 瑟维尔实验室 | Bis-pyrido [4,3-b] carbazole compounds, process for their preparation and pharmaceutical compositions containing them |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098506A (en) * | 2014-07-15 | 2014-10-15 | 华东理工大学 | Preparation method and application of benzo[c] carbazole amide compound |
| CN108997223A (en) * | 2018-08-09 | 2018-12-14 | 浙江先锋科技股份有限公司 | 5-(4- bromophenyl) -4,6- dichloro pyrimidine preparation method |
| CN108997223B (en) * | 2018-08-09 | 2020-06-30 | 浙江先锋科技股份有限公司 | Preparation method of 5- (4-bromophenyl) -4, 6-dichloropyrimidine |
| CN111961048A (en) * | 2020-08-26 | 2020-11-20 | 南通大学 | Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof |
| CN111961048B (en) * | 2020-08-26 | 2022-05-13 | 南通大学 | Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof |
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