CN1169768C - (4-alkynyl), aromatic keto-acid compound, synthesis method and its application - Google Patents
(4-alkynyl), aromatic keto-acid compound, synthesis method and its application Download PDFInfo
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Abstract
The present invention relates to a compound of (4-ynyl)-aromatous ketonic acid, a synthetic method and an application thereof, and the compound has a structural formula 1, wherein R is an alkyl radical pf H or C(1 to 10), and R<1> is an alkyl radical of H, C(1 to 10) or CH2OR<5>; R<2> is a straight chain of H or C(1 to 10) or an alkyl radical with branched chains, and R<3> and / or R<4> is H, OH, OR<5> or NHCOOR<5>; R<5> is an alkyl radical of C(1 to 10), and the alkyl radical is an alkyl radical with a straight chain, an alkyl radical with branched chains or aromatic radicals, an aromatic radical or a substituted aromatic radical. The present invention can be used as an inhibitor of stromatin enzymes, and therefore, the present invention is possible to be used for curing diseases of cancer, arthritis, canker of organism, pneumonectasis, atherosclerosis of blood vessel, etc.
Description
Technical field
The present invention relates to (4-alkynyl)-aromatic ketone acid compounds, synthetic method and application thereof.This compound can be used as the inhibitor of stromatin enzyme, thereby might be used to treat cancer, sacroiliitis, body ulcer, diseases such as pulmonary emphysema, blood vessel scleratheroma.
Background technology
Matrix metalloproteinase (matrix metalloproteinases, MMPs) be the zinciferous endopeptidase of gang, all main components that can the degradation of cell epimatrix, thereby participate in renewal (the Ryoichi Hirayama of reticular tissue, Minoru Yamamota.Bioorg.Med.Chem.1997,5,765).Studies show that, some hypotype of MMP is that the human body normal physiological activity is necessary, the other hypotype is then being played the part of extremely important role in some pathology process, as transfer and (Schwartz, the M.A. such as diffusion, multiple arteriosclerosis of osteoarthritis, tumour; Van Eart, H.E.Prog.Med.Chem.1992,29,271).The overexpression meeting of these enzymes causes a large amount of disorders such as cancers, sacroiliitis, body ulcer, generations such as pulmonary emphysema, blood vessel scleratheroma.Therefore, as the target enzyme, it is one of problems of making earnest efforts of Pharmaceutical Chemists during the last ten years that development matrix metallo-proteinase inhibitor (MMPI) is treated these diseases with MMPs.These inhibitor are different with the mechanism of action by structure, can be divided into succinyl-hydroxy acid class, sulphonyl ammonia hydroximic acid, carboxylic-acid etc.
Wherein the carboxylic-acid matrix metallo-proteinase inhibitor is because its high selectivity to each type matrix metalloproteinase more and more is subjected to the attention of various countries' Pharmaceutical Chemist.
Summary of the invention
The object of the invention provides a kind of (4-alkynyl)-aryl ketones acid compounds.
The object of the invention also provides a kind of synthetic method of above-mentioned (4-alkynyl)-aryl ketones acid compounds.
Another purpose of the present invention provides a kind of application of above-mentioned (4-alkynyl)-aryl ketones acid compounds.
Related (4-alkynyl)-aryl ketones acid compounds carboxylic-acid stromatin enzyme inhibitors among the present invention, novel structure shows that through determination of activity a part in them has the abilities that potent and selectivity suppress the different subunits of matrix metalloproteinase.Might be used to treat cancer, sacroiliitis, body ulcer, diseases such as pulmonary emphysema, blood vessel scleratheroma.
(4-alkynyl)-aryl ketones acid compounds of the present invention has following structural formula:
Wherein R is H or C
1-10Alkyl; R
1Be H, C
1-10Alkyl, CH
2OR
5, CH
2OH, OBn, OH or OCH
3R
2Be H, C
1-6Straight chain or have the alkyl of side chain; R
3Or/and R
4Be H, OH, OR
5, NHCOOR
5, C
2H
5Or Ph; R
5Be C
1-10Alkyl; Described alkyl is straight chained alkyl, have the alkyl of side chain or aryl, aryl or substituted aryl.
As following compound is example:
But the synthetic method classified description of compound of the present invention is as follows:
R
2And/or R
3The compound that replaces for chirality synthetic: with R
2And/or R
3The Succinic Acid lactone that chirality replaces is a starting raw material, in polar organic solvent and under the Lewis acid effect, and the R that chirality replaces
2And/or R
3Succinic Acid lactone, halogeno-benzene and lewis acidic mol ratio are 1: the Fu Ke acidylate, backflow 16-36 hour, take place and generate R in 1-1.5: 3-7
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric acid that chirality replaces; Perhaps resterification gets corresponding R
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric ester that chirality replaces.Reaction formula is as follows:
For R
2And/or R
3The meso compound that replaces has following two kinds of methods:
The one, with halogeno-benzene and
Be raw material, Lewis acid is a catalyzer, and under the room temperature, reaction is 16-24 hour in the organic solvent, generates molecular formula and is
Halogenophenyl ketone, wherein halogeno-benzene,
With lewis acidic mol ratio be 1: 1-2: 1-3; At-78 ℃-room temperature and C
1-8The lithium alkylide effect under, 4-halogenophenyl ketone and alpha-halogen acid esters generation alkylated reaction reacted 5-20 hour, obtained R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces, wherein 4-halogenophenyl ketone, alpha-halogen acid esters and C
1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0.This reaction is preferably under the anhydrous and oxygen-free condition He in the tetrahydrofuran solution to be carried out.
R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric acid resterification that replaces gets corresponding R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.
Described C
1-8Lithium alkylide can be butyllithium, dibutyl lithium, di-isopropyl lithium (LDA), octyl group lithium etc.
The 2nd, the Fu Ke acidylate takes place in the same condition of halogeno-benzene and halo acetyl halide, generates halo ethanoyl halogenophenyl ketone; Halo ethanoyl halogenophenyl ketone and two substituted acetic acid ester PhCH (C
2H
5) the same generation alkylated reaction under the COOR anhydrous and oxygen-free condition, promptly at-78 ℃-room temperature and C
1-8The lithium alkylide effect under, react and obtained R in 5-20 hour equally
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces.Wherein halo ethanoyl halogenophenyl ketone, two substituted acetic acid ester and C
1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0.This reaction be preferably under the anhydrous and oxygen-free condition and tetrahydrofuran solution in.Perhaps resterification gets corresponding R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.Reaction formula is as follows:
Above-mentioned R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyro-esterification that replaces is by R
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric acid that replaces and saturated alcohol roh/hydrochloric acid room temperature reaction 1-10 hour can become corresponding R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.
In organic polar solvent, R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces, corresponding alkynes CH ≡ CR
1, contain the organic compound acid binding agent and the catalyzer of lone-pair electron on the nitrogen, 4 alkynyls are introduced in 50-100 ℃ of reaction 16-36 hour, gamma-carbonyl group benzenebutanoic acid ester cpds that must the 4-alkynyl substituted
R wherein
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric ester, the alkynes CH ≡ CR that replace
1With the mol ratio of acid binding agent be 1: 1-3: 0.01-0.15, the weight ratio of 4-(4-halogenophenyl)-4-oxidation-butyric ester and catalyzer is 1: 0.001-0.010, described catalyzer are dichloro two triphenyl phosphorus palladiums, cuprous iodide, tetrabutylammonium iodide or their mixture.The organic compound acid binding agent that contains lone-pair electron on the described nitrogen is pyridine, Trimethylamine 99, triethylamine, trioctylamine, 4-Dimethylamino pyridine, N, N-diisopropyl ethyl amine or bipyridine.
Above-mentioned R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces is with the aqueous hydrolysis of sodium hydroxide or potassium, and acidifying gets corresponding R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces.
In aforesaid method, R, R
1, R
2, R
3, R
4Or R
5As previously mentioned.
(4-alkynyl)-aromatic ketone acid compounds of the present invention is simple synthetic method not only, and their inhibition activity have been tested to three kinds of stromatin enzymes, show that this compound can be used as the inhibitor of stromatin enzyme, thereby can be used to treat cancer, sacroiliitis, body ulcer, the medicine of diseases such as pulmonary emphysema, blood vessel scleratheroma.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1
Synthesizing of 4-(4-phenylacetylene base)-phenyl-4-oxidation-1-butyric acid (1)
1. aluminum chloride (10mmol) and bromobenzene (2mmol) are blended in the 50mL methylene dichloride, ice bath is cooled to 0 ℃, slowly drips the dichloromethane solution (1.8mmol/10ml) of Succinic Acid lactone again.Naturally rise to room temperature, reheat refluxed 24 hours.After reacting completely, reaction mixture is poured in the mixture that is made into by 30g ice and 50mL 3M hydrochloric acid, stirred 1 hour.Organic phase is separated water chloroform extraction three times.Merge organic phase, and use saturated common salt water washing, anhydrous Na
2SO
4Dry.Remove solvent under reduced pressure, resistates gets product 4-(4-bromophenyl)-4-oxidation-1-butyric acid through column chromatography.Productive rate 79%;
1HNMR (300MHz, CDCl
3): δ 7.86 (d, J=8.6Hz, 2H), 7.63 (d, J=8.6Hz, 2H), 3.28 (t, J=6.6Hz, 2H), 2.81 (t, J=6.5Hz, 2H); EIMS (m/z): 256 (M
+), 183,155.
2. compound 4-(4-bromophenyl)-4-oxidation-1-butyric acid (25.4mmol) is dissolved among the saturated MeOH/HCl of 100mL stirring at room 12 hours.After reacting completely, remove solvent under reduced pressure, the residuum acetic acid ethyl dissolution is used the saturated common salt water washing, anhydrous Na again
2SO
4Dry.Remove solvent under reduced pressure, resistates gets product 4-(4-bromophenyl)-4-oxidation-methyl-butyrate through column chromatography.Productive rate 84.4%.
1HNMR(300MHz,CDCl
3):δ7.85(d,J=8.0Hz,2H),7.63(d,J=7.8Hz,2H),3.72(s,3H),3.29(t,J=6.5Hz,2H),2.78(t,J=6.3Hz,2H);EIMS(m/z):270(M
+),272(M
++2),183。
3. under argon shield, 1-phenylacetylene (20mmol) and compound 4-(4-bromophenyl)-4-oxidation-methyl-butyrate are mixed in 50mL DMF and the 5mL triethylamine, add dichloro two triphenyl phosphorus palladiums (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) again.Then, being heated to 75 ℃ stirred 24 hours.After reacting completely, add methyl alcohol 15mL cancellation reaction.Remove solvent under reduced pressure, residuum acetic acid ethyl dissolution, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product 4-(4-phenylacetylene base)-phenyl-4-oxidation-1-methyl-butyrate through column chromatography.Productive rate 96%;
1HNMR (300MHz, CDCl
3): δ 7.98 (d, J=10.0Hz, 2H), 7.62 (d, J=10.8Hz, 2H), 7.56 (m, 2H), 7.39 (m, 3H), 3.72 (s, 3H), 3.33 (t, J=6.7Hz, 2H), 2.79 (t, J=6.7Hz, 2H); EIMS (m/z): 292 (M-), 205,176; HRMS (m/z) found292.11014 C
19H
16O
3Required 292.10995.
4. substrate 4-(4-phenylacetylene base)-phenyl-4-oxidation-1-methyl-butyrate is dissolved in the methyl alcohol, adds 20% aqueous sodium hydroxide solution again, stirring at room.After reacting completely, transfer PH=1, use chloroform extraction again three times with 2M hydrochloric acid.Merge organic phase, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product 4-(4-phenylacetylene base)-phenyl-4-oxidation-1-butyric acid through column chromatography.Productive rate 52%.
1HNMR(300MHz,CDCl
3):δ7.96(d,J=8.5Hz,2H),7.61(d,J=8.5Hz,2H),7.53(m 2H),7.36(m,3H),3.30(t,J=6.5Hz,2H),2.81(t,J=6.5Hz,2H);EIMS(m/z):278(M
+),205,176;HRMS(m/z)found 278.09179 C
18H
16O
3 required278.09430.
Embodiment 2
(S) 4-(4-3-methoxyl group-1-proyl)-phenyl-4-oxidation-2-methoxycarbonyl amino-1-tert-butyl acetate (7) is synthetic
1. aluminum chloride (10mmol) and bromobenzene (2mmol) are blended in the 50mL methylene dichloride, ice bath is cooled to 0 ℃, slowly drips the dichloromethane solution (1.8mmol/10ml) of compound (R)-3-methoxycarbonyl amino-succinic acid lactone again.Naturally rise to room temperature, reheat refluxed 24 hours.After reacting completely, reaction mixture is poured in the mixture that is made into by 30g ice and 50mL 3M hydrochloric acid, stirred 1 hour.Organic phase is separated water chloroform extraction three times.Merge organic phase, and use saturated common salt water washing, anhydrous Na
2SO
4Dry.Remove solvent under reduced pressure, resistates gets product (s)-2-(methoxycarbonyl) amino-4-(4-bromophenyl)-4-oxidation-butyric acid, productive rate 67% through column chromatography; [α]
20 D75.6 (c 3.8, CHCl
3);
1HNMR (300MHz, CDCl
3): δ 7.79 (d, J=8.2Hz, 2H), 7.61 (d, J=8.3Hz, 2H), 5.91 (br, 1H), 4.73 (m, 1H), 3.75 (m, 1H), 3.67 (s, 3H), 3.56 (m, 1H); EIMS (m/z): 329 (M
+), 284,183; HRMS (m/z): found 328.99471, C
12H
12BrNO
5Requires 328.98088.
2. (5.0g 15.2mmol) is dissolved in the 70mL trimethyl carbinol, adds Boc then with compound (s)-2-(methoxycarbonyl) amino-4-(4-bromophenyl)-4-oxidation-butyric acid
2O (3.82g, 7.5mmol) and DMAP (100mg).Stirring at room 3 hours, reaction removes solvent under reduced pressure, residuum acetic acid ethyl dissolution, water, saturated common salt water washing successively again, anhydrous Na after finishing
2SO
4Dry.Remove solvent under reduced pressure, resistates gets (s)-2-(methoxycarbonyl) amino-4-(4-bromophenyl)-4-oxidation-tert-butyl acetate, 5.58g, productive rate 95.3% through column chromatography.[α]
26 D26.6(c 1.20,CHCl
3);
1HNMR(300MHz,CDCl
3):δ7.81(d,J=8.6Hz,2H),7.632(d,J=8.4Hz,2H),5.74(br,1H),4.64(m,1H),3.67(s,3H),3.61(dd,J=17.6,4.0Hz,1H),3.43(dd,J=17.6,4.3Hz,1H),1.43(s,9H);EIMS(m/z):286(M
+-COOt-Bu),185。
3. under argon shield, 3-methoxyl group-1-propine (20mmol) and compound (s)-2-(methoxycarbonyl) amino-4-(4-bromophenyl)-4-oxidation-tert-butyl acetate are mixed in 50mL DMF and the 5mL triethylamine, add dichloro two triphenyl phosphorus palladiums (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) again.Then, being heated to 75 ℃ stirred 24 hours.After reacting completely, add methyl alcohol 15mL cancellation reaction.Remove solvent under reduced pressure, residuum acetic acid ethyl dissolution, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product (S) 4-(4-3-methoxyl group-1-proyl)-phenyl-4-oxidation-2-methoxycarbonyl amino-1-tert-butyl acetate, productive rate 93% through column chromatography; [α]
26 D16.7 (c 0.66, CHCl
3);
1HNMR (300MHz, CDCl
3): δ 7.89 (d, J=8.3Hz, 2H), 7.54 (d, J=8.3Hz, 2H), 5.55 (br, 1H), 4.60 (t, J=4.2Hz, 1H), 4.34 (s, 2H), 3.67 (, m, 1H), 3.64 (s, 3H), 3.46 (s, 3H), 3.43 (m, 1H), 1.42 (s, 9H); EIMS (m/z): 376 (M
++ 1), 320,302; HRMS (m/z) found 302.10371 (C
20H
25NO
5-OC
4H
9) required 302.10284.
Embodiment 3
(+/-) 4-(4-3-hydroxyl-1-proyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-butyric acid (19) synthetic
1. aluminum chloride (20mmol) and bromobenzene (10mmol) are blended in the 50mL methylene dichloride, ice bath is cooled to 0 ℃, again the dichloromethane solution of dripping bromine acetyl bromide (10mmol/10ml) slowly.Naturally rise to room temperature, continue to stir 24 hours.After reacting completely, reaction mixture is poured in the mixture that is made into by 30g ice and 50mL 3M hydrochloric acid, stirred 1 hour.Organic phase is separated saturated common salt water washing, anhydrous Na
2SO
4Dry.Remove solvent under reduced pressure, resistates gets product 4-bromophenyl-brooethyl ketone through column chromatography, yield about 75%.
1HNMR(300MHz,CDCl
3):δ7.79(d,J=10.9Hz,2H),7.57(d,J=10.8Hz,2H),4.33(s,2H);EIMS(m/z):274(M
+),276,278。
2. (2.50g 14.0mmol) is dissolved in the 100mL tetrahydrofuran (THF) α-ethylbenzene methyl acetate compound (+/-).Under the argon shield this solution is chilled to-78 ℃, slowly add again LDA (1.0M, 15mL, 15.0mmol).Under this temperature, continuing to stir 1 hour, slowly add the tetrahydrofuran solution (4.1g, 15.0mmol in 40mL THF) of compound 4-bromophenyl-brooethyl ketone again. reaction mixture continues to stir 1 hour at-78 ℃, rises to room temperature again, continues to stir 8 hours.After reacting completely, in reaction mixture, add 150mL saturated aqueous ammonium chloride cancellation reaction.Add the saturated NaCl aqueous solution of 150mL again, ethyl acetate (250mL) is extracted.The organic phase anhydrous Na
2SO
4Dry.Remove solvent under reduced pressure, resistates gets 4.5g (85.7%) alkylate (+/-) 2-ethyl-2-phenyl-4-(4-bromophenyl)-4-oxidation-methyl-butyrate through column chromatography.
1HNMR(300MHz,CDCl
3):δ7.85(d,J=8.5Hz,2H),7.61(d,J=8.5Hz,2H),7.36`7.25(m,5H),3.77(s,2H),3.30(s,3H),2.39~2.22(m,2H),0.67(t,J=7.5Hz,3H);EIMS(m/z):375(M
++1),377,314,316,185,187。
3. under argon shield, 3-hydroxyl-1-propine (20mmol) and compound (+/-) 2-ethyl-2-phenyl-4-(4-bromophenyl)-4-oxidation-methyl-butyrate is mixed in 50mL DMF and the 5mL triethylamine, adds dichloro two triphenyl phosphorus palladiums (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) again.Then, being heated to 75 ℃ stirred 24 hours.After reacting completely, add methyl alcohol 15mL cancellation reaction.Remove solvent under reduced pressure, residuum acetic acid ethyl dissolution, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product (+/-) 4-(4-3-hydroxyl-1-proyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-methyl-butyrate, productive rate 46% through column chromatography.
1HNMR(300MHz,CDCl
3):δ7.92(d,J=7.8Hz,2H),7.51(d,J=8.1Hz,2H),7.38~7.25(m,5H),4.57(d,J=5.5Hz,2H),3.79(s,2H),3.66(s,3H),2.37~2.29(m,2H),0.69(t,J=7,5Hz,3H);EIMS(m/z):351(M
++1),290,159;HRMS(m/z)found 350.15214 C
22H
22O
4 required 350.14984。
4. substrate (+/-) 4-(4-3-hydroxyl-1-proyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-methyl-butyrate is dissolved in the methyl alcohol, adds 20% aqueous sodium hydroxide solution again, stirring at room.After reacting completely, transfer PH=1, use chloroform extraction again three times with 2M hydrochloric acid.Merge organic phase, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product (+/-) 4-(4-3-hydroxyl-1-proyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-butyric acid, productive rate 83% through column chromatography.
1HNMR(300MHz,CDCl
3):δ7.92(d,J=7.5Hz,2H),7.50(d,J=7.6Hz,2H),7.42~7.25(m,5H),4.52(s,2H),3.80(m,2H),2.34~2.25(m,2H),0.72(t,J=7.0Hz,3H);EIMS(m/z):337(M
++1),319,263,174,159;HRMS(m/z)found 318.12426(C
21H
20O
4-H
2O)required 318.12559.
Embodiment 3
(+/-) 4-(the positive decynyl of 4-1-)-phenyl-4-oxidation-3-ethyl-1-methyl-butyrate (16) synthetic
1. aluminum chloride (20mmol) and bromobenzene (10mmol) are blended in the 50mL methylene dichloride, ice bath is cooled to 0 ℃, slowly drips the dichloromethane solution (10mmol in 10ml) of n-butyryl chloride again.Naturally rise to room temperature, continue to stir 24 hours.After reacting completely, reaction mixture is poured in the mixture that is made into by 30g ice and 50mL 3M hydrochloric acid, stirred 1 hour.Organic phase is separated saturated common salt water washing, anhydrous Na
2SO
4Dry.Remove solvent under reduced pressure, resistates gets product 4-bromophenyl-n-propyl ketone through column chromatography, yield about 75%
1HNMR (300MHz, CDCl
3): δ 7.83 (d, J=10.7Hz, 2H), 7.60 (d, J=10.6Hz, 2H), 2.91 (t, J=7.3Hz, 2H), 1.80 ~ 1.67 (m, 2H), 1.00 (t, J=7.4Hz, 3H); EIMS (m/z): 220 (M
+), 222,185,183.
2. (3.00g 13.6mmol) is dissolved in the 100mL tetrahydrofuran (THF) compound 4-bromophenyl-n-propyl ketone.Under the argon shield this solution is chilled to-78 ℃, slowly add again LDA (1.0M, 15mL, 15.0mmol).Under this temperature, continuing to stir 1 hour, slowly add the tetrahydrofuran solution (2.1g, 14.0mmol in 12mL THF) of methyl bromoacetate again. reaction mixture continues to stir 1 hour at-78 ℃, rises to room temperature again, continues to stir 8 hours.After reacting completely, in reaction mixture, add 50mL saturated aqueous ammonium chloride cancellation reaction.Add the saturated NaCl aqueous solution of 50mL again, ethyl acetate (250mL) is extracted.The organic phase anhydrous Na
2SO
4Dry.Remove solvent under reduced pressure, resistates gets 3.3g (81.5%) alkylate (+/-) 3-ethyl-4-(4-bromophenyl)-4-oxidation-methyl-butyrate through column chromatography.
1HNMR(300MHz,CDCl
3):δ7.78(d,J=10.8Hz,2H),7.55(d,J=10.6Hz,2H),3.72(M,1H),3.40(S,3H),2.88(DD,J=17.0,9.5Hz,1H),2.44(,dd,J=17.0,4.7Hz,1H),1.71~1.42(m,2H),0.81(t,J=7.3Hz,3H);EIMS(m/z):298(M
+),299。
3. under argon shield, positive decine (20mmol) and compound (+/-) 3-ethyl-4-(4-bromophenyl)-4-oxidation-methyl-butyrate is mixed in 50mL DMF and the 5mL triethylamine, adds dichloro two triphenyl phosphorus palladiums (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) again.Then, being heated to 75 ℃ stirred 24 hours.After reacting completely, add methyl alcohol 15mL cancellation reaction.Remove solvent under reduced pressure, residuum acetic acid ethyl dissolution, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product (+/-) 4-(the positive decynyl of 4-1-)-phenyl-4-oxidation-3-ethyl-1-methyl-butyrate, productive rate 76.6% through column chromatography.
1HNMR(300MHz,CDCl
3):δ7.82(d,J=10.8Hz,2H),7.41(d,10.6Hz,2H),3.73(m,1H),3.43(s,3H),2.98(dd,J=17.0,4.7Hz,1H),2.61~2.47(m,3H),1.78~0.86(m,17H);EIMS(m/z):356(M
+),241;HRMS(m/z)found 356.23524 C
23H
32O
3 required 356.23514。
Embodiment 4
Compound of the present invention has been tested the inhibition activity of these compounds to the stromatin enzyme through the Ye Qizhuan researcher at Shanghai Pharmaceutical Inst., Chinese Academy of Sciences national drug screening center.These compounds have been tested to MMP-1 (collagenase-1), MMP-3 (matrix lytic enzyme-1), MMP-9 (gelatinase-B), MMP-12 (scavenger cell elastoser), MMP-13 (collagenase-3), MMP-15 (membranous type 2-MMPs), the restraining effect of MMP-16 (membranous type 3-MMPs), the result is as shown in the table.
The gamma-carbonyl group benzenebutanoic acid compounds that table 14-replaces is to the inhibition activity of matrix metalloproteinase
Compound | IC50(μM) |
MMP-1 MMP-3 MMP-9 MMP-12 MMP-13 MMP-15 MMP-16 | |
2 3 4 5 10 11 12 13 14 15 17 18 19 20 21 22 | >83.25 54.331 >83.25 40.440 >83.25 >83.25 >83.25 >83.25 52.146 >83.25 33.211 >83.25 >83.25 >83.25 >83.25 5.530 10.990 3.188 68.776 47.150 >83.25 >83.25 5.323 17.884 6.096 >83.25 >83.25 >83.25 >83.25 50.006 >83.25 26.332 >83.25 >83.25 >83.25 >83.25 17.672 15.023 5.537 >83.25 >83.25 >83.25 >6.25 1.65 >6.25 0.167 >6.25 >6.25 >6.25 >83.25 3.857 >83.25 4.340 >83.25 >83.25 >83.25 >83.25 6.099 82.279 4.812 37.659 >83.25 >83.25 >83.25 3.753 21.681 3.371 >83.25 >83.25 >83.25 72.557 >83.25 0.762 87.715 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 36.255 >83.25 >83.25 >83.25 >83.25 >83.25 >83.25 31.156 15.330 31.382 >83.25 >83.25 >83.25 >83.25 46.348 >83.25 >83.25 >83.25 >83.25 |
By the table in as can be seen, the gamma-carbonyl group benzenebutanoic acid compounds of synthetic 4-alkynyl substituted has better inhibited activity to matrix metalloproteinase.They can optionally suppress MMP-3, MMP-9, MMP-12, and to almost not influence of MMP-1, MMP-13, MMP-15 and MMP-16.4 alkynyl substituted bases of this compounds are to have MMP-3, MMP-9, the inhibiting necessary group of MMP-12.And increase and the lipotropy enhancing along with 4 alkynyl substituted matrixes are long-pending, its inhibition activity to MMP-3, MMP-12 also obviously strengthens, and lipotropy weakens, and obviously strengthens the inhibition of MMP-9 is active.Substituting group is introduced in β position at ester group, can improve their inhibition activity to MMP-3, MMP-12, and introduces substituting group in ester group α position, then causes and suppresses active reduction even disappearance.Alkoxycarbonyl amido is introduced in α position at ester group, can improve the inhibition activity to MMP-3, MMP-12.
Claims (8)
1. one kind (4-alkynyl)-aryl ketones acid compounds, it has following structural formula:
Wherein R is H or C
1-10Alkyl; R
1Be H, C
1-10Alkyl, CH
2OR
5, CH
2OH, OBn, OH or OCH
3R
2Be H, C
1-6Straight chain or have the alkyl of side chain; R
3Or/and R
4Be H, OH, OR
5, NHCOOR
5, C
2H
5Or Ph; R
5Be C
1-10Alkyl; Described alkyl is straight chained alkyl, have the alkyl of side chain or aryl, aryl or substituted aryl.
3. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 1 is characterized in that synthetic respectively by the following method:
1) in polar organic solvent, the R that chirality replaces
2And/or R
3Succinic Acid lactone, halogeno-benzene and lewis acidic mol ratio are 1: 1-1.5: during 3-7, under the Lewis acid effect, backflow 16-36 hour, the Fu Ke acidylate takes place generate R
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric acid that chirality replaces
Perhaps R
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric acid that chirality replaces is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets R
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric ester that chirality replaces;
2) in the organic solvent and Louis acid catalysis under, halogeno-benzene and
Room temperature reaction 16-24 hour, the generation molecular formula was
4-halogenophenyl ketone, wherein halogeno-benzene,
With lewis acidic mol ratio be 1: 1-2: 1-3;
At-78 ℃-room temperature and C
1-8The lithium alkylide effect under, 4-halogenophenyl ketone and alpha-halogen acid esters XCH
2Alkylated reaction takes place in COOR, reacts 5-20 hour, obtains R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric acid meso compound that replaces
Wherein 4-halogenophenyl ketone, alpha-halogen acid esters and C
1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0;
R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces;
3) in polar organic solvent under the Lewis acid effect, halogeno-benzene and halo acetyl halide
With lewis acidic mol ratio be 1: 1-1.5: during 3-7, the Fu Ke acidylate took place generate halo ethanoyl halogenophenyl ketone in backflow 16-36 hour;
At-78 ℃-room temperature and C
1-8The lithium alkylide effect under, halo ethanoyl halogenophenyl ketone and two substituted acetic acid ester PhCH (C
2H
5) alkylated reaction takes place COOR, react to obtain R in 5-20 hour
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces
Wherein, halo ethanoyl halogenophenyl ketone and two substituted acetic acid ester and C
1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0;
Perhaps by R
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric acid that replaces and saturated alcohol roh/hydrochloric acid room temperature reaction 1-10 hour can become corresponding R
2And/or R
34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.
4) 4-of Qu Daiing (4-halogenophenyl)-4-oxidation-butyric acid with saturated alcohol roh/hydrochloric acid room temperature reaction 10-1 hour, becomes 4-(4-halogenophenyl)-4-oxidation-butyric ester
In organic polar solvent, 4-(4-halogenophenyl)-4-oxidation-butyric ester, corresponding alkynes CH ≡ CR
1, contain the organic compound acid binding agent and the catalyzer of lone-pair electron on the nitrogen, 4 alkynyls are introduced in 50-100 ℃ of reaction 16-36 hour, gamma-carbonyl group benzenebutanoic acid compounds that must the 4-alkynyl substituted
Wherein 4-(4-halogenophenyl)-4-oxidation-butyric ester, alkynes CH ≡ CR
1With the mol ratio of acid binding agent be 1: 1-3: 0.01-0.15, the weight ratio of 4-(4-halogenophenyl)-4-oxidation-butyric ester and catalyzer is 1: 0.001-0.010, described catalyzer is dichloro two triphenyl phosphorus palladiums, cuprous iodide, tetrabutylammonium iodide or their mixture
5) above-mentioned R
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric acid that chirality or achirality replace is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets esterification and gets R
2And/or R
34-(4-halogenophenyl)-4-oxidation-butyric ester that chirality or achirality replace.
4. the synthetic method of described a kind of (4-the alkynyl)-aryl ketones acid compounds of claim 3 is characterized in that wherein 2) and 3) reaction be under the anhydrous and oxygen-free condition He in the tetrahydrofuran solution, to carry out.
5. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 3, the organic compound acid binding agent that it is characterized in that containing on the described nitrogen lone-pair electron is pyridine, Trimethylamine 99, triethylamine, trioctylamine, 4-Dimethylamino pyridine, N, N-diisopropyl ethyl amine or bipyridine.
6. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 3 is characterized in that described C
1-8Lithium alkylide be butyllithium, di-isopropyl lithium, octyl group lithium.
7. the purposes of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 1 is characterized in that the inhibitor of stromatin enzyme.
8. the purposes of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 7 is characterized in that a kind of treatment cancer,, the medicine of sacroiliitis, body ulcer, pulmonary emphysema or blood vessel scleratheroma disease.
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