CN103054869A - Application of amino dithio formic ester compound with triazolyl in preparing medicine taking LSD1 (Lysine Specificity Demethylase 1) as target - Google Patents
Application of amino dithio formic ester compound with triazolyl in preparing medicine taking LSD1 (Lysine Specificity Demethylase 1) as target Download PDFInfo
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Abstract
Dithiocarbamates compound the invention discloses one kind containing triazolyl belongs to field of medicinal chemistry as the application of a new class of anti-tumor drug lead compound. Compound of the present invention has the following structure general formula:
Such compound is to istone lysine specificity demethylase 1(LSD1) good inhibiting effect is played, it can be used as the candidate further developed or lead compound be applied to prepare anticancer drug.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class and contain the dithiocarbamates chemical compound of triazolyl as new istone lysine specificity demethylase 1(LSD1) application of inhibitor.
Background technology
Istone lysine demethylase 1(Lysine Specific Demethylase 1, LSD1) be first histone demethylase of being found by medical college professor ShiYang of Harvard University in 2004 (
YangShi. Cell. 2004 , 119,941 – 953), can remove the single, double of histone H 3 K4, H3K9 and methylate, thereby regulate the interaction of histone and other albumen, and affect the Activation and inhibition of genetic transcription, the important life process such as x chromosome inactivation.
LSD1 is the demethylase that a flavin adenine dinucleotide (FAD) (FAD) relies on, and can generate hydrogen peroxide and the formaldehyde of a part in the process of demethylation.LSD1 or the homologous protein of amino oxidase, and PAO (Polyamine Oxidase, PAO) similarity is 22.4%, and monoamine oxidase A and B(Monoamine Oxidases A and B) similarity is 17.6%.
LSD1 expression of LSD1 in kinds of tumor cells is significantly higher than normal cell, such as neuroblastoma, cancer eye, carcinoma of prostate, breast carcinoma, pulmonary carcinoma, bladder cancer etc.And experiment showed, that the activity that reduces the LSD1 expression or reduce LSD1 at cellular level by RNAi technology or micromolecular inhibitor can suppress cell proliferation and induce the expression of some cell differentiation related genes; Under the effect of micromolecule oxidase inhibitor PCPA, also can suppress the growth of kinds of tumor cells and solid tumor.Therefore, the LSD1 inhibitor can not only be used for setting forth biological function as the research tool of epigenetics, and can be used for as the epigenetics medicine prevention and the treatment of tumor.
Click chemistry is proposed first by the Americanized scholar Sharpless of calendar year 2001 Nobel chemistry Prize winner, the triazo-compound and the alkynyl compounds reaction that mainly refer at present class Cu (I) catalysis generate 1, the reaction of 2,3-triazole 5-membered ring compounds.Because plurality of advantages such as its reaction condition is gentle, productive rate is high, and product postprocessing is simple and in the establishment of the optimization of lead compound, compound library, being widely applied.1,2,3-triazoles has shown multiple interesting biological activity, and is for example antibiotic, antiinflammatory, antiallergic, tuberculosis, HIV (human immunodeficiency virus)-resistant activity etc.All has the 1,2,3-triazoles structure fragment in the medicines structure of many listings, for example beta-lactamase inhibitor Tazobactam Sodium (formula .1).Recently, its application in the antitumor drug lead compound is found receives increasing concern.A plurality of research groups utilize click chemistry with 1,2,3-triazoles with are connected pharmacophoric group and connect synthetic some chemical compounds that have outstanding anti-tumor activity and suppress the MAO activity that obtained.For example Kamal group introduces 1,2,3-triazoles (formula .2) in podophyllotoxin, synthetic obtained the chemical compound that a series of anti-tumor activities are better than etoposide (
H.M.Sampath Kumar. European Journal of Medicinal Chemistry. 2011, 46,1983-1991); Marvin J. Miller with 1,2,3-triazoles and fragrant amide in conjunction with (formula .3), found the novel chemical compound with excellent anti-tumor activity of a class (
Marvin J. Miller. J. Med. Chem. 2010 , 53,3389-3395); And Qing Zhu group utilizes Click to synthesize a plurality of triazolyl derivatives (formula 4) and have preferably anti-MAO-A active (
Qing Zhu. Bioorganic ﹠amp; Medicinal Chemistry Letters. 2010,
20,6222-6225).
In addition, dithiocarbamates compound because its biological activity widely, as has the effect such as antibiotic, antiinflammatory, parasite killing, antitumor, radioprotective and chelating heavy metal and causes the extensive concern in pharmaceutical chemistry field.Utilize click chemistry with 1,2,3-triazole active fragment is incorporated in the dithiocarbamates structure, synthesizing new contains the dithiocarbamates chemical compound of triazolyl, study the activity that the novel dithiocarbamates compound that contains the triazolyl structure suppresses LSD1, to the new type antineoplastic medicine of further research take LSD1 as target spot, the medicine of developing one's own intellectual property is significant.
Summary of the invention
The object of the present invention is to provide the novel dithiocarbamates chemical compound that contains triazolyl of a class to suppress the application of the active lead drug of LSD1 as preparation.
The dithiocarbamates compound that a class of the present invention contains triazolyl has following general formula:
R
1Be H, single alkyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine or polysubstituted methoxyl group etc. that replace C1-C5 of diverse location.
Preferred in the general formula I: R
1Single alkyl, methoxyl group, fluorine, chlorine, trifluoromethyl or the polysubstituted fluorine of C1-C3, polysubstituted chlorine, polysubstituted methoxyl group etc. of replacing for diverse location.
Be preferably as follows chemical compound in the general formula I:
I-1:R
1=
oThe derivant of-F;
I-2:R
1=
pThe derivant of-F;
I-3:R
1=
pThe derivant of-Cl;
I-4:R
1=
oThe derivant of-Cl;
I-5:R
1=
p-CH
3Derivant;
I-6:R
1=
p-OCH
3Derivant;
I-7:R
1=
o-CF
3Derivant;
I-8:R
1=
M, pThe derivant of-diCl;
I-9:R
1=
M, p, m-triOCH
3Derivant;
I-10: R
1=
O, oThe derivant of-diF.
Preferred among the general formula I I: R
1Single alkyl, methoxyl group, fluorine, chlorine or the polysubstituted fluorine of C1-C3, polysubstituted chlorine, polysubstituted methoxyl group etc. of replacing for diverse location.
Be preferably as follows chemical compound among the general formula I I:
II-1:R
1=
oThe derivant of-F;
II-2:R
1=
pThe derivant of-Cl;
II-3:R
1=
p-CH
3Derivant;
II-4:R
1=
p-OCH
3Derivant;
II-5:R
1=
o-CF
3Derivant;
II-6:R
1=
M, pThe derivant of-diCl;
II-7:R
1=
M, p, m-triOCH
3Derivant;
II-8: R
1=
O, oThe derivant of-diF.
The dithiocarbamates compound that a class of the present invention contains triazolyl mainly makes by following method:
1. the preparation method of general formula (I)
In the organic solvent, chemical compound (
IV) and general formula (
V) in chemical compound at CuI/ organic base, CuSO
4/ sodium ascorbate or Cu/CuSO
41,3-cycloaddition reaction occurs under the condition, and used organic base is triethylamine, diisopropyl ethyl amine; Used organic solvent is acetonitrile, butanol/water, oxolane/water, DMF/water, ethanol/water etc.; Reaction temperature is at 0-90
0Between the C, usually carry out in room temperature.Products therefrom obtains net product through purifications such as column chromatography or recrystallization.The recrystallization solvent for use is a kind of in ethanol, methanol, acetonitrile, acetone, ethyl acetate, oxolane, dichloromethane, the chloroform or two kinds mixture wherein.
R
1Be H, single alkyl, methoxyl group, fluorine, chlorine, trifluoromethyl or the polysubstituted fluorine of C1-C5, polysubstituted chlorine, polysubstituted methoxyl group etc. of replacing of diverse location.
2. the preparation method of general formula (IV):
In the solvent, under alkali condition and Carbon bisulfide, propargyl bromide or propargyl chloride generation necleophilic reaction, used alkali is a kind of in sodium carbonate, potassium carbonate, sodium phosphate, 11 water sodium phosphates, potassium phosphate, potassium bicarbonate, sodium bicarbonate, the triethylamine etc. with the available tertbutyloxycarbonyl list of commerce protection piperazine; Used solvent is acetone, DMF, acetonitrile, ethanol, methanol, isopropyl alcohol, 1,2-dichloroethanes, dichloromethane, chloroform, oxolane, dioxane, distilled water one of them or any two or three mixture wherein; Products therefrom obtains net product through purifications such as column chromatography or recrystallization.The recrystallization solvent for use is a kind of in ethanol, methanol, acetonitrile, acetone, ethyl acetate, oxolane, dichloromethane, the chloroform or two kinds mixture wherein.
3. the preparation method of general formula (II):
Chemical compound is sloughed tertbutyloxycarbonyl shown in the general formula (I) under organic solvent, acid condition, gets general formula (II) chemical compound.Used acid is trifluoroacetic acid, hydrogen chloride, hydrogen bromide etc.; Used organic solvent is dichloromethane, Isosorbide-5-Nitrae-dioxane, ethyl acetate, oxolane etc.; Reaction temperature is at-10-60
0Between the C, usually carry out in room temperature.Products therefrom obtains net product through purifications such as column chromatography or recrystallization.
R
1Be H, single alkyl, methoxyl group, fluorine, chlorine, trifluoromethyl or the polysubstituted fluorine of C1-C5, polysubstituted chlorine, polysubstituted methoxyl group etc. of replacing of diverse location.
Compared with prior art, the present invention utilizes classical click chemistry that the 1,2,3-triazoles activity unit is combined with dithiocarbamates first, and is simple efficient, the synthetic dithiocarbamates compound that contains triazole structure of environmental protection.External LSD1 active suppression test shows that the dithiocarbamates compound that contains triazole structure provided by the present invention has obvious inhibitory action to the LSD1 activity, in its formula of (I)
I-1:R
1=
o-F;
I-3:R
1=
o-Cl;
I-2:R
1=
p-F;
I-5:R
1=
p-CH
3;
I-6:R
1=
p-OCH
3Derivant, in the general formula (II)
II-4:R
1=
p-OCH
3Derivant obviously is better than tranylcypromine to the inhibition activity of LSD1, can with its as active component for the preparation of istone lysine specificity demethylase 1 inhibitor medicaments.
Description of drawings
When Fig. 1 is the I-1, the I-3 that synthesize of the present invention, I-5, I-2, I-6, II-4 chemical compound final concentration 0.5 μ M in gastric carcinoma cell lines MGC-803 to the qualitative figure of regulating action Western Blot of LSD1 substrate H3K9me2, H3K4me2 expression;
When Fig. 2 is the I-1, the I-3 that synthesize of the present invention, I-5, I-2, I-6, II-4 chemical compound final concentration 0.5 μ M in gastric carcinoma cell lines MGC-803 to the regulating action Western Blot figure gray analysis sxemiquantitative bar diagram of LSD1 substrate H3K9me2 expression;
When Fig. 3 is the I-1, the I-3 that synthesize of the present invention, I-5, I-2, I-6, II-4 chemical compound final concentration 0.5 μ M in gastric carcinoma cell lines MGC-803 to the regulating action Western Blot figure gray analysis sxemiquantitative bar diagram of LSD1 substrate H3K4me2 expression.
The specific embodiment
For the present invention is better illustrated, as follows especially exemplified by embodiment:
The preparation of logical formula V is with reference to making with Publication about Document:
(a) Ina.Wilkening.; Giuseppe del Signore.; C.P.R.Hackenberger.
Chem. Commun. 2011, 47, 349-351. (b) Mingyu Hu.; Junqi Li.; ShaoQ Yao.
Org. Lett,
2008, 10, 5529-5531.。
Embodiment 1Intermediate (
IV) preparation
With CS
2(10mmol) dropwise join tertbutyloxycarbonyl list protection piperazine (10mmol) and Na
3PO
4In the acetone soln (6mmol), stirring at room adds propargyl bromide (11mmol) stirring reaction after 30 minutes, and TLC follows the tracks of detection.After reaction finishes, sucking filtration, filtrate decompression is concentrated, concentrate with dichloromethane (3 * 50mL) and the saturated aqueous common salt extraction, merge organic facies, anhydrous sodium sulfate drying, concentrating under reduced pressure, concentrate recrystallization or column chromatography for separation get chemical compound
IVYield 92%, white solid.
1H NMR (400 MHz, Actone-d
6, δ, ppm): 4.28 (br, 2H), 4.14 (d, 2H, J=2.68Hz), 4.00 (br, 2H), 3.58 (br, 4H), 2.78 (t, 1H, J=2.68Hz), 1.46 (s, 9H); HRMS (ESI) calcd for C
13H
21N
2O
2S
2 [M+H]
+:301.1044, found: 301.1046。
Embodiment 2Shown in the general formula (I), R
1=
oThe derivant of-F (
I-1) preparation
With chemical compound
IV(5mmol) use THF-H with 2-luorobenzyl nitrine (5mmol)
2The lower copper sulphate pentahydrate (0.25mmol) that adds is stirred in O (30-30mL) dissolving, sodium ascorbate (0.5mmol), stirring at room reaction 3-4 hour, tracking and monitoring reaction.Reaction adds H after finishing in reaction system
2O(40mL), reaction system merges organic facies with EtOAc(3 * 50mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-1Yield 79.0%, white solid, fusing point: 109-110
oC.IR( KBr, cm
-1) ν :3454, 2979, 1693, 1494, 1478, 1279, 1167, 1012, 986, 932, 791, 757, 695;
1H NMR (400 MHz, CDCl
3, δ , ppm): 7.66 (s, 1H), 7.09-7.38 (m, 4H), 5.55 (s, 2H), 4.69 (s, 2H), 3.52 (t, 4H, J=5.20Hz), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl
3,δ, ppm): 196.42, 161.72, 159.26, 154.41, 144.00, 130.89, 130.81, 130.51, 130.48, 124.82, 124.78, 122.96, 121.98, 121.84, 115.92, 115.71, 80.63, 47.66, 47.61, 53.4, 31.84, 28.34; HRMS(ESI) calcd for C
20H
27FN
5O
2S
2 [M+H]
+: 452.1590, found: 452.1598.。
Embodiment 3Shown in the general formula (I), R
1=
pThe derivant of-F (
I-2) preparation
With chemical compound
IV(5mmol) use THF-H with 4-luorobenzyl nitrine (5mmol)
2O(30-30mL) the lower copper sulphate pentahydrate (0.25mmol) that adds is stirred in dissolving, and sodium ascorbate (0.5mmol) finishes stirring at room reaction 1-2 hour, the tracking and monitoring reaction.Reaction adds H after finishing in reaction system
2O(30mL), reaction system merges organic facies with EtOAc(3 * 50mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-2Yield 78.7%, white solid, fusing point: 105-106
oC.IR ( KBr, cm
-1) ν : 3447, 2975, 1691, 1460, 1423, 1219, 1167, 1039, 935, 788, 746;
1H NMR (400 MHz, CDCl
3,δ, ppm): 7.59 (s, 1H), 7.34-7.87 (m, 3H), 5.55 (s, 2H), 4.72 (s, 2H), 4.26 (br, 2H), 3.92 (br, 2H), 3.56 (t, 4H, J=5.24Hz), 1.47 (s, 9H);
13C NMR (100 MHz, acetone-d
6,δ, ppm): 195.7, 154.8, 141.9, 133.7, 133.1, 133.1, 130.2, 129.71, 127.7, 123.6, 78.4, 50.8, 31.8, 27.6; HRMS(ESI) calcd for C
20H
28N
5O
3S
2 [M+H]
+: 450.1634, found: 450.1638.。
Embodiment 4Shown in the general formula (I), R
1=
pThe derivant of-Cl (
I-3) preparation
With chemical compound
IV(3mmol) use THF-H with 4-chlorobenzyl nitrine (3mmol)
2O(20-20mL) the lower copper sulphate pentahydrate (0.15mmol) that adds is stirred in dissolving, and sodium ascorbate (0.3mmol) finishes stirring at room reaction 2-3 hour, the tracking and monitoring reaction.Reaction adds H after finishing in reaction system
2O(30mL), reaction system merges organic facies with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-3Yield 85.5%, white solid, fusing point: 177-178
oC.IR ( KBr, cm
-1) ν :3446, 3130, 2979, 2914, 1678, 1491, 1422, 1224, 1161, 1024, 994, 932, 777, 543, 499;
1H NMR (400 MHz, CDCl
3,δ, ppm): 7.59 (s, 1H), 7.35 (d, 2H,
J = 8.4Hz), 7.20 (d, 2H,
J = 8.4Hz), 5.45 (s, 2H), 4.68 (s, 2H), 4.29 (br, 2H), 3.90 (br, 2H), 3.54 (t, 4H,
J = 5.2Hz), 1.47(s, 9H);
13C NMR (100 MHz, CDCl
3, δ, ppm): 196.4, 154.4, 144.4, 134.8, 134.1, 129.4, 129.3, 122.8, 80.7, 53.4, 31.7, 28.4; HRMS(ESI) calcd for C
20H
27ClN
5O
2S
2 [M+H]
+: 468.1295, found: 468.1291.。
Embodiment 5Shown in the general formula (I), R
1=
oThe derivant of-Cl (
I-4) preparation
With chemical compound
IV(3mmol) use THF-H with 4-chlorobenzyl nitrine (3mmol)
2O(20-20mL) the lower copper sulphate pentahydrate (0.15mmol) that adds is stirred in dissolving, and sodium ascorbate (0.3mmol) finishes stirring at room reaction 2-3 hour, the tracking and monitoring reaction.Reaction adds H after finishing in reaction system
2O(30mL), reaction system merges organic facies with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-4Yield 85.5%, white solid, fusing point: 177-178
oC.IR ( KBr, cm
-1) ν :3446, 3130, 2979, 2914, 1678, 1491, 1422, 1224, 1161, 1024, 994, 932, 777, 543, 499;
1H NMR (400 MHz, CDCl
3,δ, ppm): 7.59 (s, 1H), 7.35 (d, 2H,
J = 8.4Hz), 7.20 (d, 2H,
J = 8.4Hz), 5.45 (s, 2H), 4.68 (s, 2H), 4.29 (br, 2H), 3.90 (br, 2H), 3.54 (t, 4H,
J = 5.2 Hz), 1.47(s, 9H);
13C NMR (100 MHz, CDCl
3, δ, ppm): 196.4, 154.4, 144.4, 134.8, 134.1, 129.4, 129.3, 122.8, 80.7, 53.4, 31.7, 28.4; HRMS(ESI) calcd for C
20H
27ClN
5O
2S
2 [M+H]
+: 468.1295, found: 468.1291.。
Embodiment 6Shown in the general formula (I), R
1=
p-CH
3Derivant (
I-5) preparation
With chemical compound
IV(5mmol) dissolve with acetonitrile (40mL) with 4-methyl-benzyl nitrine (5mmol), stir lower adding Hydro-Giene (Water Science). (0.5mmol), triethylamine (10mmol) finishes stirring at room reaction 4-6 hour, and tracking and monitoring reacts.After reaction finishes, with the reaction system vacuum concentration, concentrate EtOAc(50mL) dissolving, use dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-5Yield 79.9%, white solid, fusing point: 182-183
oC.IR ( KBr, cm
-1) ν:3454, 2975, 1682, 1457, 1422, 1224, 1078, 994, 933, 867, 772, 524;
1H NMR (400 MHz, CDCl
3,δ, ppm): 7.55 (s, 1H), 7.16(s, 4H), 5.43 (s, 2H), 4.67 (s, 2H), 4.29 (br, 2H), 3.91 (br, 2H), 3.51 (t, 4H, J=5.16Hz), 2.35 (s, 3H), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl
3,δ, ppm): 196.5, 154.4, 138.7, 131.6, 129.8, 128.1, 80.6, 54.01, 31.9, 28.4, 21.2; HRMS(ESI) calcd for C
21H
30N
5O
2S
2 [M+H]
+: 448.1841, found: 448.1840.。
Embodiment 7Shown in the general formula (I), R
1=
p-OCH
3Derivant (
I-6) preparation
With chemical compound
IV(3mmol) dissolve with acetonitrile (30mL) with 4-methoxy-benzyl nitrine (3mmol), stir lower adding Hydro-Giene (Water Science). (0.3mmol), triethylamine (6mmol) finishes stirring at room reaction 2-3 hour, and tracking and monitoring reacts.After reaction finishes, with the reaction system vacuum concentration, concentrate EtOAc(50mL) dissolving, use dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, the saturated common salt water washing, anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, and the concentrate re-crystallizing in ethyl acetate gets product
I-6Yield 85.8%, white solid, fusing point: 129-130
oC.IR ( KBr, cm
-1) ν :3502, 3125, 2975,1686, 1542, 1453, 1281, 1173, 1016, 982, 932, 775, 698 ;
1H NMR (400 MHz, CDCl
3,δ, ppm): 7.54 (s, 2H), 7.21 (d, 2H, J=8.0), 6.88 (d, 2H, J=8.0), 5.41 (s, 2H), 4.67 (s, 2H), 4.29 (br, 2H), 3.90 (br, 2H),3.80 (s, 3H), 3.51 (t, 4H, J=5.2Hz), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl
3, δ, ppm): 196.4, 164.0, 161.6, 154.4, 130.5, 130.5, 130.0, 129.9, 116.2, 116.0, 80.7, 53.4, 31.8, 28.3; HRMS (ESI) calcd for C
21H
30N
5O
3S
2 [M+H]
+:464.1790, found:464.1794.。
Embodiment 8Shown in the general formula (I), R
1=
o-CF
3Derivant (
I-7) preparation
With chemical compound
IV(5mmol) dissolve with acetonitrile (40mL) with 2-trifluoromethyl benzyl nitrine (5mmol), stir lower adding Hydro-Giene (Water Science). (0.5mmol), diisopropyl ethyl amine (7.5mmol) finishes stirring at room reaction 2-3 hour, and tracking and monitoring reacts.After reaction finishes, with the reaction system vacuum concentration, concentrate EtOAc(50mL) dissolving, use dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, the saturated common salt water washing is used the saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-7Yield 81.5%, white solid, fusing point: 138-139
oC.IR( KBr, cm
-1) ν:3454, 2979, 1693, 1494, 1478, 1279, 1167, 1012, 986, 932, 791, 757, 695;
1H NMR (400 MHz, CDCl
3, δ , ppm): 8.15 (s, 1H), 7.04-7.39 (m, 4H), 5.54 (s, 2H), 4.83 (s, 2H), 4.30 (br, 2H), 3.91(br, 2H) 3.52 (t, 4H, J=5.24Hz), 1.47(s, 9H); HRMS (ESI) calcd for C
21H
27F
3N
5O
2S
2 [M+H]
+: 502.1558, found:502.1559.。
Embodiment 9R shown in the general formula (I)
1=
M, pThe derivant of-diCl (
I-8) preparation
With chemical compound
IV(4mmol) with 3,4-dichloro benzyl nitrine (4mmol) stirs lower adding copper sulphate pentahydrate (0.8mmol) with tertiary butanol and water (30-30mL) dissolving, and copper powder (4mmol) finishes stirring at room reaction 3-5 hour, the tracking and monitoring reaction.Reaction adds H after finishing in reaction system
2O(30mL), reaction system merges organic facies with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-8Yield 90.2%, white solid, fusing point: 153-154
oC.IR ( KBr, cm
-1) ν:3129, 2984, 1693, 1470, 1347, 1159, 1131, 990, 963, 798, 740, 698, 542 ;
1H NMR (400 MHz, CDCl
3, δ, ppm): 7.64 (s, 1H), 7.43 (d, 1H,
J = 8.3 Hz), 7.35 (d, 1H,
J = 2.0 Hz), 7.08 (dd, 1H,
J 1=2.0 Hz,
J 2=8.2 Hz), 5.44 (s, 2H), 4.70 (s, 2H), 4.30 (br, 2H), 3.91 (br, 2H), 3.52 (t, 4H,
J = 5.1Hz), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl
3, δ, ppm): 196.3, 154.4, 144.6, 134.8, 133.3, 133.1, 131.1, 129.9, 127.2, 122.9, 80.7, 52.8, 31.7, 28.3; HRMS (ESI) calcd for C
20H
26Cl
2N
5O
2S
2 [M+H]
+: 502.0905, found: 502.0900.。
Embodiment 10R shown in the general formula (I)
1=
M, p, m-triOCH
3Derivant (
I-9) preparation
With chemical compound
IV(5mmol) with 3,4,5-trimethoxy benzyl azide (5mmol) stirs lower adding copper sulphate pentahydrate (1mmol) with tertiary butanol and water (40-40mL) dissolving, and copper powder (5mmol) finishes stirring at room reaction 3-5 hour, the tracking and monitoring reaction.Reaction adds H after finishing in reaction system
2O(30mL), reaction system merges organic facies with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-9Yield 83.4%, white solid, fusing point: 134-135
oC.IR( KBr, cm
-1) ν:3453, 2979, 1693, 1494, 1478, 1279, 1167, 1012, 986, 932, 791, 757, 695 ;
1H NMR (400 MHz, CDCl
3,δ, ppm): 7.63 (s, 1H), 6.48 (s, 2H), 5.41 (s, 2H), 4.70 (s, 2H), 4.30 (br, 2H), 3.91 (br, 2H), 3.85 (s, 3H), 3.84 (s, 6H), 3.55 (t, 4H, J=5.24Hz), 1.48 (s, 9H);HRMS (ESI) calcd for C
23H
34N
5O
2S
2 [M+H]
+: 524.2001, found: 524.2005.。
Embodiment 11Shown in the general formula (I), R
1=
O, oThe derivant of-diF (
I-10) preparation
With chemical compound
IV(5mmol) with 2,6-difluorobenzyl nitrine (5mmol) is used THF-H
2O(30-30mL) the lower copper sulphate pentahydrate (1mmol) that adds is stirred in dissolving, and copper powder (5mmol) finishes stirring at room reaction 2-3 hour, the tracking and monitoring reaction.Reaction adds H after finishing in reaction system
2O(30mL), reaction system merges organic facies with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the concentrate acetone recrystallization gets product
I-10Yield 78.4%, white solid, fusing point: 141-142
oC.
1H NMR (400 MHz, CDCl
3, δ, ppm): 7.71 (s, 1H), 7.32-7.41 (m, 1H), 6.94-6.99 (m, 2H), 5.58 (s, 2H), 4.67 (s, 2H), 4.30 (br, 2H), 3.90 (br, 2H), 3.53 (s, 4H), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl
3, δ, ppm): 196.43, 162.66, 162.59, 160.16, 160.10, 154.41, 131.51, 131.40, 131.30, 111.94, 111.88, 111.75, 111.69, 110.95, 110.76, 110.57, 80.62, 41.39, 31.85, 28.35; HRMS (ESI) calcd for C
20H
26F
2N
5O
2S
2 [M+H]
+:470.1496, found:470.1498.。
Embodiment 12Shown in the general formula (II), R
1=
oThe derivant of-F (
II-1) preparation
With chemical compound
I-1(2mmol) with dichloromethane (20mL) dissolving, add CF under the ice bath
3COOH (40mmol) finishes and changes the stirring at room reaction into, the tracking and monitoring reaction.After reacting end, with the reaction system concentrating under reduced pressure, concentrate is used respectively saturated sodium bicarbonate with dichloromethane (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product
II-1Yield 96.7%, faint yellow solid, fusing point: 93-94
oC.IR ( KBr, cm
-1) ν :3138, 2910, 1693, 1474, 1425, 1219, 1132, 1031, 996, 933, 785, 763, 731, 694;
1H NMR (400 MHz, CDCl
3, δ, ppm): 7.67 (s, 1H), 7.09-7.34 (m, 4H), 5.55 (s, 2H), 4.69 (s, 2H), 4.30 (br, 2H), 3.93 (br, 2H), 2.94 (t, 4H,
J = 4.8 Hz); HRMS (ESI) calcd for C
15H
19FN
5S
2 [M+H]
+:352.1066, found: 352.1064.。
Embodiment 13Shown in the general formula (II), R
1=
pThe derivant of-Cl (
II-2) preparation
With chemical compound
I-3(2mmol) with dichloromethane (20mL) dissolving, add CF under the ice bath
3COOH (40mmol) finishes and changes the stirring at room reaction into, the tracking and monitoring reaction.After reacting end, with the reaction system concentrating under reduced pressure, concentrate is used respectively saturated sodium bicarbonate with dichloromethane (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product
II-2Yield 97.9%, pale yellow colored solid bulk melting point: 138-139
oC.IR ( KBr, cm
-1) ν:3138, 2910, 1693, 1474, 1425, 1219, 1031, 996, 933, 785, 763, 694;
1H NMR (400 MHz, CDCl
3, δ, ppm): 7.60 (s, 1H), 7.35 (d, 2H,
J = 8.1 Hz ), 7.20 (d, 2H,
J = 8.1 Hz), 5.45 (s, 2H), 4.69 (s, 2H), 3.90 (br, 2H), 2.94 (s, 4H);
13C NMR (100 MHz, CDCl
3, δ, ppm):196.03, 164.07, 161.60, 144.33, 130.47, 130.44, 129.97, 129.88, 122.74, 116.21, 116.00, 53.41, 45.15, 31.7; HRMS (ESI) calcd for C
15H
19FN
5S
2 [M+H]
+:352.1066, found: 352.1063.。
Embodiment 14Shown in the general formula (II), R
1=
p-CH
3Derivant (
II-3) preparation
With chemical compound
I-5(2.5mmol) with dichloromethane (20mL) dissolving, add CF under the ice bath
3COOH(50mmol), finish and change the stirring at room reaction into, tracking and monitoring reacts.After reacting end, with the reaction system concentrating under reduced pressure, concentrate is used respectively saturated sodium bicarbonate with dichloromethane (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product
II-3Yield 94.0%, faint yellow solid, fusing point: 74-75
oC.IR ( KBr, cm
-1) ν:3135, 2910, 1697, 1474, 1425, 1219, 1031, 996, 933, 785, 763, 731, 695;
1H NMR (400 MHz, CDCl
3, δ, ppm): 7.56 (s, 1H), 7.16-7.33 (m, 4H), 5.43 (s, 2H), 4.67 (s, 2H), 4.31 (br, 2H), 3.92 (br, 2H), 2.96 (br, 4H), 2.35 (s, 3H);
13C NMR (100 MHz, CDCl
3, δ, ppm):195.82, 138.61, 131.59, 129.74, 128.08, 122.72, 53.96, 31.80, 29.68, 21.17; HRMS (ESI) calcd for C
16H
22N
5S
2 [M+H]
+:348.1317, found: 348.1319.。
Embodiment 15Shown in the general formula (II), R
1=
p-OCH
3Derivant (
II-4) preparation
With chemical compound
I-6(4mmol) Isosorbide-5-Nitrae-dioxane solution (4mol/L, 30mL) with hydrogen chloride is dissolved under the ice bath, finishes to keep the ice bath stirring reaction tracking and monitoring reaction.After reacting end, with the reaction system concentrating under reduced pressure, concentrate is used respectively saturated sodium bicarbonate with dichloromethane (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product
II-4Yield 98.7%, faint yellow solid, fusing point: 95-96
oC.IR ( KBr, cm
-1) ν :3138, 2910, 1693, 1474, 1425, 1383, 1219, 1031, 996, 933, 785, 763, 694;
1H NMR (400 MHz, CDCl
3, δ, ppm): 7.55 (s, 1H), 7.24 (d, 2H,
J = 8.7 Hz), 6.91 (d, 2H,
J = 8.7 Hz), 5.42 (s, 2H), 4.68 (s, 2H), 4.31 (br, 2H), 3.95 (br, 2H), 3.80 (s, 3H), 2.96 (t, 4H,
J = 4.6 Hz);
13C NMR (100 MHz, CDCl
3, δ, ppm):195.75, 159.89, 144.12, 129.61, 126.61, 122.53, 114.45, 55.34, 53.69, 45.63, 31.79; HRMS (ESI) calcd for C
16H
22N
5OS
2 [M+H]
+:364.1266, found: 364.1263。
Embodiment 16Shown in the general formula (II), R
1=
o-CF
3Derivant (
II-5) preparation
With chemical compound
I-7With Isosorbide-5-Nitrae-dioxane solution (4mol/L, 30mL) dissolving of hydrogen chloride, finish maintenance ice bath stirring reaction, the tracking and monitoring reaction under (2.00g, 4mmol) ice bath.After reacting end, with the reaction system concentrating under reduced pressure, concentrate is used respectively saturated sodium bicarbonate with dichloromethane (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product
II-71.52g, yield 94.5%, faint yellow solid, fusing point: 151-152
oC.
1H NMR (400 MHz, CDCl
3, δ , ppm): 7.66 (s, 1H), 7.65 (d, 2H,
J = 8.2 Hz), 7.36 (d, 2H,
J = 8.2 Hz), 5.57 (s, 2H), 4.71 (s, 2H), 4.33 (br, 2H), 3.91(br, 2H), 2.98(s, 4H,); HRMS (ESI) calcd for C
16H
19F
3N
5S
2 [M+H]
+: 402.1034, found: 402.1035.。
Embodiment 17Shown in the general formula (II), R
1=
M, pThe derivant of-diCl (
II-6) preparation
With chemical compound
I-8(5mmol) Isosorbide-5-Nitrae-dioxane solution (4mol/L, 40mL) with hydrogen chloride is dissolved under the ice bath, finishes to keep the ice bath stirring reaction tracking and monitoring reaction.After reacting end, with the reaction system concentrating under reduced pressure, concentrate is used respectively saturated sodium bicarbonate with dichloromethane (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product
II-5Yield 95.5%, faint yellow solid, fusing point: 122-123
oC.IR ( KBr, cm
-1) ν:3138, 2910, 1693, 1474, 1425, 1219, 1163, 1031, 996, 933, 785, 763, 694;
1H NMR (400 MHz, CDCl
3, δ, ppm): 7.65 (s, 1H), 7.45 (d, 1H,
J = 8.3 Hz), 7.35（d, 1H,
J = 1.9 Hz), 7.10 (dd, 1H,
J 1 = 2.0 Hz,
J 2 = 8.3 Hz), 5.44 (s, 2H), 4.70 (s, 2H), 4.31 (br, 2H), 3.92 (br, 2H), 2.95 (s, 4H);
13C NMR (100 MHz, CDCl
3, δ, ppm):195.62, 144.87, 134.79, 133.27, 133.07, 131.09, 129.86, 127.17, 122.92, 52.81, 45.63, 31.56; HRMS (ESI) calcd for C
15H
18Cl
2N
5S
2 [M+H]
+:402.0381, found: 402.0369.。
Embodiment 18Shown in the general formula (II), R
1=
M, p, m-triOCH
3, the derivant of n=1 (
II-7) preparation
With chemical compound
I-9(2mmol) dissolve with the saturated ethyl acetate solution of hydrogen chloride (30mL) under the ice bath, finish and change the stirring at room reaction into, the tracking and monitoring reaction.Reaction is used respectively saturated sodium bicarbonate with reaction system after finishing, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates to get product
II-6Yield 96.0%, faint yellow solid, fusing point: 120-121
oC.IR ( KBr, cm
-1) ν:3138, 2910, 1693, 1474, 1425, 1219, 1031, 996, 933, 785, 763, 694;
1H NMR (400 MHz, CDCl
3, δ, ppm): 7.64 (s, 1H), 6.47 (s, 2H), 5.40 (s, 2H), 4.69 (s, 2H), 4.30 (br, 2H), 3.91 (br, 2H), 3.83(s, 3H), 3.82(s, 6H), 2.93(s, 4H);
13C NMR (100 MHz, CDCl
3, δ, ppm):195.63, 153.66, 144.42, 138.23, 130.15, 122.83, 105.16, 60.85, 56.23, 54.35, 45.72, 31.68; HRMS (ESI) calcd for C
18H
26N
5O
3S
2 [M+H]
+:424.1477, found: 424.1472.。
Embodiment 19Shown in the general formula (II), R
1=
O, o-diF, the derivant of n=1 (
II-8) preparation
With chemical compound
I-10(3mmol) with the saturated ethyl acetate solution of hydrogen chloride (40mL) dissolving, finish and change the stirring at room reaction into, the tracking and monitoring reaction.Reaction is used respectively saturated sodium bicarbonate with reaction system after finishing, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates to get product
II-7Yield 93.3%, faint yellow solid, fusing point: 144-145
oC.
1H NMR (400 MHz, CDCl
3, δ, ppm): 8.10 (s, 1H), 7.50-7.86(m, 3H), 4.89 (s, 2H), 4.37 (br, 2H), 3.93 (br, 2H), 3.05(s, 4H); HRMS (ESI) calcd for C
15H
18F
2N
5S
2 [M+H]
+:370.0792, found: 370.0795.。
Embodiment 20The LSD1 of above-claimed cpd suppresses determination of activity:
1. experimental technique:
Sample is that above-claimed cpd, the purification that embodiment synthesized gets; The sample storing solution: take by weighing 3-5 mg sample and place 1.5 mL EP pipes, then be mixed with the solution that concentration is 20 mM with DMSO, 4 ° of C preserve and place, and dilute with DMSO according to desired concn during experiment.With testing sample and LSD1 albumen after incubated at room, add LSD1 reaction substrate H3K4me2 and incubation reaction, add at last fluorescent dye Amplex and horseradish peroxidase HRP incubated at room, exciting light 530 nm on microplate reader, utilizing emitted light 590 nm detect fluorescence numerical value:
Result of the test adopts SPSS computed in software IC
50Value.
2. experimental result
Experimental result is shown in the following example
1Shown in.
Table
1Above-claimed cpd reaches gastric carcinoma cells MGC-803 LSD1, breast cancer cell MCF-7, and prostate gland cancer cell PC3, esophageal cancer cell EC-109 anti-tumor activity evaluating data:
Embodiment 21The LSD1 inhibitor that has screened is in the inhibitory action of cellular level to the LSD1 activity
1. experimental technique:
Sample is Compound I-1, I-3, I-5, I-2, I-6, the II-4 that embodiment 20 filters out.The sample storing solution: take by weighing 3-5 mg sample and place 1.5 mL EP pipes, then be mixed with the solution that concentration is 20 mM with DMSO, 4 ° of C preserve and place, and dilute with DMSO according to desired concn during experiment.The gastric carcinoma cell lines MGC-803 of trophophase takes the logarithm, digestive inoculation is cultured to 80% in the 100mL Tissue Culture Flask expire, the Compound I-1, I-3, I-5, I-2, I-6, the II-4 that add final concentration 0.5 μ M, 24 as a child extracted histone and used the BCA standard measure with acid precipitation method.Albuminous degeneration behind adding 6 * Loading Buffer, calculate the loading volume according to protein concentration, add 1.5 μ g albumen electrophoresis in the 12%SDS-PAGE glue that configures, electricity is finished and carries out half-dried turning with nitrocellulose filter afterwards, behind the nitrocellulose filter 2h that 5% milk sealing electricity has turned, add antibody H3K4me2 or H3K4me9 and carry out the primary antibodie night incubation.Inferior daily PBST washes film 3 times and adds two antibody development exposure.The band color analysis that according to exposing detects inhibitor in the inhibitory action of cellular level to the LSD1 activity.
2. experimental result
Experimental result is seen accompanying drawing
1-3Shown in.The result shows: the chemical compound that the present invention synthesizes has inhibitory action to the LSD1 activity, obviously is better than tranylcypromine, can with its as active component for the preparation of istone lysine specificity demethylase 1 inhibitor medicaments.
Claims (6)
1. a class that has a structure shown in the general formula (I) contains the application of dithiocarbamates chemical compound in the preparation medicine of triazolyl, it is characterized in that, with its as active component for the preparation of istone lysine specificity demethylase 1 inhibitor medicaments;
R
1Be H, single alkyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine or polysubstituted methoxyl group that replaces C1-C5 of diverse location.
2. a class as claimed in claim 1 contains the application of dithiocarbamates chemical compound in the preparation medicine of triazolyl, it is characterized in that, and is preferred in the general formula I: R
1Single alkyl, methoxyl group, fluorine, chlorine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine or polysubstituted methoxyl group that replaces C1-C3 for diverse location.
3. a class as claimed in claim 2 contains the application of dithiocarbamates chemical compound in the preparation medicine of triazolyl, it is characterized in that, is preferably as follows chemical compound:
I-1:R
1=
oThe derivant of-F;
I-2:R
1=
pThe derivant of-F;
I-3:R
1=
pThe derivant of-Cl;
I-4:R
1=
oThe derivant of-Cl;
I-5:R
1=
p-CH
3Derivant;
I-6:R
1=
p-OCH
3Derivant;
I-7:R
1=
o-CF
3Derivant;
I-8:R
1=
M, pThe derivant of-diCl;
I-9:R
1=
M, p, m-triOCH
3Derivant;
I-10: R
1=
O, oThe derivant of-diF.
4. a class that has structure shown in the general formula (II) contains the application of dithiocarbamates chemical compound in the preparation medicine of triazolyl, it is characterized in that, with its as active component for the preparation of istone lysine specificity demethylase 1 inhibitor medicaments;
R
1Be H, single alkyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine or polysubstituted methoxyl group that replaces C1-C5 of diverse location.
5. a class as claimed in claim 4 contains the application of dithiocarbamates chemical compound in the preparation medicine of triazolyl, it is characterized in that preferred: R1 is alkyl, methoxyl group, fluorine, chlorine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, the polysubstituted methoxyl group of single C1-C3 of replacement of diverse location.
6. a class as claimed in claim 5 contains the application of dithiocarbamates chemical compound in the preparation medicine of triazolyl, it is characterized in that, is preferably as follows chemical compound:
II-1:R
1=
oThe derivant of-F;
II-2:R
1=
pThe derivant of-Cl;
II-3:R
1=
p-CH
3Derivant;
II-4:R
1=
p-OCH
3Derivant;
II-5:R
1=
o-CF
3Derivant;
II-6:R
1=
M, pThe derivant of-diCl;
II-7:R
1=
M, p, m-triOCH
3Derivant;
II-8: R
1=
O, oThe derivant of-diF.
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