CN105481769B - A kind of benzo (c) acridine derivatives and its preparation method and application - Google Patents
A kind of benzo (c) acridine derivatives and its preparation method and application Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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Abstract
The invention discloses a kind of benzo (c) acridine derivatives and its preparation method and application, chemical name is 7 benzo (c) acridinium carboxamide base thiocarbamides, with structural formula：And the present invention applies in antitumor drug is prepared, and injection, tablet, pill, capsule, suspending agent or emulsion is made with pharmaceutically acceptable auxiliary material combination；The present invention is stronger than the activity of acridine many by the use of benzacridine as female ring, pass through 7 upper connection active group amide groups thiocarbamide structures in benzo (c) acridine ring simultaneously, synthesizing new benzo (c) acridine derivatives, activity superposition, active anticancer are greatly enhanced than acridinium carboxamide base thiourea derivatives.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly to antitumor drug technical field more particularly to a kind of benzo (c)
Acridine derivatives and its preparation method and application.
Background technology
Tumour is still a kind of most common, most serious disease that the world today directly jeopardizes human life.According to incomplete system
Meter, there are about the new cancer strickens of 7,000,000 people every year in the whole world, and there are about more than 500 ten thousand people every year to die of cancer.As people are to bioid
The research in the fields such as, immunology, acology and to the understanding of oncogene level and in field of biology and technical aspect
New development, pharmacy man and oncologist from the mechanism of tumor development more and more profoundly, it is realized that must start with, ability
Curative effect is improved, is made a breakthrough.DNA is a kind of ideal biological target in the development process of antitumor drug,
And DNA intercalators can preferably be embedded in the DNA base of double helix to centre, this is just carried for design dna anti-tumor drugs targeting
Basis is supplied.And with plane rigid structure chromophore molecule frequently as DNA target to molecule antitumor drug design and
It plays a significant role in terms of in-vitro screening.Acridine is a kind of nitrogenous organic heterocyclic molecule received significant attention, because of its structure
For big ring conjugated system, have rigid planar structure, it can be as the insert of the macromoleculars such as DNA, in antitumor, antiviral, antimalarial
Disease, antibacterial, biological fluorescent labeling and treatment AIDS etc. show very strong physiological activity, and the present inventor is in application number
For：201410521970.6 patent application document in disclose a kind of acridinium carboxamide base thiourea derivatives and preparation method thereof
And purposes, using acridine as parent, synthesis acridinium carboxamide base thiourea derivatives have active anticancer, but active anticancer is relatively
It is weak.The present inventor is stronger than the activity of acridine many by the use of benzacridine as parent by studying discovery on the basis of this, leads to simultaneously
The connection active group amide groups thiocarbamide structure on the 7- positions of benzo (c) acridine ring is crossed, synthesizing new benzo (c) acridine derives
Object, activity superposition, active anticancer are greatly enhanced than acridinium carboxamide base thiourea derivatives, and innovation of the invention is to pass through
The connection active group amide groups thiocarbamide structure on the 7- positions of benzo (c) acridine ring, synthesizing new benzo (c) acridine derivatives,
The derivative not yet has been reported that at present.
Invention content
It is an object of the invention to insufficient more than overcoming, and the blank of research is filled up, a kind of benzo (c) acridine is provided and is spread out
Biology, the present invention is stronger than the activity of acridine many by the use of benzacridine as female ring, while by the 7- positions of benzo (c) acridine ring
Upper connection active group amide groups thiocarbamide structure, synthesizing new benzo (c) acridine derivatives, activity superposition, active anticancer compare a word used for translation
Pyridine amide groups thiourea derivatives greatly enhance.
Another object of the present invention provides a kind of benzo (c) acridine derivatives preparation method.
Technical solution provided by the invention is：
A kind of benzo (c) acridine derivatives, with structural formula：
Molecular formula：C25H18N4OS
Relative molecular weight：422.12
Physicochemical property：Orange-yellow powder solid, boiling point：182-186℃；1H NMR(DMSO-d6, 400M Hz), δ：11.18
(br, s, 1H ,-NH), 10.58 (br, s, 1H ,-NH), 10.27 (br, s, 1H ,-NH), 9.40 (s, 1H, ArH), 9.38 (d, 1H,
J=8.5, ArH), 8.32 (d, 1H, J=8.5, ArH), 8.25 (s, 1H, ArH), 8.09 (d, 2H, J=7.2, ArH), 8.03
(d, 1H, J=7.2, ArH), 7.90-8.00 (m, 2H, ArH), 7.81-7.83 (m, 2H, ArH), 7.73 (d, 1H, J=7.2,
ArH), 7.59 (d, 1H, J=7.2, ArH), 7.51-7.60 (m, 2H, ArH)；13C NMR(DMSO-d6, 100MHz), δ
183.51,166.82,147.98,147.86,142.39,133.90,132.93,132.44,131.26,130.59,129.92,
129.75,128.71,128.61,127.93,126.64,125.43,123.26,122.74.
A kind of preparation method of benzo (c) acridine derivatives, the synthetic route of benzo (c) acridine derivatives are as follows：
The preparation method of benzo (c) acridine derivatives includes the following steps：
1) using o-bromobenzoic acid and naphthylamines as raw material, potassium carbonate and copper powder are catalyst, add in n-amyl alcohol as solvent, warp
1. ullmann reaction obtains compound N-naphthalene ortho-aminobenzoic acid；
2) compound 7- chlorobenzenes are made simultaneously (c) 1. with phosphorus oxychloride cyclization in the compound N-naphthalene ortho-aminobenzoic acid
Acridine is 2.；
3) the compound 7- chlorobenzenes simultaneously (c) acridine 2. in phase transfer catalyst benzyltriethylammoinium chloride and trioctylphosphine first
Under ammonium chloride effect, nucleophilic substitution occurs with sodium sulfocynanate, 7- benzos (c) acridine isothiocyanates is made 3.；
4) 3. 7- benzos (c) acridine isothiocyanates is dissolved in after absolute ethyl alcohol and adds in benzoyl hydrazine, back flow reaction, reaction
Orange-yellow powder solid is precipitated in the process, after suction filtration up to target product 7- benzos (c) acridinium carboxamide base thiocarbamide 4..
It is a further object to provide a kind of benzo (c) acridine derivatives in antitumor drug is prepared
Using.
Further, injection, piece is made with pharmaceutically acceptable auxiliary material combination in benzo (c) Acridine derivatives
Agent, pill, capsule, suspending agent or emulsion.
Further, the auxiliary material is ethyl alcohol, propylene glycol, polyethylene glycol, diethylene glycol (DEG), glyceryl triacetate, glycerine, paste
Essence, povidone, octadecyl alcolol, stearic acid, microcrystalline cellulose, starch, lactose, mannitol, sodium bicarbonate, calcium carbonate, low substitution hydroxyl
It is several in propyl methocel, magnesium stearate, talcum powder, injection is made with auxiliary material combination, tablet, pill, capsule, hangs
It is conducive to absorption of human body after floating agent or emulsion use so that drug effect gives full play to, and easy to use.
The present invention is stronger than the activity of acridine many by the use of benzacridine as female ring, while by benzo (c) acridine ring
Active group amide groups thiocarbamide structure, synthesizing new benzo (c) acridine derivatives, activity superposition, active anticancer are connected on 7- positions
It is greatly enhanced than acridinium carboxamide base thiourea derivatives, compound 7- benzos (c) the acridine benzamido thiocarbamide, through resisting in vitro
Tumor experiment shows that the compound has strong antitumor activity, prepare compound 7- benzos (c) acridine of the present invention
The method of benzamido thiocarbamide so that the original system of the productivity ratio of target product 7- benzos (c) acridine benzamido thiocarbamide
Preparation Method greatly improves, while the purity of 7- benzos (c) acridine benzamido thiocarbamide also increases, and preparation method is simple
Easily operated, the reaction time is short, is applied in antitumor drug is prepared, with pharmaceutically acceptable auxiliary material combination be made injection,
Tablet, pill, capsule, suspending agent or emulsion.
Description of the drawings
Fig. 1 is 7- benzos (c) acridine benzamido thiocarbamide nuclear magnetic resonance spectroscopy；
Fig. 2 is 7- benzos (c) acridine benzamido thiocarbamide carbon-13 nmr spectra.
Specific embodiment
With reference to example below, the present invention is described in further detail, to enable those skilled in the art with reference to specification
Word can be implemented according to this.
Embodiment 1
A kind of benzo (c) acridine derivatives, with structural formula：
The synthetic route of benzo (c) acridine derivatives is as follows：
The preparation of 7- benzos (c) acridine benzamido thiocarbamide 4., is as follows：
Following raw materials by weight portion meter：
1) in three-necked bottle, 12 parts of o-bromobenzoic acids, 8 parts of naphthylamines, 13 parts of potassium carbonate and 0.9 part of copper powder are added in, adds in 65
Part n-amyl alcohol after 100 DEG C are reacted 1 hour, after n-amyl alcohol is removed under reduced pressure, adds 400 parts of water, temperature is anti-for 60 DEG C as solvent
It answers 20 minutes, filter cake is washed with water after filtering, collect the water after washing and merge with filtrate, it is 2 to be acidified to pH value with concentrated hydrochloric acid, analysis
Go out a large amount of atropurpureus precipitations, filter, gained black solid acetone recrystallization, N- naphthalene ortho-aminobenzoic acids are obtained after dry
1. n-amyl alcohol can dissolve o-bromobenzoic acid and naphthylamines well as solvent, so as to improve the yield of reaction product；
1. and 7 parts of phosphorus oxychloride 2) in round-bottomed flask, 20 parts of N- naphthalenes ortho-aminobenzoic acid obtained above is added in,
The temperature of reactant is heated to 80 DEG C in 8 minutes, reactant boiling reaction treats that boiling eases up, raises the temperature to 120 DEG C,
After reaction 2 hours, it is cooled to room temperature, the substance in round-bottomed flask is slowly poured into the mixture of concentrated ammonia liquor, trash ice and chloroform,
It wherein treats that solid is completely dissolved, chloroform layer is isolated after static, water layer is extracted 2 times again with chloroform, merges chloroform extract liquor, with nothing
After water calcium chloride is dried 12 hours, solvent is evaporated off in filtering, and obtaining 7- chlorobenzenes, simultaneously (c) acridine is 2.；
3) in round-bottomed flask, adding in 4 parts of 7- chlorobenzenes, simultaneously (c) acridine is 2. and 120 parts of acetone, reflux add in 3 parts after dissolving
Sodium sulfocynanate, 0.05 part of benzyltriethylammoinium chloride and 0.05 part of tri-n-octyl methyl ammonium chloride after reacting 2.5h, there is yellow solid
Powder is precipitated, and filters, and obtains 7- benzos (c) acridine isothiocyanates 3. after water washing, wherein benzyltriethylammoinium chloride and three
Octylmethylammonium chloride is as phase catalyst, the reaction rate greatly improved, shortens reaction time, product 7- benzos (c) a word used for translation
Pyridine isothiocyanates purity increases；
3. and 50 parts of ethyl alcohol 4) in round-bottomed flask, 6 parts of 7- benzos (c) acridine isothiocyanates are added in, adds in 7 parts of benzene afterwards
Formylhydrazine, back flow reaction 2h have in reaction process a large amount of solids to be precipitated, cooling filter orange/yellow solid is 7- benzos (c)
Acridine benzamido thiocarbamide 4., high 7- benzos (c) the acridine isothiocyanates of purity obtained by step 3 be used as reactant from
And so that the purity of final product 7- benzos (c) acridine benzamido thiocarbamide also accordingly improves, by 7- benzos (c) acridine benzene first
Amide groups thiocarbamide.
Wherein 1 part of 7- benzos (c) the acridine benzamido thiocarbamide that step 4) can be obtained and 5 parts of ethyl alcohol, 2 parts the third two
Injection is made in alcohol, 2 parts of polyethylene glycol combinations；By wherein 2 parts of 7- benzos (c) acridine benzamido thiocarbamides and 1 portion of diethylene glycol (DEG),
1 part of glyceryl triacetate, 1 part of glycerine, 3 parts of calcium carbonate, 1 part of low substituted hydroxy-propyl methylcellulose, 0.5 part of magnesium stearate, 0.2
Tablet is made in part talcum powder, 3 parts of starch compositions；To wherein 2 parts of 7- benzos (c) acridine benzamido thiocarbamides and 1 part of glycerine, 2
Ball is made in part dextrin, 0.5 part of povidone, 1.5 parts of octadecyl alcolols, 0.5 part of stearic acid, 0.1 part of microcrystalline cellulose, 1 part of lactose combinations
Agent；By wherein 2 parts of 7- benzos (c) acridine benzamido thiocarbamides and 0.5 portion of mannitol, 1 part of sodium bicarbonate, 0.5 part of calcium carbonate,
Capsule is made in 2 parts of low substituted hydroxy-propyl methylcellulose, 1 part of magnesium stearate, the combination of 0.5 talcum powder；By wherein 2 parts of 7- benzos
(c) acridine benzamido thiocarbamide and 2 parts of ethyl alcohol, 1 part of propylene glycol, 1 part of polyethylene glycol, 0.5 part of calcium carbonate, 0.5 part of low substitution
Suspending agent is made in hydroxypropyl methyl cellulose, 1 part of magnesium stearate compositions；By wherein 1 part of 7- benzos (c) acridine benzamido sulphur
Urea and 2 parts of ethyl alcohol, 2 parts of propylene glycol, 1 part of polyethylene glycol, 0.5 part of glycerine, 1 part of dextrin, 0.5 part of starch, 0.2 part of lactose combinations system
Into emulsion, it is conducive to absorption of human body after injection, tablet, pill, capsule, suspending agent or emulsion use is made with auxiliary material combination, makes
Drug effect is obtained to give full play to, and easy to use.
1 obtained 7- benzos (c) acridine benzamido thiocarbamide of embodiment passes through hydrogen nuclear magnetic resonance spectrum analysis such as Fig. 1 institutes
Show to obtain data below：1H NMR(DMSO-d6, 400MHz), δ：11.18 (br, s, 1H ,-NH), 10.58 (br, s, 1H ,-NH),
10.27 (br, s, 1H ,-NH), 9.40 (s, 1H, ArH), 9.38 (d, 1H, J=8.5, ArH), 8.32 (d, IH, J=8.5,
ArH), 8.25 (s, 1H, ArH), 8.09 (d, 2H, J=7.2, ArH), 8.03 (d, 1H, J=7.2, ArH), 7.90-8.00 (m,
2H, ArH), 7.81-7.83 (m, 2H, ArH), 7.73 (d, 1H, J=7.2, ArH), 7.59 (d, 1H, J=7.2, ArH), 7.51-
7.60 (m, 2H, ArH)；
1 obtained 7- benzos (c) acridine benzamido thiocarbamide of embodiment is analyzed by carbon-13 nmr spectra such as Fig. 2 institutes
Show to obtain data below：13C NMR(DMSO-d6, 100MHz), δ 183.51,166.82,147.98,147.86,142.39,
133.90,132.93,132.44,131.26,130.59,129.92,129.75,128.71,128.61,127.93,126.64,
125.43 123.26,122.74.
Embodiment 2
A kind of benzo (c) acridine derivatives, with structural formula：
The synthetic route of benzo (c) acridine derivatives is as follows：
The preparation of 7- benzos (c) acridine benzamido thiocarbamide 4., is as follows：
Following raw materials by weight portion meter：
1) in three-necked bottle, 20 parts of o-bromobenzoic acids, 12 parts of naphthylamines, 10 parts of potassium carbonate and 1.0 parts of copper powders are added in, are added in
150 parts of n-amyl alcohols after 105 DEG C are reacted 1.5 hours, after n-amyl alcohol is removed under reduced pressure, add 1000 parts of water, temperature is as solvent
100 DEG C are reacted 10 minutes, and filter cake is washed with water after filtering, are collected the water after washing and are merged with filtrate, PH is acidified to concentrated hydrochloric acid
It is 1.5 to be worth, and a large amount of atropurpureus precipitations are precipitated, filters, gained black solid acetone recrystallization, N- naphthalene neighbour's ammonia is obtained after dry
1., n-amyl alcohol can dissolve o-bromobenzoic acid and naphthylamines to yl benzoic acid well as solvent, so as to improve the production of reaction product
Rate；
1. and 18 parts of phosphorus oxychloride 2) in round-bottomed flask, 30 parts of N- naphthalenes ortho-aminobenzoic acid obtained above is added in,
The temperature of reactant is heated to 90 DEG C in 20 minutes, reactant boiling reaction treats that boiling eases up, raises the temperature to 160
DEG C, after reacting 1.5 hours, it is cooled to room temperature, the substance in round-bottomed flask is slowly poured into the mixing of concentrated ammonia liquor, trash ice and chloroform
In object, wherein treating that solid is completely dissolved, chloroform layer is isolated after static, water layer is extracted 3 times again with chloroform, merges chloroform extraction
Liquid, after being dried 8 hours with anhydrous calcium chloride, solvent is evaporated off in filtering, and obtaining 7- chlorobenzenes, simultaneously (c) acridine is 2.；
3) in round-bottomed flask, adding in 10 parts of 7- chlorobenzenes, simultaneously (c) acridine is 2. and 60 parts of acetone, reflux add in 5 parts after dissolving
Sodium sulfocynanate, 0.03 part of benzyltriethylammoinium chloride and 0.1 part of tri-n-octyl methyl ammonium chloride after reacting 1.5h, there is yellow solid
Powder is precipitated, and filters, and obtains 7- benzos (c) acridine isothiocyanates 3. after water washing, wherein benzyltriethylammoinium chloride and three
Octylmethylammonium chloride is as phase catalyst, the reaction rate greatly improved, shortens reaction time, product 7- benzos (c) a word used for translation
Pyridine isothiocyanates purity increases；
3. and 100 parts of ethyl alcohol 4) in round-bottomed flask, 8 parts of 7- benzos (c) acridine isothiocyanates are added in, it is rear to add in 10 parts
Benzoyl hydrazine, back flow reaction 3h have in reaction process a large amount of solids to be precipitated, cooling filter orange/yellow solid is 7- benzos
(c) 4., high 7- benzos (c) the acridine isothiocyanates of purity obtained by step 3 is used as reaction to acridine benzamido thiocarbamide
Object is so that the purity of final product 7- benzos (c) acridine benzamido thiocarbamide also accordingly improves.
Wherein 1.5 parts of 7- benzos (c) the acridine benzamido thiocarbamides that step 4) can be obtained and 4 parts of ethyl alcohol, 5 parts the third two
Injection is made in alcohol, 1 part of polyethylene glycol combination；By wherein 3 parts of 7- benzos (c) acridine benzamido thiocarbamides and 4 portions of diethylene glycol (DEG)s,
0.5 part of glyceryl triacetate, 0.5 part of glycerine, 4 parts of calcium carbonate, 2 parts of low substituted hydroxy-propyl methylcellulose, 0.8 part of stearic acid
Tablet is made in magnesium, 0.1 part of talcum powder, 1 part of starch composition；To wherein 2 parts of 7- benzos (c) acridine benzamido thiocarbamides and 0.5
Part glycerine, 4 parts of dextrin, 1 part of povidone, 2 parts of octadecyl alcolols, 1 part of stearic acid, 0.5 part of microcrystalline cellulose, 0.5 part of lactose combinations system
Into pill；By wherein 2 parts of 7- benzos (c) acridine benzamido thiocarbamides and 1 portion of mannitol, 1 part of sodium bicarbonate, 1 part of calcium carbonate,
Capsule is made in 2 parts of low substituted hydroxy-propyl methylcellulose, 0.5 part of magnesium stearate, the combination of 0.5 talcum powder；By wherein 2 parts of 7- benzos
(c) acridine benzamido thiocarbamide and 4 parts of ethyl alcohol, 1 part of propylene glycol, 2 parts of polyethylene glycol, 1 part of calcium carbonate, 1 part of low-substituted hydroxypropyl
Suspending agent is made in ylmethyl cellulose, 1 part of magnesium stearate compositions；Will wherein 3 parts of 7- benzos (c) acridine benzamido thiocarbamides with
Emulsion is made in 3 parts of ethyl alcohol, 1 part of propylene glycol, 3 parts of polyethylene glycol, 2 parts of glycerine, 1 part of dextrin, 2 parts of starch, 0.2 part of lactose combinations.
Embodiment 3
A kind of benzo (c) acridine derivatives, with structural formula：
The synthetic route of benzo (c) acridine derivatives is as follows：
The preparation of 7- benzos (c) acridine benzamido thiocarbamide 4., is as follows：
Following raw materials by weight portion meter：
1) in three-necked bottle, 40 parts of o-bromobenzoic acids, 25 parts of naphthylamines, 31 parts of potassium carbonate and 2.5 parts of copper powders are added in, are added in
100 parts of n-amyl alcohols after 180 DEG C are reacted 1 hour, after n-amyl alcohol is removed under reduced pressure, add 1100 parts of water, temperature 50 as solvent
DEG C reaction 15 minutes, is washed with water filter cake, collects the water after washing and merge with filtrate, being acidified to pH value with concentrated hydrochloric acid is after filtering
2.5, a large amount of atropurpureus precipitations are precipitated, filters, gained black solid acetone recrystallization, N- naphthalene neighbour's aminobenzenes is obtained after dry
1., n-amyl alcohol can dissolve o-bromobenzoic acid and naphthylamines to formic acid well as solvent, so as to improve the yield of reaction product；
1. and 18 parts of phosphorus oxychloride 2) in round-bottomed flask, 35 parts of N- naphthalenes ortho-aminobenzoic acid obtained above is added in,
The temperature of reactant is heated to 98 DEG C in 20 minutes, reactant boiling reaction treats that boiling eases up, raises the temperature to 170
DEG C, after reacting 1 hour, it is cooled to room temperature, the substance in round-bottomed flask is slowly poured into the mixture of concentrated ammonia liquor, trash ice and chloroform
In, wherein treating that solid is completely dissolved, chloroform layer is isolated after static, water layer is extracted 3 times again with chloroform, merges chloroform extract liquor,
After being dried 10 hours with anhydrous calcium chloride, solvent is evaporated off in filtering, and obtaining 7- chlorobenzenes, simultaneously (c) acridine is 2.；
3) in round-bottomed flask, adding in 18 parts of 7- chlorobenzenes, simultaneously (c) acridine is 2. and 150 parts of acetone, reflux add in 5 parts after dissolving
Sodium sulfocynanate, 0.08 part of benzyltriethylammoinium chloride and 0.03 part of tri-n-octyl methyl ammonium chloride after reacting 1h, there is yellow solid powder
End is precipitated, and filters, and obtains 7- benzos (c) acridine isothiocyanates 3. after water washing, wherein benzyltriethylammoinium chloride and three pungent
Methyl ammonium is as phase catalyst, the reaction rate greatly improved, shortens reaction time, product 7- benzos (c) acridine
Isothiocyanates purity increases；
3. and 80 parts of ethyl alcohol 4) in round-bottomed flask, 20 parts of 7- benzos (c) acridine isothiocyanates are added in, it is rear to add in 30 parts
Benzoyl hydrazine, back flow reaction 3h have in reaction process a large amount of solids to be precipitated, cooling filter orange/yellow solid is 7- benzos
(c) 4., high 7- benzos (c) the acridine isothiocyanates of purity obtained by step 3 is used as reaction to acridine benzamido thiocarbamide
Object is so that the purity of final product 7- benzos (c) acridine benzamido thiocarbamide also accordingly improves.
Wherein 1 part of 7- benzos (c) the acridine benzamido thiocarbamide that step 4) can be obtained and 5 parts of ethyl alcohol, 2 parts the third two
Injection is made in alcohol, 2 parts of polyethylene glycol combinations；By wherein 2 parts of 7- benzos (c) acridine benzamido thiocarbamides and 1 portion of diethylene glycol (DEG),
1 part of glyceryl triacetate, 3 parts of calcium carbonate, 1 part of low substituted hydroxy-propyl methylcellulose, 0.5 part of magnesium stearate, 0.2 part of talcum
Tablet is made in powder, 3 parts of dextrin combinations；By wherein 2 parts of 7- benzos (c) acridine benzamido thiocarbamides and 1 part of glycerine, 2 parts of dextrin,
Pill is made in 0.5 part of povidone, 1.5 parts of octadecyl alcolols, 0.5 part of stearic acid, 1 part of lactose combinations；By wherein 2 parts of 7- benzos (c) a word used for translations
Pyridine benzamido thiocarbamide and 0.5 portion of mannitol, 1.5 parts of sodium bicarbonates, 2 parts of low substituted hydroxy-propyl methylcellulose, 1 part of tristearin
Capsule is made in sour magnesium, the combination of 0.5 talcum powder；By wherein 2 parts of 7- benzos (c) acridine benzamido thiocarbamides and 3 parts of ethyl alcohol, 1 part
Suspending agent is made in propylene glycol, 0.5 part of calcium carbonate, 1 part of low substituted hydroxy-propyl methylcellulose, 1 part of magnesium stearate compositions；It will wherein
1 part of 7- benzos (c) acridine benzamido thiocarbamide and 2 parts of ethyl alcohol, 2 parts of propylene glycol, 1.5 parts of polyethylene glycol, 1 part of glycerine, 1 part of shallow lake
Emulsion is made in powder, 0.3 part of lactose combinations.
7- benzos (c) acridine benzamido thiocarbamide pharmaceutical activity and its application are further illustrated below by experiment
Anti tumor activity in vitro is tested
Using MTT methods, vitro cytotoxicity measure is carried out.7- benzos (c) the acridine benzoyl that embodiment 1-3 is obtained
Amido thiocarbamide respectively with Gastric Cancer MGC -803, BEL-7404, NCI-H460 cell strain action time 72 hours, as a result such as 1 institute of table
Show：
1 7- benzos (c) acridine benzamido thiocarbamide of table is to the medium effective concentration (IC of tumor cell line50)
From the results shown in Table 1,7- benzos (c) acridine benzamido thiocarbamide of the invention is through extracorporeal anti-tumor reality
It tests and shows that the compound has strong antitumor activity.The present invention is researchs and develops new 7- benzos (c) acridine type antineoplastic
Object provides new thinking.
Although the embodiment of invention is disclosed as above, it is not restricted to listed fortune in specification and embodiment
With it can be fully applied to various fields suitable for the present invention, for those skilled in the art, can be easily real
Now other modification, therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is not limited to
Specific details and proportioning example shown and described herein.
Claims (5)
1. a kind of benzo (c) acridine derivatives, it is characterised in that：Its with structural formula 4.：
A kind of 2. preparation method of benzo (c) acridine derivatives according to claim 1, which is characterized in that the benzo
(c) synthetic route of acridine derivatives is as follows：
The preparation method of benzo (c) acridine derivatives includes the following steps：
1) using o-bromobenzoic acid and naphthylamines as raw material, potassium carbonate and copper powder are catalyst, n-amyl alcohol are added in as solvent, through Wu Er
It is graceful that compound N-naphthalene ortho-aminobenzoic acid is obtained by the reaction 1.；
2) compound 7- chlorobenzenes are made simultaneously 1. with phosphorus oxychloride by ring closure reaction in the compound N-naphthalene ortho-aminobenzoic acid
(c) acridine is 2.；
3) the compound 7- chlorobenzenes simultaneously (c) acridine 2. in phase transfer catalyst benzyltriethylammoinium chloride and tricaprylmethyl chlorine
Change under ammonium effect, 3. nucleophilic substitution, which occurs, with sodium sulfocynanate is made 7- benzos (c) acridine isothiocyanates；
4) 3. 7- benzos (c) acridine isothiocyanates is dissolved in after absolute ethyl alcohol and adds in benzoyl hydrazine, back flow reaction, reaction process
In orange-yellow powder solid be precipitated, after suction filtration up to target product 7- benzos (c) acridinium carboxamide base thiocarbamide 4..
3. a kind of benzo (c) acridine derivatives application in preparation of anti-tumor drugs according to claim 1.
4. the application of benzo (c) Acridine derivatives according to claim 3, it is characterised in that：Benzo (c) acridine
Injection, tablet, pill, capsule, suspending agent or emulsion is made with auxiliary material combination in analog derivative.
5. the application of benzo (c) Acridine derivatives according to claim 4, it is characterised in that：The auxiliary material for ethyl alcohol,
Propylene glycol, polyethylene glycol, diethylene glycol (DEG), glyceryl triacetate, glycerine, dextrin, povidone, octadecyl alcolol, stearic acid, microcrystalline cellulose
In element, starch, lactose, mannitol, sodium bicarbonate, calcium carbonate, low substituted hydroxy-propyl methylcellulose, magnesium stearate, talcum powder
It is several.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1036763A (en) * | 1988-03-10 | 1989-11-01 | 美克德株式会社 | The fused quinoline compounds, condense the method for acridine compound, the such compound of preparation and contain such compound control the cancer composition |
| CN104326979A (en) * | 2014-09-30 | 2015-02-04 | 广西中医药大学 | 2-methyl-9-acridine(p-methoxy benzamido)thiourea, preparation method and uses thereof |
| CA2942891A1 (en) * | 2014-03-15 | 2015-09-24 | Wake Forest University | Design, synthesis, and biological activity of platinum-benz[c]acridine hybrid agents and methods associated therewith |
-
2015
- 2015-12-02 CN CN201510870081.5A patent/CN105481769B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1036763A (en) * | 1988-03-10 | 1989-11-01 | 美克德株式会社 | The fused quinoline compounds, condense the method for acridine compound, the such compound of preparation and contain such compound control the cancer composition |
| CA2942891A1 (en) * | 2014-03-15 | 2015-09-24 | Wake Forest University | Design, synthesis, and biological activity of platinum-benz[c]acridine hybrid agents and methods associated therewith |
| CN104326979A (en) * | 2014-09-30 | 2015-02-04 | 广西中医药大学 | 2-methyl-9-acridine(p-methoxy benzamido)thiourea, preparation method and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| Potential Antitumor Agents. 48.3′-Dimethylamino Derivatives of Amsacrine:Redox Chemistry and in Vivo Solid Tumor Activity;Graham J. Atwell et al.;《Journal of Medicinal Chemistry》;19871231;第30卷(第4期);653-658 * |
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