CN101619063B - 3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation - Google Patents
3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation Download PDFInfo
- Publication number
- CN101619063B CN101619063B CN2009100622899A CN200910062289A CN101619063B CN 101619063 B CN101619063 B CN 101619063B CN 2009100622899 A CN2009100622899 A CN 2009100622899A CN 200910062289 A CN200910062289 A CN 200910062289A CN 101619063 B CN101619063 B CN 101619063B
- Authority
- CN
- China
- Prior art keywords
- general formula
- compound
- expression
- pyrimidine
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 Cc(nc1SC)c(C(N(*)C=N2)=C)c2c1C#N Chemical compound Cc(nc1SC)c(C(N(*)C=N2)=C)c2c1C#N 0.000 description 4
- CCLRBYQEFMMDNN-UHFFFAOYSA-N CC1(N(CCCc2ccccc2)C=Nc2c1c(C)nc(NC)c2C#N)O Chemical compound CC1(N(CCCc2ccccc2)C=Nc2c1c(C)nc(NC)c2C#N)O CCLRBYQEFMMDNN-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to a 3,7,8-polysubstituted pyrido -[4,3-d] pyrimidine derivative with anti-tumor activity, which has a general formula I. In the general formula, X represents CN and CONH2; Y represents a methylthio group, a thiamphenicol group and an alkylamino group of C1-C3; R represents alkyl of C1-C6, and a heterocyclic radical is a heterocyclic substituted C1-C2 alkyl of pyridine, thiophene or furan, a phenyl C1-C3 alkyl or a substituted phenyl C1-C3 alkyl, a phenyl or a substituted phenyl. Related substituent groups on a benzene ring mainly comprise halogen, the alkyl or an alkoxy of C1-C3, wherein the substituent groups have single-substitute or multi-substitute at any positions of the benzene ring, and the substituent groups on the benzene ring are the same or different. The compound has obvious inhibiting effect on various tumor cells such as human oral cavity bottom cancer cells KB, leurocristine resistant human oral cavity bottom cancer cells KBv200, human breast cancer cell lines MCF-7, amycin resistant human breast cancer cell lines MCF-7/Adr, human nasopharyngeal carcinoma cell lines 6-10B, CNE 1, CNE 2, HONE 1 and SUNE 1, human lung cancer cell lines H460 and Calu-3, human leukemia cell lines HL-60, and the like and can be used as an effective component of anti-tumor medicaments.
Description
Technical field
The present invention relates to have 3,7 of anti-tumor activity, the 8-polysubstituted pyridine is the preparation of [4,3-d] pyrimidine derivatives and intermediate thereof also, and it is as the biological activity of antitumour drug.
Background technology
Pyrido [4,3-d] pyrimidines is the fused heterocycle compounds of the extensive bioactive functions of a class, especially physiology and pharmacologically active widely aspect medical research, have been shown, can be used for treating various types of tumours, cancer, leukemia, acquired immune deficiency syndrome (AIDS) and many nervous system diseases, and be used for pain relieving, anti-inflammatory, antianaphylaxis etc.
The applicant studies the pyridine synthesis method of [4,3-d] pyrimidines also of having invented a kind of novelty of not seeing bibliographical information in previous work, can be via synthetic multi-functional pyrido [4, the 3-d] pyrimidines that obtains having general formula A structure of ether amidine.Discover and not only have good sterilization and weeding activity by this compounds (Chinese invention patent: a class has also [4,3-d] pyrimidine and preparation of polysubstituted pyridine of bactericidal and herbicidal activity, ZL200510019576.3; And Chinese invention patent: have 2,3,4 of fungicidal activity, 7-polysubstituted pyridine also [4,3-d] pyrimidine derivatives and preparation, application number: 200810047941.5), also shown notable antitumor activity (Chinese invention patent: have 2 of anti-tumor activity simultaneously, 3,4,7,8-polysubstituted pyridine also [4,3-d] pyrimidine derivatives, application number: 200910060650.4).
In order more systematically to study the anti-tumor activity of this compounds, the applicant has carried out more deep research to this synthetic method, expanded the substrate scope, and the structure of target compound modified and optimizes, obtained structure various and novel 3,7,8-polysubstituted pyridine also [4,3-d] pyrimidine derivatives, and test its anti-tumor activity, have the more compound of high biological activity in the hope of finding.
Summary of the invention
The objective of the invention is to explore also [4,3-d] pyrimidine derivatives of the polysubstituted pyridine that has new texture and have an anti-tumor activity, also [4,3-d] pyrimidines and synthetic method thereof of novel polysubstituted pyridine that a class has anti-tumor activity is provided.
A class polysubstituted pyridine of the present invention is the general structure such as the I of [4,3-d] pyrimidine derivatives also:
Among the formula I, X represents: CN, CONH
2
Y represents: methylthio group, methylsulfonyl, C
1-C
3Alkylamino;
R represents: C
1-C
6Alkyl, heterocyclic radical is the heterocyclic substituted C of pyridine, thiophene or furans
1-C
2Alkyl, phenyl C
1-C
3Alkyl or substituted-phenyl C
1-C
3Alkyl, phenyl or substituted-phenyl; Substituting group on the related phenyl ring is mainly: halogen, C
1-C
3Alkyl or alkoxyl group, substituting group is in phenyl ring arbitrary locational single replace or polysubstituted, the substituting group on phenyl ring is identical or inequality;
Wherein, general formula I has been contained three compounds shown in following general formula I-1, general formula I-2 and the general formula I-3:
R among general formula I-1, I-2, the I-3 is identical with implication in the general formula I, and the Y in the general formula I-1 represents C
1-C
3Alkylamino.
Inventor test show have general structure I compound to human oral at the bottom of cancer cells KB, to cancer cells KBv200, human breast cancer cell strain MCF-7 at the bottom of the drug-fast human oral of vincristine(VCR), to the drug-fast human breast cancer cell strain of Zorubicin MCF-7/Adr, human nasopharyngeal carcinoma cell line 6-10B, CNE1, CNE2, HONE1, SUNE1; Human lung carcinoma cell line H460, Calu-3; Kinds of tumor cells such as leukemia cell line HL-60 have significant inhibitory effect, can be used as the effective constituent of anti-tumor agents.
With the polysubstituted pyridine of general formula I-1 expression preparation method's (A method) of [4,3-d] pyrimidine derivatives also, be to make represented compound of Formula B and triethyl orthoformate reaction generation pyridine ether amidine intermediate C, C again with C
1-C
6Fat primary amine, phenyl C
1-C
4Kiber alkyl amine or substituted-phenyl C
1-C
4Kiber alkyl amine or heterocyclic substituted C
1-C
2Alkylamine is closed ring in room temperature or heating condition, obtains Compound I-1, and the synthetic route of the compound of general formula I-1 is as follows:
Y among Formula B, C and the I-1 represents C
1-C
3Alkylamino; RNH
2Expression C
1-C
6Alkyl, heterocyclic radical is the heterocyclic substituted C of pyridine, thiophene or furans
1-C
2Alkyl, phenyl C
1-C
3Alkyl or substituted-phenyl C
1-C
3Alkyl.
B compound in the above-mentioned reaction formula and triethyl orthoformate mol ratio are 1: 1-6, directly adopting triethyl orthoformate is solvent, without catalyzer, perhaps use catalyzer, the catalyzer of selecting for use has tosic acid or acetic anhydride, reaction is 10-25 hour between 80 ℃-140 ℃, obtain intermediate C, intermediate C is 1 with primary amine with mol ratio again: 1-3, organic solvent is acetonitrile, dioxane or methylene dichloride, 20 ℃-100 ℃ reactions 2-12 hour, promptly yield synthesized the product that obtains general formula I-1 preferably.
With the polysubstituted pyridine of general formula I-2 expression preparation method's (B method) of [4,3-d] pyrimidine derivatives also, be to make the represented compound of general formula D obtain Compound I-2 through hydrolysis reaction:
R among general formula D and the I-2 with and general formula I in implication identical.
With the polysubstituted pyridine of general formula I-3 expression preparation method's (C method) of [4,3-d] pyrimidine derivatives also, be to make the represented compound of general formula D obtain Compound I-3 through oxidizing reaction,
R among general formula D, the I-3 is identical with implication in the general formula I.
(concrete synthesizing seen Chinese invention patent: a class has also [4,3-d] pyrimidine and preparation of polysubstituted pyridine of bactericidal and herbicidal activity, ZL200510019576.3 to above-mentioned D compound; And Chinese invention patent: have 2 of fungicidal activity, 3,4,7-polysubstituted pyridine also [4,3-d] pyrimidine derivatives and preparation, application number: 200810047941.5) in the miscible system of organic solvent and water, organic solvent is ethanol or acetone etc., under 10 ℃-80 ℃ through alkalescence or acid hydrolytic reaction 0.5-6 hour, i.e. the synthetic product that obtains general formula I-2 of yield preferably; Perhaps in organic solvent acetic acid or acetonitrile, obtain the product of I-3 through oxidation under 50 ℃-100 ℃, used oxygenant has hydrogen peroxide, metachloroperbenzoic acid etc.
Embodiment
Specifically describe the preparation method of formula I compound of the present invention below by example, only the present invention will be described for these embodiment, rather than limit the invention.
Embodiment 1
Compound 11
3-(4-methyl-benzyl)-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
15 mmole 2-methyl-3-ethanoyl-5-cyano group-6-methylamino--4-pyridine amine joined in 50 milliliters the reaction flask; add 45 mmole triethyl orthoformates; add the catalytic amount tosic acid; 130 ℃ of reactions 12 hours; the back decompression that reacts completely steams responseless triethyl orthoformate; resistates decompression column chromatography gets yellow crystals pyridine ether amidine, 118.2~120.7 ℃ of fusing points, productive rate 62.0%.
1H?NMR(CDCl
3,TMS,600MHz)δ(ppm):1.39(t,3H,J=7.2Hz,-OCH
2CH
3),2.38(s,3H,-CH
3),2.41(s,3H,-COCH
3),3.08(m,3H,-NHCH
3),4.34(q,2H,J=7.2Hz,-OCH
2CH
3),5.26(s,1H,NH),7.61(s,1H,N=CH)。
Again 2 mmole 2-methyl-3-ethanoyl-5-cyano group-6-methylamino pyridine-4-imines methene benzyl ethyl ether, 15 milliliters of acetonitriles are joined in 50 milliliters the reaction flask; add 3 mmoles to xylylamine; be heated to 40~50 ℃ of reactions 2 hours; separate out solid; suction filtration, acetone and sherwood oil mixed solvent recrystallization, the pure product of gained are white solid; yield is 86.6%, 186.9~187.2 ℃ of fusing points.
Molecular formula: C
19H
21N
5O
2:
Ultimate analysis (%), calculated value: C 64.94, H 6.02, and N 19.93; Measured value: C 64.74, H 6.08, and N 19.87; IR (KBr, υ/cm
-1): 3361 (N-H); 3091,762 (=C-H); 1637,1592,1517,1455 (C=N, C=C); 1352 (C-H); 1266 (C-N);
1H NMR (δ, CDCl
3, TMS, 400MHz): 2.35 (s, 3H, Ph-CH
3), 2.42 (s, 3H, pyrimidine-CH
3), 2.59 (s, 3H, pyridine-CH
3), 3.04 (d, 3H ,-NHCH
3, J=6.6Hz), 4.86 (s, 2H ,-CH
2-), 6.69 (s, 1H ,-NH), 7.12 (d, 2H, ArH, J=7.8Hz), 7.20 (d, 2H, ArH, J=7.8Hz), 7.79 (s, 1H, pyrimidine-H), 10.16 (s, 1H ,-OH).
Following compound is according to the method preparation of compound 11, and its structure appraising datum is as follows:
Compound 1
3-ethyl-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are yellow solid, yield 50.2%, 146.0~147.4 ℃ of fusing points.
Molecular formula: C
13H
17N
5O
Ultimate analysis (%), calculated value: C 60.21, H 6.61, and N 27.01; Measured value: C 60.63, H 6.89, and N 27.17;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 1.39 (t, 3H ,-CH
2 CH 3 , J=7.2Hz), 2.41 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.09 (q, 3H ,-NHCH
3, J=4.2Hz), 3.78 (q, 3H ,-CH
2 CH 3 , J=7.2Hz), 6.72 (s, 1H ,-NH), 7.68 (s, 1H, pyrimidine-H), 10.30 (s, 1H ,-OH;
IR(KBr)υ(cm
-1):3355(N-H);3050,755(=C-H);2992,1348(C-H);2200(C≡N);1638,1587,1517,1434(C=N,C=C);1259(C-N)。
Compound 2
3-propyl group-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are brown solid, yield 59.2%, 89.8~91.8 ℃ of fusing points.
Molecular formula: C
14H
19N
5O
Ultimate analysis (%), calculated value: C 61.52, H 7.01, and N 25.62; Measured value: C 61.88, H 7.45, and N 25.92;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 1.02 (t, 3H ,-CH
2CH
2 CH 3 , J=7.5Hz), 1.78 (q, 2H ,-CH
2 CH 2 CH
3, J=7.4Hz), 2.41 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.10 (d, 3H ,-NHCH
3, J=4.8Hz), 3.68 (t, 2H ,-
CH 2 CH
2CH
3, J=7.2Hz), 6.70 (s, 1H ,-NH), 7.65 (s, 1H, pyrimidine-H), 10.36 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3332(N-H);3209,758(=C-H);2967,1353(C-H);1638,1587,1530,1436(C=N,C=C);1260(C-N)。
Compound 3
3-butyl-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are yellow solid, yield 52.6%, 86.8~88.5 ℃ of fusing points.
Molecular formula: C
15H
21N
5O
Ultimate analysis (%), calculated value: C 62.70, H 7.37, and N 24.37; Measured value: C 63.06, H 7.66, and N 23.96;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 0.94 (t, 3H ,-CH
2CH
2CH
2 CH 3 , J=7.5Hz), 1.39~1.46 (m, 2H ,-CH
2CH
2 CH 2 CH
3), 1.67~1.73 (m, 2H ,-CH
2 CH 2 CH
2CH
3), 2.41 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.12 (d, 3H ,-NHCH
3, J=4.8Hz), 3.70 (t, 2H ,-
CH 2 CH
2CH
2CH
3, J=7.5Hz), 6.70 (s, 1H ,-NH), 7.65 (s, 1H, pyrimidine-H), 10.30 (s, 1H ,-OH).
Compound 4
3-hexyl-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 63.3%, 125.8~126.1 ℃ of fusing points.
Molecular formula: C
17H
25N
5O
Ultimate analysis (%), calculated value: C 64.73, H 7.99, and N 22.20; Measured value: C 65.11, H 8.04, and N 22.44;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 0.90 (t, 3H ,-CH
2CH
2CH
2CH
2CH
2 CH 3 , J=6.9Hz), 1.32~1.39 (m, 6H ,-CH
2CH
2 CH 2 CH 2 CH 2 CH
3), 1.70~1.75 (m, 2H ,-CH
2 CH 2 CH
2CH
2CH
2CH
3), 2.41 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.10 (d, 3H ,-NHCH
3, J=5.4Hz), 3.69 (q, 2H ,-
CH 2 CH
2CH
2CH
2CH
2CH
3, J=7.2Hz), 6.69 (s, 1H ,-NH), 7.65 (s, 1H, pyrimidine-H), 10.30 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3329(N-H);2932,2860,1391(C-H);1634,1596,1520,1468(C=N,C=C);1280(C-N);609(=C-H)。
Compound 5
3-furfuryl group-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are yellow solid, yield 61.7%, 155.6~156.9 ℃ of fusing points.
Molecular formula: C
16H
17N
5O
2
Ultimate analysis (%), calculated value: C 61.72, H 5.50, and N 22.49; Measured value: C 61.84, H 5.88, and N 22.81;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.41 (s, 3H, pyrimidine-CH
3), 2.57 (s, 3H, pyridine-CH
3), 3.07 (d, 3H ,-NHCH
3, J=5.4Hz), 4.83 (s, 2H ,-CH
2), 6.38~6.42 (m, 2H, furans-H), 6.98 (s, 1H ,-NH), 7.42 (t, 1H, furans-H, J=0.9Hz), 7.76 (s, 1H, pyrimidine-H), 10.19 (s, 1H, OH);
IR(KBr)υ(cm
-1):3363(N-H);3119,749(=C-H);2934,1344(C-H);1641,1586,1517,1433(C=N,C=C);1258(C-N)。
Compound 6
3-benzyl-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 43.8%, 181.9~183.1 ℃ of fusing points.
Molecular formula: C
18H
19N
5O
Ultimate analysis (%), calculated value: C 67.27, H 5.96, and N 21.79; Measured value: C 67.66, H 6.30, and N 21.85;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.42 (s, 3H, pyrimidine-CH
3), 2.60 (s, 3H, pyridine-CH
3), 3.05 (d, 3H ,-NHCH
3, J=7.2Hz), 4.91 (s, 2H ,-CH
2-), 6.69 (s, 1H ,-NH), 7.24~7.42 (m, 5H, ArH), 7.80 (s, 1H, pyrimidine-H), 10.19 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3332(N-H);3196,731(=C-H);2942,1352(C-H);1637,1591,1517,1452(C=N,C=C);1262(C-N)。
Compound 7
3-hydrocinnamyl-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 51.4%, 150.2~151.0 ℃ of fusing points.
Molecular formula: C
20H
23N
5O
Ultimate analysis (%), calculated value: C 68.74, H 6.63, and N 20.04; Measured value: C 68.55, H 6.56, and N 20.25;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.08 (m, 2H, PhCH
2 CH 2CH
2-), 2.41 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 2.73 (t, 2H, Ph
CH 2 CH
2CH
2-, J=6.9Hz), 3.09 (q, 3H ,-NHCH
3, J=2.2Hz), 3.66 (t, 2H, PhCH
2CH
2 CH 2 -, J=6.9Hz), 6.56 (s, 1H ,-NH), 7.19~7.58 (m, 5H, ArH), 7.58 (s, 1H, pyrimidine-H), 10.26 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3353(N-H);3085,759(=C-H);2944,1348(C-H);1639,1592,1518,1455(C=N,C=C);1265(C-N)。
Compound 8
3-(2-luorobenzyl)-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are faint yellow solid, yield 67.6%, 138.0~140.0 ℃ of fusing points.
Molecular formula: C
18H
18FN
5O
Ultimate analysis (%), calculated value: C 63.70, H 5.35, and N 20.64; Measured value: C 63.83, H 5.47, and N 20.52;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 2.42 (s, 3H, pyrimidine-CH
3), 2.59 (s, 3H, pyridine-CH
3), 3.06 (d, 3H ,-NHCH
3, J=4.2Hz), 4.93 (s, 2H ,-CH
2-), 6.79 (s, 1H ,-NH), 7.15~7.26 (m, 4H, ArH), 7.83 (s, 1H, pyrimidine-H), 10.18 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3431(N-H);2926,1348(C-H);1639,1593,1519,1457(C=N,C=C);1264(C-N);759(=C-H)。
Compound 9
3-(4-luorobenzyl)-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 69.1%, 163.3~163.6 ℃ of fusing points.
Molecular formula: C
18H
18FN
5O
Ultimate analysis (%), calculated value: C 63.70, H 5.35, and N 20.64; Measured value: C 63.64, H 5.35, and N 20.66;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.42 (s, 3H, pyrimidine-CH
3), 2.59 (s, 3H, pyridine-CH
3), 3.05 (d, H ,-NHCH
3, J=7.2Hz), 4.88 (s, 2H ,-CH
2-), 6.64 (s, 1H ,-NH), 7.08~7.23 (m, 4H, ArH), 7.78 (s, 1H, pyrimidine-H), 10.12 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3353(N-H);3208,747(=C-H);2941,1352(C-H);1641,1590,1512,1457(C=N,C=C);1267(C-N)。
Compound 10
3-(2-benzyl chloride base)-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 50.0%, 240.5~241.0 ℃ of fusing points.
Molecular formula: C
18H
18ClN
5O
Ultimate analysis (%), calculated value: C 60.76, H 5.10, and N 19.68; Measured value: C 60.89, H 5.33, and N 20.09;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 2.43 (s, 3H, pyrimidine-CH
3), 2.60 (s, 3H, pyridine-CH
3), 3.07 (d, 3H ,-NHCH
3, J=4.8Hz), 4.98 (s, 2H ,-CH
2-), 6.66 (s, 1H ,-NH), 7.07~7.48 (m, 4H, ArH), 7.77 (s, 1H, pyrimidine-H), 10.20 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3350(N-H);3136,760(=C-H);2954,1345(C-H);1641,1591,1522,1450(C=N,C=C);1250(C-N)。
Compound 12
3-(4-methoxy-benzyl)-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 70.0%, 203.5~204.1 ℃ of fusing points.
Molecular formula: C
19H
21N
5O
Ultimate analysis (%), calculated value: C 68.04, H 6.31, and N 20.88; Measured value: C 67.98, H 6.51, and N 20.91;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.39 (s, 3H, pyrimidine-CH
3), 2.59 (s, 3H, pyridine-CH
3), 3.05 (d, 3H ,-NHCH
3, J=4.8Hz), 3.80 (s, 3H, Ph-OCH
3), 4.84 (s, 2H ,-CH
2-), 6.71 (s, 1H ,-NH), 6.92 (d, 2H, ArH, J=8.4Hz), 7.17 (d, 2H, ArH, J=8.4Hz), 7.79 (s, 1H, pyrimidine-H), 10.19 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3360(N-H);3122,746(=C-H);2935,1349(C-H);1638,1591,1514,1456(C=N,C=C);1251(C-N)。
Compound 13
3-(4-fluorobenzene ethyl)-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are faint yellow solid, yield 74.3%, 162.0~163.0 ℃ of fusing points.
Molecular formula: C
19H
20FN
5O
Ultimate analysis (%), calculated value: C 64.57, H 5.70, and N 19.82; Measured value: C 64.56, H 5.83, and N 20.10;
1H NMR (δ, CDCl
3, TMS, 600MHz): 2.43 (s, 3H, pyrimidine-CH
3), 2.52 (s, 3H, pyridine-CH
3), 3.01 (t, 2H ,-CH
2CH
2-, J=6.9Hz), 3.12 (q, 3H ,-NHCH
3, J=4.8Hz), 3.93 (t, 2H ,-CH
2CH
2-, J=6.9Hz), 6.79 (s, 1H ,-NH), 7.03 (d, 2H, ArH, J=8.7Hz), 7.10 (d, 2H, ArH, J=8.7Hz), 7.26 (s, 1H, pyrimidine-H), 10.38 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3331(N-H);3087,797(=C-H);2928,1349(C-H);1636,1590,1510,1471(C=N,C=C);1223(C-N)。
Compound 14
3-(4-chlorobenzene ethyl)-4,5-dimethyl-4-hydroxyl-7-methylamino--3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are faint yellow solid, yield 47.3%, 153.8~154.3 ℃ of fusing points.
Molecular formula: C
19H
20ClN
5O
Ultimate analysis (%), calculated value: C 61.70, H 5.45, and N 18.94; Measured value: C 61.74, H 5.58, and N 19.07;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.41 (s, 3H, pyrimidine-CH
3), 2.51 (s, 3H, pyridine-CH
3), 2.98 (t, 2H ,-CH
2CH
2-, J=6.9Hz), 3.12 (d, 3H ,-NHCH
3, J=4.8Hz), 3.91 (t, 2H ,-CH
2CH
2-, J=6.9Hz), 6.77 (s, 1H ,-NH), 7.06 (d, 2H, ArH, J=8.4Hz), 7.24 (s, 1H, pyrimidine-H), 7.29 (d, 2H, ArH, J=8.4Hz), 10.36 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3358(N-H);3133,752(=C-H);2935,1393(C-H);1640,1591,1517,1454(C=N,C=C);1265(C-N)。
Embodiment 2
Compound 25
3-(4-methyl-benzyl)-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
15 mmole 2-methyl-3-ethanoyl-5-cyano group-6-ethylamino-4-pyridine amine joined in 50 milliliters the reaction flask; add 90 mmole triethyl orthoformates; 140 ℃ of reactions 10 hours; the back decompression that reacts completely steams responseless triethyl orthoformate and solvent; resistates gets white crystal pyridine ether amidine through silica gel column chromatography; 89.3~90.0 ℃, yield 74%.
1H?NMR(CDCl
3,TMS,400MHz)δ(ppm):1.25(t,3H,J=8.0Hz,-NHCH
2CH
3),1.39(t,3H,J=8.0Hz,-OCH
2CH
3),2.36(s,3H,-CH
3),2.37(s,3H,-COCH
3),3.56(q,2H,J=8.0Hz,-NHCH
2CH
3),4.34(q,2H,J=8.0Hz,-OCH
2CH
3),5.20(s,1H,NH),7.60(s,1H,N=CH)。
2 mmole 2-methyl-3-ethanoyl-5-cyano group-6-ethylamino pyridine-4-imines methene benzyl ethyl ether, 15 milliliters of methylene dichloride joined in 50 milliliters the reaction flask; add 4 mmoles to methylbenzylamine; 20 ℃ of stirring reactions 12 hours; separate out white solid; filter, ethyl alcohol recrystallization, the pure product of gained are white solid; yield is 91.4%, 182.7~183.0 ℃ of fusing points.
Molecular formula: C
20H
23N
5O:
Ultimate analysis (%), calculated value: C 68.74, H 6.63, and N 20.04; Measured value: C 68.50, H 6.40, and N 19.81;
IR(KBr,υ/cm
-1):3363(N-H);3056,763(=C-H);2966,2869,1382(C-H);1639,1594,1514,1457(C=N,C=C);1258(C-N);
1H NMR (δ, CDCl
3, TMS, 400MHz): 1.23 (t, 3H ,-NHCH
2 CH 3, J=7.2Hz), 2.35 (s, 3H, Ph-CH
3), 2.41 (s, 3H, pyrimidine-CH
3), 2.59 (s, 3H, pyridine-CH
3), 3.54 (m, 2H ,-NH
CH 2 CH
3), 4.85 (s, 2H ,-CH
2-), 6.70 (s, 1H ,-NH), 7.12~7.22 (m, 4H, ArH), 7.79 (s, 1H, pyrimidine-H), 10.23 (s, 1H ,-OH);
13C?NMR(δ,DMSO,TMS,150MHz)14.60,20.65,23.15,33.13,35.07,49.31,97.50,119.45,127.03,129.35,132.10,137.16,150.85,151.07,151.23,156.65,156.67,203.83;
MS(EI,m/z,%):351(M
++24),350(M
++122),349(M
+47),245(41),244(100),106(18),105(69),77(17)。
Following compound is pressed compound 25 similar method preparations, and its structure appraising datum is as follows:
Compound 15
3-ethyl-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 81.5%, 149.4~149.8 ℃ of fusing points.
Molecular formula: C
14H
19N
5O
Ultimate analysis (%), calculated value: C 61.52, H 7.01, and N 25.62; Measured value: C 61.61, H 7.19, and N 25.46;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.28 (t, 3H ,-NHCH
2 CH 3 ,J=7.2Hz), 1.39 (t, 3H ,-CH
2 CH 3 , J=7.2Hz), 2.39 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.56~3.63 (m, 2H ,-NH
CH 2 CH
3), 3.78 (q, 3H ,-CH
2 CH 3 , J=7.3Hz), 6.72 (s, 1H ,-NH), 7.68 (s, 1H, pyrimidine-H), 10.36 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3344(N-H);3198,755(=C-H);2969,2933,1386(C-H);1641,1590,1509,1441(C=N,C=C);1259(C-N);
EI-MS(m/z,%):275(M
++29),273(M
+88),258(88),243(100),228(31),227(13),202(17),201(27),185(19),171(16),157(24),105(12),43(20)。
Compound 16
3-propyl group-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 62.7%, 87.0~88.5 ℃ of fusing points.
Molecular formula: C
15H
21N
5O
Ultimate analysis (%), calculated value: C 62.70, H 7.37, and N 24.37; Measured value: C 62.73, H 7.22, and N 24.11;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.02 (t, 3H ,-CH
2CH
2 CH 3 , J=7.6Hz), 1.29 (t, 3H ,-NHCH
2 CH 3, J=6.8Hz), 1.79 (q, 2H ,-CH
2 CH 2 CH
3, J=7.3Hz), 2.39 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.56~3.62 (m, 2H ,-NH
CH 2 CH
3), 3.67 (q, 2H ,-
CH 2 CH
2CH
3, J=7.2Hz), 6.71 (s, 1H ,-NH), 7.65 (s, 1H, pyrimidine-H), 10.36 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3433(N-H);3188,753(=C-H);2967,2878,1389(C-H);1641,1591,1512,1441(C=N,C=C);1253(C-N);
EI-MS(m/z,%):287(M
+100),271(85),228(21),226(18),212(15),201(32),184(21),159(17),43(45)。
Compound 17
3-butyl-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 43.3%, 80.0~81.5 ℃ of fusing points.
Molecular formula: C
16H
23N
5O
Ultimate analysis (%), calculated value: C 63.76, H 7.69, and N 23.24; Measured value: C 63.71, H 7.43, and N 22.98;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 0.99 (t, 3H ,-CH
2CH
2CH
2 CH 3 , J=8.0Hz), 1.29 (t, 3H ,-NHCH
2 CH 3), 1.37~1.45 (m, 2H ,-CH
2CH
2 CH 2 CH
3), 1.68~1.75 (m, 2H ,-CH
2 CH 2 CH
2CH
3), 2.39 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.56~3.62 (m, 2H ,-NH
CH 2 CH
3), 3.70 (t, 2H ,-
CH 2 CH
2CH
2CH
3, J=7.4Hz), 6.70 (s, 1H ,-NH), 7.64 (s, 1H, pyrimidine-H), 10.36 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3385(N-H);3282,965(=C-H);2973,2868,1390(C-H);2197(C≡N);1624,1581,1505,1445(C=N,C=C);1266(C-N);
EI-MS(m/z,%):301(M
+100),286(91),243(99),230(47),228(17),226(22),218(13),217(10),216(17),212(28),203(16),202(14),201(22),184(18),175(13),159(15),157(16),132(10),43(26)。
Compound 18
3-hexyl-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 63.8%, 126.0~126.5 ℃ of fusing points.
Molecular formula: C
18H
27N
5O
Ultimate analysis (%), calculated value: C 65.62, H 8.26N 21.26; Measured value: C 65.65, H 8.20, and N 21.47;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 0.90 (t, 3H ,-CH
2CH
2CH
2CH
2CH
2 CH 3 , J=7.0Hz), 1.27~1.34 (m, 9H ,-NHCH
2 CH 3And-CH
2CH
2 CH 2 CH 2 CH 2 CH
3), 1.72 (q, 2H ,-CH
2 CH 2 CH
2CH
2CH
2CH
3, J=7.4Hz), 2.39 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.56~3.62 (m, 2H ,-NH
CH 2 CH
3), 3.69 (q, 2H ,-
CH 2 CH
2CH
2CH
2CH
2CH
3, J=7.4Hz), 6.70 (s, 1H ,-NH), 7.65 (s, 1H, pyrimidine-H), 10.36 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3315(N-H);2961,2863,1387(C-H);1628,1587,1558,1468(C=N,C=C);1273(C-N);
EI-MS(m/z,%):329(M
+100),314(75),243(97),230(35),229(18),227(53),216(16),213(10),212(15),211(20),203(25),201(20),199(41),184(34),157(27),130(16),105(14),43(62)。
Compound 19
3-furfuryl group-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 89.0%, 142.5~143.0 ℃ of fusing points.
Molecular formula: C
17H
19N
5O
2
Ultimate analysis (%), calculated value: C 62.75, H 5.89, and N 21.52; Measured value: C 62.92, H 5.57, and N 21.18;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.26 (t, 3H ,-NHCH
2 CH 3, J=7.4Hz), 2.39 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 3.57 (m, 2H ,-NH
CH 2 CH
3), 4.83 (s, 2H ,-CH
2), 6.38~6.42 (m, 2H, furans-H), 6.99 (s, 1H ,-NH), 7.42 (d, 1H, furans-H), 7.76 (s, 1H, pyrimidine-H), 10.24 (s, 1H, OH);
IR(KBr)υ(cm
-1):3371(N-H);3119,764(=C-H);2965,2931,1351(C-H);1641,1591,1516,1455(C=N,C=C);1259(C-N);
EI-MS(m/z,%):325(M
+84),296(29),81(100),53(56),43(29)。
Embodiment 3
Compound 26
3-(4-methoxy-benzyl)-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
15 mmole 2-methyl-3-ethanoyl-5-cyano group-6-ethylamino-4-pyridine amine joined in 50 milliliters the reaction flask; add 15 mmole triethyl orthoformates; add the catalytic amount acetic anhydride; 80 ℃ of reactions 25 hours; the back decompression that reacts completely steams responseless triethyl orthoformate, and resistates decompression column chromatography gets white crystal pyridine ether amidine.
1 mmole 2-methyl-3-ethanoyl-5-cyano group-6-ethylamino pyridine-4-imines methene benzyl ethyl ether, 15 milliliters of anhydrous dioxane joined in 50 milliliters the reaction flask; add 1 mmole 4-Methoxybenzylamine; be heated to 100 ℃ of reactions 6 hours; separate out solid; filter, acetone and sherwood oil mixed solvent recrystallization, the pure product of gained are white solid; yield is 86.5%, 194.0~194.6 ℃ of fusing points.
Molecular formula: C
20H
23N
5O
2:
Ultimate analysis (%), calculated value: C 65.73, H 6.34, and N 19.16; Measured value: C 65.56, H 6.12, and N 19.00;
IR(KBr,υ/cm
-1):3367(N-H);2964,2927,1381(C-H);1640,1592,1514,1458(C=N,C=C);1255(C-N);744(=C-H);
1H NMR (δ, CDCl
3, TMS, 400MHz): 1.23 (t, 3H ,-NHCH
2 CH 3, J=7.2Hz), 2.40 (s, 3H, pyrimidine-CH
3), 2.59 (s, 3H, pyridine-CH
3), 3.53~3.56 (m, 2H ,-NH
CH 2 CH
3), 3.80 (s, 3H, Ph-OCH
3), 4.83 (s, 2H ,-CH
2-), 6.72 (s, 1H ,-NH), 6.91~7.18 (m, 4H, ArH), 7.78 (s, 1H, pyrimidine-H), 10.23 (s, 1H ,-OH);
MS(EI,m/z,%):366(M
++14),365(M
+14),244(66),122(12),121(100)。
Following compound is according to the method preparation of compound 26, and its structure appraising datum is as follows:
Compound 20
3-benzyl-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 89.6%, 140.0~140.8 ℃ of fusing points.
Molecular formula: C
19H
21N
5O
Ultimate analysis (%), calculated value: C 68.04, H 6.31, and N 20.88; Measured value: C 67.78, H 6.13, and N 20.63;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.23 (t, 3H ,-NHCH
2 CH 3, J=7.0Hz), 2.40 (s, 3H, pyrimidine-CH
3), 2.60 (s, 3H, pyridine-CH
3), 3.53~3.56 (m, 2H ,-NH
CH 2 CH
3), 4.90 (s, 2H ,-CH
2-), 6.70 (s, 1H ,-NH), 7.24~7.43 (m, 5H, ArH), 7.80 (s, 1H, pyrimidine-H), 10.20 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3351(N-H);3087,736(=C-H);2977,2937,1378(C-H);1641,1592,1521,1460(C=N,C=C);1249(C-N);
EI-MS(m/z,%):337(M
++213),336(M
++111),335(M
+17),317(24),246(22),244(77),243(57),227(21),214(23),202(29),91(100),90(26)。
Compound 21
3-styroyl-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 91.7%, 124.3~125.0 ℃ of fusing points.
Molecular formula: C
21H
25N
5O
Ultimate analysis (%), calculated value: C 69.40, H 6.93, and N 19.27; Measured value: C 69.22, H 6.71, and N 18.94;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.27 (t, 3H ,-NHCH
2 CH 3, J=7.0Hz), 2.08 (m, 2H ,-CH
2 CH 2CH
2-), 2.39 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H, pyridine-CH
3), 2.73 (t, 2H ,-CH
2 CH 2CH
2-, J=7.4Hz), 3.58 (m, 2H ,-NH
CH 2 CH
3), 3.66 (t, 2H ,-CH
2 CH 2CH
2-, J=7.6Hz), 6.59 (s, 1H ,-NH), 7.19~7.33 (m, 5H, ArH), 7.57 (s, 1H, pyrimidine-H), 10.35 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3323(N-H);3053,760(=C-H);2971,2927,1383(C-H);1629,1591,1509,1451(C=N,C=C);1264(C-N);
EI-MS(m/z,%):363(M
+100),348(58),245(38),243(32),91(52),43(11)。
Compound 22
3-(3-luorobenzyl)-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 91.4%, 125.4~128.4 ℃ of fusing points.
Molecular formula: C
19H
20FN
5O
Ultimate analysis (%), calculated value: C 64.57, H 5.70, and N 19.82; Measured value: C 64.59, H 5.76, and N 19.60;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.23 (t, 3H ,-NHCH
2 CH 3, J=7.2Hz), 2.41 (s, 3H, pyrimidine-CH
3), 2.60 (s, 3H, pyridine-CH
3), 3.54~3.57 (m, 2H ,-NH
CH 2 CH
3), 4.89 (s, 2H ,-CH
2-), 6.65 (s, 1H ,-NH), 6.93~7.39 (m, 4H, ArH), 7.79 (s, 1H, pyrimidine-H), 10.18 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3359(N-H);3053,760(=C-H);2963,1382(C-H);1639,1591,1511,1454(C=N,C=C);1257(C-N);
EI-MS(m/z,%):355(M
++25),354(M
++116),353(M
+15),246(11),245(100),244(73),243(67)。
Compound 23
3-(4-luorobenzyl)-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 45.7%, 139.5~140.5 ℃ of fusing points.
Molecular formula: C
19H
20FN
5O
Ultimate analysis (%), calculated value: C 64.57, H 5.70, and N 19.82; Measured value: C 64.71, H 5.67, and N 19.85;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.23 (t, 3H ,-NHCH
2 CH 3, J=7.2Hz), 2.40 (s, 3H, pyrimidine-CH
3), 2.59 (s, 3H, pyridine-CH
3), 3.53~3.56 (m, 2H ,-NH
CH 2 CH
3), 4.87 (s, 2H ,-CH
2-), 6.65 (s, 1H ,-NH), 7.08~7.24 (m, 4H, ArH), 7.78 (s, 1H, pyrimidine-H), 10.18 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3363(N-H);3127,748(=C-H);2967,1383(C-H);1642,1591,1513,1459(C=N,C=C);1264(C-N);
EI-MS(m/z,%):353(M
+24),351(13),336(22),245(73),244(44),243(16),203(18),150(17),110(81),109(100),107(27)。
Compound 24
3-(2-benzyl chloride base)-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 89.2%, 190.5~191.0 ℃ of fusing points.
Molecular formula: C
19H
20ClN
5O
Ultimate analysis (%), calculated value: C 61.70, H 5.45, and N 18.94; Measured value: C 61.51, H 5.68, and N 18.73
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.24 (t, 3H ,-NHCH
2 CH 3, J=7.2Hz), 2.41 (s, 3H, pyrimidine-CH
3), 2.60 (s, 3H, pyridine-CH
3), 3.55 (m, 2H ,-NH
CH 2 CH
3), 4.98 (s, 2H ,-CH
2-), 6.67 (s, 1H ,-NH), 7.07~7.40 (m, 4H, ArH), 7.76 (s, 1H, pyrimidine-H), 10.21 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3356(N-H);3063,760(=C-H);2975,2940,1375(C-H);1641,1591,1517,1448(C=N,C=C);1250(C-N);
EI-MS(m/z,%):369(M
+7),329(19),312(17),245(31),244(100),243(75),209(28),208(22)。
Compound 27
3-(4-fluorobenzene ethyl)-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 89.2%, 162.8~163.2 ℃ of fusing points.
Molecular formula: C
20H
22FN
5O
Ultimate analysis (%), calculated value: C 65.38, H 6.04, and N 19.06; Measured value: C 65.47, H 6.16, and N 18.95;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.30 (t, 3H ,-NHCH
2 CH 3, J=7.2Hz), 2.39 (s, 3H, pyrimidine-CH
3), 2.50 (s, 3H, pyridine-CH
3), 2.99 (t, 2H ,-CH
2CH
2-, J=6.6Hz), 3.57~3.62 (m, 2H ,-NH
CH 2 CH
3), 3.90 (t, 2H ,-CH
2CH
2-, J=6.8Hz), 6.79 (s, 1H ,-NH), 6.99~7.11 (m, 4H, ArH), 7.22 (s, 1H, pyrimidine-H), 10.38 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3362(N-H);3128,749(=C-H);2968,1382(C-H);1641,1592,1511,1454(C=N,C=C);1222(C-N);
EI-MS(m/z,%):368(M
++19),367(M
+43),352(21),245(23),244(100),123(23),103(20)。
Compound 28
3-(4-chlorobenzene ethyl)-4,5-dimethyl-4-hydroxyl-7-ethylamino-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile
The pure product of gained are white solid, yield 71.1%, 164.0~164.6 ℃ of fusing points.
Molecular formula: C
20H
22ClN
5O
Ultimate analysis (%), calculated value: C 62.58, H 5.78, and N 18.24; Measured value: C 62.68, H 5.52, and N 18.14;
1H NMR (CDCl
3, TMS, 400MHz) δ (ppm): 1.30 (t, 3H ,-NHCH
2 CH 3, J=7.2Hz), 2.39 (s, 3H, pyrimidine-CH
3), 2.51 (s, 3H, pyridine-CH
3), 2.99 (t, 2H ,-CH
2CH
2-, J=7.2Hz), 3.59~3.64 (m, 2H ,-NH
CH 2 CH
3), 3.91 (t, 2H ,-CH
2CH
2-, J=7.0Hz), 6.78 (s, 1H ,-NH), 7.05~7.30 (m, 4H, ArH), 7.24 (s, 1H, pyrimidine-H), 10.38 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3362(N-H);3116,749(=C-H);2961,1383(C-H);2219(C≡N);1641,1592,1512,1453(C=N,C=C);1263(C-N);
EI-MS(m/z,%):386(M
++33),385(M
++211),384(M
++18),383(M
+34),368(21),245(30),244(100),230(16),227(16),216(12),212(17.84),139(22),103(26)。
Adopt above-mentioned similar method, can prepare other compound of general formula I-1.Listedly in the table 1 be synthetic general formula I-1 part of compounds of the present invention.
The implication of elliptical symbol in the table: Me-methyl Et-ethyl Ph-phenyl furfuryl-furfuryl group
Table 1 is the synthetic part of compounds
Compound 1 | Substituting group Y NHMe | Substituent R CH 3CH 2- | Compound 15 | Substituting group Y NHEt | Substituent R CH 3CH 2- |
2 | NHMe | CH 3CH 2CH 2- | 16 | NHEt | CH 3CH 2CH 2- |
3 | NHMe | CH 3(CH 2) 2CH 2- | 17 | NHEt | CH 3(CH 2) 2CH 2- |
4 | NHMe | CH 3(CH 2) 4CH 2- | 18 | NHEt | CH 3(CH 2) 4CH 2- |
5 | NHMe | 2-furanyl-CH 2- | 19 | NHEt | 2-furanyl-CH 2- |
6 | NHMe | PhCH 2- | 20 | NHEt | PhCH 2- |
7 | NHMe | PhCH 2CH 2CH 2- | 21 | NHEt | PhCH 2CH 2CH 2- |
8 | NHMe | 2-FPhCH 2- | 22 | NHEt | 3-FPhCH 2- |
9 | NHMe | 4-FPhCH 2- | 23 | NHEt | 4-FPhCH 2- |
10 | NHMe | 2-ClPhCH 2- | 24 | NHEt | 2-ClPhCH 2- |
11 | NHMe | 4-CH 3PhCH 2- | 25 | NHEt | 4-CH 3PhCH 2- |
12 | NHMe | 4-OCH 3PhCH 2- | 26 | NHEt | 4-OCH 3PhCH 2- |
13 14 | NHMe NHMe | 4-FPhCH 2CH 2- 4-ClPhCH 2CH 2- | 27 28 | NHEt NHEt | 4-FPhCH 2CH 2- 4-ClPhCH 2CH 2- |
Embodiment 4
Compound 29
3-n-hexyl-4,5-dimethyl-4-hydroxyl-7-methylthio group-3,4-dihydro pyrido [4,3-d] pyrimidine-8-methane amide
With 3-n-hexyl-5-methyl-4-methylene radical-7-methylthio group-8-cyano group-3 of 1mmol, 4-dihydro pyrido [4,3-d] pyrimidine is dissolved in the 1mL ethanol, adds the 2mL aqueous solution of the sodium hydroxide of 0.5mmol, 80 ℃ of following backflow stirring reactions 6 hours.Reaction is finished, suction filtration, and washing (2mL * 2) gets crude product, gets the product white solid with the acetone-water recrystallization again, yield 69.7%, 71.4~73.0 ℃ of fusing points.
Molecular formula: C
17H
26N
4O
2S
Ultimate analysis (%), calculated value: C 58.26, H 7.48, and N 15.99; Measured value: C 58.08, H 7.70, and N 15.54;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 0.89 (t, 3H ,-CH
2CH
2CH
2CH
2CH
2 CH 3 , J=6.9Hz), 1.31~1.37 (m, 6H ,-CH
2CH
2 CH 2 CH 2 CH 2CH
3), 1.78 (m, 2H ,-CH
2 CH 2 CH
2CH
2CH
2CH
3), 2.46 (s, 3H, pyrimidine-CH
3), 2.58 (s, 3H ,-SCH
3), 2.67 (s, 3H, pyridine-CH
3), 3.90 (m, 2H ,-
CH 2 CH
2CH
2CH
2CH
2CH
3), 7.76 (s, 1H, pyrimidine-H), 8.60 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3338(N-H);2927,2856,1390(C-H);1689(C=O),1621,1548,1527,1412(C=N,C=C);1218(C-N),1107(C-O);809(=C-H)。
The method preparation of following compound reference compound 29, the structure appraising datum is as follows:
Compound 30
3-(2-luorobenzyl)-4,5-dimethyl-4-hydroxyl-7-methylthio group-3,4-dihydro pyrido [4,3-d] pyrimidine-8-methane amide
The pure product of gained are white solid, yield 92.9%, 168.7~169.4 ℃ of fusing points.
Molecular formula: C
18H
19FN
4O
2S
Ultimate analysis (%), calculated value: C 57.74, H 5.11, and N 14.96; Measured value: C 57.81, H 4.97, and N 15.32;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.45 (s, 3H, pyrimidine-CH
3), 2.57 (s, 3H ,-SCH
3), 2.68 (s, 3H, pyridine-CH
3), 5.19 (s, 2H ,-
CH 2 -), 7.07~7.51 (m, 4H, ArH), 7.94 (s, 1H, pyrimidine-H), 8.71 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3343(N-H);3071,809(=C-H);3005,2926,1386(C-H);1696(C=O),1623,1554,1492,1443(C=N,C=C);1219(C-N);1108(C-O)。
Compound 31
3-(4-methoxy-benzyl)-4,5-dimethyl-4-hydroxyl-7-methylthio group-3,4-dihydro pyrido [4,3-d] pyrimidine-8-methane amide
The pure product of gained are white solid, yield 70.7%, 139.4~140.1 ℃ of fusing points.
Molecular formula: C
19H
22N
4O
3S
Ultimate analysis (%), calculated value: C 59.05, H 5.74, and N 14.50; Measured value: C 59.25, H 5.69, and N 14.37;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.45 (s, 3H, pyrimidine-CH
3), 2.56 (s, 3H ,-SCH
3), 2.69 (s, 3H, pyridine-CH
3), 3.79 (s, 3H, Ph-OCH
3), 5.09 (s, 2H ,-
CH 2 -), 6.88 (d, 2H, ArH, J=7.2Hz), 7.29 (d, 2H, ArH, J=7.2Hz), 7.82 (s, 1H, pyrimidine-H), 8.70 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3347(N-H);3003,776(=C-H);2930,2835,1389(C-H);1690(C=O),1641,1596,1515,1455(C=N,C=C);1253(C-N);1113(C-O)。
Embodiment 5
Compound 32
3-(4-luorobenzyl)-4,5-dimethyl-4-hydroxyl-7-methylthio group-3,4-dihydro pyrido [4,3-d] pyrimidine-8-methane amide
To luorobenzyl-5-methyl-4-methylene radical-7-methylthio group-8-cyano group-3,4-dihydro pyrido [4,3-d] pyrimidine is dissolved in the 1mL acetone with the 3-of 1mmol, adds the 2mL aqueous solution of the sodium hydroxide of 1mmol, stirring at room reaction 0.5 hour.Reaction is finished, suction filtration, and washing (2mL * 2) gets crude product, gets the product white solid with the acetone-water recrystallization again, yield 77.5%, 147.6~148.9 ℃ of fusing points.
Molecular formula: C
18H
19FN
4O
2S
Ultimate analysis (%), calculated value: C 57.74, H 5.11, and N 14.96; Measured value: C 57.92, H 5.56, and N 14.89;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.47 (s, 3H, pyrimidine-CH
3), 2.58 (s, 3H ,-SCH
3), 2.68 (s, 3H, pyridine-CH
3), 5.13 (s, 2H ,-
CH 2 -), 7.05 (t, 2H, ArH, J=12.9Hz), 7.33 (s, 2H, ArH), 7.85 (s, 1H, pyrimidine-H), 8.70 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3332(N-H);3076,808(=C-H);1386(C-H);1694(C=O),1624,1600,1549,1510(C=N,C=C);1215(C-N);1124(C-O);
EI-MS(m/z,%)356(M-H
2O?100),341(54),323(31),299(29),247(88),109(43)。
The method preparation of following compound reference compound 32, the structure appraising datum is as follows:
Compound 33
3-(4-fluorobenzene ethyl)-4,5-dimethyl-4-hydroxyl-7-methylthio group-3,4-dihydro pyrido [4,3-d] pyrimidine-8-methane amide
The pure product of gained are white solid, yield 63.3%, 96.5~98.0 ℃ of fusing points.
Molecular formula: C
19H
21FN
4O
2S
Ultimate analysis (%), calculated value: C 58.75, H 5.45, and N 14.42; Measured value: C 58.44, H 5.77, and N 14.72;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.50 (s, 3H, pyrimidine-CH
3), 2.65 (s, 3H ,-SCH
3), 2.71 (s, 3H, pyridine-CH
3), 3.02 (t, 2H ,-
CH 2 CH
2-), 3.93 (t, 2H ,-
CH 2 CH
2-), 7.00~7.27 (m, 4H, ArH), 7.37 (s, 1H, pyrimidine-H), 8.58 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3399(N-H);2933,2863,1409(C-H);1700(C=O),1567,1536,1510(C=N,C=C);1296(C-N);1216(C-O);824(=C-H);
EI-MS(m/z,%)370(M-H
2O?68),355(26),261(100),248(60),233(26),215(51)。
Compound 34
3-(3-anisole ethyl)-4,5-dimethyl-4-hydroxyl-7-methylthio group-3,4-dihydro pyrido [4,3-d] pyrimidine-8-methane amide
The pure product of gained are white solid, yield 73.7%, 131.4~131.8 ℃ of fusing points.
Molecular formula: C
20H
24N
4O
3S
Ultimate analysis (%), calculated value: C 59.98, H 6.04, and N 13.99; Measured value: C 60.09, H 5.68, and N 14.26;
1H NMR (CDCl
3, TMS, 600MHz) δ (ppm): 2.46 (s, 3H, pyrimidine-CH
3), 2.52 (s, 3H ,-SCH
3), 2.72 (s, 3H, pyridine-CH
3), 3.08 (t, 2H ,-
CH 2 CH
2-, J=6.6Hz), 3.75 (s, 3H, Ph-OCH
3), 6.70~7.22 (m, 4H, ArH), 7.37 (s, 1H, pyrimidine-H), 8.69 (s, 1H ,-OH); IR (KBr) υ (cm
-1): 3332 (N-H); 2942,2837,1350 (C-H); 1705 (C=O), 1621,1554,1443 (C=N, C=C); 1155 (C-N); 1049 (C-O); 881,781 (=C-H).
Adopt above-mentioned similar method, can prepare other compound of general formula I-2.Listedly in the table 2 be synthetic general formula I-2 part of compounds of the present invention.
The implication of elliptical symbol in the table: Ph-phenyl
Table 2 is the synthetic part of compounds
Compound 29 | MH-1 | R CH 3(CH 2) 4CH 2- |
30 | MH-2 | 2-FPhCH 2- |
31 | MH-3 | 4-OCH 3PhCH 2- |
32 | MH-4 | 4-FPhCH 2- |
33 | MH-5 | 4-FPhCH 2CH 2- |
34 | MH-6 | 3-OCH 3PhCH 2CH 2- |
Embodiment 6
Compound 35
3-n-hexyl-4,5-dimethyl-4-hydroxyl-7-methylsulfonyl-8-cyano group-3,4-dihydro pyrido [4,3-d] pyrimidine
3-n-hexyl-5-methyl-4-methylene radical-7-methylthio group-3 with 1mmol, 4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile, the sodium wolframate of 10mL acetonitrile and catalytic amount adds in the three-necked flask of 50mL, is warmed up to 50 ℃ and begins to drip 0.68g (6mmmol) 30% hydrogen peroxide.Dropwise, back flow reaction to raw material point disappears.Add water and make solid separate out fully, suction filtration obtains crude product and gets pure product yellow solid with acetone-sherwood oil recrystallization again, yield 57.8%, 198.0~199.0 ℃ of fusing points.
Molecular formula: C
17H
24N
4O
3S
Ultimate analysis (%), calculated value: C 56.02, H 6.64, and N 15.37; Measured value: C 55.62, H 6.24, and N 15.83;
1H NMR (DMSO, TMS, 600MHz) δ (ppm): 0.86 (t, 3H ,-CH
2CH
2CH
2CH
2CH
2 CH 3 , J=6.6Hz), 1.28 (s, 6H ,-CH
2CH
2 CH 2 CH 2 CH 2CH
3), 1.69 (t, 2H ,-CH
2 CH 2 CH
2CH
2CH
2CH
3, J=6.6Hz), 3.03 (s, 3H, pyridine-CH
3), 3.51 (s, 3H ,-SO
2CH
3), 3.98 (t, 2H ,-
CH 2 CH
2CH
2CH
2CH
2CH
3, J=7.5Hz), 8.87 (s, 1H, pyrimidine-H);
IR(KBr)υ(cm
-1):3426(O-H);3008,761(=C-H);2923,2856,1377(C-H);2242(C≡N);1597,1548,1450(C=N,C=C);1332(O=S=O),1149(C-O);
EI-MS(m/z,%):203(3),355(26),88(20),43(100)。
The method preparation of following compound reference compound 35, the structure appraising datum is as follows:
Compound 36
The adjacent luorobenzyl-4 of 3-, 5-dimethyl-4-hydroxyl-7-methylsulfonyl-8-cyano group-3,4-dihydro pyrido [4,3-d] pyrimidine
The pure product of gained are yellow solid, yield 21.6%, 263.0~264.5 ℃ of fusing points.
Molecular formula: C
18H
17FN
4O
3S
Ultimate analysis (%), calculated value: C 55.66, H 4.41, and N 14.42; Measured value: C 55.97, H 4.19, and N 14.58;
1H NMR (DMSO, TMS, 600MHz) δ (ppm): 2.98 (s, 3H, pyridine-CH
3), 3.49 (s, 3H ,-SO
2CH
3), 5.27 (s, 2H ,-
CH 2 -), 7.16~7.39 (m, 4H, ArH), 9.03 (s, 1H, pyrimidine-H); IR (KBr) υ (cm
-1): 3424 (O-H); 3010,756 (=C-H); 2927,1387 (C-H); 2232 (C ≡ N); 1601,1578,1453 (C=N, C=C); 1313 (O=S=O), 1144 (C-O);
EI-MS(m/z,%):109(17),58(100),42(78)。
Compound 37
3-is to methoxy-benzyl-4,5-dimethyl-4-hydroxyl-7-methylsulfonyl-8-cyano group-3,4-dihydro pyrido [4,3-d] pyrimidine
The pure product of gained are white solid, yield 48.9%, 178.5~180.0 ℃ of fusing points.
Molecular formula: C
19H
20N
4O
4S
Ultimate analysis (%), calculated value: C 56.99, H 5.03, and N 13.99; Measured value: C 6.68, H 5.21, and N 13.64;
1H NMR (DMSO, TMS, 600MHz) δ (ppm): 2.71 (s, 3H, pyridine-CH
3), 3.40 (s, 3H ,-SO
2CH
3), 3.70 (t, 2H ,-
CH 2 -), 3.75 (s, 3H, Ph-OCH
3), 6.94 (d, 2H, ArH, J=7.8Hz), 7.38 (d, 2H, ArH, J=7.8Hz), 7.68 (s, 1H, pyrimidine-H), 7.75 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3396(O-H);2930,2838,1398(C-H);2229(C≡N);1610,1543,1518,1443(C=N,C=C);1312(O=S=O),1256(C-N);1138(C-O);758(=C-H);EI-MS(m/z,%):279(10),136(63),121(100),106(28),77(32),62(48)。
Embodiment 7
Compound 38
3-is to luorobenzyl-4,5-dimethyl-4-hydroxyl-7-methylsulfonyl-8-cyano group-3,4-dihydro pyrido [4,3-d] pyrimidine
With the 3-of 1mmol to luorobenzyl-5-methyl-4-methylene radical-7-methylthio group-3,4-dihydro pyrido [4,3-d] pyrimidine-8-nitrile, the sodium wolframate of 10mL acetic acid and catalytic amount adds in the three-necked flask of 50mL, adds 0.68g (6mmmol) 30% hydrogen peroxide again.Dropwise, 100 ℃ are reacted to raw material point and disappear.Add water and make solid separate out fully, suction filtration obtains crude product and gets pure product yellow solid with acetone-sherwood oil recrystallization again, yield 43.2%, 150.3~151.8 ℃ of fusing points.
Molecular formula: C
18H
17FN
4O
3S
Ultimate analysis (%), calculated value: C 55.66, H 4.41, and N 14.42; Measured value: C 55.74, H 4.70, and N 14.10;
1H NMR (DMSO, TMS, 600MHz) δ (ppm): 2.71 (s, 3H, pyridine-CH
3), 3.42 (s, 3H ,-SO
2CH
3), 3.69 (t, 2H ,-
CH 2 -), 7.20~7.50 (m, 4H, ArH), 7.67 (s, 1H, pyrimidine-H), 7.82 (s, 1H ,-OH);
IR(KBr)υ(cm
-1):3426(O-H);3004,757(=C-H);2922,1399(C-H);2226(C≡N);1609,1578,1517,1442(C=N,C=C);1314(O=S=O),1233(C-N);1138(C-O);
EI-MS(m/z,%):218(14),178(63),176(100),160(57),121(43),109(57),75(21),43(60)。
The method preparation of following compound reference compound 38, the structure appraising datum is as follows:
Compound 39
3-is to fluorobenzene ethyl-4,5-dimethyl-4-hydroxyl-7-methylsulfonyl-8-cyano group-3,4-dihydro pyrido [4,3-d] pyrimidine
The pure product of gained are yellow solid, yield 60.5%, 150.3~151.8 ℃ of fusing points.
Molecular formula: C
19H
19FN
4O
3S
Ultimate analysis (%), calculated value: C 56.70, H 4.76, and N 13.92; Measured value: C 56.46, H 4.41, and N 14.35;
1H NMR (DMSO, TMS, 600MHz) δ (ppm): 3.02 (t, 2H ,-CH
2 CH 2 -, J=7.5Hz), 3.06 (s, 3H, pyridine-CH
3), 3.51 (s, 3H ,-SO
2CH
3), 4.23 (t, 2H ,-CH
2 CH 2 -, J=7.2Hz), 7.12~7.30 (m, 4H, ArH), 8.65 (s, 1H, pyrimidine-H);
IR(KBr)υ(cm
-1):3425(O-H);3042,756(=C-H);2934,1379(C-H);2239(C≡N);1601,1550,1510,1451(C=N,C=C);1308(O=S=O),1220(C-N);1148(C-O);EI-MS(m/z,%):122(26),109(41),96(48),77(13),46(100),44(86)。
Compound 40
3-meta-methoxy styroyl-4,5-dimethyl-4-hydroxyl-7-methylsulfonyl-8-cyano group-3,4-dihydro pyrido [4,3-d] pyrimidine
The pure product of gained are yellow solid, yield 23.2%, 226.0~227.0 ℃ of fusing points.
Molecular formula: C
20H
22N
4O
4S
Ultimate analysis (%), calculated value: C 57.96, H 5.35, and N 13.52; Measured value: C 57.55, H 5.16, and N 13.73;
1H NMR (DMSO, TMS, 600MHz) δ (ppm): 2.98 (t, 2H ,-CH
2 CH 2 -, J=7.5Hz), 3.05 (s, 3H, pyridine-CH
3), 3.50 (s, 3H ,-SO
2CH
3), 3.72 (s, 3H, Ph-OCH
3), 4.23 (t, 2H ,-
CH 2 CH
2-, J=7.5Hz), 6.78~7.22 (m, 4H, ArH), 8.63 (s, 1H, pyrimidine-H);
IR(KBr)υ(cm
-1):3424(O-H);3035,753(=C-H);2928,1385(C-H);2229(C≡N);1596,1550,1456(C=N,C=C);1307(O=S=O),1274(C-N);1153(C-O)。
Adopt above-mentioned similar method, can prepare other compound of general formula I-3.Listedly in the table 3 be synthetic general formula I-3 part of compounds of the present invention.
The implication of elliptical symbol in the table: Ph-phenyl
Table 3 is the synthetic part of compounds
Compound 35 | MI-1 | R CH 3(CH 2) 4CH 2- |
36 | MI-2 | 2-FPhCH 2- |
37 | MI-3 | 4-OCH 3PhCH 2- |
38 | MI-4 | 4-FPhCH 2- |
39 | MI-5 | 4-FPhCH 2CH 2- |
40 | MI-6 | 3-OCH 3PhCH 2CH 2- |
Embodiment 8 anti-tumor activity tests
For trying target: cancer cells KB at the bottom of the oral cavity; Cancer therapy drug Chang Chunxin alkali is induced down and is produced cancer cells KBv200 at the bottom of the chemical sproof oral cavity; Human breast cancer cell MCF-7; Induce the chemical sproof human breast cancer cell strain MCF-7/Adr of generation down at the antitumor drug Zorubicin; KB cell CNE1.
Test method: MTT cell in vitro poison test method
The human cancer cell of taking the logarithm vegetative period makes 2 * 10
4The cell suspension of individual cell/mL is inoculated into 96 orifice plates by the 0.19mL/ hole, in 37 ℃, 5%CO
2Cultivate after 24 hours, press the sample solution that the 0.01mL/ hole adds different concns, other establishes the physiological saline control wells, and every concentration is established 4 parallel holes, cultivates after the dosing 72 hours again, cultivating end was the 3-(4 of 10mg/mL by 0.01mL/ hole adding concentration in preceding 3 hours, 5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt (MTT) is cultivated sucking-off nutrient solution when finishing, every hole adds the dimethyl sulfoxide (DMSO) (DMSO) of 0.1mL, measures the OD value down in measuring wavelength 540nm reference wavelength 655nm.Be calculated as follows inhibitory rate of cell growth (IR), with simplified probit method calculation of half inhibitory concentration (IC
50).IR%=(the average OD value of 1-
The dosing group/ average OD value
Control group) * 100%.Measurement result sees Table 4.
Anti-tumor activity data (the IC of table 4 segment bounds I-1 compound
50Value)
Embodiment 9 anti-tumor activity tests
For examination target: KB cell 6-10B, CNE1, HONE1, SUNE1; Human lung carcinoma cell H460, Calu-3; Leukemia cell HL-60.
Test method: MTT cell in vitro poison test method.Measurement result sees Table 5.
Anti-tumor activity data (the IC of table 5 segment bounds I-1 compound
50Value)
Compound | 6-10B | CNE1 | HONE1 | SUNE1 | H460 | Calu-3 | HL-60 |
11 | 3.62 | 0.94 | 4.60 | 3.32 | 4.10 | 27.0 | NT |
12 | 3.19 | 0.73 | 3.14 | 2.82 | 3.04 | 35.4 | 0.32 |
25 | 69.2 | 3.53 | 28.4 | 15.9 | 71.0 | 32.0 | NT |
26 | 4.06 | 1.16 | 5.55 | 3.64 | 6.88 | 36.3 | 0.37 |
Embodiment 10 anti-tumor activity tests
For trying target: cancer cells KB at the bottom of the oral cavity; KB cell CNE1, CNE2.
Test method: MTT cell in vitro poison test method.Measurement result sees Table 6.Vincristine(VCR) and Ro 2-9757 are as positive control drug in the table.
Anti-tumor activity data (the IC of table 6 segment bounds I-2, I-3 compound
50Value)
Annotate: the Vincristin-vincristine(VCR); The Fluorouracil-Ro 2-9757.
The growth-inhibiting effect of embodiment 12 pairs of rat liver cancers of 11 compounds (Hep-S) transplanted tumor
Getting ascitic type mouse bearing liver cancer ascites, by dilution in 1: 3, be inoculated in the subcutaneous 0.2mL/ of mouse armpit only with physiological saline, inoculation divides 2 groups next day at random, i.e. physiological saline control group and compound 12 administration groups, every group of 9 animals.Inoculation plays compound 12 administration groups next day by dosage intraperitoneal injection every day of per kilogram of body weight 100mg 2 times, successive administration drug withdrawal in 4 days 1 day, and administration is 8 times altogether, the corresponding dosage intraperitoneal injection of saline by per kilogram of body weight 10mL of physiological saline control group.Put to death animal on 2nd after the last administration, peel off the knurl piece and claim knurl heavy, calculate inhibition rate of tumor growth (IR%) as follows.
The average knurl of the average knurl weight-administration of IR%=[(control group group is heavy)/the average knurl of control group is heavy] * 100%
The result shows that the growth inhibition ratio of 12 pairs of rat liver cancer transplanted tumors of compound is 52.3%, and compound 12 administration group knurls are heavy relatively to have highly significant difference (P<0.01) with control group, shows that compound 12 has the effect of the tumor growth of inhibition.
Claims (19)
1. a class 3,7, the 8-polysubstituted pyridine is [4,3-d] pyrimidine derivatives also, it is characterized in that having the represented structural formula of general formula I:
Among the formula I, X represents: CN, CONH
2
Y represents: methylthio group, methylsulfonyl, C
1-C
3Alkylamino;
R represents: C
1-C
6Alkyl, the cyclosubstituted methyl of furans, phenyl C
1-C
3Alkyl or substituted-phenyl C
1-C
3Alkyl, phenyl or substituted-phenyl; Substituting group on the related phenyl ring is: halogen, C
1-C
3Alkyl or alkoxyl group, substituting group is in phenyl ring arbitrary locational single replace or polysubstituted, the substituting group on phenyl ring is identical or inequality.
2. a class 3,7 according to claim 1,8-polysubstituted pyridine be [4,3-d] pyrimidine derivatives also ,-1 represented structural formula that it is characterized in that having general formula I:
R in the formula is identical with implication in claim 1 general formula I; Y represents C
1-C
3Alkylamino.
5. the polysubstituted pyridine with general formula I-1 expression as claimed in claim 2 is the preparation method of [4,3-d] pyrimidine derivatives also, it is characterized in that making the represented compound of Formula B and triethyl orthoformate reaction generation intermediate C, C again with C
1-C
6The cyclosubstituted methyl primary amine of kiber alkyl amine, furans, phenyl C
1-C
3Kiber alkyl amine or substituted-phenyl C
1-C
3The kiber alkyl amine reaction is closed ring in room temperature or heating condition, obtains Compound I-1:
Y among Formula B, C and the I-1 represents C
1-C
3Alkylamino; RNH
2Middle R represents C
1-C
6Alkyl, the cyclosubstituted methyl of furans, phenyl C
1-C
3Alkyl or substituted-phenyl C
1-C
3Alkyl.
6. the polysubstituted pyridine of representing with general formula I-2 as claimed in claim 3 is the preparation method of [4,3-d] pyrimidine derivatives also, it is characterized in that making the represented compound of general formula D to obtain Compound I-2 through the NaOH hydrolysis reaction:
General formula D is identical with the definition among the claim 1 formula I with R among the I-2.
7. the purposes of the described compound of representing with general formula I of claim 1 is characterized in that, the compound that general formula I is represented is as the effective ingredient of preparation antitumor drug.
8. the purposes of the described compound of representing with general formula I of claim 1 is characterized in that, the compound that general formula I is represented has the effective ingredient of the antitumor drug of cytotoxic activity for JEG-3 KB at the bottom of the human oral as preparation.
9. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for cancer cells KBv200 at the bottom of the drug-fast human oral of vincristine(VCR) as preparation.
10. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for human breast cancer cell strain MCF-7 as preparation.
11. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for the drug-fast human breast cancer cell strain of Zorubicin MCF-7/Adr as preparation.
12. the purposes of the described compound of representing with general formula I of claim 1 is characterized in that, the compound that general formula I is represented has the effective ingredient of the antitumor drug of cytotoxic activity for KB cell CNE1 as preparation.
13. the purposes of the described compound of representing with general formula I of claim 1 is characterized in that, the compound that general formula I is represented has the effective ingredient of the antitumor drug of cytotoxic activity for KB cell CNE2 as preparation.
14. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for KB cell 6-10B as preparation.
15. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for KB cell HONE1 as preparation.
16. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for KB cell SUNE1 as preparation.
17. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for human lung carcinoma cell H460 as preparation.
18. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for human lung carcinoma cell Calu-3 as preparation.
19. the purposes of the described compound with general formula I-1 expression of claim 2 is characterized in that the compound of general formula I-1 expression has the effective ingredient of the antitumor drug of cytotoxic activity for human leukemia cell HL-60 as preparation.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009100622899A CN101619063B (en) | 2009-06-02 | 2009-06-02 | 3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009100622899A CN101619063B (en) | 2009-06-02 | 2009-06-02 | 3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101619063A CN101619063A (en) | 2010-01-06 |
CN101619063B true CN101619063B (en) | 2011-08-10 |
Family
ID=41512480
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2009100622899A Expired - Fee Related CN101619063B (en) | 2009-06-02 | 2009-06-02 | 3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101619063B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105481781B (en) * | 2014-09-17 | 2019-06-25 | 华中师范大学 | Compound and its preparation method and application |
CN107382837A (en) * | 2017-08-01 | 2017-11-24 | 大理大学 | Beak tail Chinese lute A prime E and preparation method thereof and medical usage |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1351497A (en) * | 1999-04-01 | 2002-05-29 | 辉瑞产品公司 | Aminopyrimidines as sorbitol dehydrogenase inhibitors |
WO2004039774A2 (en) * | 2002-05-23 | 2004-05-13 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
WO2004106308A1 (en) * | 2003-05-27 | 2004-12-09 | Pfizer Products Inc. | Quinazolines and pyrido [3,4-d] pyrimidines as receptor tyrosine kinase inhibitors |
CN1711260A (en) * | 2002-11-05 | 2005-12-21 | 瑟维尔实验室 | Pyridopyrimidinone compounds, method for production thereof and medicaments comprising the same |
CN1962658A (en) * | 2005-11-10 | 2007-05-16 | 北京大学 | Tetrahydropyridine [3,2-d] pyridine compound and its uses for preparing antineoplastic drug |
CN101006086A (en) * | 2004-06-11 | 2007-07-25 | 日本烟草产业株式会社 | 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido'2,3-d! pyrimidine derivatives and related compounds for the treatment of cancer |
WO2008041118A2 (en) * | 2006-10-04 | 2008-04-10 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists |
-
2009
- 2009-06-02 CN CN2009100622899A patent/CN101619063B/en not_active Expired - Fee Related
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1351497A (en) * | 1999-04-01 | 2002-05-29 | 辉瑞产品公司 | Aminopyrimidines as sorbitol dehydrogenase inhibitors |
WO2004039774A2 (en) * | 2002-05-23 | 2004-05-13 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
CN1711260A (en) * | 2002-11-05 | 2005-12-21 | 瑟维尔实验室 | Pyridopyrimidinone compounds, method for production thereof and medicaments comprising the same |
WO2004106308A1 (en) * | 2003-05-27 | 2004-12-09 | Pfizer Products Inc. | Quinazolines and pyrido [3,4-d] pyrimidines as receptor tyrosine kinase inhibitors |
CN101006086A (en) * | 2004-06-11 | 2007-07-25 | 日本烟草产业株式会社 | 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido'2,3-d! pyrimidine derivatives and related compounds for the treatment of cancer |
CN1962658A (en) * | 2005-11-10 | 2007-05-16 | 北京大学 | Tetrahydropyridine [3,2-d] pyridine compound and its uses for preparing antineoplastic drug |
WO2008041118A2 (en) * | 2006-10-04 | 2008-04-10 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists |
Also Published As
Publication number | Publication date |
---|---|
CN101619063A (en) | 2010-01-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2684402C2 (en) | New type of cytidine derivatives and use thereof | |
CN108864057A (en) | Bis- target spot inhibitor of JAK and HDAC containing 4- amino-pyrazol structure and its preparation method and application | |
CN104341425A (en) | Deuterated acetylenic derivative, pharmaceutical composition and application thereof | |
CN104402831B (en) | -5-cyanopyrimidine derivative containing uride construction unit and its production and use | |
CN107417628A (en) | Diaryl quianzolinones, its preparation method and its medical usage and the pharmaceutical composition comprising such compound | |
CN101323617B (en) | 2,3,4,7-polysubstituted naphthyridine [4,3-d] pyrimidine derivates with sterilization activity and preparation thereof | |
CN103880822B (en) | Containing 2,4,6-trisubstituted pyrimidine compounds of 1,2,3-triazole, preparation method and application thereof | |
CN110381950A (en) | Substituted [5,6] ring -4 (3H)-pyrimidone as anticancer agent | |
CN101619063B (en) | 3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation | |
CN102153508B (en) | 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs | |
CN109912571A (en) | Biologically active novel benzoquinoline substituted trinitrogen azole compound and its synthetic method and application | |
CN102746281A (en) | 4-1,2,3-triazole-coumarin derivative and its preparation method and application | |
CN103965175A (en) | 4-(substituted phenylamino)quinazoline compounds, and preparation method and application thereof | |
CN104945388A (en) | Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs | |
CN107151232A (en) | The ternary cyclics of one class STAT3 protein inhibitors | |
CN112225742B (en) | Compound for inhibiting VEGFR activity, preparation method and application | |
CN102746212B (en) | Beta-elemene indole derivative, preparation and application thereof | |
CN108148053A (en) | Sulfanilamide (SN) triazole Tubulin polymerization inhibitors and its synthetic method and application | |
JP7299307B2 (en) | Thymine nucleobase-based triazolopyrimidines and methods for their preparation | |
CN105481778A (en) | Pyrimidine derivative, preparation method and applications thereof | |
Kumar et al. | Design, synthesis and biological potential of 5-(2-amino-6-(3/4-bromophenyl) pyrimidin-4-yl) benzene-1, 3-diol scaffolds as promising antimicrobial and anticancer agents | |
CN104530018B (en) | Indole compounds containing alpha-methylene-gamma-butyrolactone structures, preparation method and application thereof | |
CA3090876C (en) | Dioxinoquinoline compounds, preparation method and uses thereof | |
CN116096372A (en) | EGFR inhibitor, preparation method and pharmaceutical application thereof | |
CN106243130A (en) | 3,6 diaryl [1,2,4] triazole also [3,4 b] [1,3,4] diazthines compound and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110810 Termination date: 20180602 |