CN109053697A - A kind of pyrimidines and preparation method thereof for anticancer - Google Patents
A kind of pyrimidines and preparation method thereof for anticancer Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The present invention provides a kind of pyrimidines and preparation method thereof for anticancer.Novel pyrimidines compound provided by the invention can effectively inhibit the growth of knurl, and can increase the weight of cancer mouse to improve its immunity.On the other hand, the preparation method of novel pyrimidines compound of the present invention is simple to operation, can be effectively reduced and be produced into original realization industrialized production.
Description
Technical field
Field of the present invention belongs to drug field, and in particular to a kind of for the pyrimidines of anticancer and its preparation side
Method.
Background technique
" cancer " described in general people traditionally refers to all malignant tumours.Medically, cancer (cancer) refers to
Malignant tumour originating from epithelial tissue is most common one kind in malignant tumour.Cancer have cell differentiation and proliferative disorder,
The biological properties such as out of hand, wellability and metastatic are grown, are a multiple-factor, the complex process of multi-step,
It is divided into carcinogenic, rush three cancer, evolution processes, with smoking, infection, occupational exposure, environmental pollution, unreasonable diet, inherent cause
It is closely related.
There are many kinds of cancers, and property type is different, the tissue that involves is different with organ, stadium is different, to various treatments
Reaction it is also different, therefore most of patient needs to carry out complex treatment.So-called complex treatment is exactly the body shape according to patient
Condition, is invaded situations such as range the histological type of tumour, comprehensive to be controlled using operation, chemotherapy, radiotherapy, immunization therapy, traditional Chinese medicine
The means such as treatment, interventional therapy, micro-wave therapeutic to greatly improve cure rate, and improve the quality of life of patient.But
Various treatment methods are all that there are certain Pros and Cons, such as chemotherapy usually to use two kinds or more of medicine simultaneously
Object, referred to as " polychemotherapy ", the chemotherapy of most of sufferers is all to carry out in such a way, but costly, and pair is made
With it is big the features such as allow small part poverty patient to hang back.Come in consideration of it, the present invention provides the novel pyrimidines of one kind
Prevent and treat lung cancer.
Summary of the invention
For problems in the prior art, it is an object of that present invention to provide a kind of pyrimidines for anticancer
And preparation method thereof.
To achieve the goals above, the invention adopts the following technical scheme:
A kind of pyrimidines for anticancer, the structure of the compound are shown in formula I:
Wherein, R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3, benzyl or replace benzyl；N is whole between 1-4
Number, integer of the m between 0-4；
R1For phenyl, substituted phenyl,Or the alkyl of C1-C4.
In above-mentioned pyrimidines, the R is-(CH as a preferred implementation manner,2)nO(CH2)mCH3Or it takes
The benzyl in generation；Integer of the n between 1-4, integer of the m between 0-4.
In above-mentioned pyrimidines, the R as a preferred implementation manner,1For phenyl, substituted phenyl,
A second object of the present invention is to provide a kind of preparation methods of above-mentioned pyrimidines, include the following steps:
Wherein, R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3, benzyl or replace benzyl；N is whole between 1-4
Number, integer of the m between 0-4；
R1For phenyl, substituted phenyl,Or the alkyl of C1-C4.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound B synthetic method
It is as follows:
Take N- tertbutyloxycarbonyl -2- (amino methyl) -3- bromine pyrroles,Condensing agent, alkaline matter are added to solvent
In, it is stirred 2-6 hours at 25-60 DEG C, obtains reaction solution；
R1For phenyl, substituted phenyl,Or the alkyl of C1-C4；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, organic phase concentration are added into the reaction solution
Column purification is crossed afterwards, is collected refined solution and is evaporated under reduced pressure to obtain compound B in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound B synthesis side
In method, the dosage relation of compound A and the solvent is 0.1-0.5mol/L in the Formula II；
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound B synthesis side
It is described in methodMole be 1-1.1 times of compound A mole in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound B synthesis side
In method, the mole of the condensing agent is 1.1-2 times of compound A mole in the Formula II；The condensing agent is preferably
HATU (2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester), (dicyclohexyl carbon two is sub- by DCC
Amine), any one of PyBOP (hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus).
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound B synthesis side
In method, the mole of the alkaline matter is 1.1-2 times of compound A mole in the Formula II；It is highly preferred that the alkalinity
Substance selects one of triethylamine, pyridine, diisopropyl ethyl amine, DMAP or a variety of.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound B synthesis side
In method, the solvent is one of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, dioxane or a variety of.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound C synthetic method
It is as follows:
The Formula II compound B is added to the hydrochloric acid dioxane solution of 2-4M, stirs 1-2 hours, obtains at room temperature
To reaction solution；
The reaction solution is evaporated under reduced pressure to obtain compound C in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound C synthetic method
In, compound B and the magnitude relation that is used in of the hydrochloric acid dioxane solution are 0.1-0.5mol/L in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound D synthesis condition
It is as follows:
Compound C, R-Br, alkaline matter are added in solvent in modus ponens II, stir 2-6 hours at 25-60 DEG C, obtain anti-
Answer liquid；
Wherein, the R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3, benzyl or replace benzyl；N is between 1-4
Integer, integer of the m between 0-4；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, organic phase concentration are added into the reaction solution
Column purification is crossed afterwards, is collected refined solution and is evaporated under reduced pressure to obtain compound D in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound D synthesis item
In part, the dosage relation of compound C and the solvent is 0.1-0.5mol/L in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound D synthesis item
In part, the mole of the R-Br is 1-2 times of compound C mole in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound D synthesis item
In part, the mole of the alkaline matter is 1.1-2 times of compound C mole in the Formula II；It is highly preferred that the alkalinity
Substance selects one of triethylamine, pyridine, diisopropyl ethyl amine, DMAP or a variety of.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound D synthesis item
In part, the solvent is one of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, dioxane, chloroform or a variety of.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound E synthesis condition
It is as follows:
Compound D in modus ponens II,Alkaline matter is added in solvent, and it is small that 2-6 is stirred at 25-60 DEG C
When, obtain reaction solution；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, organic phase concentration are added into the reaction solution
Column purification is crossed afterwards, is collected refined solution and is evaporated under reduced pressure to obtain compound E in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound E synthesis item
In part, the dosage relation of compound D and the solvent is 0.1-0.5mol/L in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound E synthesis item
It is described in partMole be 1-1.5 times of compound D mole in the Formula II.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound E synthesis item
In part, the mole of the alkaline matter is 1.1-2 times of compound D mole in the Formula II；It is highly preferred that the alkalinity
Substance is selected from sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, pyridine, two
One of diisopropylethylamine is a variety of.
In above-mentioned pyrimidines, as a preferred implementation manner, in the Formula II compound E synthesis item
In part, the solvent is one of dimethyl sulfoxide, dimethylformamide, dimethyl acetamide, tetrahydrofuran, dioxane
Or it is a variety of.
Compared with prior art, the present invention has the following technical effect that
Novel pyrimidines compound provided by the invention can effectively inhibit the growth of knurl, and it is small to increase cancer
The weight of mouse improves its immunity.On the other hand, the preparation method of novel pyrimidines compound of the present invention is simple to operation, energy
It is enough effectively reduced and is produced into original realization industrialized production.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but these exemplary embodiments are not intended to
Any type of any restriction is constituted to real protection scope of the invention.
Various drugs used in the following embodiment, reagent are commercial product, and the instrument not marked especially is conventional instrument
Device.
Embodiment 1
Preparation method:
(1)(N- tertbutyloxycarbonyl -2- (acetamide methyl) -3- bromine pyrroles) synthetic method: uncle N- is taken
Butoxy carbonyl -2- (amino methyl) -3- bromine pyrroles (10mmol), formic acid (11mmol), DCC (12mmol), diisopropyl ethyl
Amine (15mmol), is added in 20mLDMF, stirs 2 hours at 25 DEG C, obtains reaction solution；It is added into the reaction solution full
It is extracted with sodium-chloride water solution, methylene chloride, crosses column purification after organic phase concentration, collected refined solution and be evaporated under reduced pressure to obtain
2.75gN- tertbutyloxycarbonyl -2- (acetamide methyl) -3- bromine pyrroles, yield 86%.
(2)The synthetic method of (2- (acetamide methyl) -3- bromine pyrroles): by N- tertbutyloxycarbonyl -2- (second
Amide methyl) -3- bromine pyrroles (2mmol) is added to the hydrochloric acid dioxane solution of 4mL4M, and it stirs 2 hours, obtains at room temperature
Reaction solution；Reaction solution is evaporated under reduced pressure to obtain 418mg2- (acetamide methyl) -3- bromine pyrroles, yield 95%.
(3)The synthetic method of (N- propyl -2- (acetamide methyl) -3- bromine pyrroles): 2- (acetyl is taken
Amine methyl) -3- bromine pyrroles (1mmol), N-Propyl Bromide (1.5mmol), pyridine (2mmol), it is added in 10mL dimethylformamide,
It is stirred 3 hours at 60 DEG C, obtains reaction solution；Saturated sodium-chloride water solution, methylene chloride extraction are added into the reaction solution,
Column purification is crossed after organic phase concentration, refined solution is collected and is evaporated under reduced pressure to obtain 220mgN- propyl -2- (acetamide methyl) -3- bromine pyrrole
It coughs up, yield 84%.
(4)(N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -
1- propyl pyrrole -2- base yl) methyl) acetamide) and synthetic method: take N- propyl -2- (acetamide methyl) -3- bromine pyrroles
(0.5mmol), 4- (azacyclo- octyl- 1- yl) pyridine -2- amine (0.6mmol), triethylamine (0.75mmol), is added to 5mL diformazan
In base formamide, is stirred 3 hours at 60 DEG C, obtain reaction solution；Saturated sodium-chloride water solution, two are added into the reaction solution
Chloromethanes extraction crosses column purification after organic phase concentration, collects refined solution and is evaporated under reduced pressure to obtain 159mgN- ((3- ((4- (azacyclo-
Octyl- 1- yl) pyridine -2- base) amino) -1- propyl pyrrole -2- base yl) methyl) acetamide, yield 82%.
N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- propyl pyrrole -2- base yl) methyl) acetyl
The hydrogen spectrum of amine is as follows:1H NMR (400MHz, DMSO-d6) δ (ppm)=0.90 (t, 3H), 1.31-1.33 (m, 6H), 1.45 (q,
2H),1.51-1.53(m,4H),1.84(s,3H),2.21(t,2H),2.33(t,2H),2.43(t,2H),2.70-2.72(m,
1H),3.05-3.07(m,4H),3.11(d,1H),3.18(d,2H),5.69(d,1H),7.82(d,1H)。
Embodiment 2
Preparation method:
(1)(N- tertbutyloxycarbonyl -2- (benzamide methyl) -3- bromine pyrroles) synthetic method: uncle N- is taken
Butoxy carbonyl -2- (amino methyl) -3- bromine pyrroles (5mmol), benzoic acid (5.5mmol), HATU (5.5mmol), diisopropyl
Ethylamine (6mmol), is added in 10mLDMF, stirs 2 hours at 25 DEG C, obtains reaction solution；It is added into the reaction solution
Saturated sodium-chloride water solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain
1.68gN- tertbutyloxycarbonyl -2- (benzamide methyl) -3- bromine pyrroles, yield 88%.
(2)The synthetic method of (2- (benzamide methyl) -3- bromine pyrroles): by N- tertbutyloxycarbonyl -2- (benzene
Formamide methyl) -3- bromine pyrroles (4mmol) is added to the hydrochloric acid dioxane solution of 8mL4M, and it stirs 2 hours, obtains at room temperature
To reaction solution；Reaction solution is evaporated under reduced pressure to obtain 1.08g2- (benzamide methyl) -3- bromine pyrroles, yield 96%.
(3)The synthetic method of (N- ethoxyethyl -2- (benzamide methyl) -3- bromine pyrroles): 2- is taken
(benzamide methyl) -3- bromine pyrroles (2mmol), the bromo- 2- ethoxy ethane (3mmol) of 1-, triethylamine (4mmol), are added to
In 20mL dimethylformamide, is stirred 3 hours at 40 DEG C, obtain reaction solution；Saturated sodium-chloride is added into the reaction solution
Aqueous solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain 587mgN- ethoxy second
Base -2- (benzamide methyl) -3- bromine pyrroles, yield 83%.
(4)(N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) ammonia
Base) -1- ethoxyethyl pyrroles -2- base yl) methyl) benzamide) synthetic method: take N- ethoxyethyl -2- (benzamide first
Base) -3- bromine pyrroles (1mmol), 4- (azacyclo- octyl- 1- yl) pyridine -2- amine (1.2mmol), pyridine (1.5mmol), it is added to
In 10mL dimethylformamide, is stirred 4 hours at 40 DEG C, obtain reaction solution；Saturated sodium-chloride is added into the reaction solution
Aqueous solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain 379mgN- ((3-
((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- ethoxyethyl pyrroles -2- base yl) methyl) benzamide, yield is
79%.
N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- ethoxyethyl pyrroles -2- base yl) methyl)
The hydrogen spectrum of benzamide is as follows:1H NMR (400MHz, DMSO-d6) δ (ppm)=1H NMR(400MHz,DMSO-d6)δ(ppm)
=1.30 (t, 3H), 1.31-1.33 (m, 6H), 1.51-1.53 (m, 4H), 2.21 (t, 2H), 2.33 (t, 2H), 2.53 (t,
2H),2.70-2.72(m,1H),3.05-3.07(m,4H),3.12(d,1H),3.17(d,2H),3.47(t,2H),3.51(q,
2H),5.69(d,1H),7.63-7.70(m,3H),7.81(d,1H),8.03-8.05(m,2H)。
Embodiment 3
Preparation method:
(1)The synthetic method of (N- is to benzyl -2- (benzamide methyl) -3- bromine pyrroles): it takes
2- (benzamide methyl) -3- bromine pyrroles (2mmol), to fluorobenzyl bromide (3mmol), triethylamine (4mmol), be added to 20mL diformazan
In base formamide, is stirred 3 hours at 25 DEG C, obtain reaction solution；Saturated sodium-chloride water solution, two are added into the reaction solution
Chloromethanes extraction crosses column purification after organic phase concentration, collects refined solution and is evaporated under reduced pressure to obtain 663mgN- to benzyl -2- (benzene
Formamide methyl) -3- bromine pyrroles, yield 85%.
(2)(N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -
1- is to benzyl pyrroles -2- base yl) methyl) benzamide) and synthetic method: take N- to benzyl -2- (benzamide first
Base) -3- bromine pyrroles (1mmol), 4- (azacyclo- octyl- 1- yl) pyridine -2- amine (1.2mmol), triethylamine (1.5mmol), it is added
Into 10mL dimethylformamide, is stirred 3 hours at 60 DEG C, obtain reaction solution；Saturation chlorination is added into the reaction solution
Sodium water solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain 403mgN- ((3-
((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- is to benzyl pyrroles -2- base yl) methyl) benzamide, yield
It is 81%.
N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- is to benzyl pyrroles -2- base yl) first
Base) benzamide hydrogen spectrum it is as follows:1H NMR (400MHz, DMSO-d6) δ (ppm)=1.31-1.33 (m, 6H), 1.51-1.53
(m,4H),2.21(t,2H),2.33(t,2H),2.70-2.72(m,1H),3.05-3.07(m,4H),3.12(d,1H),3.17
(d,2H),3.62(s,2H),5.69(d,1H),6.77(s,1H),7.02(d,1H),7.07(d,1H),7.32(t,1H),
7.63-7.70(m,3H),7.81(d,1H),8.03-8.05(m,2H)。
Embodiment 4
Preparation method:
(1)(N- tertbutyloxycarbonyl -2- (niacinamide methyl) -3- bromine pyrroles) synthetic method: the tertiary fourth of N- is taken
Oxygen carbonyl -2- (amino methyl) -3- bromine pyrroles (10mmol), niacin (11mmol), HATU (12mmol), diisopropyl ethyl amine
(15mmol), is added in 20mLDMF, stirs 2 hours at 25 DEG C, obtains reaction solution；Saturation is added into the reaction solution
Sodium-chloride water solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain 3.14gN-
Tertbutyloxycarbonyl -2- (niacinamide methyl) -3- bromine pyrroles, yield 82%.
(2)The synthetic method of (2- (niacinamide methyl) -3- bromine pyrroles): by N- tertbutyloxycarbonyl -2- (cigarette
Amide methyl) -3- bromine pyrroles (5mmol) is added to the hydrochloric acid dioxane solution of 4mL4M, and it stirs 2 hours, obtains at room temperature
Reaction solution；Reaction solution is evaporated under reduced pressure to obtain 1.27g2- (niacinamide methyl) -3- bromine pyrroles, yield 90%.
(3)The synthetic method of (N- (3- luorobenzyl) -2- (niacinamide methyl) -3- bromine pyrroles): it takes
2- (niacinamide methyl) -3- bromine pyrroles (2mmol), 3- fluoro benzyl bromide (2.4mmol), triethylamine (2mmol), are added to 20mL bis-
In methylformamide, is stirred 3 hours at 25 DEG C, obtain reaction solution；Into the reaction solution be added saturated sodium-chloride water solution,
Methylene chloride extraction crosses column purification after organic phase concentration, collects refined solution and is evaporated under reduced pressure to obtain 633mgN- (3- luorobenzyl) -2-
(niacinamide methyl) -3- bromine pyrroles, yield 81%.
(4)(N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) ammonia
Base) -1- (3- luorobenzyl) pyrroles -2- base yl) methyl) niacinamide) synthetic method: take N- (3- luorobenzyl) -2- (niacinamide first
Base) -3- bromine pyrroles (1mmol), 4- (azacyclo- octyl- 1- yl) pyridine -2- amine (1.2mmol), diisopropyl ethyl amine
(1.5mmol) is added in 10mL dimethylformamide, is stirred 4 hours at 60 DEG C, is obtained reaction solution；To the reaction solution
Middle addition saturated sodium-chloride water solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to
To 414mgN- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- (3- luorobenzyl) pyrroles -2- base yl) methyl)
Niacinamide, yield 79%.
N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- (3- luorobenzyl) pyrroles -2- base yl) first
Base) niacinamide hydrogen spectrum it is as follows:1H NMR (400MHz, DMSO-d6) δ (ppm)=1.31-1.33 (m, 6H), 1.51-1.53
(m,4H),2.21(t,2H),2.33(t,2H),2.70-2.72(m,1H),3.05-3.07(m,4H),3.12(d,1H),3.17
(d,2H),3.62(s,2H),5.69(d,1H),6.77(s,1H),7.02(d,1H),7.07(d,1H),7.32(t,1H),7.61
(t,1H),7.81(d,1H),8.23(d,1H),8.71(d,1H),9.02(s,1H)。
Embodiment 5
Preparation method:
(1)The synthetic method of (N- ethoxymethyl -2- (niacinamide methyl) -3- bromine pyrroles): 2- is taken
(niacinamide methyl) -3- bromine pyrroles (2mmol), methylamino ethoxy bromide (2.4mmol), triethylamine (2mmol), are added to 20mL diformazan
In base formamide, is stirred 3 hours at 40 DEG C, obtain reaction solution；Saturated sodium-chloride water solution, two are added into the reaction solution
Chloromethanes extraction crosses column purification after organic phase concentration, collects refined solution and is evaporated under reduced pressure to obtain 593mgN- ethoxymethyl -2- (nicotinoyl
Amine methyl) -3- bromine pyrroles, yield 87%.
(2)(N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1-
Ethoxymethyl pyrroles -2- base yl) methyl) niacinamide) and synthetic method: take N- ethoxymethyl -2- (niacinamide methyl) -3- bromine pyrrole
(1mmol), 4- (azacyclo- octyl- 1- yl) pyridine -2- amine (1.2mmol), diisopropyl ethyl amine (1.5mmol) are coughed up, is added to
In 10mL dimethylformamide, is stirred 3 hours at 60 DEG C, obtain reaction solution；Saturated sodium-chloride is added into the reaction solution
Aqueous solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain 355mgN- ((3-
((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- ethoxymethyl pyrroles -2- base yl) methyl) niacinamide, yield is
76%.
N- ((3- ((4- (azacyclo- octyl- 1- yl) pyridine -2- base) amino) -1- ethoxymethyl pyrroles -2- base yl) methyl)
The hydrogen spectrum of niacinamide is as follows:1H NMR (400MHz, DMSO-d6) δ (ppm)=1.30 (t, 3H), 1.31-1.33 (m, 6H),
1.51-1.53(m,4H),2.21(t,2H),2.33(t,2H),2.70-2.72(m,1H),3.05-3.07(m,4H),3.12(d,
1H),3.17(d,2H),3.51(q,2H),4.45(s,2H),5.69(d,1H),7.61(t,1H),7.81(d,1H),8.23(d,
1H),8.71(d,1H),9.02(s,1H)。
Test example:
Weight 16-20g mouse 70 is taken, half male and half female is selected 10 at random and is only used as the 1st group (normal group), 60 remaining
Mouse subcutaneous injection rectum cancer cell suspension carries out modeling, is then randomly divided into 6 groups, every group 10；2nd group is model group；
3-7 group is administration group.Start to be administered within the 6th day after mouse modeling, normal group and model group give physiological saline, by each
15ml/kg stomach-filling, is given once daily twice；3-7 group gives the embodiment 1-6 compound of preparation respectively, gives 15mg/ every time
Kg is given once daily twice.Change in the 11st day observation mouse weight, specific data are referring to table 1；2-7 group each component other places are dead
Mouse 5, take out the knurl for putting to death mouse and weighing, calculate the inhibition rate of tumor growth of each group mouse, specific data referring to
Table 2.
The changes of weight of 11st day each group mouse after table 1 is administered
Mouse tumor weight and knurl growth inhibition ratio situation after table 2 is administered
| Group | Tumor weight (g) | Inhibiting rate (%) |
| 2nd group | 3.18±0.53 | / |
| 3rd group | 1.28±0.45 | 59.7% |
| 4th group | 1.09±0.52 | 65.7% |
| 5th group | 1.02±0.42 | 67.9% |
| 6th group | 1.05±0.39 | 66.9% |
| 7th group | 1.12±0.46 | 64.8% |
By Tables 1 and 2 it is found that the compound of the present invention can effectively increase the weight of lung cancer in mice, to improve its immunity；
On the other hand, also it is capable of the growth of effective inhibition knurl.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit protection model of the invention
It encloses.In addition, it should also be understood that, after reading the technical contents of the present invention, those skilled in the art can make the present invention each
Kind change, modification and/or variation, all these equivalent forms equally fall within guarantor defined by the appended claims of the present invention
Within the scope of shield.
Claims (8)
1. a kind of pyrimidines for anticancer, which is characterized in that the structure of the compound is shown in formula I:
Wherein, R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3, benzyl or replace benzyl；Integer of the n between 1-4, m
Integer between 0-4；
R1For phenyl, substituted phenyl,Or the alkyl of C1-C4.
2. pyrimidines according to claim 1, which is characterized in that the R is-(CH2)nO(CH2)mCH3Or replace
Benzyl；Integer of the n between 1-4, integer of the m between 0-4.
3. pyrimidines according to claim 1, which is characterized in that the R1For phenyl, substituted phenyl,
4. the preparation method of pyrimidines described in claim 1-3, which comprises the steps of:
Wherein, R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3, benzyl or replace benzyl；Integer of the n between 1-4, m
Integer between 0-4；
R1For phenyl, substituted phenyl,Or the alkyl of C1-C4.
5. the preparation method according to claim 4, which is characterized in that the synthetic method of compound B is as follows in the Formula II:
Take N- tertbutyloxycarbonyl -2- (amino methyl) -3- bromine pyrroles,Condensing agent, alkaline matter are added in solvent,
It is stirred 2-6 hours at 25-60 DEG C, obtains reaction solution；
R1For phenyl, substituted phenyl,Or the alkyl of C1-C4；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, mistake after organic phase concentration are added into the reaction solution
Column purification collects refined solution and is evaporated under reduced pressure to obtain compound B in the Formula II；
Preferably, the dosage relation of compound A and the solvent is 0.1-0.5mol/L in the Formula II；
Preferably, describedMole be 1-1.1 times of compound A mole in the Formula II；
Preferably, the mole of the condensing agent is 1.1-2 times of compound A mole in the Formula II；The condensing agent is excellent
It is selected as any one of HATU, DCC, PyBOP；
Preferably, the mole of the alkaline matter is 1.1-2 times of compound A mole in the Formula II；It is highly preferred that institute
It states alkaline matter and selects one of triethylamine, pyridine, diisopropyl ethyl amine, DMAP or a variety of；
Preferably, the solvent is one of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, dioxane or a variety of.
6. preparation method according to claim 4 or 5, which is characterized in that the synthetic method of compound C is such as in the Formula II
Under:
The Formula II compound B is added to the hydrochloric acid dioxane solution of 2-4M, is stirred 1-2 hours at room temperature, is obtained anti-
Answer liquid；
The reaction solution is evaporated under reduced pressure to obtain compound C in the Formula II；
Preferably, the dosage relation of compound B and the hydrochloric acid dioxane solution is 0.1-0.5mol/ in the Formula II
L。
7. according to the described in any item preparation methods of claim 4-6, which is characterized in that the synthesis of compound D in the Formula II
Condition is as follows:
Compound C, R-Br, alkaline matter are added in solvent in modus ponens II, stir 2-6 hours, are reacted at 25-60 DEG C
Liquid；
Wherein, the R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3, benzyl or replace benzyl；N is whole between 1-4
Number, integer of the m between 0-4；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, mistake after organic phase concentration are added into the reaction solution
Column purification collects refined solution and is evaporated under reduced pressure to obtain compound D in the Formula II；
Preferably, the dosage relation of compound C and the solvent is 0.1-0.5mol/L in the Formula II；
Preferably, the mole of the R-Br is 1-2 times of compound C mole in the Formula II；
Preferably, the mole of the alkaline matter is 1.1-2 times of compound C mole in the Formula II；It is highly preferred that institute
It states alkaline matter and selects one of triethylamine, pyridine, diisopropyl ethyl amine, DMAP or a variety of；
Preferably, the solvent be one of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, dioxane, chloroform or
It is a variety of.
8. according to the described in any item preparation methods of claim 4-7, which is characterized in that the synthesis of compound E in the Formula II
Condition is as follows:
Compound D in modus ponens II,Alkaline matter is added in solvent, stirs 2-6 hours, obtains at 25-60 DEG C
To reaction solution；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, mistake after organic phase concentration are added into the reaction solution
Column purification collects refined solution and is evaporated under reduced pressure to obtain compound E in the Formula II；
Preferably, the dosage relation of compound D and the solvent is 0.1-0.5mol/L in the Formula II；
Preferably, describedMole be 1-1.5 times of compound D mole in the Formula II；
Preferably, the mole of the alkaline matter is 1.1-2 times of compound D mole in the Formula II；It is highly preferred that institute
It states alkaline matter and is selected from sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, pyrrole
One of pyridine, diisopropyl ethyl amine are a variety of；
Preferably, the solvent is dimethyl sulfoxide, in dimethylformamide, dimethyl acetamide, tetrahydrofuran, dioxane
It is one or more.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1571146A1 (en) * | 2002-12-10 | 2005-09-07 | Ono Pharmaceutical Co., Ltd. | Nitrogen-containing heterocyclic compounds and medicinal use thereof |
| EP1852432A1 (en) * | 2005-02-25 | 2007-11-07 | Ono Pharmaceutical Co., Ltd. | Nitrogenous heterocyclic compound and medicinal use thereof |
| EP2397148A2 (en) * | 2006-02-02 | 2011-12-21 | Allergan, Inc. | Compositions and methods for the treatment of ophthalmic disease |
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2018
- 2018-09-27 CN CN201811130510.5A patent/CN109053697A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1571146A1 (en) * | 2002-12-10 | 2005-09-07 | Ono Pharmaceutical Co., Ltd. | Nitrogen-containing heterocyclic compounds and medicinal use thereof |
| EP1852432A1 (en) * | 2005-02-25 | 2007-11-07 | Ono Pharmaceutical Co., Ltd. | Nitrogenous heterocyclic compound and medicinal use thereof |
| EP2397148A2 (en) * | 2006-02-02 | 2011-12-21 | Allergan, Inc. | Compositions and methods for the treatment of ophthalmic disease |
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