CN106674136B - Pyrimidine anti-tumor compounds and preparation method thereof - Google Patents
Pyrimidine anti-tumor compounds and preparation method thereof Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
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Abstract
The invention belongs to field of medicaments, and in particular to a kind of compound of the specified chemical structure of anti-tumor activity, and the method for preparing such compound.Such compound belongs to novel VEGFR-2 inhibitor, in vitro to VEGFR-2 kinase inhibiting activity experiment in show good inhibitory activity.The compound can be used for preparing anti-tumor drug.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of compound of the specified chemical structure of anti-tumor activity, and
The method for preparing such compound.
Background technique
Cancer is initiated by the malignant tumour of epithelial tissue, the disease with the characteristics of the fast breeding of cell and transfer, extremely
The rate of dying occupy the first place of all diseases.The newest cancer data in the whole world announced according to international cancer research institution, the whole world in 2012
It increases 14,100,000 cancer patients newly, and will be also incremented by with 11% annual growth rate.Therefore, the research one in terms for the treatment of of cancer
Directly paid close attention to by the whole world.
Currently, there are mainly four types of the modes of clinical treatment cancer: operative treatment, radiation cure, chemotherapy
And immunization therapy.Compared with other three kinds of methods, chemotherapy is usually painless, and is to the lethality of cancer cell
The means institute of other treatment cancer is unapproachable.But most of chemicals simultaneously do not have specificity, are killing cancer cell
While, the normal tissue cell around tumour can be caused to damage, these tissues can be repaired voluntarily usually only after chemotherapy
It is multiple.So searching targeting is strong, significant effect, highly-safe anti-tumor drug have become global medical developer's research
One of hot spot.
With the continuous development of oncomolecularbiology technology, people to Incidence mechanism further insight,
Continuous announcement to a variety of oncogenic pathways, has developed different kinds of molecules target therapeutic agent.Molecular targeted therapy is in tumour
The target molecule and its associated signal paths for occurring, playing a crucial role in development and transfer process, interfere or block its effect, reach
Inhibit tumour growth, the purpose of transfer.Drug in conjunction with carcinogenic site, keeps tumor cell specific dead into internal targeting
Die, will not normal tissue cell bring damage.Currently, the drug for having entered clinical stage includes the small molecule epidermal growth factor
Receptor (epidermal growth factorreceptor, EGFR) inhibitor, the monoclonal marked for certain specific cells
Antibody, the drug of Antineoplastic angiogenesis, multiple target point kinase inhibitor (multi-targeted tyrosine kinase
Inhibitors, TKIs) etc..In short, with the development of molecular biology, treatment of cancer comes into the treatment epoch of targeting.
Therefore, strong, efficient, low toxicity the new anticancer drug of targeting is further researched and developed, oneself becomes the weight that current anti-tumor drug is studied
Want direction.
Summary of the invention
In view of the above-mentioned problems, the present invention provides pyrimidine anti-tumor compounds and preparation method thereof, such compound category
Belong to novel VEGFR-2 inhibitor in novel such compound, in vitro to VEGFR-2 kinase inhibiting activity experiment in show
Good inhibitory activity.
To achieve the goals above, the general structure of pyrimidine anti-tumor compounds provided by the invention is general formula I or leads to
Formula II is specific as follows:
。
Wherein: the position of acid hydrazide group can be 2,3 or 4；X is hydrogen atom, methyl, fluorine atom, chlorine atom
Or bromine atom；The position of fragrant ring substituents can be 2,3 or 4 substitutions, and substitution can be monosubstituted or polysubstituted.
The general structure of the antitumoral compounds is preferred are as follows:。
Wherein: X H, Cl or CH3。
The general formula be the structure of the compound of I be selected from it is following any one, but be not limited only to following compound, as long as
Structural formula of compound meets general formula, is restriction range of the invention.
N'Phenyl -2- (uracil -5- formamido) benzoyl hydrazine.
N'(2- tolyl) -2- (uracil -5- formamido) benzoyl hydrazine.
N'(3- tolyl) -2- (uracil -5- formamido) benzoyl hydrazine.
N'(3- chlorphenyl) -2- (uracil -5- formamido) benzoyl hydrazine.
N'Phenyl -3- (uracil -5- formamido) benzoyl hydrazine.
N'(2- tolyl) -3- (uracil -5- formamido) benzoyl hydrazine.
N'(3- tolyl) -3- (uracil -5- formamido) benzoyl hydrazine.
N'(3- chlorphenyl) -3- (uracil -5- formamido) benzoyl hydrazine.
N'Phenyl -4- (uracil -5- formamido) benzoyl hydrazine.
N'(2- tolyl) -4- (uracil -5- formamido) benzoyl hydrazine.
N'(3- tolyl) -4- (uracil -5- formamido) benzoyl hydrazine.
N'(3- chlorphenyl) -4- (uracil -5- formamido) benzoyl hydrazine.
The general structure of the antitumoral compounds is preferred are as follows:。
Wherein: X H, Cl or CH3。
The structure for the compound that the general formula is II be selected from it is following any one, but be not limited only to following compound, only
It wants structural formula of compound to meet general formulae IV, is restriction range of the invention.
N'Phenyl -2- (uracil -6- formamido) benzoyl hydrazine.
N'(2- tolyl) -2- (uracil -6- formamido) benzoyl hydrazine.
N'(3- tolyl) -2- (uracil -6- formamido) benzoyl hydrazine.
N'- (3- chlorphenyl) -2- (uracil -6- formamido) benzoyl hydrazine.
N'- phenyl -3- (uracil -6- formamido) benzoyl hydrazine.
N'(2- tolyl) -3- (uracil -6- formamido) benzoyl hydrazine.
N'(3- tolyl) -3- (uracil -6- formamido) benzoyl hydrazine.
N'(3- chlorphenyl) -3- (uracil -6- formamido) benzoyl hydrazine.
N'Phenyl -4- (uracil -6- formamido) benzoyl hydrazine.
N'(2- tolyl) -4- (uracil -6- formamido) benzoyl hydrazine.
N'(3- tolyl) -4- (uracil -6- formamido) benzoyl hydrazine.
N'(3- chlorphenyl) -4- (uracil -6- formamido) benzoyl hydrazine.
To achieve the goals above, the present invention also provides the preparation methods that described one kind prepares the antitumoral compounds.
The preparation method of compound shown in the general formula I and II, specifically includes following steps.
Step 1, carboxylic acid uracil obtain uracil acyl chlorides by halogenation.
Step 2, nitrobenzoic acid and substituted phenylhydrazines, which pass through dehydrating condensation and restore, obtains aminobenzoyl aryl hydrazines.
Step 3 obtains step 1 gained pyrimidine acyl chlorides with amino benzoyl aryl hydrazines obtained by 2 steps through acylation reaction
Compound shown in general formula I and II.
The compound can be used for preparing anti-tumor drug.
Beneficial effects of the present invention.
The present invention is when designing the compound, to micromolecular inhibitor and ligand-receptor phase in VEGFR-2 composite structure
The characteristics of interaction, is analyzed, and extracts key pharmacophore and carries out virtual screening, devises a kind of brand new type
VEGFR-2 inhibitor.Pharmacological research shows that the compound of the present invention is thin to human gastric cancer, human gastric cancer MGC-803
Born of the same parents, K562 cell and human leukemia HL60 cell have certain inhibitory activity.
Specific embodiment
Embodiment 1.
N'The preparation method of phenyl -2- (uracil -5- formamido) benzoyl hydrazine.
Step (1),N'The preparation of phenyl -2- nitro-benzoyl hydrazine: o-nitrobenzoic acid is added in 100ml reaction flask
(4g, 23.94mmol), I-hydroxybenzotriazole (3.4g, 25.13mmol), DMF 40ml under the conditions of 0 DEG C, are slowly added to EDCI
(4.82g, 25.13mmol) stirs half an hour, moves to and reacts 2h at room temperature to get active ester solution；It is reacted in another 250ml
Hydrazinobenzene hydrochloride salt (25.13mmol) is added in bottle, 30min is stirred at room temperature, in 0 in pyridine (3.98g, 50.26ml), DMF 30ml
Under the conditions of DEG C, it is slowly added to the active ester solution of above-mentioned preparation, 2h is reacted, moves to and react 6h at room temperature；End of reaction will react
Liquid is poured into water, and crude product is precipitated, and stands 30min, is filtered, is obtained filter cake, is washed, and 40 DEG C are dried overnight, and obtains white solid 4.20g,
Yield: 68.21%.
Step (2),N'The preparation of phenyl -2- amino-benzoyl hydrazine: in 250ml reaction flask be added zinc powder (4.07g,
62.20mmol), ammonium chloride (2.5g, 46.65mmol), ethyl alcohol 90ml, water 60ml, a small amount of glacial acetic acid react 30min at 50 DEG C,
Activated zinc powder；Let cool, reaction flask moved in cold well, temperature control at 0 DEG C hereinafter, be slowly added to N'- substituted-phenyl-neighbour//
P-nitrobenzoylhydrazide (15.55mmol) stirs 10min, moves under room temperature and react 4h, after completion of the reaction, stands half an hour；It will
Reaction solution pours into 20% NaHCO3In solution, ethyl acetate extraction is spin-dried for ethyl acetate and obtains crude product, re-crystallizing in ethyl acetate obtains
Sterling 1.20g, yield 33.96%.
The preparation of step (3), uracil -5- formyl chloride: in 100 mL reaction flasks be added urea pyrimidine -5-carboxylic acid (2g,
12.81mmol), thionyl chloride (1.73ml, 19.22mmol), 30 mL of toluene, two drop DMF, back flow reaction is for 24 hours, cooling, takes out
Filter is to get urea pyrimidine -5- formyl chloride, white powder 2.12g, yield 94.80%.
Step (4),N'The preparation of phenyl -2- (uracil -5- formamido) benzoyl hydrazine (A1): in 100ml reaction flask
Middle additionN'Phenyl -2- amino-benzoyl hydrazine (2.86 mmol), DMF 20ml, pyridine (0.45 g, 5.73 mmol), 0 DEG C
Under be slowly added to urea pyrimidine -5- formyl chloride (0.5 g, 2.86 mmol), react 1h, the reaction was continued under room temperature 12h；End of reaction
Afterwards, reaction solution is poured slowly into water, solid is precipitated, adjusted solution ph to 2-3 with 10% dilute hydrochloric acid, filter to obtain solid, use
It is saturated Na2CO3Solution washing, obtains white solid powder, 40 DEG C are dried overnight to obtain target compound 0.35g, yield: 33.44%.1H NMR (600 MHz, DMSO) δ 11.63 (s, 1H), 10.27 (s, 1H), 8.34 – 8.19 (m, 2H),
7.86 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.18 (dt, J
= 15.6, 7.5 Hz, 3H), 6.83 (d, J = 7.8 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H)。13C
NMR (151 MHz, DMSO-d6) δ167.6, 164.0, 161.9, 152.9, 152.1, 149.6, 137.4,
131.3, 129.1, 128.5, 125.0, 123.7, 123.7, 119.0, 112.7, 103.8。
Embodiment 2.
N'The preparation method of (2- tolyl) -2- (uracil -5- formamido) benzoyl hydrazine.
Using o-methyl-benzene hydrazine as raw material, synthesized according to 1 step of embodiment (1)N'(2- aminomethyl phenyl) -2- nitro-benzene first
Hydrazides, and light yellow solid, as target compound is made according to 1 step of embodiment (4).1H NMR (600 MHz, DMSO)
δ 11.64 (s, 3H), 10.34 (s, 1H), 8.25 (d, J = 6.0 Hz, 2H), 7.75 (d, J = 7.5
Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.23 (dd, J = 16.6, 9.1 Hz, 2H), 7.02 (dd,J = 18.1, 7.5 Hz, 2H), 6.77 (d, J = 8.0 Hz, 1H), 6.68 (t, J = 7.3 Hz, 1H),
2.21 (s, 3H)。13C NMR (151 MHz, DMSO-d6) δ 167.5, 163.6, 161.2, 151.0, 149.3,
146.8, 137.3, 131.5, 130.4, 128.4, 126.8, 124.9, 124.0, 123.8, 122.3, 119.2,
111.4, 104.8, 17.7。
Embodiment 3.
N'The preparation method of (3- tolyl) -2- (uracil -5- formamido) benzoyl hydrazine.
It is synthesized using procarbazine as raw material according to 1 step of embodiment (1)N'(3- aminomethyl phenyl) -2- nitro-benzoyl
Hydrazine, and white solid, as target compound is made according to 1 step of embodiment (4).1H NMR (600 MHz, DMSO) δ
11.63 (s, 2H), 10.27 (s, 1H), 8.24 (s, 2H), 7.76 (d, J = 40.7 Hz, 2H), 7.51
(s, 1H), 7.23 (s, 1H), 7.02 (s, 1H), 6.71 – 6.50 (m, 3H), 2.20 (s, 3H)。13C NMR
(151 MHz, DMSO-d6) d 167.5, 163.6, 161.3, 151.2, 149.6, 138.2, 137.3, 131.4,
129.0, 128.4, 124.9, 123.8, 119.9, 113.2, 110.0, 21.7。
Embodiment 4.
N'(3- chlorphenyl) -2- (uracil -5- formamido) benzoyl hydrazine preparation method.
N'- (3- aminomethyl phenyl) -2- nitro-benzoyl is synthesized according to 1 step of embodiment (1) using procarbazine as raw material
Hydrazine, and white solid, as target compound is made according to 1 step of embodiment (4).1H NMR (600 MHz, DMSO) δ
11.59 (s, 3H), 10.34 (s, 1H), 8.23 (dd, J = 20.5, 11.5 Hz, 3H), 7.71 (d, J =
7.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.16 (t, J =
7.9 Hz, 1H), 6.86 – 6.68 (m, 3H)。13C NMR (151 MHz, DMSO-d6) δ 167.6, 163.7,
161.3, 151.3, 151.1, 149.7, 137.1, 133.9, 131.5, 130.8, 128.4, 125.0, 124.0,
123.9, 118.4, 111.9, 111.3, 104.5。
Embodiment 5.
N'The preparation method of phenyl -3- (uracil -5- formamido) benzoyl hydrazine.
Using gavaculine as raw material, synthesized according to 1 step of embodiment (1)N'Phenyl -3- nitro-benzoyl hydrazine, and
White solid 0.38g, as target compound, yield: 36.31% is made according to 1 step of embodiment (4).1H NMR (600
MHz, DMSO) δ 11.89 (s, 2H), 11.07 (s, 1H), 10.39 (d, J = 2.7 Hz, 1H), 8.30
(s, 1H), 8.10 (s, 1H), 7.91 (d, J = 2.4 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H),
7.48 (t, J = 7.9 Hz, 1H), 7.16 (t, J = 7.8 Hz, 2H), 6.79 (d, J = 7.9 Hz, 2H),
6.72 (t, J = 7.3 Hz, 1H)。 13C NMR (151 MHz, DMSO-d6) δ 166.4, 165.0, 160.9,
150.8, 149.8, 149.3, 138.7, 134.3, 129.6, 129.1, 123.0, 122.8, 119.0, 119.0,
112.7, 104.2。
Embodiment 6.
N'The preparation method of (2- tolyl) -3- (uracil -5- formamido) benzoyl hydrazine.
Using gavaculine and o-methyl-benzene hydrazine as raw material, synthesized according to 1 step of embodiment (1)N'(2- methylbenzene
Base) -3- nitro-benzoyl hydrazine, and yellow solid powder 0.42g, as target chemical combination is made according to 1 step of embodiment (4)
Object, yield: 38.65%.1H NMR (600 MHz, DMSO) δ 11.10 (s, 1H), 10.43 (dd, J = 18.5,
2.5 Hz, 1H), 8.30 (s, 1H), 8.12 (d, J = 11.2 Hz, 1H), 7.92 (dd, J = 8.1, 1.3
Hz, 1H), 7.82 – 7.73 (m, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.50 (dt, J = 15.9,
7.9 Hz, 1H), 7.29 (t, J = 3.2 Hz, 1H), 7.02 (dd, J = 12.1, 7.4 Hz, 2H), 6.73
– 6.65 (m, 2H), 2.21 (s, 3H)。13C NMR (151 MHz, DMSO-d6) δ 166.4, 165.0, 161.0,
151.1, 149.7, 147.1, 138.8, 134.3, 130.4, 129.6, 126.8, 123.0, 122.7, 122.3,
119.1, 119.0, 111.4, 104.1, 17.7。
Embodiment 7.
N'The preparation method of (3- tolyl) -3- (uracil -5- formamido) benzoyl hydrazine.
Using gavaculine and procarbazine as raw material, N'- (3- methylbenzene is synthesized according to 1 step of embodiment (1)
Base) -3- nitro-benzoyl hydrazine, and yellow solid powder 0.46g, as target chemical combination is made according to 1 step of embodiment (4)
Object, yield: 42.33%.1H NMR (DMSO-d6 ,600MHz): δ 8.30 (br. s., 1H), 7.98 (d, J=7.3
Hz, 1H), 7.83 (s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.03
(t, J=7.6 Hz, 1H), 6.61 (br. s., 1H), 6.54 (d, J=7.3 Hz, 1H), 2.21 (s, 3H)。13C
NMR (151 MHz, DMSO-d6) δ 166.4, 149.9, 138.2, 134.3, 129.6, 129.0, 128.9,
123.0, 119.9, 119.0, 113.2, 113.2, 113.2, 110.0, 21.7。
Embodiment 8.
N'The preparation method of (3- chlorphenyl) -3- (uracil -5- formamido) benzoyl hydrazine.
Using gavaculine and chlorophenyl hydrazine as raw material, N'- (3- chlorphenyl) -3- is synthesized according to 1 step of embodiment (1)
Nitro-benzoyl hydrazine, and white solid powder 0.40g, as target compound is made according to 1 step of embodiment (4), yield:
34.93%。1H NMR (600 MHz, DMSO) δ 11.33 (s, 1H), 10.44 (s, 1H), 8.39 (s, 1H),
8.23 (s, 1H), 8.09 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.7 Hz,
1H), 7.46 (t, J = 7.9 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.75 (dd, J = 11.2,
4.9 Hz, 3H)。13C NMR (151 MHz, DMSO-d6) δ 166.6, 165.7, 162.4, 151.5, 139.4,
133.9, 133.9, 130.8, 129.6, 122.9, 122.2, 118.7, 118.4, 111.9, 111.3, 102.3。
Embodiment 9.
N'The preparation method of phenyl -4- (uracil -5- formamido) benzoyl hydrazine.
With p-aminobenzoic acid raw material, synthesized according to 1 step of embodiment (1)N'Phenyl -4- nitro-benzoyl hydrazine, and press
Target compound 0.41g, yield: 39.18% is made according to 1 step of embodiment (4).1H NMR (600 MHz, DMSO) δ
10.34 (s, 1H), 9.83 (s, 1H), 8.28 (s, 1H), 7.99 (dd, J = 18.2, 7.7 Hz, 1H),
7.90 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.21 (dt, J
= 15.6, 7.5 Hz, 3H), 6.82 (d, J = 7.8 Hz, 2H), 6.50 (t, J = 7.3 Hz, 1H)。13C
NMR (151 MHz, DMSO-d6) δ166.1, 164.9, 161.0, 150.7, 150.0, 149.3, 141.4,
129.2, 129.1, 128.9, 128.8, 128.5, 125.3, 123.2, 122.9, 119.4, 119.0, 112.8,
112.7, 104.2。
Embodiment 10.
N'The preparation method of (2- tolyl) -4- (uracil -5- formamido) benzoyl hydrazine.
Using p-aminobenzoic acid and o-methyl-benzene hydrazine as raw material, synthesized according to 1 step of embodiment (1)N'(2- tolyl)-
4- nitro-benzoyl hydrazine, and yellow solid powder 0.41g, as target compound is made according to 1 step of embodiment (4), it receives
Rate: 37.73%.1H NMR (600 MHz, DMSO) δ 11.49 (s, 1H), 10.30 (s, 1H), 8.42 (d, J =
8.3 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.22 (s,
1H), 7.02 (dd, J = 11.6, 7.5 Hz, 2H), 6.73 – 6.63 (m, 2H), 2.21 (s, 3H)。13C
NMR (151 MHz, DMSO-d6) δ 166.1, 147.3, 142.3, 130.3, 128.8, 127.5, 126.8,
122.3, 119.0, 111.5, 17.7。13C NMR (151 MHz, DMSO-d6) δ 166.4, 165.0, 161.0,
151.1, 149.7, 147.1, 138.8, 134.3, 130.4, 129.6, 126.8, 123.0, 122.7, 122.3,
119.1, 119.0, 111.4, 104.1, 17.7。
Embodiment 11.
N'The preparation method of (3- tolyl) -4- (uracil -5- formamido) benzoyl hydrazine.
Using p-aminobenzoic acid and procarbazine as raw material, synthesized according to 1 step of embodiment (1)N'(3- tolyl)-
4- nitro-benzoyl hydrazine, and yellow solid powder 0.39g, as target compound is made according to 1 step of embodiment (4), it receives
Rate: 35.89%.1H NMR (600 MHz, DMSO) δ 11.75 (s, 1H), 10.22 (s, 1H), 8.50 (s,
1H), 7.88 (d, J = 8.6 Hz, 2H), 7.79 – 7.67 (m, 3H), 7.02 (t, J = 7.7 Hz, 1H),
6.63 – 6.56 (m, 2H), 6.53 (d, J = 7.4 Hz, 1H), 2.21 (s, 3H)。13C NMR (151 MHz,
DMSO-d6) δ 166.7, 166.3, 164.4, 163.2, 160.1, 150.1, 143.0, 138.1, 129.0,
128.7, 126.8, 119.8, 118.6, 113.3, 110.1, 99.5, 60.1, 21.7。
Embodiment 12.
N'The preparation method of (3- chlorphenyl) -4- (uracil -5- formamido) benzoyl hydrazine.
Using p-aminobenzoic acid and chlorophenyl hydrazine as raw material, synthesized according to 1 step of embodiment (1)N'(3- tolyl) -4-
Nitro-benzoyl hydrazine, and yellow solid powder 0.38g, as target compound is made according to 1 step of embodiment (4), yield:
33.18%。1H NMR (600 MHz, DMSO) δ 11.59 (s, 1H), 10.31 (s, 1H), 8.45 (s, 1H),
8.18 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.16 (t, J
= 8.0 Hz, 1H), 6.83 – 6.67 (m, 3H)。13C NMR (151 MHz, DMSO-d6) δ 166.3, 166.2,
163.4, 159.1, 157.3, 151.7, 142.7, 133.8, 130.8, 128.8, 126.9, 118.9, 118.3,
111.9, 111.3, 100.9。
Embodiment 13.
N'The preparation method of phenyl -2- (uracil -6- formamido) benzoyl hydrazine.
Using uracil -6- formic acid as raw material, uracil -6- formyl chloride is synthesized according to 1 step of embodiment (3), and according to reality
It applies 1 step of example (4) and white solid powder 0.42g, as target compound, yield: 40.13% is made.1H NMR (600
MHz, DMSO) δ 10.14 (d, J = 83.4 Hz, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.06 (s,
1H), 7.93 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.20 (dt, J = 41.3,
7.7 Hz, 4H), 6.87 (d, J = 7.8 Hz, 2H), 6.73 (t, J = 7.0 Hz, 1H), 5.92 (s,
1H)。13C NMR (151 MHz, DMSO-d6) δ 166.4, 166.2, 162.6, 151.6,149.6, 137.4,
131.3, 129.1, 128.5, 125.0, 123.7, 123.7, 119.0, 112.7, 103.8。
Embodiment 14.
N'The preparation method of (2- tolyl) -2- (uracil -6- formamido) benzoyl hydrazine.
Using o-methyl-benzene hydrazine as raw material, synthesized according to 1 step of embodiment (1)N'(2- aminomethyl phenyl) -2- nitro-benzene first
Hydrazides, then using uracil -6- formic acid as raw material, uracil -6- formyl chloride is synthesized according to 1 step of embodiment (3), finally according to reality
It applies 1 step of example (4) and white solid powder 0.44g, as target compound, yield: 40.49% is made.1H NMR (600
MHz, DMSO) δ 10.09 (d, J = 27.4 Hz, 1H), 8.57 (d, J = 7.9 Hz, 1H), 7.95 (d, J
= 7.4 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.24 (t, J = 6.9 Hz, 1H), 7.05 (s,
2H), 6.86 (s, 1H), 6.74 – 6.65 (m, 1H), 5.90 (s, 1H), 2.24 (s, 3H)。13C NMR
(151 MHz, DMSO-d6) δ 169.1, 166.9, 166.8, 166.8, 150.3, 146.6, 138.4, 132.5,
130.4, 128.9, 126.9, 123.6, 122.7, 121.0, 119.3, 119.0, 111.2, 17.8。
Embodiment 15.
N'The preparation method of (3- tolyl) -2- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using procarbazine as raw material according to 1 step of embodiment (1)N'(3- aminomethyl phenyl) -2- nitro-benzoyl
Hydrazine, then using uracil -6- formic acid as raw material, uracil -6- formyl chloride is synthesized according to 1 step of embodiment (3), finally according to implementation
White solid 0.46g, as target compound, yield: 42.33% is made in 1 step of example (4).1H NMR (600 MHz,
DMSO) δ 10.03 (s, 1H), 8.58 (d, J = 8.3 Hz, 1H), 8.03 – 7.86 (m, 2H), 7.56
(t, J = 7.2 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.70
(d, J = 7.9 Hz, 2H), 6.56 (d, J = 7.0 Hz, 1H), 5.88 (s, 1H), 2.22 (s, 3H)。13C
NMR (151 MHz, DMSO-d6) δ 167.0, 149.4, 138.5, 138.3, 129.1, 128.8, 123.5,
120.8, 120.3, 113.6, 110.3, 96.3, 21.7。
Embodiment 16.
N'The preparation method of (3- chlorphenyl) -2- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using chlorophenyl hydrazine as raw material according to 1 step of embodiment (1)N'(3- chlorphenyl) -2- nitro-benzoyl hydrazine,
Again using uracil -6- formic acid as raw material, uracil -6- formyl chloride is synthesized according to 1 step of embodiment (3), finally according to embodiment 1
White solid 0.36g, as target compound, yield: 31.43% is made in step (4).1H NMR (600 MHz, DMSO) δ
10.11 (s, 1H), 8.09 (s, 1H), 7.64 (s, 2H), 7.16 (s, 2H), 6.73 (s, 4H), 6.55
(s, 1H), 6.39 (s, 2H)。13C NMR (151 MHz, DMSO-d6) δ 169.2, 151.8, 150.3, 133.8,
132.7, 130.8, 128.3, 118.3, 116.8, 115.1, 112.8, 111.8, 111.2。
Embodiment 17.
N'The preparation method of phenyl -3- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using gavaculine as raw material according to 1 step of embodiment (1)N'Phenyl -3- nitro-benzoyl hydrazine, then
Using uracil -6- formic acid as raw material, uracil -6- formyl chloride is synthesized according to 1 step of embodiment (3), finally according to 1 step of embodiment
Suddenly white solid powder 0.39g, as target compound, yield: 37.26% is made in (4).1H NMR (600 MHz, DMSO)
δ 10.35 (s, 1H), 9.84 (s, 1H), 8.29 (s, 1H), 8.04 – 7.87 (m, 2H), 7.64 (d, J
= 7.6 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.16 (t, J = 7.8 Hz, 2H), 6.86 –
6.65 (m, 3H), 5.87 (s, 1H)。13C NMR (151 MHz, DMSO-d6) δ 167.4, 166.7, 163.8,
159.9, 149.8, 138.7, 134.2, 129.3, 129.1, 123.0, 122.7, 119.2, 119.0, 112.7,
95.4。
Embodiment 18.
N'The preparation method of (2- tolyl) -3- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using gavaculine and o-methyl-benzene hydrazine as raw material according to 1 step of embodiment (1)N'(2- tolyl)-
3- nitro-benzoyl hydrazine, then using uracil -6- formic acid as raw material, uracil -6- formyl is synthesized according to 1 step of embodiment (3)
Finally white solid powder 0.33g, as target compound, yield: 30.37% is made according to 1 step of embodiment (4) in chlorine.1H
NMR (DMSO-d6 ,600MHz): δ 8.30 (s, 1H), 8.08 - 8.14 (m, 1H), 7.88 - 7.98 (m,
1H), 7.65 (d, J=7.7 Hz, 1H), 7.46-7.53 (m, 1H), 7.28-7.30 (m, 1H), 7.03 (d, J
=7.2 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 2.18 - 2.22 (m, 4H)。13C NMR (151 MHz,
DMSO-d6) δ 166.1, 151.4, 151.2, 148.1, 143.8, 134.2, 134.0, 133.9, 133.9,
130.9, 130.9, 129.7, 124.7, 121.6, 118.6, 118.5, 112.0, 111.9, 111.4, 111.3。
Embodiment 19.
N'The preparation method of (3- tolyl) -3- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using gavaculine and procarbazine as raw material according to 1 step of embodiment (1)N'(3- tolyl)-
3- nitro-benzoyl hydrazine, then using uracil -6- formic acid as raw material, uracil -6- formyl is synthesized according to 1 step of embodiment (3)
Finally white solid powder 0.35g, as target compound, yield: 33.21% is made according to 1 step of embodiment (4) in chlorine.1H
NMR (DMSO-d6 ,600MHz): δ 8.31 (d, J=7.7 Hz, 1H), 8.07 (s, 1H), 7.85 - 7.94
(m, 1H), 7.75 - 7.84 (m, 1H), 7.66 - 7.74 (m, 1H), 7.62 (d, J=7.3 Hz, 1H),
7.46 (t, J=7.9 Hz, 1H), 7.03 - 7.13 (m, 1H), 6.60 - 6.66 (m, 1H), 2.14 - 2.24
(m, 4H)。13C NMR (151 MHz, DMSO-d6) δ 166.0, 165.9, 161.7, 147.3, 138.2, 134.3,
129.6, 129.0, 128.9, 123.0, 119.9, 119.0, 113.2, 113.2, 113.2, 110.0, 21.7。
Embodiment 20.
N'The preparation method of (3- chlorphenyl) -3- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using gavaculine and chlorophenyl hydrazine as raw material according to 1 step of embodiment (1)N'(3- chlorphenyl) -3-
Nitro-benzoyl hydrazine, then using uracil -6- formic acid as raw material, uracil -6- formyl chloride is synthesized according to 1 step of embodiment (3),
White solid powder 0.42g, as target compound, yield: 36.67% finally is made according to 1 step of embodiment (4).1H
NMR (DMSO-d6 ,600MHz): δ 11.32 (s, 1H), 10.43 (br. s., 1H), 8.39 (s, 1H),
8.19 - 8.27 (m, 1H), 8.08 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.5 Hz,
1H), 7.45 (t, J=7.9 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.68 - 6.81 (m, 3H)。13C
NMR (151 MHz, DMSO-d6) δ166.1, 151.4, 151.2, 148.1, 143.8, 134.2, 134.0,
133.9, 133.9, 130.9, 130.9, 129.7, 124.7, 121.6, 118.6, 118.5, 112.0, 111.9,
111.4, 111.3。
Embodiment 21.
N'The preparation method of phenyl -4- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using p-aminobenzoic acid as raw material according to 1 step of embodimentN'Phenyl -3- nitro-benzoyl hydrazine, then with urine
Pyrimidine -6- formic acid is raw material, uracil -6- formyl chloride is synthesized according to 1 step of embodiment (3), finally according to 1 step of embodiment
(4) white solid powder 0.38g, as target compound, yield: 36.31% is made.1H NMR (DMSO-d6 ,
600MHz): δ 8.40 (d, J=8.7 Hz, 1H), 8.26 - 8.32 (m, 1H), 8.18 (s, 1H), 8.15
(d, J=2.3 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.01 - 8.06 (m, 1H), 7.97 (dd, J=
13.0, 2.6 Hz, 1H), 7.86 (d, J=2.6 Hz, 1H)。 13C NMR (151 MHz, DMSO-d6) δ150.0,
149.8, 149.7, 149.6, 129.2, 129.1, 128.9, 128.6, 128.5, 125.3, 123.2, 122.9,
119.6, 119.2, 119.1, 119.0, 112.8, 112.7。
Embodiment 22.
N'The preparation method of (2- tolyl) -4- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using p-aminobenzoic acid and o-methyl-benzene hydrazine as raw material according to 1 step of embodiment (1)N'(2- tolyl)-
3- nitro-benzoyl hydrazine, then using uracil -6- formic acid as raw material, uracil -6- formyl is synthesized according to 1 step of embodiment (3)
Finally white solid powder 0.38g, as target compound, yield: 34.79% is made according to 1 step of embodiment (4) in chlorine.1H
NMR (DMSO-d6 ,600MHz): δ 7.85 - 7.95 (m, J=8.5 Hz, 2H), 7.70 - 7.77 (m, J=8.5
Hz, 2H), 7.21 (br. s., 1H), 6.96 - 7.05 (m, 2H), 6.58 - 6.76 (m, 2H), 2.11 -
2.24 (m, 3H)。 13C NMR (151 MHz, DMSO-d6) δ 166.0, 165.9, 161.7, 147.3, 141.3,
130.3, 128.8, 128.6, 126.8, 122.3, 119.8, 119.1, 111.5, 98.5, 17.7。
Embodiment 23.
N'The preparation method of (3- tolyl) -4- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using p-aminobenzoic acid and procarbazine as raw material according to 1 step of embodiment (1)N'(3- tolyl)-
3- nitro-benzoyl hydrazine, then using uracil -6- formic acid as raw material, uracil -6- formyl is synthesized according to 1 step of embodiment (3)
Finally white solid powder 0.44g, as target compound, yield: 40.49% is made according to 1 step of embodiment (4) in chlorine.1H
NMR (600 MHz, DMSO) δ 9.86 (d, J = 2.5 Hz, 1H), 7.64 (s, 1H), 7.63 (s, 1H),
7.60 (d, J = 2.5 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.60 – 6.48 (m, 6H), 5.68
(s, 2H), 2.19 (s, 3H)。13C NMR (151 MHz, DMSO-d6) d 166.7, 152.4, 150.5, 139.7,
138.0, 134.1, 133.0, 129.9, 128.9, 123.0, 121.0, 119.8, 119.6, 113.4, 113.2,
113.0, 110.0, 21.7。
Embodiment 24.
N'The preparation method of (3- chlorphenyl) -4- (uracil -6- formamido) benzoyl hydrazine.
It is synthesized using p-aminobenzoic acid and chlorophenyl hydrazine as raw material according to 1 step of embodiment (1)N'(3- chlorphenyl) -3-
Nitro-benzoyl hydrazine, then using uracil -6- formic acid as raw material, uracil -6- formyl chloride is synthesized according to 1 step of embodiment (3),
White solid powder 0.40g, as target compound, yield: 34.93% finally is made according to 1 step of embodiment (4).1H
NMR (600 MHz, DMSO) δ 10.36 (s, 3H), 8.20 (s, 1H), 7.91 (dd, J = 26.9, 8.5
Hz, 4H), 7.16 (t, J = 8.0 Hz, 1H), 6.83 – 6.68 (m, 3H), 5.99 (s, 1H)。13C NMR
(151 MHz, DMSO-d6) d 166.4, 166.2, 162.6, 151.6, 141.5, 133.8, 130.8, 128.6,
128.2, 119.7, 118.4, 111.9, 111.3, 97.4。
One, VEGFR-2 kinase inhibiting activity is tested in vitro.
Using the method for Mobility Shift Assay, in the case where Km ATP, vitro kinase VEGFR-2 is carried out
The screening of compound, using compound staurosporine as standard control, each diluted chemical compound is clicked through at 10 concentration
The detection of row single hole.
1. the dilution of compound.
It is separately added into the 10 mM compound prepared by the present invention of 30pL in EP pipe, is then respectively adding the 100% of 7 μ L
DMSO is made into the 2.5 mM compound prepared by the present invention of 100 μ L.Compound in the EP pipe is transferred to 96 orifice plates respectively
Two column in, therefrom take 20^iL to be added in its metapore, at the same be added 60 μ L, 100% DMSO, in this ratio successively dilute 10 it is dense
Degree, compound concentration variation range i.e. 2.5 mM to 9.5 nM.Every row first on 96 orifice plate, and most latter two hole are added 60
100% DMSO of μ L does blank control.Every hole draws 5 μ L and another 96 orifice plate is added from above-mentioned 96 orifice plate, and it is super that 45 μ L are added
Pure water.5 μ L are shifted into 384 orifice plates from every hole again, i.e. solution in the A1 of 96 orifice plates is transferred to the A1 and A2 two of 384 orifice plates
In a hole, and the solution (maximum concentration of compound) in A2 is transferred in two holes A3, A4 of 384 orifice plates, successively class
It pushes away.Therefore, just there are 5 times of compounds of the 10% DMSO dissolution of 5 μ L in 384 hole reaction plates.
2. kinase reaction.
1 times of kinase buffer liquid is added in kinases, forms 2.5 times of enzyme solutions；The polypeptide of FAM label and ATP are added 1 times to swash
Enzyme buffer liquid forms 2.5 times of substrate solutions；On 384 hole reaction plates of 5 times of compounds of the 10% DMSO dissolution of existing 5 μ L
2.5 times of enzyme solutions of lO μ L are added；Then it is incubated at room temperature 10 minutes；It is added 10 μ L's into the 384 hole reaction plate again
2.5 times of substrate solutions；It is incubated at 28 DEG C after a certain period of time, 25 μ L terminate liquids is added to terminate reaction.
3. inhibiting rate calculates.
The reading and converting rate data from Caliper, conversion at inhibiting rate data.
Percent inhibition=(max-conversion)/(max-min) * 100, max refers to that DMSO is compareed
Conversion ratio, min refers to the conversion ratio of no enzyme activity control.
IC is obtained after XLfit50Data.
Equation is as follows.
。
Experimental result is shown in Table 1.
1 target compound of table is to VEGFR-2 kinase inhibiting activity IC50 value.
Wherein A1-12 is the compound of embodiment 1-12 preparation；B1-12 is the compound of embodiment 13-24 preparation；More than
Experimental data shows that the compound in the present invention has preferable VEGFR-2 kinase inhibiting activity, thus for further investigation and opens
The anti-tumor drug for sending out new opens new approach.
Claims (7)
1. pyrimidine anti-tumor compounds, which is characterized in that the general structure of the compound is general formula I or general formula II, tool
Body is as follows, and the position of acid hydrazide group can be 2,3 or 4 in the general formula；X be hydrogen atom, methyl, fluorine atom,
Chlorine atom or bromine atom；The position of X substituent group can be 2,3 or 4 substitutions of phenyl ring, and substitution can be monosubstituted or more
Replace
。
2. pyrimidine anti-tumor compounds as described in claim 1, which is characterized in that the general formula of the antitumoral compounds
It is preferred that are as follows:
Wherein: X H, Cl or CH3。
3. pyrimidine anti-tumor compounds as claimed in claim 2, which is characterized in that the general formula is the compound of I are as follows:N'Phenyl -2- (uracil -5- formamido) benzoyl hydrazine；N'(2- tolyl) -2- (uracil -5- formamido) benzene first
Hydrazides；N'(3- tolyl) -2- (uracil -5- formamido) benzoyl hydrazine；N'(3- chlorphenyl) -2- (uracil -5- first
Amide groups) benzoyl hydrazine；N'Phenyl -3- (uracil -5- formamido) benzoyl hydrazine；N'(urine is phonetic by (2- tolyl) -3-
Pyridine -5- formamido) benzoyl hydrazine；N'(3- tolyl) -3- (uracil -5- formamido) benzoyl hydrazine；N'(3- chlorobenzene
Base) -3- (uracil -5- formamido) benzoyl hydrazine；N'Phenyl -4- (uracil -5- formamido) benzoyl hydrazine；N'-
(2- tolyl) -4- (uracil -5- formamido) benzoyl hydrazine；N'(3- tolyl) -4- (uracil -5- formamido)
Benzoyl hydrazine；N'(3- chlorphenyl) -4- (uracil -5- formamido) benzoyl hydrazine.
4. pyrimidine anti-tumor compounds as described in claim 1, which is characterized in that the general formula of the antitumoral compounds
It is preferred that are as follows:
Wherein: X H, Cl or CH3。
5. pyrimidine anti-tumor compounds as claimed in claim 4, which is characterized in that the compound that the general formula is II
Are as follows:N'Phenyl -2- (uracil -6- formamido) benzoyl hydrazine；N'(2- tolyl) -2- (uracil -6- formamido)
Benzoyl hydrazine；N'(3- tolyl) -2- (uracil -6- formamido) benzoyl hydrazine；N'- (3- chlorphenyl) -2- (uracil -
6- formamido) benzoyl hydrazine；N'- phenyl -3- (uracil -6- formamido) benzoyl hydrazine；N'(2- tolyl) -3- (urine
Pyrimidine -6- formamido) benzoyl hydrazine；N'(3- tolyl) -3- (uracil -6- formamido) benzoyl hydrazine；N'(3- chlorine
Phenyl) -3- (uracil -6- formamido) benzoyl hydrazine；N'Phenyl -4- (uracil -6- formamido) benzoyl hydrazine；N'-
(2- tolyl) -4- (uracil -6- formamido) benzoyl hydrazine；N'(3- tolyl) -4- (uracil -6- formamido)
Benzoyl hydrazine；N'(3- chlorphenyl) -4- (uracil -6- formamido) benzoyl hydrazine.
6. the preparation method of antitumoral compounds a method as claimed in any one of claims 1 to 5, feature is in specifically including following step
It is rapid:
Step 1, carboxylic acid uracil obtain uracil acyl chlorides by halogenation；
Step 2, nitrobenzoic acid and substituted phenylhydrazines pass through dehydrating condensation and restore the amino benzoyl phenyl hydrazine replaced；
Step 3 obtains step 1 gained uracil acyl chlorides with the aminobenzoyl phenyl hydrazine replaced obtained by 2 steps through acylation reaction
To compound shown in general formula I and II.
7. compound a method as claimed in any one of claims 1 to 5 is used to prepare anti-tumor drug, the mechanism of the anti-tumor drug is
Inhibit the activity of VEGFR-2 kinases.
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