CN107033148A - Triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor, its preparation method and application - Google Patents
Triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor, its preparation method and application Download PDFInfo
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Abstract
The invention belongs to medicinal chemistry art, the compound of a class triazole containing pyrimido-mercapto tetrazole class formation, its preparation method are disclosed and its with the specific demethylase of lysine（Hereinafter referred to as LSD1）It is used as application of the target in antineoplastic is prepared.The compounds of this invention formula is as shown in I.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to the compound of pyrimido triazole-mercapto tetrazole class, it
Preparation method and its with the specific demethylase (hereinafter referred to as LSD1) of istone lysine for target antineoplastic
Application in thing.
Background technology
Tumour is the disease for seriously endangering human health and being difficult to overcome, and the antineoplastic listed at present also has
A lot, but in these medicines or there are problems that, such as toxicity is big, targeting is weak and easy produces drug resistance etc..Cause
This, the research and development of new type antineoplastic medicine are particularly important.
Covalent histone modifications are a kind of important epigenetic patterns, including acetylation of histone, methylate, phosphorylation
And ubiquitination etc., wherein acetylation is to be directed in histone modification Mechanism Study to be compared many histone modification sides with methylating
Formula.Histone methylated before 2004 is considered as irreversible, lysine specific histone demethylase (lysine
Specific demethylase 1, LSD1) be first be found can be catalyzed histone H 3 K4me1/2 and H3K9me1/
The specific demethylase of 2 demethylations, so as to adjust the transcription of downstream target gene.
Expression quantity of the LSD1 in kinds of tumor cells is significantly higher than normal cell, such as neuroblastoma, cancer eye, prostatitis
Gland cancer, breast cancer, lung cancer, carcinoma of urinary bladder etc..And it is demonstrated experimentally that by RNAi technology or micromolecular inhibitor in cellular level reduction
LSD1 expression quantity or reduction LSD1 activity can suppress the expression that cell is bred and induces some cell differentiation related genes；Small
It can also suppress the growth of kinds of tumor cells and solid tumor in the presence of molecule MAOI PCPA.Therefore, LSD1
The research tool that inhibitor not only serves as epigenetics is used to illustrate biological function, and can be used as epigenetics medicine
Thing is used for the prevention and treatment of tumour, has caused the extensive concern of scientific research circle, the focus as current research.
Meanwhile, such as miazines and triazole heterocycle compound antiviral, anti-with bioactivity widely
Bacterium, anti-inflammatory and antitumor etc..But pyrimidine is with the compound of triazole-mercapto tetrazole class formation and based on LSD1 target spots
Antitumor action combine research report it is less, therefore this research have very important value.
The content of the invention
To develop existing clinical medicine resource, present invention aims at provide a class using pyrimido triazole as mother
The derivative of core, and mercapto tetrazole is introduced in the female ring, thus for find a class it is new based on the antitumor of LSD1 target spots
Medicine opens up a new way；Another object of the present invention is to provide its preparation method and its is preparing antineoplastic and LSD1
Application in inhibitor.
To realize the object of the invention, the knot of pyrimido triazole of the present invention-mercapto tetrazole class LSD1 inhibitor
Structure formula is as follows：
In formula I, R2For C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, In
Any one, wherein, R is halogen, H ,-OH ,-NO2,
R1For any one in following group：
C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, hydrogen atom, wherein, X is nitrogen, oxygen or sulphur atom, and R is halogen
Element, H ,-OH ,-NO2,-OCH3, C1-4 acyl groups, n=1~6；
R3For C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl,Pyridine radicals, decahydronaphthalene
Base, wherein, R is halogen, H ,-OH ,-NO2,-OCH3, CF3, C1-4 alkyl or acyl group, n=0~6.
It is preferred that：
R2For C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, In any one, wherein, R be chlorine, bromine, H ,-
OH ,-NO2,-OCH3, C1-4 acyl groups, C1-3 straight chained alkyls, C1-3 branched alkyls, n=1~3；
R1For any one in following group： Wherein, X is sulphur atom, and R is chlorine, bromine, H ,-OH ,-NO2,-OCH3, C1-4
Acyl group, n=1~3；
R3For C1-3 straight chained alkyls, C1-3 branched alkyls or C3-5 cycloalkyl,Pyridine radicals, decahydronaphthalene
Base, wherein, R is chlorine, bromine, H ,-OH ,-NO2,-OCH3, n=0~3.
In formula I preferably：
One of more preferably following compound：
8:R1=propyl-S-,R3=Me-；
9:R1=propyl-S-,R3=Me-；
10:R1=propyl-S-,R3=Me-；
11:R1=propyl-S-,R3=Me-；
12:R1=propyl-S-,R3=Me-；
13:R1=propyl-S-, R2=Bn-, R3=Me-；
14:R1=propyl-S-, R2=2-Cl-Bn-, R3=Me-；
15:R1=propyl-S-, R2=3-Cl-Bn-, R3=Me-；
16:R1=propyl-S-, R2=4-Cl-Bn-, R3=Me-；
17:R1=propyl-S-, R2=4-Br-Bn-, R3=Me-；
18:R1=Bn-S-, R2=4-Cl-Bn-, R3=Me-；
19:R1=Me-S-, R2=2-Cl-Bn-, R3=Me-；
20:R1=Propargyl-S-, R2=4-OMe-Bn-, R3=Ph；
21:R1=Propargyl-S-, R2=2-Cl-Bn-, R3=3,4,5-tri-OMe-Ph-；
22:R1=Propargyl-S-, R2=2-Cl-Bn-, R3=Ph-；
23:R1=Propargyl-S-, R2=4-Isopropyl-Bn-, R3=Ph-；
24:R1=Me-S-, R2=2-Cl-Bn-, R3=Ph-；
25:R2=2-Cl-Bn-, R3=Ph-；
26:R1=Propargyl-S-, R2=2-Cl-Bn-, R3=1-Naphthalene-；
27:R1=Propargyl-S-, R2=2-Cl-Bn-,
The preparation method of pyrimido triazole of the present invention-mercapto tetrazole class LSD1 inhibitor, mainly by following
Step is made：
1. the preparation method of formula 2：
In solvent, by compound 1 and bromo-hydrocarbons, under alkaline matter effect, heating stirring reaction, after reaction terminates, mistake
Filter, is washed, and is dried, is obtained series compound 2.In this reaction, solvent for use can be acetone, methanol, ethanol, propyl alcohol, isopropanol,
One of tetrahydrofuran, acetonitrile, water, DMF, dichloromethane, chloroform, dioxane or two or more mixtures.Alkali used
Property material can be one kind in triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide.The bromo-hydrocarbons correspondence
R1 substituents in formula；2. the preparation method of formula 3：
In acetic acid, nitrating agent is added, series compound 2 is then added portionwise, stirring reaction after reaction terminates, is fallen
Enter in water, suction filtration, wash, dry, obtain series compound 3.In this reaction, the nitrating agent can be fuming nitric aicd, concentrated nitric acid.
15-60 DEG C of preferable temperature.
3. the preparation method of formula 4：
In solvent, chlorination reagent is added, series compound 3 is then added portionwise, organic base, back flow reaction, reaction is added dropwise
After end, it is cooled to room temperature, hydrolyzes, extracted with organic solvent, wash, neutralize, dries organic phase and produce the crude product of series compound 4
(can directly carry out next step without further optimization, sterling can be through being made with column chromatography).In this reaction, the chlorination examination
Agent can be POCl3, phosphorus pentachloride, and solvent can be toluene, dioxane, THF, ethyl acetate etc., and the organic base can
To be triethylamine, DMA, N, N- diethylanilines, dimethyl acetamide (DMA) or pyridine etc..Preferable temperature 40
~120 DEG C.4. the preparation method of formula 5：
Series compound 4 is dissolved in the in the mixed solvent of ethanol and acetic acid, reduced iron powder, temperature rising reflux is then added portionwise
Reaction, suction filtration is spin-dried for solvent, then is extracted with organic solvent, washing, dries organic phase, obtains the crude product of series compound 5, pure
Product can be made through column chromatography.
5. the preparation method of formula 6：
Series compound 5 and aminated compounds are dissolved in solvent, organic base is added, back flow reaction is reacted after terminating,
Solvent evaporated, adds ethyl acetate, and organic phase is dried in washing, and the crude product for obtaining series compound 6 is (straight without further purification
Connect for next step reaction).In this reaction, reaction solvent for use can be methanol, ethanol, isopropanol, DMF, dioxane,
THF, acetonitrile etc., the organic base can be triethylamine, pyridine or diisopropylethylamine etc..Preferable reaction temperature is 60~120
℃.R in described aminated compounds correspondence formula2Substituent；
6. the preparation method of formula 7：
In the mixed liquor that series compound 6 is dissolved in acetic acid and water, the reactant aqueous solution of natrium nitrosum is added dropwise under ice bath, instead
After should terminating, ethyl acetate and water are added, is layered, is washed, is neutralized, organic phase is dried, obtains the crude product of series compound 7, without entering
The purifying of one step directly carries out next step reaction.
7. the preparation method of compound 8~27 in formula：
Series compound 7 and mercapto tetrazole class compound are dissolved in solvent, acid binding agent is added, room temperature or backflow are anti-
Should, after reaction terminates, solvent evaporated is dissolved in ethyl acetate, is washed with water, and dries, and crosses post, and mobile phase is the petroleum ether of different proportion
And ethyl acetate.In this reaction, the solvent is methanol, ethanol, isopropanol, THF, acetonitrile, DMF, dioxane etc., acid binding agent
For triethylamine, pyridine, wopropyl ethyl amine etc..Preferable reaction temperature is 20~100 DEG C.
Pyrimido triazole-mercapto tetrazole analog derivative of the present invention, passes through the experiment discovery pair of LSD1 enzymatic activitys
LSD1 has good inhibiting effect.Therefore, three nitrogen of pyrimido-mercapto tetrazole analog derivative that the present invention is provided is new for exploitation
Type antineoplastic, the drug combination of medicine and new LSD1 inhibitor medicaments open another effective way, such chemical combination
Rationally, reaction condition is gentle, simple to operate for the compounding design of thing, and reaction yield is high, and total recovery is up to more than 60%, if being developed into
New drug will have good market application foreground.
Embodiment
It is as follows especially exemplified by embodiment in order to be better illustrated to the present invention：
The compound 8, R of embodiment 11=Propyl-S-,R3=Me- preparation
(1) (the R of compound 21=Propyl-S-) preparation
Barbiturates (3g, 1eq) and triethylamine (2.9ml, 1eq) are added in 30ml methanol, are heated to reflux down, slowly
N-Propyl Bromide (1.8ml, 1eq) is added dropwise, continues to flow back 1 hour after adding, cooling, suction filtration obtains 3.7g pink solid compound 2b,
Yield 97%.
(2) (the R of compound 31=Propyl-S-) preparation
Under ice bath, 3ml fuming nitric aicd is carefully dissolved in 6ml acetic acid, 2.9g compound 2b are then added portionwise, plus
After complete, continue to stir 2 hours, then reaction solution is added in 18ml frozen water, suction filtration, wash, obtain the powdered of kermesinus
Compound 3b, yield 77.5%.
(3) (the R of compound 41=Propyl-S-) preparation
Compound 3b (12.4g, 1eq) is dissolved in 50ml POCl3, DMA (12ml, 1.8eq) is slowly added dropwise, so
After be warming up to backflow, react 5 hours.It is cooled to room temperature, hydrolyzes, then extracted with EA, washes, then washed with the sodium carbonate liquor of saturation
Wash, after organic phase is dried, produce brown compound 4b crude product 13g, yield 90.2%.
(4) (the R of compound 51=Propyl-S-) preparation
Compound 4b (0.5g, 1eq) is dissolved in 4ml methanol and 2ml acetic acid, reduced iron powder is then added portionwise
(0.3g, 3eq), flows back 2 hours, it is cooled to room temperature, suction filtration, filtrate is evaporated, and is dissolved in ethyl acetate, with the sodium carbonate liquor of saturation
Organic phase is dried in washing, washing, and 0.44g compound 5b crude products, yield 95% are obtained after being evaporated.
(5) (the R of compound 61=Propyl-S-,) preparation
By compound 5b (3.9g, 1eq), monoethanolamine (1.0g, 1eq) and triethylamine (3ml, 1.3eq) are dissolved in ethanol, are returned
Stream 48 hours, solvent evaporated is dissolved in ethyl acetate, and neutrality is then neutralized to watery hydrochloric acid, washes three times, dries, after being evaporated
Compound 6b crude products, without further purification, directly carry out next step.
(6) (the R of compound 71=Propyl-S-,) preparation
Upper step compound 6b crude product is dissolved in the mixed liquor of acetic acid and water, under 0 DEG C of ice bath, natrium nitrosum is added dropwise
The aqueous solution of (1.13g, 1eq), keeping temperature is not more than 10 DEG C, then proceedes to stirring reaction 1 hour, reaction solution is dissolved in into acetic acid
In ethyl ester, it is washed with water three times, is then neutralized to neutrality with the sodium bicarbonate solution of saturation again, wash, organic phase is dried, after being evaporated
Obtain compound 7b crude products, not purified direct carry out next step.
(7) preparation of compound 8
Midbody compound 7b (100mg, 1eq), first mercapto tetrazole (50mg, 1eq) are dissolved in ethanol, three second are added
Amine (37mg, 1eq) is heated to a few hours of flowing back, and is monitored and reacted with TLC (PE/EA), terminated rear solvent evaporated, be dissolved in acetic acid second
Ester, is washed, and is dried, and is crossed post, is obtained white solid 70mg, yield 60%.1HNMR(400MHz,DMSO-d6,ppm):δ4.93-4.96
(t, J=5.8Hz, 2H), 4.62-4.65 (t, J=5.2Hz, 2H), 4.12 (s, 3H), 3.89-3.93 (m, 2H), 2.85-2.88
(t, J=7.2Hz, 2H), 1.48-1.57 (m, 2H), 0.90-0.94 (t, J=7.4Hz, 3H)13CNMR(100MHz,DMSO-
d6,ppm):δ169.51,158.74,149.91,145.89,131.52,59.23,50.32,35.17,33.09,22.38,
13.51.。
The compound 9, R of embodiment 21=Propyl-S-,R3=Me- preparation
Chaff amine replaces monoethanolamine, takes the same method of embodiment 7 to prepare 9.1HNMR(400MHz,CDCl3,ppm):δ
7.36-7.37 (d, J=1.2Hz, 1H), 6.50-6.51 (d, J=3.2Hz, 1H), 6.35-6.36 (m, 1H), 5.74 (s, 2H),
4.13 (s, 3H), 2.91-2.94 (t, J=7.4Hz, 2H), 1.62-1.67 (m, 2H), 0.99-1.03 (t, J=7.4Hz, 3H)
.13CNMR(100MHz,CDCl3,ppm):δ171.46,158.02,149.18,146.81,145.05,143.51,131.09,
110.81,110.48,43.43,34.82,33.54,22.14,13.37..Yield 66%.
The compound 10, R of embodiment 31=Propyl-S-,R3=Me- preparation
Thiophene ethamine replaces monoethanolamine, takes the same method of embodiment 7 to prepare 10.1HNMR(400MHz,CDCl3,
ppm):δ 7.13-7.14 (m, 1H), 6.87-6.89 (m, 1H), 6.75-6.76 (d, J=3.2Hz, 1H), 4.83-4.86 (t, J
=7.2Hz, 2H), 4.14 (s, 3H), 3.55-3.59 (t, J=7.2Hz, 2H), 2.87-2.91 (t, J=7.2Hz, 2H),
1.58-1.65 (m, 2H), 0.99-1.02 (t, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ171.18,
157.92,149.45,145.08,138.36,131.06,127.16,126.08,124.68,48.37,34.83,33.50,
29.59,22.17,13.40..Yield 72%.
The compound 11, R of embodiment 41=Propyl-S-,R3=Me-, preparation
Monoethanolamine is replaced with isobutyl amine, takes the same method of embodiment 7 to prepare 11.1HNMR(400MHz,CDCl3,
ppm):δ 4.39-4.41 (d, J=7.2Hz, 2H), 4.16 (s, 3H), 2.89-2.92 (t, J=7.2Hz, 2H), 2.37-2.47
(m,1H),1.56-1.70(m,2H),0.97-1.02(m,9H).13CNMR(100MHz,CDCl3,ppm):δ170.97,
157.89,149.62,145.14,131.04,54.27,34.84,33.52,29.05,22.21,19.99,13.34..Yield
70%.
The compound 12, R of embodiment 51=Propyl-S-,R3=Me- preparation
Monoethanolamine is replaced with cyclopentamine, takes the same method of embodiment 7 to prepare 12.1HNMR(400MHz,CDCl3,
ppm):δ 5.23-5.30 (m, 1H), 4.15 (s, 3H), 2.90-2.94 (t, J=7.2Hz, 2H), 2.25-2.30 (m, 4H),
2.02-2.06 (m, 2H), 1.77-1.86 (m, 2H), 1.62-1.67 (m, 2H), 0.99-1.02 (t, J=7.2Hz, 3H)
.13CNMR(100MHz,CDCl3,ppm):δ170.41,157.81,148.99,145.20,131.53,59.76,34.81,
33.50,32.48,24.55,22.20,13.32..Yield 60%.
The compound 13, R of embodiment 61=Propyl-S-, R2=Bn-, R3=Me- preparation
Monoethanolamine is replaced with benzylamine, takes the same method of embodiment 7 to prepare 13.1HNMR(400MHz,CDCl3,ppm):δ
7.44-7.46 (m, 2H), 7.34-7.38 (m, 3H), 5.75 (s, 2H), 4.14 (s, 3H), 2.92-2.95 (t, J=7.2Hz,
2H), 1.62-1.67 (m, 2H), 1.01-1.04 (t, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ171.28,
157.98,149.15,145.06,134.09,131.21,129.00,128.85,128.61,50.97,34.83,33.52,
22.17,13.41..Yield 64%.
The compound 14, R of embodiment 71=Propyl-S-, R2=2-Cl-Bn-, R3=Me- preparation
Monoethanolamine is replaced with 2- chlorobenzylamines, takes the same method of embodiment 7 to prepare 14.1HNMR(400MHz,CDCl3,
ppm):δ7.41-7.43(m,1H),7.28-7.32(m,1H),7.21-7.25(m,2H),5.88(s,2H),4.14(s,3H),
2.90-2.93 (t, J=7.4Hz, 2H), 1.59-1.64 (m, 2H), 0.97-1.01 (t, J=7.4Hz, 3H)13CNMR
(100MHz,CDCl3,ppm):δ171.50,158.10,149.44,145.06,133.71,131.63,131.02,130.47,
130.21,129.97,127.29,48.18,34.82,33.49,22.14,13.35..Yield 69%.
The compound 15, R of embodiment 81=Propyl-S-, R2=3-Cl-Bn-, R3=Me- preparation
Monoethanolamine is replaced with 3- chlorobenzylamines, takes the same method of embodiment 7 to prepare 15.1HNMR(400MHz,CDCl3,
ppm):δ 7.43 (s, 1H), 7.28-7.33 (m, 3H), 5.71 (s, 2H), 4.13 (s, 3H), 2.91-2.95 (t, J=7.4Hz,
2H), 1.60-1.69 (m, 2H), 0.99-1.03 (t, J=7.4Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ171.56,
158.15,149.15,144.99,135.80,134.82,131.19,130.35,129.08,128.75,126.75,50.25,
34.85,33.56,22.11,13.39..Yield 70%.
The compound 16, R of embodiment 91=Propyl-S-, R2=4-Cl-Bn-, R3=Me- preparation
Monoethanolamine is replaced with 4- chlorobenzylamines, takes the same method of embodiment 7 to prepare 16.1HNMR(400MHz,CDCl3,
ppm):δ 7.37-7.39 (m, 2H), 7.31-7.33 (m, 2H), 5.70 (s, 2H), 4.12 (s, 3H), 2.88-2.92 (t, J=
7.2Hz, 2H), 1.59-1.65 (m, 2H), 0.99-1.03 (t, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ
171.49,158.15,149.12,144.99,134.97,132.43,131.22,130.01,129.22,50.20,34.80,
33.54,22.15,13.37..Yield 73%.
The compound 17, R of embodiment 101=Propyl-S-, R2=4-Br-Bn-, R3=Me- preparation
Monoethanolamine is replaced with 4- bretylium tosylates, takes the same method of embodiment 7 to prepare 17.1HNMR(400MHz,CDCl3,
ppm):δ 7.47-7.49 (m, 2H), 7.30-7.32 (m, 2H), 5.68 (s, 2H), 4.12 (s, 3H), 2.89-2.91 (t, J=
7.2Hz, 2H), 1.59-1.65 (m, 2H), 0.99-1.02 (t, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ
171.51,158.16,149.13,144.98,132.91,132.21,131.22,130.29,123.12,50.26,34.79,
33.55,22.15,13.37..Yield 65%.
The compound 18, R of embodiment 111=Bn-S-, R2=4-Cl-Bn-, R3=Me- preparation
The third sulfydryl is replaced with benzyl-mercapto, takes the same method of embodiment 9 to prepare 18.1H NMR(400MHz,CDCl3,
ppm):δ7.32-7.33(m,1H),7.29-7.31(m,6H),7.27-7.28(m,2H),5.70(s,2H),4.24(s,2H),
4.06(s,3H).13C NMR(100MHz,CDCl3,ppm):δ170.69,158.51,149.03,144.89,136.10,
134.97,132.37,131.27,129.91,129.27,128.68,127.59,50.18,35.78,34.77..Yield 68%.
The compound 19, R of embodiment 121=Me-S-, R2=2-Cl-Bn-, R3=Me- preparation
The third sulfydryl is replaced with first sulfydryl, takes the same method of embodiment 9 to prepare 19.1H NMR(400MHz,DMSO-d6)δ
7.51-7.53(m,1H),7.34-7.43(m,3H),5.91(s,2H),4.10(s,3H),2.34(s,3H).13C NMR
(100MHz,DMSO)δ169.96,158.59,149.03,145.37,132.79,131.91,131.30,130.82,130.42,
129.61,127.57,47.92,34.69,13.94..Yield 70%.
The compound 20, R of embodiment 131=Propargyl-S-, R2=4-OMe-Bn-, R3=Ph preparation
The same method of embodiment 7 is taken to prepare 20,1H NMR(400MHz,CDCl3)δ7.56–7.59(m,2H),7.46-
7.47 (m, 3H), 7.39-7.41 (m, 2H), 6.83-6.85 (d, J=8.7Hz, 2H), 5.64 (s, 2H), 2.11-2.12 (t, J
=2.6Hz, 1H)13C NMR(101MHz,CDCl3)δ173.32,164.64,163.39,153.43,138.18,135.98,
135.53,134.98,134.32,130.65,129.62,129.57,118.98,83.36,75.81,60.01,55.32,
24.73..Yield 65%.
The compound 21, R of embodiment 141=Propargyl-S-, R2=2-Cl-Bn-, R3=3,4,5-tri-OMe-Ph-'s
Prepare
The same method of embodiment 7 is taken to prepare 21,1H NMR(400MHz,DMSO-d6)δ7.46-7.51(m,2H),
7.33-7.42 (m, 2H), 7.00 (s, 2H), 5.88 (s, 2H), 3.91 (d, J=2.6Hz, 2H), 3.69 (s, 6H), 3.65 (s,
3H), 3.14 (t, J=2.6Hz, 1H)13C NMR(101MHz,DMSO)δ167.65,159.12,152.94,148.82,
145.92,138.91,132.82,131.73,131.48,130.67,130.44,129.56,128.39,127.55,103.28,
79.27,73.39,60.12,56.17,54.82,48.00,19.34..Yield 68%.
The compound 22, R of embodiment 151=Propargyl-S-, R2=2-Cl-Bn-, R3=Ph- preparation
The same method of embodiment 7 is taken to prepare 22,1H NMR(400MHz,CDCl3,ppm):δ7.58-7.60(m,2H),
7.47-7.49 (m, 3H), 7.40-7.42 (d, J=8.0Hz, 1H), 7.25-7.31 (m, 3H), 5.85 (s, 2H), 3.72-3.73
(d, J=2.4Hz, 2H), 2.09-2.10 (t, J=2.4Hz, 1H)13C NMR(100MHz,CDCl3,ppm):δ168.98,
158.89,149.15,144.72,133.82,133.57,131.44,131.13,130.80,130.73,130.29,129.98,
129.63,127.30,124.93,78.53,71.09,48.33,20.05..Yield 70%.
The compound 23, R of embodiment 161=Propargyl-S-, R2=4-Isopropyl-Bn-, R3=Ph- preparation
The same method of embodiment 7 is taken to prepare 23,1H NMR(400MHz,DMSO-d6)δ7.68-7.71(m,2H),
7.54-7.56 (m, 3H), 7.34 (m, 2H), 7.22 (m, 2H), 5.74 (s, 2H), 3.91 (d, J=2.6Hz, 2H), 3.18 (t, J
=2.6Hz, 1H), 2.85 (m, 2H), 1.15 (d, J=6.9Hz, 6H)13C NMR(101MHz,DMSO)δ167.61,159.20,
148.62,148.57,145.65,133.10,132.05,130.86,130.83,129.62,128.47,126.66,124.98,
79.35,73.44,49.93,33.09,23.69,19.43..Yield 71%.
The compound 24, R of embodiment 171=Me-S-, R2=2-Cl-Bn-, R3=Ph- preparation
The same method of embodiment 7 is taken to prepare 24,1H NMR(400MHz,DMSO-d6)δ7.70(m,2H),7.56-
7.58(m,3H),7.49-7.52(m,1H),7.34-7.42(m,3H),5.86(s,2H),2.37(s,3H).13C NMR
(101MHz,DMSO)δ169.90,158.73,148.94,145.77,133.11,132.76,131.80,131.32,130.89,
130.47,130.40,129.67,129.58,127.54,124.95,47.95,13.99..Yield 74%.
The compound 25 of embodiment 18,R2=2-Cl-Bn-, R3=Ph- preparation
The same method of embodiment 7 is taken to prepare 25,1H NMR(400MHz,Chloroform-d)δ7.58-7.62(m,
2H), 7.49 (m, 3H), 7.40 (m, 1H), 7.27-7.31 (m, 1H), 7.22 (m, 2H), 5.83 (s, 2H), 2.91 (d, J=
7.2Hz,2H),1.00(m,1H),0.58(m,2H),0.26(m,2H).13C NMR(101MHz,CDCl3)δ171.06,
158.14,149.12,144.94,133.56,133.41,131.44,130.72,130.50,130.12,129.80,129.51,
127.17,124.78,123.74,48.09,37.27,9.90,5.78..Yield 70%.
The compound 26, R of embodiment 191=Propargyl-S-, R2=2-Cl-Bn-, R3=1-Naphthalene- system
It is standby
The same method of embodiment 7 is taken to prepare 26,1H NMR(400MHz,Chloroform-d)δ8.02(m,1H),
7.91-7.94(m,1H),7.56-7.60(m,3H),7.49-7.53(m,1H),7.37-7.41(m,2H),7.28-7.31(m,
1H), (t, J=2.6Hz, the 1H) of 7.22-7.24 (m, 2H), 5.82 (s, 2H), 3.78 (d, J=2.6Hz, 2H), 2.1213C NMR
(101MHz,DMSO)δ167.77,158.88,148.65,147.32,133.43,132.82,131.79,131.68,131.47,
130.57,130.42,129.55,128.69,128.24,128.13,127.87,127.54,127.28,125.78,125.15,
121.92,79.29,73.48,47.93,19.41..Yield 66%.
The compound 27, R of embodiment 201=Propargyl-S-, R2=2-Cl-Bn-,Preparation
The same method of embodiment 7 is taken to prepare 27,1H NMR(400MHz,Chloroform-d)δ8.91(m,1H),
8.74(m,1H),8.00(m,1H),7.47-7.50(m,1H),7.40-7.42(m,1H),7.28-7.32(m,2H),7.22-
(t, J=2.7Hz, the 1H) of 7.24 (m, 1H), 5.86 (s, 2H), 3.73 (d, J=2.7Hz, 2H), 2.0913C NMR(101MHz,
CDCl3)δ173.61,163.25,156.54,153.88,150.22,150.10,138.49,137.41,136.01,135.68,
135.34,135.10,134.66,132.07,128.90,128.87,83.14,76.12,53.15,24.74..Yield 63%.
The LSD1 inhibitory activity of the above-claimed cpd of embodiment 21 is determined：
1. experimental method：
Sample is the above-claimed cpd synthesized by embodiment, purifying is obtained；Stock sample solution：3-5mg samples are weighed to be placed in
In 1.5mL EP pipes, the solution that concentration is 20mM is then configured to DMSO, 4 DEG C preserve placement, according to required concentration during experiment
Diluted with DMSO.By testing sample and LSD1 albumen in after incubation at room temperature, addition LSD1 reaction substrates H3K4me2 is simultaneously incubated anti-
Should, it is eventually adding fluorescent dye Amplex and HRPO HRP incubations at room temperature, the exciting light 530nm on ELIASA, transmitting
Light 590nm detects fluorescence values:
Result of the test calculates IC using SPSS softwares50Value.
Experimental result is as follows.
1. above-claimed cpds of Table, 8~27 couples of LSD1 inhibitory activity data:
Claims (5)
1. triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor, it is characterised in that with structure described in formula I,
In formula I, R2For C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, In any one；Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, C1-4 acyl groups,
C1-5 straight chained alkyls, C1-5 branched alkyls, n=1~6；
R1For any one in following group：
C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, hydrogen atom, wherein, X is nitrogen, oxygen or sulphur atom, and R is halogen
Element, H ,-OH ,-NO2,-OCH3, C1-4 acyl groups, n=1~6；
R3For C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl,Pyridine radicals, decahydro naphthyl, its
In, R is halogen, H ,-OH ,-NO2,-OCH3, CF3, C1-4 alkyl or C1-4 acyl groups, n=0~6.
2. triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor as claimed in claim 1, it is characterised in that formula
In I preferably：
R2For C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, In any one, wherein, R be chlorine, bromine, H ,-
OH ,-NO2,-OCH3, C1-4 acyl groups, C1-3 straight chained alkyls, C1-3 branched alkyls, n=1~3；
R1For any one in following group： Its
In, X is sulphur atom, and R is chlorine, bromine, H ,-OH ,-NO2,-OCH3, C1-4 acyl groups, n=1~3；
R3For C1-3 straight chained alkyls, C1-3 branched alkyls or C3-5 cycloalkyl,Pyridine radicals, decahydro naphthyl, its
In, R is chlorine, bromine, H ,-OH ,-NO2,-OCH3, n=0~3.
3. triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor as claimed in claim 1, it is characterised in that：It is preferred that
One of following compound：
8:R1=propyl-S-,R3=Me-；
9:R1=propyl-S-,R3=Me-；
10:R1=propyl-S-,R3=Me-；
11:R1=propyl-S-,R3=Me-；
12:R1=propyl-S-,R3=Me-；
13:R1=propyl-S-, R2=Bn-, R3=Me-；
14:R1=propyl-S-, R2=2-Cl-Bn-, R3=Me-；
15:R1=propyl-S-, R2=3-Cl-Bn-, R3=Me-；
16:R1=propyl-S-, R2=4-Cl-Bn-, R3=Me-；
17:R1=propyl-S-, R2=4-Br-Bn-, R3=Me-；
18:R1=Bn-S-, R2=4-Cl-Bn-, R3=Me-；
19:R1=Me-S-, R2=2-Cl-Bn-, R3=Me-；
20:R1=Propargyl-S-, R2=4-OMe-Bn-, R3=Ph；
21:R1=Propargyl-S-, R2=2-Cl-Bn-, R3=3,4,5-tri-OMe-Ph-；
22:R1=Propargyl-S-, R2=2-Cl-Bn-, R3=Ph-；
23:R1=Propargyl-S-, R2=4-Isopropyl-Bn-, R3=Ph-；
24:R1=Me-S-, R2=2-Cl-Bn-, R3=Ph-；
25:R2=2-Cl-Bn-, R3=Ph-；
26:R1=Propargyl-S-, R2=2-Cl-Bn-, R3=1-Naphthalene-；
27:R1=Propargyl-S-, R2=2-Cl-Bn-,
4. the method for triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor as described in being required claim 1 is prepared,
It is characterized in that：Synthesize as follows：
(1) preparation method of formula 2：
In solvent, by compound 1 and bromo-hydrocarbons, under alkaline matter effect, heating stirring reaction, after reaction terminates, filtering is washed
Wash, dry, obtain series compound 2；Solvent for use select acetone, methanol, ethanol, propyl alcohol, isopropanol, tetrahydrofuran, acetonitrile, water,
One of DMF, dichloromethane, chloroform, dioxane or two of which thing mixed above；Alkaline matter used selects three second
One kind in amine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide；R1 substituents in the bromo-hydrocarbons correspondence formula；
(2) preparation method of formula 3：
In acetic acid, nitrating agent is added, series compound 2 is then added portionwise, stirring reaction after reaction terminates, pours into water
In, suction filtration is washed, and is dried, is obtained series compound 3；The nitrating agent selects fuming nitric aicd or concentrated nitric acid；
(3) preparation method of formula 4：
In solvent, chlorination reagent is added, series compound 3 is then added portionwise, organic base is added dropwise, back flow reaction, reaction terminates
Afterwards, it is cooled to room temperature, hydrolyzes, extracted with organic solvent, wash, neutralize, dries organic phase and produce series compound 4；The chlorination
Reagent selects POCl3, phosphorus pentachloride；Solvent selects toluene, dioxane, THF, ethyl acetate；The organic base select triethylamine,
DMA, N, N- diethylanilines, dimethyl acetamide or pyridine；
(4) preparation method of formula 5：
Series compound 4 is dissolved in the in the mixed solvent of ethanol and acetic acid, reduced iron powder is then added portionwise, temperature rising reflux is anti-
Should, suction filtration is spin-dried for solvent, then is extracted with organic solvent, washing, dries organic phase, obtains series compound 5；
(5) preparation method of formula 6：
Series compound 5 and aminated compounds are dissolved in solvent, organic base is added, back flow reaction after reaction terminates, is evaporated
Solvent, adds ethyl acetate, and washing dries organic phase, obtains series compound 6；Solvent for use selects methanol, ethanol, isopropanol,
DMF, dioxane, THF, acetonitrile；The organic base selects triethylamine, pyridine or diisopropylethylamine；Described aminated compounds
R in correspondence formula2Substituent；
(6) preparation method of formula 7：
In the mixed liquor that series compound 6 is dissolved in acetic acid and water, the reactant aqueous solution of natrium nitrosum, reaction knot are added dropwise under ice bath
Shu Hou, adds ethyl acetate and water, is layered, and washes, and neutralizes, and dries organic phase, obtains series compound 7；
(7) in formula compound 8~27 preparation method：
Series compound 7 and mercapto tetrazole class compound are dissolved in solvent, acid binding agent, room temperature or back flow reaction is added,
After reaction terminates, solvent evaporated is dissolved in ethyl acetate, is washed with water, and dries, and crosses post；The solvent be methanol, ethanol, isopropanol,
THF, acetonitrile, DMF, dioxane；Acid binding agent is triethylamine, pyridine, wopropyl ethyl amine.
5. triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor as described in one of claim 1-3 in medicine
Application in thing preparation, it is characterised in that：The targeting antitumor lead compounds of LSD1 are based on as preparing.
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