CN100551907C - Virtue methylamino dithiocarbamate formic ether compounds and its production and application - Google Patents
Virtue methylamino dithiocarbamate formic ether compounds and its production and application Download PDFInfo
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- CN100551907C CN100551907C CNB2004100546869A CN200410054686A CN100551907C CN 100551907 C CN100551907 C CN 100551907C CN B2004100546869 A CNB2004100546869 A CN B2004100546869A CN 200410054686 A CN200410054686 A CN 200410054686A CN 100551907 C CN100551907 C CN 100551907C
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Abstract
The present invention relates to the compound or pharmaceutically acceptable salt thereof of the brand-new following general formula (I) with anti-tumor activity of a class formation and comprise the pharmaceutical composition of this compound, wherein, Ar is selected from the aryl or the heteroaryl of unsubstituted or various replacements; R
1Be selected from H or alkyl, thiazolinyl, alkynyl, aryl, aralkyl or alkaryl, heterocyclic radical or heterocyclic radical alkyl, cycloalkyl or cycloalkylalkyl etc., perhaps R
1Can connect together with the annular atoms of Ar forms ring, constitutes condensed ring with Ar; R
2Be selected from R
2Be selected from-(CH
2)
n-R
3,-CH
2-R
4,-(CH
2)
m-COR
5Or-(CH
2)
m-COCO
2R
6
Description
Technical field
The present invention relates to a class dithiocarbamates compound or its pharmacologically acceptable salt, particularly relate to fragrant methylamino dithiocarbamate formic ether compounds or its pharmacologically acceptable salt, and preparation method thereof and in the application of preparation in the antitumor drug.
Background technology
Dithiocarbamates compound has a wide range of applications in a lot of fields, especially is commonly used for sterilant in pesticide field.Yet the research of the anti-tumor activity aspect of relevant this compounds but seldom.
Recently, people such as Gerhauser C are at Cancer Research 57,272-278, report in 1997, from cress, isolate a kind of isosulfocyanate compound Brassinium, this compound has stronger tumor prevention effect, by the further structure of modification to this compound, has found the dithiocarbamates compound Sulforamate that the tumor prevention effect is stronger.
Summary of the invention
The dithiocarbamates compound or its pharmacologically acceptable salt that the purpose of this invention is to provide general formula (I):
Wherein,
Ar is the phenyl that does not replace or replace, and described substituting group is C
1-C
6Alkoxy or halogen; Perhaps contain 1-3 and be selected from N, heteroatomic five yuan or six membered heteroaryl that O or S formed;
R
1Be H or C
1-C
12Alkyl;
R
2For-(CH
2)
n-R
3, n=0-4 wherein, R
3For O or S for acetal radical or ketal group, the alcohol that wherein forms described acetal radical or ketal group is C
1-C
6Aliphatic monobasic alcohol or dibasic alcohol, the aldehydes or ketones that forms described acetal radical or ketal group is C
1-C
6The fat aldehydes or ketones;
Perhaps,
Work as R
1Be H, R
2For-(CH
2)
m-COR
5Or-(CH
2)
m-COCO
2R
6The time, R
2With R
1Circularize an accepted way of doing sth (III) compound, wherein m=1-3;
R
5Be selected from and replace or do not replace C
1-C
6Alkyl (linearity or branching) replaces or does not replace C
6-C
10Aryl (as benzene, naphthalene etc.), or replace or do not replace C
3-C
10Heteroaryl;
R
6Be selected from H or replacement or not replacement, linearity or branching C
1-C
10Alkyl, preferred C
1-C
6Alkyl.
Another object of the present invention provides a kind of method for preparing above-claimed cpd.This method comprises allows ArCH
2NH-R
1, CS
2And R
2-X reaction in appropriate solvent (as acetone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, ether solvent) under the existence of an alkali metal salt or alkaline earth salt (for example potassiumphosphate, salt of wormwood, cesium carbonate etc.),
Wherein:
Ar is the phenyl that does not replace or replace, and described substituting group is halogen or C
1-C
6Alkoxyl group; Perhaps contain 1-3 and be selected from N, heteroatomic five yuan or the hexa-atomic or heteroaryl of the group that O or S formed;
R
1Be H or C
1-C
12Alkyl,
R
2For-(CH
2)
n-R
3, n=0-4 wherein, R
3For O or S for acetal radical or ketal group, the alcohol that wherein forms described acetal radical or ketal group is C
1-C
6Aliphatic monobasic alcohol or dibasic alcohol, the aldehydes or ketones that forms described acetal radical or ketal group is C
1-C
6The fat aldehydes or ketones;
Perhaps,
Work as R
1Be H, R
2For-(CH
2)
m-COR
5Or-(CH
2)
m-COCO
2R
6The time, R
2With R
1Circularize an accepted way of doing sth (III) compound, wherein m=1-3.
R
5Be selected from and replace or do not replace C
1-C
6Alkyl (linearity or branching) replaces or does not replace C
6-C
10Aryl (as benzene, naphthalene etc.), or replace or do not replace C
3-C
10Heteroaryl;
R
6Be selected from H or replacement or not replacement, linearity or branching C
1-C
10Alkyl, preferred C
1-C
6Alkyl.
X is a leavings group.
The temperature of reaction is not special restriction, can be 0-100 ℃, preferred 10-40 ℃, and more preferably about room temperature (25 ℃).
The process of reaction can detect by TLC to be monitored.Reacted product can by filter, concentrate, post-treating methods such as extraction, recrystallization or column chromatography process.
Raw material A r-CH
2-NH-R
1, R
2-X all can be purchased or be synthetic by currently known methods in the art.
The 3rd purpose of the present invention provides the application of compound or its salt in the preparation antitumor drug of following general formula:
Wherein each group definition and preferred definition are as implied above.
Another object of the present invention provides the pharmaceutical composition that contains this compounds.Compound or pharmaceutically acceptable salt thereof of the present invention can be used as activeconstituents and one or more pharmaceutically acceptable carriers, vehicle or thinner are formed the pharmaceutical composition with antitumor action.The content of compound in pharmaceutical composition of its formula of (I) for example can be 1-95wt%, is preferably 20-90wt%.
Pharmaceutical composition of the present invention also routinely technology make capsule, tablet, oral liquid, injection or transfusion formulation, and make controlled release or slow-released system administration as required.
The compound of general formula of the present invention (I) can use alone or use with the form of composition.
The dosage of the compound of general formula of the present invention (I) decides according to the factors such as weight of patient age, body weight, the course of disease, disease.For example, as a reference, under the situation of oral dosage form, the consumption of compound of the present invention can be 0.1-12mg/kg/d, and under the situation of injection type, compound amount of the present invention can be 0.1-8mg/kg/d.
Purpose compound of the present invention has very strong antitumor action and has showed low toxicity.
Embodiment
The following examples are used to further specify the present invention, but do not limit the present invention in any way:
The preparation of embodiment 1 compound 1
(compound 1)
With 2-furylamine (0.49g, 5 * 10
-3Mol) be dissolved in acetone (or dimethyl formamide) (5mL) in, stir and to add anhydrous phosphoric acid potassium (1.06g, 5 * 10 down
-3Mol), dithiocarbonic anhydride (1mL, excessive), behind the 30min, add 2-bromacetal (0.99g, 5 * 10
-3Mol) acetone soln.Behind the stirring at room 2h, stopped reaction.Filter, filtrate concentrates, and adds 20mL water, uses ethyl acetate extraction.Ethyl acetate layer is washed and with after the Calcium Chloride Powder Anhydrous drying, rotary evaporation concentrates, and gets weak yellow liquid compound 1 (1.32g, 91%).
Ultimate analysis: C
12H
19NO
3S
2Calculated value (%): C 49.80, and H 6.62, and N 4.84; Measured value (%): C 49.56, and H 6.50, and N 5.12.
1H-NMR(CDCl
3，δ)：1.18(t，6H)，3.29(d，2H)，3.52～3.75(m，4H)，4.64(t，1H)，4.86(d，2H)，6.34～6.36(m，2H)，7.38(t，1H)，8.51(br，1H)。
The preparation of embodiment 2 compounds 2
(compound 2)
Compound 2 synthetic, post-treating method is identical with compound 1, just the 2-bromacetal is replaced with o-chloro benzyl chloride.
Productive rate: 93%, weak yellow liquid.Ultimate analysis: C
13H
12ClNOS
2Calculated value (%): C 52.43, and H 4.06, and N 4.70; Measured value (%): C 52.64, and H 4.46, and N 5.01.
1H-NMR(CDCl
3，δ)4.58～4.88(m，2H)，6.31～6.34(m，2H)，7.17～7.56(m，7H)。
The preparation of embodiment 3 compounds 3
Compound 3 synthetic, post-treating method is identical with compound 1, just the 2-bromacetal is replaced with Mono Chloro acetone.
Productive rate: 96%.The rhombus white crystal, 75～77 ℃ of mp.Ultimate analysis: C
9H
11NO
2S
2Calculated value (%): C 47.14, and H 4.83, and N 6.11; Measured value (%): C 47.38, and H 4.82, and N 6.18.FAB (MH
+): calculated value 230.3; Measured value 230.1.
The preparation of embodiment 4 compounds 4
(compound 4)
Compound 4 synthetic, post-treating method is identical with compound 1, just the 2-furylamine is replaced with benzylamine.
Yellow oily liquid, yield: 83%.
1H-NMR(300MHz，CDCl
3)：δ＝1.12(t，6H)，3.31(d，2H)，3.49～3.71(m，4H)，4.63(t，1H)，4.88(t，2H)，7.30～7.39(m，5H)，8.36(br，1H).
13C?NMR(75MHz，CDCl
3)：δ＝196.96，136.06，128.83，128.26，128.06，102.42，63.22，51.03，38.87，15.02.
Ultimate analysis: calculated value C
14H
21NO
2S
2: C, 56.15; H, 7.07; N, 4.68. measured value: C, 56.07; H, 7.00; N, 4.71.
The preparation of embodiment 5 compounds 5
(compound 5)
Compound 5 synthetic, post-treating method is identical with compound 4, just the 2-bromacetal is replaced with 2-(2-bromotrifluoromethane)-1,3-dioxolane.
Yellow oily liquid, yield: 65%.
1H-NMR(300MHz，CDCl
3)：δ＝2.06～2.17(m，2H)，3.34(t，2H)，3.79～3.96(m，4H)，4.89～4.97(m，3H)，7.31～7.37(m，5H).
Ultimate analysis: calculated value C
13H
17NO
2S
2: C, 55.09; H, 6.05; N, 4.94. measured value: C, 55.25; H, 6.01; N, 5.02.
The preparation of embodiment 6 compounds 6
(compound 6)
Compound 6 synthetic, post-treating method is identical with compound 5, just benzylamine is replaced with 3, the 4-dichloro-benzylamine.
Yellow oily liquid, yield: 53%.
1H-NMR(300MHz，CDCl
3)：δ＝2.05～2.14(m，2H)，3.35(t，2H)，3.83～4.02(m，4H)，4.89～4.99(m，3H)，7.16～7.42(m，3H).EI-MS(m/z)：351[M]
+，159[M-192]
+.
The preparation of embodiment 7 compounds 7
(compound 7)
Compound 7 synthetic, post-treating method is identical with compound 5, just benzylamine is replaced with 4-Methoxybenzylamine.
Yellow oily liquid, yield: 71%.
1H-NMR(300MHz，CDCl
3)：δ＝2.03～2.12(m，2H)，3.33(t，2H)，3.81～4.00(m，7H)，4.82(d，2H)，4.96(t，1H)，6.86～6.90(m，2H)，7.21～7.27(m，3H).
Ultimate analysis: calculated value C
14H
19NO
3S
2: C, 53.65; H, 6.11; N, 4.47. measured value: C, 53.45; H, 6.14; N, 4.28.
(compound 8)
The preparation of embodiment 8 compounds 8
Compound 8 synthetic, post-treating method is identical with compound 5, just benzylamine is replaced with the benzyl methylamine.
Yellow oily liquid, yield: 95%.
1H-NMR(300MHz，CDCl
3)：δ＝2.11～2.17(m，2H)，3.25(s，2H)，3.45，(s，3H)，3.88～4.03(m，4H)，5.00(s，2H)，5.38(s，1H)，7.22～7.32(m，5H).
Ultimate analysis: calculated value C
14H
19NO
2S
2: C, 56.53; H, 6.44; N, 4.71. measured value: C, 56.29; H, 6.44; N, 4.57.
The preparation of embodiment 9 compounds 9
(compound 9)
Compound 9 synthetic, post-treating method is identical with compound 5, just benzylamine is replaced with the furfuryl methylamine.
Yellow oily liquid, yield: 84%.
1H-NMR(300MHz，CDCl
3)：δ＝2.07～2.13(m，2H)，3.33～3.52(m，5H)，3.82～4.04(m，4H)，4.98(t，2H)，5.30(s，1H)，6.35(d，2H)，7.38(s，1H).
Ultimate analysis: calculated value C
12H
17NO
3S
2: C, 50.15; H, 5.96; N, 4.87. measured value: C, 49.97; H, 5.85; N, 4.80.
The preparation of embodiment 10 compounds 10
(compound 10)
Compound 10 synthetic, post-treating method is identical with compound 4, just the 2-bromacetal is replaced with ethyl bromide acetone.
Faint yellow prismatic crystal, mp111～112 ℃, yield 57%.1.02(3H，t，Me)，3.34(1H，br，OH)，3.44(1H，d，ArCH
2)，3.66(1H，q，MeCH
2)，3.86(1H，d，ArCH
2)，3.88(1H，q，MeCH
2)，4.76(1H，d，SCH
2)，5.01(1H，d，SCH
2)，7.28(4H，m，Ar).
13C-NMR(CDCl
3，δ)：13.47，37.84，48.30，62.23，96.59，127.07，127.65，127.96，135.91，167.73，196.85.
The preparation of embodiment 11 compounds 11
(compound 11)
Compound 11 synthetic, post-treating method is identical with compound 10, just benzylamine is replaced with the 2-furylamine.
Yellow liquid, yield 93%.
1H-NMR(CDCl
3，δ)：1.13(3H，t，Me)，3.34(1H，d，ArCH
2)，3.67(1H，d，ArCH
2)，3.89(1H，m，MeCH
2)，4.16(1H，m，MeCH
2)，4.61(1H，d，SCH
2)，4.81(1H，br，OH)，5.19(1H，d，SCH
2)，6.24(1H，dd，Ar)，6.31(1H，d，Ar)，7.26(1H，dd，Ar)；
13C-NMR(CDCl
3，δ)：13.70，38.02?41.03?64.46，94.78，110.62，110.68，142.27148.24，169.51?198.03。
The preparation of embodiment 12 compounds 12
(compound 12)
Compound 12 synthetic, post-treating method is identical with compound 10, just benzylamine is replaced with chlorobenzylamine.
Water white transparency, be hexagonal plate crystal, 116～117 ℃ of mp, yield 59%.
1H-NMR(CDCl
3，δ)：1.09(3H，t，Me)，3.38(1H，d，ArCH
2)，3.53(1H，q，MeCH
2)，3.72(1H，d，ArCH
2)，4.01(1H，q，MeCH
2)，4.46(1H，d，SCH
2)，4.91(1H，br，OH)，5.40(1H，d，SCH
2)，7.25～7.30(4H，m，Ar)
13C-NMR(CDCl
3，δ)：13.53，37.90，47.55，64.59，94.58，128.40，130.04，133.62，169.68，198.92.
The preparation of embodiment 13 compounds 13
(compound 13)
Compound 13 synthetic, post-treating method is identical with compound 10, just benzylamine is replaced with a chlorobenzylamine.
Colourless plate crystal, mp112～113 ℃, yield 78%.
1H-NMR(CDCl
3，δ)：1.11(3H，t，Me)，3.40(1H，d，ArCH
2)，3.54(1H，q，MeCH
2)，3.73(1H，d，ArCH
2)，4.02(1H，q，MeCH
2)，4.43(1H，d，SCH
2)，4.93(1H，br，OH)，5.43(1H，d，SCH
2)，7.25(4H，m，Ar).
13C-NMR(CDCl
3，δ)：15.52，37.92，47.69，64.49，94.58，126.76，128.08，128.49，129.56，134.25，137.11，169.66，199.02.
The preparation of embodiment 14 compounds 14
(compound 14)
Compound 14 synthetic, post-treating method is identical with compound 10, just benzylamine is replaced with 4-Methoxybenzylamine.
Colourless needle crystal, mp101～102 ℃, yield 74%.
1H-NMR(CDCl
3，δ)：1.07(3H，t，Me)，3.36(1H，d，ArCH
2)，3.49(1H，q，MeCH
2)，3.67(1H，d，ArCH
2)，3.78(3H，s，CH
3O)，3.96(1H，q，MeCH
2)，4.45(1H，d，SCH
2)，5.30(1H，br，OH)，5.40(1H，d，SCH
2)，6.82(2H，m，Ar)，7.29(2H，m，Ar).
13C-NMR(CDCl
3，δ)：13.54，29.66，37.94，47.77，55.28，63.99，94.84，113.56，127.21，130.17，159.27，169.51，198.39.
The preparation of embodiment 15 compounds 15
(compound 15)
Compound 15 synthetic, post-treating method is identical with compound 10, just benzylamine is replaced with NSC 158269.
Colourless needle crystal, mp122～123 ℃, yield 32%.
1H-NMR(CDCl
3，δ)：1.08(3H，t，Me)，3.38(1H，d，ArCH
2)，3.52(1H，q，MeCH
2)，3.69(1H，d，ArCH
2)，3.99(1H，q，MeCH
2)，4.46(1H，d，SCH
2)，4.90(1H，br，OH)，5.42(1H，d，SCH
2)，6.98(2H，m，Ar)，7.35(2H，m，Ar).
13C-NMR(CDCl
3，δ)：13.56，29.69，37.91，47.49，64.35，94.58，115.07，115.24，130.49，130.56，161.41，163.37，169.72，198.83.
The preparation of embodiment 16 compounds 16
(compound 16)
Compound 16 synthetic, post-treating method is identical with compound 10, just benzylamine is replaced with tetrahydroisoquinoline.
White, needle-shaped crystals, mp.69～70 ℃, yield 11%.
Embodiment 17
With above-claimed cpd 50mg of the present invention, after the adding tween 80 stirs hydrotropy, add injection physiological saline 5ml, sterilization filling is made injection after filtration.
Embodiment 18
With above-claimed cpd 100mg of the present invention and lactose 100mg, after Mierocrystalline cellulose 180mg and Magnesium Stearate 10mg mixed evenly, technology was made tablet routinely.
The biological activity test of compound and interpretation of result
1. anti-tumor activity testing method
1. mtt assay: tetrazolium reduction method
2. srb assay: sulphonyl rhodamine B protein staining method
2. activity experiment data and interpretation of result
Test compound 1-16 inhibiting rate to five kinds of tumor cell lines (HL-60 human leukemia, BGC-823 people's cancer of the stomach, Bel-7402 people's liver cancer, Hela human cervical carcinoma, MDA-MB-435 human breast carcinoma) under 0.1 μ M, 1 μ M, the 10 μ M concentration respectively with in vitro method, found all to have better antitumor activity and lower toxicity.
Wherein, when compound 1 is 10 μ M in concentration, the inhibiting rate of Bel-7402 people's liver cancer (srb assay), Hela human cervical carcinoma (srb assay) cell strain is respectively 72.57% (P＜0.01), 73.46% (P＜0.01).
When compound 7 is 10 μ M in concentration, the inhibiting rate of HL-60 human leukemia (srb assay), BGC-823 people's cancer of the stomach (srb assay), MDA-MB-435 human breast carcinoma (srb assay) cell strain 51.95% (P＜0.01), 85.56% (P＜0.01), 97.45% (P＜0.01) have been reached respectively.
When compound 15 is 10 μ M in concentration, inhibiting rate to Bel-7402 people's liver cancer (srb assay), Hela human cervical carcinoma (srb assay) cell strain and PC-3MIE8 human prostata cancer is respectively 62.3% (P＜0.01), 83.4% (P＜0.01) and 64.0% (P＜0.01).
Benzyl dithiocarbamates compound of the present invention has very strong antitumor action and lower toxicity, is the potential antitumor drug of a class.
Claims (4)
1, following dithiocarbamates compound or its pharmacologically acceptable salt:
2, compound or pharmaceutically acceptable salt thereof as claimed in claim 1 is characterized in that, described compound is:
3, claim 1 or the 2 described compound or its salts application in the preparation antitumor drug.
4, contain the compound or its salt of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.
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| CN102657647A (en) * | 2012-04-06 | 2012-09-12 | 澳门大学 | Application of IC-4 in antiangiogenesis |
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| CN107226789B (en) * | 2017-05-09 | 2019-11-08 | 北京大学 | Dithiocarbamates compound, preparation method and purposes in the preparation of antitumor drugs |
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