CN110194741A - 4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative and its preparation method and application - Google Patents
4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative and its preparation method and application Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses a kind of 4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivatives and its preparation method and application.Shown in the structure of the derivative such as following formula (I), 1) synthetic method, which mainly comprises the steps that, takes 1- benzoyl piperazine and bromo- 1, the 8- naphthalene anhydride of 3- nitro -4- to be placed in organic solvent and be performed under heating conditions reaction, obtain intermediate product；2) it takes compound shown in intermediate product and formula (II) to be placed in organic solvent and is performed under heating conditions reaction to get target compound.Certain derivatives in derivative of the present invention are active higher compared with mitonafide；R‑NH2(II)；Wherein, R N, N- dimethyl ethyl, ethoxy, 4,5- dihydroxy benzenes ethyl or p-chlorobenzyl.
Description
Technical field
The present invention relates to a kind of 4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative and preparation method thereof and answer
With belonging to pharmaceutical technology field.
Background technique
Since cancer has serious harmfulness to human health, therefore researching and developing efficient anti-tumor drug is medical personnel
Vital task.Existing research shows that 1,8- naphthalimide derivative has important anti-tumor activity, derivative ammonia naphthalene
Fitow (amonafide) and mitonafide (mitonafide) have entered the II clinical trial phase stage.Therefore, it is desirable to be based on
The structure of ammonia naphthalene Fitow and mitonafide can obtain more efficient novel naphthoyl imide compounds.It has had not yet to see at 4
The upper open report for introducing functional groups benzoyl piperazine and preparing 4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative
Road.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of structure novel and with the 4- benzene first of preferable bioactivity
Acyl piperazine -3- nitro -1,8- naphthalimide derivative and its preparation method and application.
4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative of the present invention has as shown in following formula (I)
Structure:
Wherein, R N, N- dimethyl ethyl, ethoxy, 4,5- dihydroxy benzenes ethyl or p-chlorobenzyl.
4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative of the present invention is prepared (R by following routes
As previously described):
Specific preparation method mainly comprises the steps that
1) take 1- benzoyl piperazine (being also referred to as compound 1 in this application) and the bromo- 1,8- naphthalene anhydride of 3- nitro -4- (in this Shen
Please in also referred to as BNA) be placed in organic solvent, reacted under heating condition, reactant is cooling, collects precipitating, obtains centre
Product (is also referred to as compound 2) in this application；The structure of the intermediate product is shown below:
2) it takes compound shown in intermediate product and formula (II) to be placed in organic solvent, is reacted under heating condition, instead
It answers object cooling, collects precipitating to get target compound (corresponding to 3a-3d totally 4 compounds in this application) is arrived；
R-NH2(II)；
Wherein, R N, N- dimethyl ethyl, ethoxy, 4,5- dihydroxy benzenes ethyl or p-chlorobenzyl.
In preparation method of the present invention, the organic solvent be alcohols solvent and/or non-protonic solvent,
In, the alcohols solvent specifically can be the group selected from one or more of methanol, ethyl alcohol, propyl alcohol and n-butanol
It closes；The non-protonic solvent specifically can be sub- selected from ethylene glycol monomethyl ether, N,N-dimethylformamide (DMF), dimethyl
The combination of one or more of sulfone (DMSO), toluene, carbon tetrachloride and acetone.The dosage of the organic solvent can basis
It needs to be determined that, it is generally the case that on the basis of bromo- 1, the 8- naphthalene anhydride of 3- nitro -4- of 1mmol, all reaction raw materials 25-50mL
Organic solvent dissolve.When the additional amount of organic solvent is larger, after fully reacting after preferred elder generation's recovery section organic solvent
(usually removing the organic solvent for accounting for additional amount 40-50%) is cooling by reactant again.
It is whether complete with the condensation reaction of thin-layer chromatography tracing detection in the step 1) of preparation method of the present invention.Reaction
It is preferred that being carried out under the conditions of≤130 DEG C, further preferably carried out under the conditions of 60-130 DEG C, more preferably under the conditions of 80-130 DEG C
It carries out.When reaction carries out under the conditions of 80-130 DEG C, reaction to the time for needing 6-8h completely.It is obtained by step 1) to be
Between product crude product, in order to be further reduced the impurity being introduced into step 2), preferably by intermediate product obtained by step 1) into
Row is used further to after purification in operation described in step 2).The purifying can be purification process conventional in the prior art, this
In application, it is used further in the operation of step 2) after preferably being recrystallized intermediate product with solvent.It is described to be used to recrystallize
Solvent it is identical as being used to synthesize to obtain the organic solvent of intermediate product in synthetic method, preferably methanol or ethyl alcohol.
It is whether complete with the condensation reaction of thin-layer chromatography tracing detection in the step 2) of preparation method of the present invention.Reaction
It is preferred that being carried out under the conditions of≤100 DEG C, further preferably carried out under the conditions of 50-100 DEG C, more preferably under the conditions of 60-80 DEG C
It carries out.When reaction carries out under the conditions of 60-80 DEG C, reaction to the time for needing 3-6h completely.
What above-mentioned synthetic method was prepared is the crude product of target compound, and existing conventional purification process can be used to it
It is purified with the purity of compound shown in raising formula (I), can specifically be purified using recrystallization or silica gel column chromatography.
When being purified using recrystallization, for being used to synthesize to obtain having for target compound in the solvent and synthetic method of recrystallization
Solvent is identical, preferably methanol or ethyl alcohol.When being purified using column chromatography, specifically by the resulting targeted of step 2)
Close object on silica gel column chromatography, the eluent formed with the methylene chloride and methanol for being 1-50:1 by volume ratio (preferably with by
The eluent of methylene chloride and methanol composition that volume ratio is 15:1), solvent is evaporated off in eluent, obtains target after purification
Compound.
Further include the steps that purifying gained target compound.
The invention also includes above-mentioned formula (I) compound or its pharmaceutically acceptable salt answering in the preparation of antitumor drugs
With.
The present invention further comprises a kind of pharmaceutical composition, contains chemical combination shown in the above-mentioned formula (I) for treating upper effective dose
Object or its pharmaceutically acceptable salt.
Compared with prior art, the present invention provides 4- benzoyl piperazine -3- nitro -1,8- naphthoyls of a kind of structure novel
Imine derivative, short preparation period, post-processing is simple, at low cost, and obtained derivative purity is high, quality are stablized；Application
The in vitro test of people the result shows that, pass through 4 in 3- nitro -1,8- naphthalimide and upper introduce functional groups benzoyl piperazines
Make gained 4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative that there is preferable bioactivity, some of them derivative
With extremely significant bioactivity, exploitation is expected into anti-tumor drug.
Specific embodiment
The present invention is described in further detail combined with specific embodiments below, content to better understand the invention, but
The present invention is not limited to following embodiments.
In following embodiment, BNA indicates that bromo- 1, the 8- naphthalene anhydride of 3- nitro -4-, compound 1 indicate 1- benzoyl piperazine, changes
Closing object 2 indicates intermediate product (i.e. 4- benzoyl piperazine -3- nitro -1,8- naphthalene anhydride).
Embodiment 1: the synthesis of compound 2
5.7g (18mmol) BNA is weighed in 100 milliliters of round-bottomed flasks, 10.26g (54mmol) compound 1 is added, adds
Enter ethylene glycol monomethyl ether 50mL, 120 DEG C of reflux 6h, remove partial solvent while hot, stand cool overnight, filter, collects filter cake, use second
Alcohol recrystallization, obtains 4.50g yellow crystals, yield 49.3%.
Structural characterization is carried out to gained yellow crystals, data are as follows:
1H NMR(600MHz,CDCl3) δ 8.62 (d, J=8.5Hz, 1H), 8.50 (d, J=7.2Hz, 1H), 8.46 (s,
1H), 7.92 (t, J=7.9Hz, 1H), 7.49 (s, 5H), 4.79 (dd, J=7.5,4.6Hz, 1H), 4.07 (t, J=6.4Hz,
2H),4.00–3.64(m,4H),3.61–3.55(m,2H).13C NMR(100MHz,DMSO-d6)δ169.53,162.87,
161.76,146.67,142.17,135.60,132.71,131.31,129.71,129.46,128.91,128.53,128.43,
127.05,126.16,122.94,117.77,57.65,51.29.MS m/z:432[M+H]+.
Accordingly, it can be determined that yellow crystals obtained by the present embodiment are compound 2, i.e. 4- benzoyl piperazine -3- nitro -1,8- naphthalene
Acid anhydride, structural formula are shown below:
Embodiment 2: the synthesis of compound 2
2.88g (9mmol) BNA is weighed in 50mL round-bottomed flask, adds 1.71g (9mmol) compound 1, second is added
Alcohol 50mL, 100 DEG C of reflux 6h remove partial solvent while hot, stand cool overnight, filter, and collect filter cake, obtain 1.01g yellow
Powder, yield 20.0%.
Structural characterization is carried out to gained yellow crystals, data are as follows:
1H NMR(600MHz,CDCl3) δ 8.62 (d, J=8.5Hz, 1H), 8.50 (d, J=7.2Hz, 1H), 8.46 (s,
1H), 7.92 (t, J=7.9Hz, 1H), 7.49 (s, 5H), 4.79 (dd, J=7.5,4.6Hz, 1H), 4.07 (t, J=6.4Hz,
2H),4.00–3.64(m,4H),3.61–3.55(m,2H).13C NMR(100MHz,DMSO-d6)δ169.53,162.87,
161.76,146.67,142.17,135.60,132.71,131.31,129.71,129.46,128.91,128.53,128.43,
127.05,126.16,122.94,117.77,57.65,51.29.MS m/z:432[M+H]+.
Accordingly, it can be determined that yellow powder obtained by the present embodiment is compound 2, i.e. 4- benzoyl piperazine -3- nitro -1,8- naphthalene
Acid anhydride.
Embodiment 3: the synthesis of compound 2
2.88g (9mmol) NBA is weighed in 50mL round-bottomed flask, adds 1.71g (9mmol) 1, it is sub- that dimethyl is added
Mixed solvent 50mL, the 80 DEG C of reflux 6h that sulfone and n,N-Dimethylformamide are formed by the volume ratio of 1:1, it is molten to remove part while hot
After agent, cool overnight is stood, filter cake is collected, obtains 1.12g yellow powder, yield 24.46%.
Structural characterization is carried out to gained yellow crystals, data are as follows:
1H NMR(600MHz,CDCl3) δ 8.62 (d, J=8.5Hz, 1H), 8.50 (d, J=7.2Hz, 1H), 8.46 (s,
1H), 7.92 (t, J=7.9Hz, 1H), 7.49 (s, 5H), 4.79 (dd, J=7.5,4.6Hz, 1H), 4.07 (t, J=6.4Hz,
2H),4.00–3.64(m,4H),3.61–3.55(m,2H).13C NMR(100MHz,DMSO-d6)δ169.53,162.87,
161.76,146.67,142.17,135.60,132.71,131.31,129.71,129.46,128.91,128.53,128.43,
127.05,126.16,122.94,117.77,57.65,51.29.MS m/z:432[M+H]+.
Accordingly, it can be determined that yellow powder obtained by the present embodiment is compound 2, i.e. 4- benzoyl piperazine -3- nitro -1,8- naphthalene
Acid anhydride.
Embodiment 4:4- benzoyl piperazine -3- nitro-N- (N, N- dimethyl) ethyl -1,8- naphthalimide (compound 3a)
Synthesis
It weighs 0.60g compound 2 (1.39mmol) in a round bottom flask, adds 0.123g (1.40mmol) N, N- diformazan
Base ethylenediamine adds the dissolution of 50mL ethyl alcohol, and 80 DEG C of reflux 3h, thin-layer chromatography monitoring reaction is after reaction, cooling, filters,
Obtain yellow powder 3a 0.312g, Yield, 44.4%；1H NMR(600MHz,CDCl3) δ δ 8.63 (d, J=8.1Hz, 1H),
8.52 (d, J=7.2Hz, 1H), 8.49 (s, 1H), 7.93 (dd, J=8.4,7.5Hz, 1H), 7.49 (s, 5H), 4.08 (t, J=
6.8Hz,2H),3.99–3.58(m,4H),3.24(s,4H),2.50–2.45(m,2H),2.19(s,6H).13C NMR
(100MHz,DMSO-d6)δ169.50,162.75,161.63,146.78,142.20,135.58,132.82,131.45,
129.69,129.45,128.99,128.51,128.44,127.03,126.34,122.79,117.59,56.29,45.33,
37.68.MS m/z:503[M+H]+.
Accordingly, it can be determined that yellow powder 3a obtained by the present embodiment is 4- benzoyl piperazine -3- nitro-N- (N, N- dimethyl)
Ethyl -1,8- naphthalimide, structural formula are shown below:
The synthesis of embodiment 5:4- benzoyl piperazine -3- nitro-N-hydroxyethyl -1,8- naphthalimide (compound 3b)
It weighs 0.60g compound 2 (1.39mmol) in a round bottom flask, adds 0.115g (1.40mmol) ethanol amine,
The dissolution of 50mL methanol is added, 70 DEG C of reflux 6h, thin-layer chromatography monitoring reaction, after reaction, cooling, filtering obtains yellow
Powder 3b 0.372g, Yield, 52.7%；1H NMR(400MHz,DMSO-d6) δ 8.60 (dd, J=8.5,0.7Hz, 1H),
8.51 (dd, J=7.3,0.8Hz, 1H), 8.47 (s, 1H), 7.92 (dd, J=8.4,7.4Hz, 1H), 4.79 (t, J=5.9Hz,
1H), 4.08 (t, J=6.5Hz, 2H), 3.66 (s, 4H), 3.61-3.56 (m, 2H), 3.22-3.08 (m, 4H), 1.46 (s,
9H).13C NMR(100MHz,DMSO-d6)δ162.90,161.79,153.98,146.90,142.13,132.71,131.30,
129.47,128.94,128.42,126.18,122.95,117.71,79.30,57.64,51.05,41.91,28.03.MS m/
z:475[M+H]+.
Accordingly, it can be determined that yellow powder 3b obtained by the present embodiment is 4- benzoyl piperazine -3- nitro-N-hydroxyethyl -1,8-
Naphthalimide, structural formula are shown below:
The synthesis of embodiment 6:4- benzoyl piperazine -3- nitro-N- p-chlorobenzyl -1,8- naphthalimide (compound 3c)
It weighs 0.60g compound 2 (1.39mmol) in a round bottom flask, adds 0.20g (1.40mmol) to chlorobenzylamine,
The dissolution of 50mL ethyl alcohol is added, 80 DEG C of reflux 4h, thin-layer chromatography monitoring reaction, after reaction, cooling, filtering obtains yellow
Powder 3c 0.402g, Yield, 50.7%；1H NMR (400MHz, DMSO) δ 8.66 (d, J=8.4Hz, 1H), 8.58 (d, J=
7.2Hz, 1H), 8.55 (s, 1H), 7.96 (dd, J=8.3,7.6Hz, 1H), 7.35 (q, J=8.7Hz, 4H), 5.18 (s, 2H),
3.66(s,4H),3.23–3.11(m,4H),1.45(s,9H).13C NMR(100MHz,DMSO-d6)δ162.97,161.86,
153.97,147.24,142.21,136.01,133.07,131.73,129.71,129.51,129.08,128.49,128.27,
126.67,122.81,117.47,79.29,51.10,42.41,28.02.MS m/z:556[M+H]+.
Accordingly, it can be determined that yellow powder 3c obtained by the present embodiment is p-chlorobenzyl -1 4- benzoyl piperazine -3- nitro-N-,
8- naphthalimide, structural formula are shown below:
Embodiment 7:4- benzoyl piperazine -3- nitro-N- (4,5- dihydroxy base) phenethyl -1,8- naphthalimide (chemical combination
Object 3d) synthesis
It weighs 0.60g compound 2 (1.39mmol) in a round bottom flask, adds 0.27g (1.40mmol) hydrochloric acid DOPA
Amine adds 50mL acetone solution, and 60 DEG C of reflux 5h, thin-layer chromatography monitoring reaction is after reaction, cooling, in solvent evaporated
(eluant, eluent is methylene chloride-methanol (V to silica gel column chromatographyMethylene chloride:VMethanol=15:1)), yellow powder 3d 0.422g is obtained,
Yield, 48.5%；1H NMR(400MHz,DMSO-d6) δ 8.79 (s, 1H), 8.65 (d, J=7.8Hz, 2H), 8.57-8.48
(m, 2H), 8.00-7.90 (m, 1H), 7.49 (s, 5H), 6.63 (dd, J=9.9,5.0Hz, 2H), 6.46 (dd, J=8.0,
1.9Hz,1H),4.15–4.06(m,2H),3.94–3.70(m,4H),3.25(s,4H),2.75–2.63(m,2H).13C NMR
(100MHz,DMSO-d6)δ169.52,162.67,161.55,146.82,145.16,143.73,142.21,135.61,
132.80,131.47,129.71,129.51,129.27,129.02,128.54,128.48,127.05,126.29,122.88,
119.21,117.69,115.94,115.59,56.02,51.30,41.48,32.79.MS m/z:567[M+H]+.
Accordingly, it can be determined that yellow powder 3d obtained by the present embodiment is 4- benzoyl piperazine -3- nitro-N- (4,5- dihydroxy
Base) phenethyl -1,8- naphthalimide, structural formula is shown below:
The antitumor action of 4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative to illustrate the invention, Shen
It asks someone (to hold in the palm the anti-tumor activity experiment carried out by target compound made from above-described embodiment 4-7 the method with rice
Naphthylamines and ammonia naphthalene Fitow are reference), and carry out to by target compound made from the various embodiments described above the method to normal thin
The toxicity test of born of the same parents.
Using the anti tumor activity in vitro of mtt assay test compound.Take the cell in logarithmic growth phase, every 180 μ L of hole
(about 4500-5000 cell) celliferous culture medium inoculated is in 96 well culture plates, in 37 DEG C, 5%CO2Under the conditions of abundant humidifying
Culture is for 24 hours.After cell is adherent, sample is added by the amount of every 20 μ L of hole, each sample sets 6 multiple holes, concurrently sets corresponding
Blank control.Continue after cultivating 48h, 10 μ L MTT reagents (concentration 5mg/mL) are added in every hole, continue after being incubated for 4h, inhale on abandoning
Clear liquid, every hole, which adds 150 μ L DMSO, slight 5~8min of concussion reaction, dissolves crystalline particle sufficiently.Blank control group tune
Zero, with microplate reader with 490nm wavelength measure removal background absorbance value after absorbance value (Value), calculate cell inhibitory effect
Rate, the test-compound good to primary dcreening operation antitumous effect continue the IC for being continued to do corresponding cell strain with 5 concentration gradients50Value, institute
It is averaged after thering is experiment to be repeated 3 times.Experimental result is detailed in the following table 1.
Half-suppressed rate concentration (IC of 1. target compound of table to different tumor cell lines50, μM)
From data in table 1: compound 3a-3d is to gastric carcinoma cells MGC-803, to human liver cancer cell HepG2, people
Ovarian cancer cell SKOV-3 and human bladder cancer cell T24 illustrate apparent inhibitory activity, wherein compound 3a to this four plants
The inhibitory activity of human tumor cell line is superior to ammonia naphthalene Fitow, rate concentration (IC half-suppressed50) it is respectively 1.57 ± 0.19 μM, 0.42
± 0.05 μM, 1.88 ± 0.08 μM and 1.88 ± 0.08 μM, mitonafide is even better than to the inhibiting rate of MGC-803 and T24.
The above result shows that by the way that benzoyl piperazine introducing 1,8- naphthalimide structure is prepared novel 4- benzoyl
Piperazine -3- nitro -1,8- naphthalimide antitumoral compounds be it is feasible, be expected to filter out the new antitumoral of high-efficiency low-toxicity
Object is closed, compared with mitonafide, certain 4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivatives (such as compound 3a)
Activity is more efficient.
Claims (10)
1. compound shown in following formula (I)s or its pharmaceutically acceptable salt:
Wherein, R N, N- dimethyl ethyl, ethoxy, 4,5- dihydroxy benzenes ethyl or p-chlorobenzyl.
2. the preparation method of compound described in claim 1, it is characterised in that: mainly comprise the steps that
1) it takes 1- benzoyl piperazine and bromo- 1, the 8- naphthalene anhydride of 3- nitro -4- to be placed in organic solvent, is carried out under heating condition anti-
It answers, reactant is cooling, collects precipitating, obtains intermediate product；The structure of the intermediate product is shown below:
2) it takes compound shown in intermediate product and formula (II) to be placed in organic solvent, is reacted under heating condition, reactant
It is cooling, precipitating is collected to get target compound is arrived；
R-NH2(II)；
Wherein, R N, N- dimethyl ethyl, ethoxy, 4,5- dihydroxy benzenes ethyl or p-chlorobenzyl.
3. preparation method according to claim 2, it is characterised in that: the organic solvent is alcohols solvent and/or non-
Protonic solvent.
4. preparation method according to claim 3, it is characterised in that: the alcohols solvent is selected from methanol, ethyl alcohol, third
The combination of one or more of pure and mild n-butanol.
5. preparation method according to claim 3, it is characterised in that: the non-protonic solvent is selected from ethylene glycol first
The combination of one or more of ether, N,N-dimethylformamide, dimethyl sulfoxide, toluene, carbon tetrachloride and acetone.
6. preparation method according to claim 2, it is characterised in that: in step 1), reaction under the conditions of≤130 DEG C into
Row；In step 2), reaction carries out under the conditions of≤100 DEG C.
7. preparation method according to claim 2, it is characterised in that: in step 1), gained intermediate product is carried out after purification
It is used further to subsequent operation.
8. preparation method according to claim 2, it is characterised in that: further include being purified to gained target compound
Step.
9. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
10. a kind of pharmaceutical composition goes up compound described in the claim 1 of effective dose containing treatment or its is pharmaceutically acceptable
Salt.
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