CN104119280A - Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, and preparation methods and applications of pyrimidine derivatives - Google Patents
Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, and preparation methods and applications of pyrimidine derivatives Download PDFInfo
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- CN104119280A CN104119280A CN201410295919.8A CN201410295919A CN104119280A CN 104119280 A CN104119280 A CN 104119280A CN 201410295919 A CN201410295919 A CN 201410295919A CN 104119280 A CN104119280 A CN 104119280A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention belongs to the field of medicinal chemistry, and discloses pyrimidine compounds containing semicarbazide and terminal alkyne structural units, and preparation methods and applications of the pyrimidine compounds in preparation of antitumor drugs by taking lysine specific demethylase 1 (hereafter referred to as LSD1) as a target. A pyrimidine active fragment is built by adopting a three-component one-pot method, and then the target compounds are prepared by substitution, chlorination and ammonification reaction. The general formulas of the compounds are as shown in the formula I in the specification. An in vitro anti-tumor activity experiment and an LSD1 inhibition activity experiment prove that the compounds have obvious inhibiting and killing action on a plurality of tumor cells by inhibiting the activity of the LSD1, can be used as lead compounds for further development, and are applied to preparation of the antitumor drugs.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a class containing Urea,amino-with the pyrimidine compound of Terminal Acetylenes structural unit, they preparation method and in preparation, take the application of istone lysine specificity demethylase (hereinafter to be referred as LSD1) in target antitumor drug.
Background technology
Tumour is serious harm human health and the disease that is difficult to overcome, and the antitumor drug having gone on the market at present also has a lot, but in these medicines, still has some problems, such as toxicity is large, a little less than targeting and easily produce resistance etc.Therefore, the research and development of new type antineoplastic medicine seem particularly important.
Covalent histone modifications is a kind of important epigenetic pattern, comprises acetylation of histone, methylates, phosphorylation and ubiquitination etc., and wherein acetylize is the histone modification mode for many in histone modification Mechanism Study with methylating.Histone methylatedly before 2004 be considered to forever irreversible, Methionin specificity histone demethylase (lysine specific demethylase 1, LSD1) be the 1st time found can catalysis histone H 3 K4 and the specificity demethylase of H3K9 demethylation, can remove the single, double of histone K4, K9 methylates, thereby regulate the interaction of histone and other albumen, and affect the Activation and inhibition of genetic transcription, the important vital process such as x chromosome inactivation.
LSD1 expression amount of LSD1 in kinds of tumor cells is significantly higher than normal cell, as neuroblastoma, cancer eye, prostate cancer, mammary cancer, lung cancer, bladder cancer etc.And experiment showed, that the activity that is reduced LSD1 expression amount or reduce LSD1 at cell levels by RNAi technology or micromolecular inhibitor can suppress cell proliferation and induce the expression of some cytodifferentiation genes involveds; Under the effect of small molecules oxidase inhibitor PCPA, also can suppress the growth of kinds of tumor cells and solid tumor.Therefore, LSD1 inhibitor can not only be used for setting forth biological function as the research tool of epigenetics, and can as epigenetics medicine, be used for prevention and the treatment of tumour, has caused the extensive concern of scientific research circle, becomes the focus of current research.
Meanwhile, also have report to confirm, pyrimidines has biological activity very widely, such as antiviral, antibacterial, anti-inflammatory and antitumor etc.But the report that pyrimidines and antitumor action based on LSD1 target spot is combined to research is less, so this research has very important value.
Summary of the invention
For developing existing clinical medicine resource, the object of the invention is to provide a class 2-(3,4-sulphur proyl)-4-replacement-5-cyano group-6-amino urea pyrimidine derivant, thus for finding the new antitumor drug based on LSD1 target spot of a class, open up a new way; Another object of the present invention is to provide its preparation method; Another object is to provide its application in preparing antitumor drug and LSD1 inhibitor.
The amino ureas pyrimidine derivatives of 2-of the present invention (3,4-sulphur proyl)-4-replacement-5-cyano group-6-general structure is as follows:
I
R in general formula I
1for Cl,
,
,
in any one;
R
2for any one in following group:
、
、
、
、
、
、
、
、
、
、
。
Preferred:
R
1for Cl,
in any one;
R
2for any one in following group:
、
、
、
、
、
、
、
、
、
、
、
。
Preferred:
R
1for
;
R
2for any one in following group:
、
、
、
、
、
、
、
。
Preferred:
R
1for
;
R
2for any one in following group:
,
。
More preferably one of following compound:
R
1during for Cl: III-1 R
2=Phenyl;
III-2 R
2=4-Chlorophenyl ;
III-3 R
2=3,4,5-Trimethoxylphenyl;
III-4 R
2=3,4-Difluorophenyl;
III-5 R
2=4-Bromophenyl;
III-6 R
2=4-Isoproplphenyl;
III-7 R
2=4-Fluorophenyl;
III-8 R
2=4-Methylphenyl;
III-9 R
2=4-Nitrophenyl;
III-10 R
2=3-Chlorophenyl;
III-11 R
2=2-Thienyl;
R
1for
time: I-1 R
2=Phenyl;
I-2 R
2= 4-Chlorophenyl;
I-3 R
2= 3,4,5-Trimethoxylphenyl;
I-4 R
2= 3,4-Difluorophenyl;
I-5 R
2= 4-Bromophenyl;
I-6 R
2=4-Isoproplphenyl;
I-7 R
2= 4-Fluoropheny;
I-8 R
2=4-Methylphenyl;
I-9R
2= 4-Nitrophenyl;
I-10R
2=3-Chlorophenyl;
I-11R
2=3-Methoxylphenyl;
I-12 R
2=2-Thienyl;
R
1for
time: I-13 R
2=3,4-Difluorophenyl;
I-14 R
2=4-Methylphenyl;
I-15 R
2=3-Chlorophenyl;
I-16 R
2= 4-Nitrophenyl;
I-17 R
2= 4-Bromophenyl;
I-18 R
2=4-Chlorophenyl;
I-19R
2=4-Isoproplphenyl;
R
1for
time: I-20 R
2=4-Nitrophenyl.
The amino ureas pyrimidine derivatives of 2-of the present invention (3,4-sulphur proyl)-4-replacement-5-cyano group-6-, mainly makes by following steps:
(1) preparation method of general formula I I:
In solvent, by ethyl cyanacetate under alkaline condition and thiocarbamide, substituted benzoyl aldehyde reaction obtain Compound I I, alkali used is a kind of in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium phosphate, ten phosphate dihydrate sodium, potassiumphosphate, saleratus, sodium bicarbonate, triethylamine; Solvent used is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1, one of in 2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water or wherein any two or three mixture; Reaction is carried out conventionally between 0-90 ℃.Products therefrom obtains sterling through suction filtration, recrystallization.Recrystallization solvent used is a kind of in ethanol, methyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, chloroform or the mixture of two kinds wherein.
Preferred temperature 25-60 ℃.
(2) preparation method of general formula III:
In solvent, general formula I I reacts and obtains intermediate product with propargyl bromide, with thin-layer chromatography, monitors reaction process, until reacted; Without separation, directly in reaction system, drip phosphorus oxychloride, after having reacted, be poured in frozen water, stir, there is solid to separate out, suction filtration, obtains solid, obtains the solid of sterling compound III through column chromatography.Solvent used is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1, one of in 2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water or wherein any two or three mixture; Reaction is carried out conventionally between 0-90 ℃.
Preferred temperature 25-60 ℃.
(3) preparation method of target compound I:
In solvent, compound corresponding in general formula III reacts with Urea,amino-compounds, after question response completes, separates out solid, and suction filtration obtains corresponding compound in general formula I.Solvent used is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1, one of in 2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water or wherein any two or three mixture; Reaction is carried out conventionally between 0-90 ℃.Products therefrom can obtain straight product through appropriate means as purifications such as column chromatography or recrystallizations.Crystallization solvent for use is a kind of in ethanol, methyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, chloroform or the mixture of two kinds wherein; In reaction amino ureas used be aminoguanidine, Urea,amino-, thiosemicarbazide.
Preferred temperature 25-60 ℃.
2-(3 of the present invention, 4-sulphur proyl) the amino ureas pyrimidine derivatives of-4-replacement-5-cyano group-6-has good restraining effect to stomach cancer cell (MGC-803, HGC-27, SGC-7901), liver cancer cell (HepG-2) and prostate cancer cell (PC-3), contrast with the antitumor drug 5 FU 5 fluorouracil having used clinically, be better than the latter.Meanwhile, by the experiment of LSD1 enzymic activity, find that LSD1 is also had to good restraining effect.Wherein the activity of compound is less than 2 μ M mostly, is better than positive control tranylcypromine (2-PCPA).Therefore, this type of 2-(3 provided by the invention, 4-sulphur proyl) drug combination and novel LSD1 inhibitor medicaments that the amino ureas pyrimidine derivatives of-4-replacement-5-cyano group-6-is development of new antitumor drug, medicine have been opened up another effective way, this compounds synthetic reasonable in design, reaction conditions is gentle, simple to operate, reaction yield is high, if exploitation becomes new drug, will have good market application foreground.
embodiment:
For the present invention is better illustrated, as follows especially exemplified by embodiment:
General formula (
iI) preparation with reference to making with Publication about Document:
H.I. Skulnick, J.H. Ludens, M.G. Wendling.
Journal of Medicinal Chemistry,
1986, 29, 1499-1504.
embodiment 1general formula (
iI) shown in, R
2the derivative of=Phenyl (
iI-1) preparation
By ethyl cyanacetate (2.3g, 20mmol) with sodium hydroxide (1.2g, 30mmol) add in ethanolic soln, under reflux conditions, reaction for some time, then by thiocarbamide (2.3g, 30mmol) and phenyl aldehyde (3.2g, 30mmol) add in reaction system, stirring reaction, TLC follows the tracks of detection.After reaction finishes, suction filtration, recrystallization obtains sterling.Yield 92%, yellow solid.
embodiment 2general formula (
iII) shown in, R
1=Cl, R
2the derivative of=Phenyl (
iII-1) preparation
Propargyl bromide (3.6g, 30mmol) is dropwise added in Isosorbide-5-Nitrae-dioxane solution of II-1 (2.7g, 10mmol) to 60 ℃ of heated and stirred reactions.With TLC, monitor reaction process, until reacted; Without separation, directly in reaction system, drip phosphorus oxychloride (4.6g, 30mmol), after having reacted, be poured in frozen water, stir, there is solid to separate out, suction filtration, obtains solid, obtains the solid of sterling compound III-1 through column chromatography.Productive rate 64%, faint yellow solid.Fusing point: 131-132
oc.
1H NMR (400 MHz, CDCl
3, δ, ppm) δ 8.20 – 8.07 (m, 2H, Ar-H), 7.70 – 7.52 (m, 3H, Ar-H), 4.01 (d,
J = 2.6 Hz, 2H, -CH
2-), 2.28 (t,
J = 2.6 Hz, 1H, ≡C-H).
13C NMR (100 MHz, CDCl
3, δ, ppm): δ 174.02, 168.73, 163.95, 134.07, 132.72, 129.35, 129.02, 114.43, 101.42, 78.17, 71.63, 20.36. HR-MS (ESI): Calcd. C
14H
9ClN
3S, [M+H]
+m/z: 286.0206, found: 286.0202.
embodiment 3general formula (
iII) shown in, R
1=Cl, R
2the derivative of=4-Chlorophenyl (
iII-2) preparation
Take the same method preparation of embodiment 1
iI-2, R
2=4-Chlorophenyl; Take the same method preparation of embodiment 2
iII-2, R
1=Cl, R
2=4-Chlorophenyl; 80 ° of C. of Mp:79 –
1h NMR (400 MHz, CDCl
3, δ, ppm) and δ 8.17 – 8.01 (m, 2H, Ar-H), 7.63 – 7.47 (m, 2H, Ar-H), 4.00 (d,
j=2.6 Hz, 2H ,-CH
2-), 2.28 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 174.20,167.41,164.04,139.39,132.39,130.69,129.40,114.27,101.19,78.07,71.66,20.40. HR-MS (ESI): Calcd. C
14h
8cl
2n
3s, [M+H]
+m/z:319.9816, found:319.9818.
embodiment 4general formula (
iII) shown in, R
1=Cl, R
2=3, the derivative of 4,5-Trimethoxylphenyl (
iII-3) preparation
Take the same method preparation of embodiment 1
iI-3, R
2=3,4,5-Trimethoxylphenyl; Take the same method preparation of embodiment 2
iII-3, R
1=Cl, R
2=3,4,5-Trimethoxylphenyl; 105 ° of C. of Mp:104 –
1h NMR (400 MHz, CDCl
3, δ, ppm) and δ 7.50 (s, 2H, Ar-H), 3.98 (d,
j=2.7 Hz, 2H ,-CH
2-), 3.97 (s, 9H ,-CH
3), 2.26 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 173.60,167.69,164.07,153.33,142.24,128.70,114.87,106.98,100.65,78.72,71.22,61.08,56.43,20.35. HR-MS (ESI): Calcd. C
17h
15clN
3o
3s, [M+H]
+m/z:376.0523, found:376.0517.
embodiment 5general formula (
iII) shown in, R
1=Cl, R
2the derivative of=3,4-Difluorophenyl (
iII-4) preparation
Take the same method preparation of embodiment 1
iI-4, R
2=3,4-Difluorophenyl; Take the same method preparation of embodiment 2
iII-4, R
1=Cl, R
2=3,4-Difluorophenyl; 79 ° of C. of Mp:78 –
1h NMR (400 MHz, CDCl
3, δ, ppm) and δ 8.15 – 7.90 (m, 2H, Ar-H), 7.56 – 7.30 (m, 1H, Ar-H), 3.99 (t,
j=3.7 Hz, 2H ,-CH
2-), 2.29 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 174.35,166.08,164.16,130.83,126.20,119.11,118.90,118.20,118.02,114.10,101.15,78.07,71.70,20.44. HR-MS (ESI): Calcd. C
14h
7clF
2n
3s, [M+H]
+m/z:322.0017, found:322.0013.
embodiment 6general formula (
iII) shown in, R
1=Cl, R
2the derivative of=4-Bromophenyl (
iII-5) preparation
Take the same method preparation of embodiment 1
iI-5, R
2=4-Bromophenyl; Take the same method preparation of embodiment 2
iII-5, R
1=Cl, R
2=4-Bromophenyl; 138 ° of C. of Mp:137 –
1h NMR (400 MHz, CDCl
3, δ, ppm) and δ 8.08 – 7.96 (m, 2H, Ar-H), 7.84 – 7.60 (m, 2H, Ar-H), 4.00 (d,
j=2.6 Hz, 2H ,-CH
2-), 2.27 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 174.24,167.54,164.06,132.85,132.39,130.78,127.98,114.24,101.19,78.09,71.65,20.40. HR-MS (ESI): Calcd. C
14h
8brClN
3s, [M+H]
+m/z:363.9311, found:363.9314.
embodiment 7general formula (
iII) shown in, R
1=Cl, R
2the derivative of=4-Isoproplphenyl (
iII-6) preparation
Take the same method preparation of embodiment 1
iI-6, R
2=4-Isoproplphenyl; Take the same method preparation of embodiment 2
iII-6, R
1=Cl, R
2=4-Isoproplphenyl; 110 ° of C. of Mp:109 –
1h NMR (400 MHz, CDCl
3, δ, ppm) and δ 8.15 – 8.00 (m, 2H, Ar-H), 7.44 (m, 2H, Ar-H), 4.01 (d,
j=2.6 Hz, 2H ,-CH
2-), 3.03 (hept,
j=6.9 Hz, 1H, CH), 2.28 (t,
j=2.6 Hz, 1H, ≡ C-H), 1.33 (d,
j=6.9 Hz, 6H ,-CH
3).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 173.81,168.55,163.92,131.62,129.53,127.21,114.66,100.97,84.40,78.06,71.57,34.29,23.66,20.31. HR-MS (ESI): Calcd. C
17h
15clN
3s, [M+H]
+m/z:328.0675, found:328.0677.
embodiment 8general formula (
iII) shown in, R
1=Cl, R
2the derivative of=4-Fluorophenyl (
iII-7) preparation
Take the same method preparation of embodiment 1
iI-7, R
2=4-Fluorophenyl; Take the same method preparation of embodiment 2
iII-7, R
1=Cl, R
2=4-Fluorophenyl; 97 ° of C. of Mp:96 –
1h NMR (400 MHz, CDCl
3, δ, ppm) and δ 8.23 – 8.12 (m, 2H, Ar-H), 7.35 – 7.19 (m, 2H, Ar-H), 4.00 (d,
j=2.6 Hz, 2H ,-CH
2-), 2.28 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 174.07,167.36,164.02,131.84,130.17,116.25,114.41,101.04,84.21,78.14,71.63,20.37. HR-MS (ESI): Calcd. C
14h
8clFN
3s, [M+H]
+m/z:304.0111, found:304.0114.
embodiment 9general formula (
iII) shown in, R
1=Cl, R
2the derivative of=4-Methylphenyl (
iII-8) preparation
Take the same method preparation of embodiment 1
iI-8, R
2=4-Methylphenyl; Take the same method preparation of embodiment 2
iII-8, R
1=Cl, R
2=4-Methylphenyl; 122 ° of C. of Mp:121 –
1h NMR (400 MHz, CDCl
3, δ, ppm) δ 8.05 (d,
j=8.2 Hz, 2H, Ar-H), 7.39 (d,
j=8.1 Hz, 2H, Ar-H), 4.01 (d,
j=2.6 Hz, 2H ,-CH
2-), 2.28 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 173.79,168.53,163.91,143.76,131.30,129.76,114.64,100.96,84.11,78.30,71.57,21.69,20.32. HR-MS (ESI): Calcd. C
15h
11clN
3s, [M+H]
+m/z:300.0362, found:300.0363.
embodiment 10general formula (
iII) shown in, R
1=Cl, R
2the derivative of=4-Nitrophenyl (
iII-9) preparation
Take the same method preparation of embodiment 1
iI-9, R
2=4-Nitrophenyl; Take the same method preparation of embodiment 2
iII-9, R
1=Cl, R
2=4-Nitrophenyl; 102 ° of C. of Mp:101 –
1h NMR (400 MHz, CDCl
3) δ 8.43 (d,
j=8.9 Hz, 2H, Ar-H), 8.28 (d,
j=8.9 Hz, 2H, Ar-H), 4.01 (d,
j=2.6 Hz, 2H ,-CH
2-), 2.29 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 8.45,8.42,8.30,8.27,4.01,4.00,2.30,2.29,2.29.HR-MS (ESI): Calcd. C
14h
8clN
4o
2s, [M+H]
+m/z:331.0056, found:331.0056.
embodiment 11general formula (
iII) shown in, R
1=Cl, R
2the derivative of=3-Chlorophenyl (
iII-10) preparation
Take the same method preparation of embodiment 1
iI-10, R
2=3-Chlorophenyl; Take the same method preparation of embodiment 2
iII-10, R
1=Cl, R
2=3-Chlorophenyl; 137 ° of C. of Mp:136 –
1h NMR (400 MHz, CDCl
3, δ, ppm) and δ 8.17 – 8.01 (m, 2H, Ar-H), 7.63 – 7.47 (m, 2H, Ar-H), 4.00 (d,
j=2.6 Hz, 2H ,-CH
2-), 2.28 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 174.20,167.41,164.04,139.39,132.39,130.69,129.40,114.27,101.19,78.07,71.66,20.40. HR-MS (ESI): Calcd. C
14h
8cl
2n
3s, [M+H]
+m/z:319.9816, found:319.9818.
embodiment 12general formula (
iII) shown in, R
1=Cl, R
2the derivative of=2-Thenyl (
iII-11) preparation
Take the same method preparation of embodiment 1
iI-11, R
2=2-Thenyl; Take the same method preparation of embodiment 2
iII-11, R
1=Cl, R
2=2-Thenyl; 120 ° of C. of Mp:119 –
1h NMR (400 MHz, CDCl
3, δ, ppm) δ 8.52 (dd,
j=4.0,0.9 Hz, 1H, Ar-H), 7.78 (dd,
j=5.0,0.9 Hz, 1H, Ar-H), 7.27 (dd,
j=4.9,4.1 Hz, 1H, Ar-H), 3.99 (d,
j=2.6 Hz, 2H ,-CH
2-), 2.26 (t,
j=2.6 Hz, 1H, ≡ C-H).
13c NMR (100 MHz, CDCl
3, δ, ppm): δ 8.45,8.42,8.30,8.27,4.01,4.00,2.30,2.29,2.29. HR-MS (ESI): Calcd. C
12h
7clN
3s
2, [M+H]
+m/z:291.9770, found:291.9771.
embodiment 13general formula (
i) shown in, R
1=
, R
2the derivative of=Phenyl (
i-1)preparation
Will
iII-1(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml ethanol, after dissolving, adds thiosemicarbazide (223mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-1, with ethyl alcohol recrystallization, obtain
i-1sterling.Yield 87%, yellow solid.Fusing point: 213-214
oc.
1H NMR (400 MHz, DMSO-d6, δ, ppm) δ 10.21 (s, 1H, pyrimidine-NH, D
2O exchangeable), 9.57 (s, 1H, thiourea-NH, D
2O exchangeable), 7.95 (d,
J = 11.0 Hz, 1H, thiourea-NH
2, D
2O exchangeable), 7.91 (d,
J = 6.0 Hz, 2H, Ar-H), 7.77 (s, 1H, thiourea-NH
2, D
2O exchangeable), 7.61 (t,
J = 7.4 Hz, 3H, Ar-H).4.04 (s, 2H, -CH
2-), 3.20 (s, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ182.71, 172.32, 167.56, 162.94, 136.04, 131.83, 129.18, 129.12, 115.60, 84.37, 80.25, 74.21, 19.63;HRMS (ESI) calcd for C
15H
13N
6S
2 [M+H]
+:341.0643, found: 341.0641.
embodiment 14general formula (
i) shown in, R
1=
, R
2the derivative of=4-Chlorophenyl (
i-2)preparation
Will
iII-2(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml chloroform, after dissolving, adds thiocarbamide (169mg, 2mmol) under amino heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-2, with ethyl alcohol recrystallization, obtain
i-2sterling.Yield 88%, yellow solid.Fusing point: 191-192
oc.
1H NMR (400 MHz, DMSO-d6 , δ , ppm)δ10.25 (s, 1H, pyrimidine-NH, D2O exchangeable), 9.58 (s, 1H, thiourea-NH, D2O exchangeable), 8.15–7.71 (m, 4H, Ar-H), 7.68 (d, J = 8.5 Hz, 2H, thiourea-NH2, D2O exchangeable), 4.03 (d, J = 2.5 Hz, 2H, -CH2-), 3.19 (t, J = 2.6 Hz, 1H, ≡C-H).
13C NMR (101 MHz, DMSO-d6)δ182.62,172.32,166.31,162.69,136.77,134.79,131.04,129.29,115.45,84.07,80.17,74.27,19.64;HRMS (ESI) calcd for C
15H
12ClN
6O
5S
2 [M+H]
+: 375.0253, found: 375.0256.
embodiment 15general formula (
i) shown in, R
1=
, R
2=3, the derivative of 4,5-Trimethoxylphenyl (
i-3)preparation
Will
iII-3(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml acetone, after dissolving, adds thiosemicarbazide (100mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-3, with ethyl alcohol recrystallization, obtain
i-3sterling.Yield 85.7%, yellow solid.Fusing point: 196-197
oc.
1H NMR (400 MHz, DMSO-d6, δ, ppm) δ 10.15 (s, 1H, pyrimidine-NH, D
2O exchangeable), 9.57 (s, 1H, thiourea-NH, D
2O exchangeable), 7.95 (s, 1H, thiourea-NH
2, D
2O exchangeable), 7.75 (s, 1H, thiourea-NH
2, D
2O exchangeable), 7.31 (s, 2H, Ar-H), 4.02 (d,
J = 2.3 Hz, 2H, -CH
2-), 3.86 (s, 6H, -OCH
3), 3.78 (s, 3H, -OCH
3), 3.22 (t,
J = 2.5 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ 182.63, 172.11, 166.67, 163.11, 153.17, 140.63, 131.00, 115.88, 106.97, 83.94, 80.74, 73.76, 60.69, 56.58, 19.77;HRMS (ESI) calcd for C
18H
18N
6NaO
3S
2 [M+Na]
+: 453.0779, found: 453.0779.
embodiment 16general formula (
i) shown in, R
1=
, R
2the derivative of=3,4-Difluorophenyl (
i-4)preparation
Will
iII-4(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml tetrahydrofuran (THF), after dissolving, adds thiosemicarbazide (202mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-4, with ethyl alcohol recrystallization, obtain
i-4sterling.Yield 85.7%, yellow solid.Fusing point: 186-187
oc.
1H NMR (400 MHz, DMSO-d
6 ,δ , ppm) δ 10.28 (s, 1H, pyrimidine-NH, D
2O exchangeable), 9.60 (s, 1H, thiourea-NH, D
2O exchangeable), 7.97 (s, 2H, thiourea-NH
2, D
2O exchangeable), 7.87 – 7.60 (m, 3H, Ar-H), 4.04 (d,
J = 2.5 Hz, 2H, -CH
2-), 3.21 (t,
J = 2.6 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ182.63, 172.47, 165.02, 162.85, 153.09, 148.60, 141.22, 133.43, 126.68, 118.61, 115.35, 84.67, 80.25, 74.22, 19.69;HRMS (ESI) calcd for C
15H
10F
2N
6NaS
2 [M+Na]
+: 399.0274, found: 399.0276.
embodiment 17general formula (
i) shown in, R
1=
, R
2the derivative of=4-Bromophenyl (
i-5)preparation
Will
iII-5(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml methylene dichloride, after dissolving, adds thiosemicarbazide (181mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-5, with ethyl alcohol recrystallization, obtain
i-5sterling.Yield 85%, yellow solid.Fusing point: 185-186
oc.
1H NMR (400 MHz, DMSO-d
6 ,δ , ppm) δ 10.26 (s, 1H, pyrimidine-NH, D
2O exchangeable), 9.58 (s, 1H, thiourea-NH, D
2O exchangeable), 8.64 (s, 2H, thiourea-NH
2, D
2O exchangeable), 8.01 – 7.47 (m, 4H, Ar-H), 4.03 (d,
J = 2.5 Hz, 2H, -CH
2-), 3.19 (t,
J = 2.6 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ 181.73, 172.33, 166.99, 162.69, 135.16, 132.22, 131.19, 125.66, 115.46, 84.09, 80.18, 74.26, 19.64;HRMS (ESI) calcd for C
15H
11B
rN
6NaS
2 [M+Na]
+: 440.9568, found: 440.9567.
embodiment 18general formula (
i) shown in, R
1=
, R
2the derivative of=4-Isoproplphenyl (
i-6)preparation
Will
iII-6(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml dioxy six alkane, after dissolving, adds thiosemicarbazide (202mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-6, with ethyl alcohol recrystallization, obtain
i-6sterling.Yield 85.7%, yellow solid.Fusing point: 191 – 192
oc.
1H NMR (400 MHz, DMSO-d
6, δ, ppm)δ10.15 (s, 1H, pyrimidine-NH, D
2O exchangeable), 9.53 (s, 1H, thiourea-NH, D
2O exchangeable), 7.96 (s, 1H, thiourea-NH
2, D
2O exchangeable), 7.87 (d, J = 7.9 Hz, 2H, Ar-H), 7.75 (s, 1H, thiourea-NH
2, D
2O exchangeable), 7.47 (d, J = 8.1 Hz, 2H, Ar-H), 4.03 (d,
J = 2.4 Hz, 2H, -CH
2-), 3.19 (t,
J = 2.5 Hz, 1H, ≡C-H), 3.00 (dt,
J = 13.9, 6.9 Hz, 1H, CH), 1.27 (d,
J = 6.9 Hz, 6H, CH
3).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ 188.67, 176.31, 169.69, 161.63, 137.70, 133.70, 129.33, 127.10, 115.71, 85.74, 80.31, 74.16, 33.90, 24.07, 19.59;HRMS (ESI) calcd for C
18H
19N
6S
2 [M+H]
+: 383.1113, found: 383.1117.
embodiment 19general formula (
i) shown in, R
1=
, R
2the derivative of=4-Fluoropheny (
i-7)preparation
Will
iII-7(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml ethanol, after dissolving, adds thiosemicarbazide (212mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-7, with ethyl alcohol recrystallization, obtain
i-7sterling.Yield 84.2%, faint yellow solid.Fusing point: 198-199
oc.
1H NMR (400 MHz, DMSO-d6, δ, ppm) δ 10.23 (s, 1H, pyrimidine-NH, D2O exchangeable), 9.58 (s, 1H, thiourea-NH, D2O exchangeable),8.01 (s, 1H, thiourea-NH2, D2O exchangeable), 7.98 (d, J = 5.5 Hz, 2H, Ar-H), 7.75 (s, 1H, thiourea-NH, D2O exchangeable2), 7.44 (t, J = 8.8 Hz, 2H, Ar-H), 4.03 (d, J = 2.5 Hz, 2H, -CH2-), 3.19 (t, J = 2.6 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ 182.66, 172.30, 165.57, 163.09, 132.48, 131.77, 116.37, 115.58, 112.98, 84.20, 80.23, 74.22, 19.63;HRMS (ESI) calcd for C
15H
12FN
6S
2 [M+H]
+: 359.0549, found: 359.0551.
embodiment 20general formula (
i) shown in, R
1=
, R
2the derivative of=4-Methylphenyl (
i-8)preparation
Will
iII-8(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml DMF, after dissolving, adds thiocarbamide (215mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-8, with ethyl alcohol recrystallization, obtain
i-8sterling.Yield 86%, yellow solid.Fusing point: 178 – 179
oc.
1H NMR (400 MHz, DMSO-d6, δ, ppm) δ 10.13 (s, 1H, pyrimidine-NH, D
2O exchangeable), 9.52 (s, 1H, thiourea-NH, D
2O exchangeable), 7.92 (s, 1H, thiourea-NH
2, D
2O exchangeable), 7.80 (d, J = 7.8 Hz, 2H, Ar-H), 7.73 (s, 1H, thiourea-NH
2, D
2O exchangeable), 7.37 (d,
J = 8.0 Hz, 2H, Ar-H), 4.00 (d,
J = 2.5 Hz, 2H, -CH
2-), 3.16 (t,
J = 2.6 Hz, 1H, ≡C-H), 2.39 (s, 3H).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ 182.71, 175.33, 172.16, 163.06, 142.04, 133.23, 129.68, 129.18, 115.73, 83.93, 80.28, 74.18, 21.52, 19.60;HRMS (ESI) calcd for C
16H
15N
6S
2 [M+H]
+: 355.0800, found: 355.0803.
embodiment 21general formula (
i) shown in, R
1=
, R
2the derivative of=4-Nitrophenyl (
i-9)preparation
Will
iII-9(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml acetonitrile, after dissolving, adds thiosemicarbazide (198mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-9, with ethyl alcohol recrystallization, obtain
i-9sterling.Yield 84%, yellow solid.Mp: 152–153°C.
1H NMR (400 MHz, DMSO-d
6, δ, ppm) δ 10.38 (s, 1H, pyrimidine-NH, D
2O exchangeable), 9.65 (s, 1H, thiourea-NH, D
2O exchangeable), 8.43 (d,
J = 8.4 Hz, 2H, Ar-H), 8.13 (d,
J = 7.0 Hz, 2H, Ar-H), 8.01 (s, 1H, thiourea-NH
2, D
2O exchangeable), 7.76 (s, 1H, thiourea-NH
2, D
2O exchangeable), 4.04 (s, 2H, -CH
2-), 3.22 (s, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d
6, δ, ppm): δ 180.60, 172.70, 168.33, 165.85, 149.41, 141.86, 130.69, 124.27, 115.04, 85.22, 80.06, 74.35, 19.70. HR-MS (ESI): Calcd. C
15H
12N
7O
2S
2, [M+H]
+m/z: 386.0494, found: 386.0497.
embodiment 22general formula (
i) shown in, R
1=
, R
2the derivative of=3-Chlorophenyl (
i-10)preparation
Will
iII-10(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml distilled water, after dissolving, adds thiosemicarbazide (200mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-10, with ethyl alcohol recrystallization, obtain
i-10sterling.Yield 79%, yellow solid.Fusing point: 178-179
oc.
1H NMR (400 MHz, DMSO-d6 , δ , ppm)δ10.25 (s, 1H, pyrimidine-NH, D2O exchangeable), 9.58 (s, 1H, thiourea-NH, D2O exchangeable), 8.15–7.71 (m, 4H, Ar-H), 7.68 (d, J = 8.5 Hz, 2H, thiourea-NH2, D2O exchangeable), 4.03 (d, J = 2.5 Hz, 2H, -CH2-), 3.19 (t, J = 2.6 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d6)δ 182.62,172.32,166.31,162.69,136.77,134.79,131.04,129.29,115.45,84.07,80.17,74.27,19.64;HRMS (ESI) calcd for C
15H
12ClN
6O
5S
2 [M+H]
+: 375.0253, found: 375.0256.
embodiment 23general formula (
i) shown in, R
1=
, R
2the derivative of=3-Methoxylphenyl (
i-11)preparation
Take the same method preparation of embodiment 1
iI-11, R
2=3-Methoxylphenyl; Take the same method preparation of embodiment 2
iII-11, R
1=Cl, R
2=3-Methoxylphenyl;
Will
iII-11(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml ethanol, after dissolving, adds thiosemicarbazide (210mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-11, with ethyl alcohol recrystallization, obtain
i-11sterling.Yield 82%, yellow solid.Fusing point: 163-164
oc.
embodiment 24general formula (
i) shown in, R
1=
, R
2=2-Thienyl derivative (
i-12)preparation
Will
iII-12(500mg, 1mmol) adds in 50ml round-bottomed flask, adds 20ml methyl alcohol, after dissolving, adds thiosemicarbazide (230mg, 2mmol) under heated and stirred, heating reflux reaction, TLC tracking monitor.After question response completes, condensation, separates out solid, and suction filtration obtains compound
i-12, with ethyl alcohol recrystallization, obtain
i-12sterling.Yield 82%, yellow solid.Mp: 204–205°C.
1H NMR (400 MHz, DMSO-d
6, δ, ppm) δ 10.20 (s, 1H, NH, D
2O exchangeable), 9.53 (s, 1H, NH, D
2O exchangeable), 8.26 (d,
J = 2.7 Hz, 1H, Ar-H), 8.01 (d,
J = 4.4 Hz, 1H, Ar-H), 7.95 (s, 1H, NH, D
2O exchangeable), 7.76 (s, 1H, NH, D
2O exchangeable), 7.42 – 7.24 (m, 1H, Ar-H), 4.02 (d,
J = 2.5 Hz, 2H, -CH
2-), 3.17 (t,
J = 2.6 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d
6, δ, ppm): δ 182.64, 172.00, 163.11, 158.83, 140.12, 134.20, 131.39, 129.62, 115.93, 80.13, 74.13, 19.61. HR-MS (ESI): Calcd. C
13H
11N
6S
3, [M+H]
+m/z: 347.0207, found: 347.0210.
embodiment 25general formula (
i) shown in, R
1=
, R
2the derivative of=3,4-Difluorophenyl (
i-13)preparation
Prepare
iII-4,take the same method of embodiment 16 that thiosemicarbazide is replaced with to Urea,amino-, preparation
i-13.
Fusing point: 186-187
oc.
1H NMR (400 MHz, DMSO-d
6, δ, ppm) δ 9.94 (s, 1H, pyrimidine-NH, D
2O exchangeable), 8.14 (s, 1H, urea-NH, D
2O exchangeable), 8.03 – 7.63 (m, 3H, Ar-H), 6.14 (s, 2H, urea-NH
2, D
2O exchangeable), 4.02 (d,
J = 2.4 Hz, 2H, -CH
2-), 3.21 (t,
J = 2.5 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d
6) δ 179.64, 175.66, 172.63, 163.32, 148.70, 133.71, 126.78, 123.15, 118.84, 118.35, 115.72, 83.70, 80.26, 74.18, 19.58;HRMS (ESI) calcd for C
15H
10F
2N
6N
aOS[M+N
a]
+: 383.0503, found: 383.0504.
embodiment 26general formula (
i) shown in, R
1=
, the derivative of 4-Methylphenyl (
i-14)preparation
Prepare
iII-8,take the same method of embodiment 20 that thiosemicarbazide is replaced with to Urea,amino-, preparation
i-14.fusing point: 193-194
oc.
1H NMR (400 MHz, DMSO-d
6, δ, ppm) δ 9.96 (s, 1H, pyrimidine-NH, D
2O exchangeable), 8.22 (s, 1H, urea-NH, D
2O exchangeable), 7.67 (m, 4H, Ar-H), 6.20 (d,
J = 47.3 Hz, 2H, urea-NH
2, D
2O exchangeable), 4.08 (d,
J = 54.9 Hz, 2H, -CH
2-), 3.33 (s, 1H, ≡C-H), 2.51 (s, 1H, -CH
3).
13C NMR (100 MHz, DMSO-d
6) δ 186.63, 172.33, 167.66, 163.67, 141.68, 129.59, 129.23, 115.99, 109.68, 86.04, 80.38, 74.13, 21.51, 19.48;HRMS (ESI) calcd for C
16H
14N
6N
aS[M+N
a]
+: 361.0847, found: 361.0845.
embodiment 27general formula (
i) shown in, R
1=
, R
2the derivative of=3-Chlorophenyl (
i-15)preparation
Prepare
iII-10,take the same method of embodiment 22 that thiosemicarbazide is replaced with to Urea,amino-, preparation
i-15.yield 86%, yellow solid.Fusing point: 187-188
oc.
1H NMR (400 MHz, DMSO-d
6, δ, ppm) δ 9.91 (s, 1H, pyrimidine-NH, D
2O exchangeable), 8.11 (s, 1H, urea-NH, D
2O exchangeable), 7.93 – 7.53 (m, 4H, Ar-H), 6.12 (s, 2H, urea-NH
2, D
2O exchangeable), 3.99 (d,
J = 2.5 Hz, 2H, -CH
2-), 3.18 (t,
J = 2.5 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d
6) δ 186.02, 176.32, 166.01, 163.38, 138.08, 133.77, 131.52, 131.02, 128.96, 127.89, 115.45, 83.41, 80.27, 74.18, 19.56;HRMS (ESI) calcd for C
15H
11ClN
6N
aOS[M+N
a]
+: 381.0301, found: 381.0301.
embodiment 28general formula (
i) shown in, R
1=
, R
2the derivative of=4-Nitrophenyl (
i-16)preparation
Prepare
iII-9,take the same method of embodiment 21 that thiosemicarbazide is replaced with to Urea,amino-, preparation
i-16.yield 85.3%, yellow solid.Fusing point: 193-194
oc.
1H NMR (400 MHz, DMSO-d
6, δ, ppm) δ 10.03 (s, 1H, pyrimidine-NH, D
2O exchangeable), 8.42 (s, 1H, urea-NH, D
2O exchangeable), 8.40 (s, 1H, Ar-H), 8.15 (s, 3H, Ar-H), 6.16 (s, 2H, urea-NH
2, D
2O exchangeable), 4.03 (d,
J = 2.3 Hz, 2H, -CH
2-), 3.20 (t,
J = 2.6 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d
6) δ 172.69, 165.70, 163.22, 159.16, 149.35, 141.96, 130.75, 124.19, 115.21, 84.38, 80.05, 74.32, 19.59;HRMS (ESI) calcd for C
15H
12N
7O
3S[M+H]
+: 370.0722, found: 370.0723.
embodiment 29general formula (
i) shown in, R
1=
, R
2the derivative of=4-Bromophenyl (
i-17)preparation
Prepare
iII-5,take the same method of embodiment 17 that thiosemicarbazide is replaced with to Urea,amino-, preparation
i-17.fusing point: 178-179
oc.
1H NMR (400 MHz, DMSO-d6, δ, ppm) δ 9.92 (s, 1H, pyrimidine-NH, D
2O exchangeable), 8.13 (s, 1H, urea-NH, D
2O exchangeable), 7.82 (m, 4H, Ar-H), 6.15 (s, 2H, urea-NH
2, D
2O exchangeable), 4.02 (d,
J = 2.4 Hz, 2H, -CH
2-), 3.19 (t,
J = 2.5 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ 187.68, 179.33, 169.31, 163.44, 135.25, 132.14, 131.26, 125.59, 115.58, 83.40, 80.21, 74.22, 19.50;HRMS (ESI) calcd for C
15H
11B
rN
6N
aOS[M+N
a]
+: 424.9796, found: 424.9798.
embodiment 30general formula (
i) shown in, R
1=
, R
2the derivative of=4-Chlorophenyl (
i-18)preparation
Prepare
iII-2,take the same method of embodiment 14 that thiosemicarbazide is replaced with to Urea,amino-, preparation
i-18.fusing point: 159 160 ° of – C.
1H NMR (400 MHz, DMSO-d6, δ, ppm) δ 10.25 (s, 1H, pyrimidine-NH, D
2O exchangeable), 9.58 (s, 1H, urea-NH, D
2O exchangeable), 7.95 (s, 1H, urea-NH
2, D
2O exchangeable), 7.93 (d, J = 8.1 Hz, 2H, Ar-H),7.74 (s, 1H, urea-NH
2, D
2O exchangeable), 7.68 (d,
J = 8.5 Hz, 2H, Ar-H), 4.03 (d,
J = 2.5 Hz, 2H, -CH
2-), 3.19 (t,
J = 2.6 Hz, 1H, ≡C-H).
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ 182.68, 172.40, 166.67, 162.87, 136.78, 134.80, 131.04, 129.29, 115.45, 84.39, 80.17, 74.27, 19.64;HRMS (ESI) calcd for C
15H
12N
8O
2S[M+H]
+: 368.0804, found: 368.0806.
embodiment 31general formula (
i) shown in, R
1=
, R
2the derivative of=4-Isoproplphenyl (
i-19)preparation
Prepare
iII-6,take the same method of embodiment 18 that thiosemicarbazide is replaced with to Urea,amino-, preparation
i-18.Mp: 178–179°C.
1H NMR (400 MHz, DMSO-d
6, δ, ppm) δ 9.84 (s, 1H, pyrimidine-NH, D
2O exchangeable), 8.11 (s, 1H, thiourea-NH, D
2O exchangeable), 7.85 (s, 2H, Ar-H), 7.45 (d,
J = 7.8 Hz, 2H, Ar-H), 6.16 (s, 2H, thiourea-NH
2, D
2O exchangeable), 4.01 (d,
J = 2.4 Hz, 2H, -CH
2-), 3.20 (t,
J = 2.5 Hz, 1H), 2.99 (dt,
J = 13.7, 6.8 Hz, 1H, ≡C-H), 1.26 (d,
J = 6.9 Hz, 6H).
13C NMR (100 MHz, DMSO-d
6, δ, ppm): δ 172.28, 167.48, 159.10, 152.51, 133.74, 129.36, 127.00, 115.99, 82.99, 80.37, 74.09, 33.90, 24.07, 19.46. HR-MS (ESI): Calcd. C
18H
19N
6OS, [M+H]
+m/z: 367.1341, found: 367.1343.
embodiment 32general formula (
i) shown in, R
1=
, R
2the derivative of=4-Nitrophenyl (
i-20)preparation
Prepare
iII-9,take the same method of embodiment 21 that thiosemicarbazide is replaced with to Urea,amino-, preparation
i-20.fusing point: 193-194
oc.
1H NMR (400 MHz, DMSO-d6, δ, ppm) δ 12.82 (s, 1H, NH, D
2O exchangeable), 8.64 – 8.27 (m, 2H, Ar-H), 8.12 (m, 2H, Ar-H), 5.25 (s, 2H, guanidine-NH
2, D
2O exchangeable), 4.05 (d,
J = 2.5 Hz, 2H, -CH
2-), 3.16 (t,
J = 2.5 Hz, 1H, ≡C-H) .
13C NMR (100 MHz, DMSO-d6, δ, ppm): δ 186.63, 174.36, 166.47, 161.34, 149.05, 142.73, 131.18, 124.27, 115.70, 84.09, 80.88, 73.68, 19.25;HRMS (ESI) calcd for C
15H
12ClN
6OS[M+H]
+: 359.0482, found: 359.0486.
application examples 1the LSD1 of above-claimed cpd suppresses determination of activity:
1. experimental technique:
Sample is that above-claimed cpd, the purifying of embodiment synthesized obtains; Sample storing solution: take 3-5 mg sample and be placed in 1.5 mL EP pipes, be then mixed with DMSO the solution that concentration is 20 mM, 4 ° of C preserve and place, and dilute during experiment according to desired concn with DMSO.By testing sample and LSD1 albumen after incubated at room, add LSD1 reaction substrate H3K4me2 incubation reaction, finally add fluorescence dye Amplex and horseradish peroxidase HRP incubated at room, exciting light 530 nm in microplate reader, utilizing emitted light 590 nm detect fluorescence numerical value:
Test-results adopts SPSS computed in software IC
50value.
3. experimental result
Experimental result is shown in the following example
1shown in.
application examples 2above-claimed cpd is to tumour cell:
1. experimental technique:
Sample is that above-claimed cpd, the purifying of embodiment synthesized obtains; Sample storing solution: take 3-5 mg sample and be placed in 1.5 mL EP pipes, be then mixed with DMSO the solution that concentration is 10mM, 4 ° of C preserve and place, and utilize substratum dilution during experiment according to desired concn.
2. screening:
The cell of taking the logarithm vegetative period, after digestion counting, with substratum, adjust cell density, with 4000-8000 cell/ hole, be seeded in 96 orifice plates, every hole 100 μ L, cultivate after 24 h, discard substratum, add the medicine having diluted with substratum, each concentration is established 3 multiple holes, separately establishes blank group and positive controls.After drug effect 72 h, every hole adds 20 μ L MTT solution, continues to cultivate after 4 h, sucks liquid, adds the DMSO of 150 μ L, and evenly, absorbance is detected at microplate reader 490nm place in vibration, calculates inhibiting rate, and calculation formula is as follows:
Inhibiting rate (%)=(1-administration group absorbance/blank group absorbance) * 100%
Test-results adopts SPSS computed in software IC
50value and relation conefficient, result is as shown in table 2 below.
3. experimental result
Table 1 above-claimed cpd is to LSD1 and the inhibition activity data to LSD1:
The above-mentioned part preferred compound of table 2 is to gastric carcinoma cells (MGC-803, HGC-27, SGC-7901), liver cancer cell (HepG-2) and prostate cancer cell (PC-3) anti-tumor activity evaluating data:
Claims (5)
- Containing Urea,amino-with the pyrimidine derivatives of Terminal Acetylenes structural unit, it is characterized in that thering is structure described in general formula I,IR in general formula I 1for Cl, , , in any one;R 2for any one in following group:、 、 、 、 、 、 、 、 、 、 、 。
- 2. the Urea,amino-that contains as claimed in claim 1, with the pyrimidine derivatives of Terminal Acetylenes structural unit, is characterized in that: one of preferred following compound:R 1during for Cl: III-1 R 2=Phenyl;III-2 R 2=4-Chlorophenyl;III-3 R 2=3,4,5-Trimethoxylphenyl;III-4 R 2=3,4-Difluorophenyl;III-5 R 2=4-Bromophenyl;III-6 R 2=4-Isoproplphenyl;III-7 R 2=4-Fluorophenyl;III-8 R 2=4-Methylphenyl;III-9 R 2=4-Nitrophenyl;III-10 R 2=3-Chlorophenyl;III-11 R 2=2-Thienyl;R 1for time:I-1 R 2= Phenyl;I-2 R 2= 4-Chlorophenyl;I-3 R 2= 3,4,5-Trimethoxylphenyl;I-4 R 2= 3,4-Difluorophenyl;I-5 R 2= 4-Bromophenyl;I-6 R 2=4-Isoproplphenyl;I-7 R 2= 4-Fluoropheny;I-8 R 2=4-Methylphenyl;I-9R 2= 4-Nitrophenyl;I-10R 2=3-Chlorophenyl;I-11R 2=3-Methoxylphenyl;I-12 R 2=Thiophene;R 1for time:I-13 R 2= 3,4-Difluorophenyl;I-14 R 2=4-Methylphenyl;I-15 R 2=3-Chlorophenyl;I-16 R 2= 4-Nitrophenyl;I-17 R 2= 4-Bromophenyl;I-18 R 2=4-Chlorophenyl;I-19R 2=4-Isoproplphenyl;R 1for time:I-20 R 2= 4-Nitrophenyl。
- 3. prepare the method with the pyrimidine derivatives of Terminal Acetylenes structural unit containing Urea,amino-as described in claim 1 requirement, it is characterized in that: comprise following synthesis step:(1) preparation method of general formula I I:In solvent, ethyl cyanacetate is obtained to Compound I I with thiocarbamide, substituted benzoyl aldehyde reaction under alkaline condition; Alkali used is a kind of in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium phosphate, ten phosphate dihydrate sodium, potassiumphosphate, saleratus, sodium bicarbonate, triethylamine; Solvent used is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1, one of in 2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water or wherein any two or three mixture; Reaction is carried out between 0-90 ℃;(2) preparation method of general formula III:In solvent, general formula I I reacts and obtains intermediate product with propargyl bromide, with thin-layer chromatography, monitors reaction process, until reacted; Without separation, directly in reaction system, drip phosphorus oxychloride, after having reacted, be poured in frozen water, stir, there is solid to separate out, suction filtration, obtains solid, obtains the solid of sterling compound III through column chromatography; Solvent used is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1, one of in 2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water or wherein any two or three mixture; Reaction is carried out between 0-90 ℃;(3) preparation method of target compound I:In solvent, compound corresponding in general formula III reacts with Urea,amino-compounds, and after question response completes, condensation, separates out solid, and suction filtration obtains corresponding compound in general formula I;Solvent used is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1, one of in 2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water or wherein any two or three mixture; Reaction is carried out between 0-90 ℃; Described Urea,amino-compounds is aminoguanidine, Urea,amino-or thiosemicarbazide;。
- 4. the application of the pyrimidine derivatives containing Urea,amino-and Terminal Acetylenes structural unit as claimed in claim 1 or 2 in medicine preparation, is characterized in that: using it as preparing based on the antitumor lead compound of target spot Methionin specificity demethylase.
- 5. the application of the pyrimidine derivatives containing Urea,amino-and Terminal Acetylenes structural unit as claimed in claim 4 in medicine preparation, is characterized in that: medicine or LSD1 inhibitor as activeconstituents for the preparation of anti-stomach cancer cell, liver cancer cell, prostate cancer cell.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000067900A1 (en) * | 1999-05-10 | 2000-11-16 | Prometic Biosciences Ltd. | Novel triazine-based detoxification agents and their use |
CN103848815A (en) * | 2014-03-13 | 2014-06-11 | 郑州大学 | 4-substituent-6-phenyl pyrimidine derivatives comprising carbamido fragments and preparation method and use of derivatives |
CN103880822A (en) * | 2014-04-02 | 2014-06-25 | 郑州大学 | 2,4,6-trisubstituted pyrimidine compounds containing 1,2,3-triazole, preparation method and application thereof |
-
2014
- 2014-06-27 CN CN201410295919.8A patent/CN104119280B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000067900A1 (en) * | 1999-05-10 | 2000-11-16 | Prometic Biosciences Ltd. | Novel triazine-based detoxification agents and their use |
CN103848815A (en) * | 2014-03-13 | 2014-06-11 | 郑州大学 | 4-substituent-6-phenyl pyrimidine derivatives comprising carbamido fragments and preparation method and use of derivatives |
CN103880822A (en) * | 2014-04-02 | 2014-06-25 | 郑州大学 | 2,4,6-trisubstituted pyrimidine compounds containing 1,2,3-triazole, preparation method and application thereof |
Non-Patent Citations (2)
Title |
---|
HEBA T. ABDEL-MOHSEN等: "Novel benzimidazole-pyrimidine conjugates as potent antitumor agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
PENG-JU CHEN等: "Synthesis, in vitro antimicrobial and cytotoxic activities of novel pyrimidine-benzimidazol combinations", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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