CN102212068A - Thiofuran derivative, preparation method thereof and application thereof in medicaments - Google Patents
Thiofuran derivative, preparation method thereof and application thereof in medicaments Download PDFInfo
- Publication number
- CN102212068A CN102212068A CN2010101393921A CN201010139392A CN102212068A CN 102212068 A CN102212068 A CN 102212068A CN 2010101393921 A CN2010101393921 A CN 2010101393921A CN 201010139392 A CN201010139392 A CN 201010139392A CN 102212068 A CN102212068 A CN 102212068A
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- pyridine
- formula
- optical isomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a pharmaceutical compound, a preparation method thereof and application thereof in medicaments, and specifically relates to a thiofuran derivative which is a structural compound shown in formula (I) or a pharmaceutically acceptable salt or optical isomer thereof and a pharmaceutical composition containing the same. The invention also discloses a preparation method of the thiofuran derivative and application of the thiofuran derivative in preparing medicaments for treating thrombotic diseases. The thiofuran derivative compound has good antithrombotic action and high application value in the medicament field.
Description
Technical field
The present invention relates to a kind of medicinal compound and preparation method thereof and the application on medicine, be specifically related to new thiophene derivant of a class and its production and application.
Background technology
Cardiovascular and cerebrovascular diseases is common disease, the frequently-occurring disease of serious harm human health, and along with the astogeny of social population, sickness rate rises day by day.According to statistics, the whole world has 1,600 ten thousand people to die from all kinds of cardiovascular and cerebrovascular diseases every year, is the No.1 killer who threatens human health.
Thromboembolism is one of important factor that causes cardiovascular and cerebrovascular diseases, coronary artery disease and corresponding ischemic complication thereof can cause the various clinical syndromes, as apoplexy, myocardial infarction or peripheral arterial disease, the thrombus artery-clogging of main diseases because of forming in artery exactly causes severe ischemic.With coronary artery thrombosis and cerebral thrombosis is that the thrombotic disease of core also has very high M ﹠ M in China, and therefore, anti-hemostasis suppository has also just become one of current the most popular research topic in cardiovascular disorder field.Mainly contain anti-freezing medicine, platelet aggregation inhibitor and the thrombolysis medicine three major types that are used at present treatment of thrombotic disorders are clinically formed.
Adenosine diphosphate (ADP) (ADP) is the important agonist that platelet activation, buildup effect are amplified, suppressing the thrombocyte effect by the blocking-up adp receptor has become the important means that stops pathologic thrombosis (coronary heart disease, cerebro-vascular diseases, pulmonary infarction, thrombophlebitis etc.) and myocardial infarction, unstable angina pectoris, peripheral vascular disease, congestive heart failure etc., obtains the extensive concern of the world of medicine as the platelet aggregation inhibitor of adp receptor antagonist.The adp receptor antagonist that uses clinically has thiophene chloropyridine at present, and all there are certain defective in clopidogrel and prasugrel, therefore, needs to seek such new compound.
US 4,529,596, US4, and 740,510 and US5,288,726 disclose the compound of similar structures.
Summary of the invention
The objective of the invention is for provide the new thiophene derivant of a class with anti-thrombosis function and
Pharmacy acceptable salt, optical isomer, its structural formula is shown in (I).
Wherein, R
1For: C
1-C
3Alkyl;
R
2For: hydrogen, chlorine, fluorine;
R
3For: C
1-C
4Alkyl.
Among the present invention, C
1-C
3Alkyl as the part of a kind of group or group, be meant and contain the branched-chain or straight-chain alkyl of 3 carbon atoms at the most, comprise methyl, ethyl, propyl group, sec.-propyl, preferable methyl, ethyl.C
1-C
4Alkyl as the part of a kind of group or group, mean and contain the branched-chain or straight-chain alkyl of 4 carbon atoms at the most, comprise methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl and the tertiary butyl, preferable methyl, ethyl.
Among the present invention, what described thiophene derivant was preferable is:
α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-chlorobenzene acetic acid methyl esters,
α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-chlorobenzene acetic acid ethyl ester,
α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid methyl esters,
α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid ethyl ester,
α-(2-propionyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-methyl phenylacetate or
α-[2-isobutyl acyl-oxygen-4,5,6,7-tetramethylene sulfide be [3,2-c] pyridine-5-yl also]-Phenylacetic acid ethylester.
Among the present invention, described pharmacy acceptable salt is thiophene derivant and mineral acids such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid, organic acids such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, Phenylsulfonic acid, tosic acid, citric acid, picric acid or methylsulfonic acid, the salt that acidic amino acids such as aspartic acid or L-glutamic acid form.
The invention still further relates to a class pharmaceutical composition, this pharmaceutical composition comprises the above-mentioned thiophene derivant for the treatment of significant quantity or it is at pharmacy acceptable salt, optical isomer and pharmaceutically acceptable carrier.Among the present invention, described pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, as thinner, vehicle (as water etc.), tackiness agent (as derivatived cellulose, gelatin, polyvinylpyrrolidone etc.), weighting agent (as starch etc.), the agent of bursting apart (as lime carbonate, sodium bicarbonate).In addition, other auxiliarys can also be added, as flavouring agent and sweeting agent etc. in composition.
Pharmaceutical composition of the present invention can put on the patient who needs treatment by oral form.Be used for when oral, it can be prepared into conventional solid preparation such as tablet or capsule etc.The various formulations of pharmaceutical composition of the present invention can adopt the method for pharmaceutical field routine to be prepared, and wherein the content of activeconstituents is 0.1-99.9%, and preferred content is 0.5-90%.
Further purpose of the present invention provides the preparation method of thiophene derivant of the present invention, and is specific as follows:
In organic solvent, basic catalyst exists down, the compound of general formula (II) and different acid anhydrides (R
1CO-O-COR
1) reaction make suc as formula the compound shown in (I);
The compound of general formula (II) can be with reference to existent method, by compound (III) and compound (IV) reaction make as:
In the said structure formula, R
1For: C
1-C
3Alkyl;
R
2For: hydrogen, chlorine, fluorine;
R
3For: C
1-C
4Alkyl.
Described basic catalyst is one or both in organic bases triethylamine, the 4-Dimethylamino pyridine.
Described organic solvent is a kind of of methylene dichloride, trichloromethane, dimethyl formamide.
Described temperature of reaction is 10 ℃-40 ℃.
Among the above-mentioned preparation method, compound (III) is the raw material of a key.Can buy its hydrochloride from market, the time spent obtains with the alkali neutralization or directly reacts with its hydrochloride.Different is, during directly with its hydrochloride reaction, organic bases add into amount (mole number mol) is its hydrochloride amount (mole number, preparation of 1-1.2 mol) times of III free alkali: with the III hydrochloride of buying, soluble in water, cooling transfers PH to being alkalescence with the unsaturated carbonate aqueous solutions of potassium down, uses dichloromethane extraction, the siccative drying, solvent is to the greatest extent steamed in decompression, promptly.
Among the above-mentioned preparation method, key intermediate compound (IV) can be with reference to EP420706, and the method that EP465358 and J.Org.Chem.1968.33 (6): 2565-2566 provides is synthetic by following route:
Concrete operations:
With ortho position substituted benzaldehyde (1) is raw material, obtains alpha-brominated ortho position substituted phenylacetic acid (2) through reaction, again with alcohol (R
3OH) esterification taking place obtains alpha-brominated ortho position substituted phenylacetic acid ester (IV).
The compound reaction of compound III and general formula (IV) makes suc as formula the compound shown in (II), come down to secondary amine and generate tertiary amine with the reaction of (replacement) bromoalkane, it is the organic chemical reactions of class classics, similarly the existing bibliographical information of reaction is used for the preparation of the compound shown in the formula (II) after the improvement.
Compound shown in (I) of the present invention formula and mineral acid or organic acid generate salt with chemically conventional method reaction, compound shown in (I) of the present invention formula and mineral acid or organic acid mol ratio are 1: 1-1.2, the preferred mole that waits to prevent the residual of acid, influences the quality of salt.Salifiable solvent is selected dehydrated alcohol, ethyl acetate, acetone, methyl alcohol etc. for use.
The compound of formula of the present invention (I) structure, contain a chiral carbon, except can be directly with pharmaceutically acceptable organic acid or mineral acid salify, can be after acid resolving agent splits, again with pharmaceutically acceptable organic acid or mineral acid salify, this is the common method in the organic synthesis, for those skilled in the art are afamiliar with.Acid resolving agent has (-)-camphor-10-sulfonic acid, (+)-camphor-10-sulfonic acid, (+)-tartrate etc.As, α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-chlorobenzene acetic acid methyl esters splits following isomer through aforesaid method:
For another example, α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid ethyl ester is split as following isomer:
Further purpose of the present invention provides the compound shown in (I) of the present invention formula or its pharmacologically acceptable salts, optical isomer and composition thereof application in preparation treatment thrombotic disease medicine.Particularly these materials should be adapted to effectively prevent and/or treat thrombotic disease and avoid shortcoming of the prior art at least to a certain extent, wherein " thrombotic disease ", be interpreted as serious disease in the present invention especially, form as the obstruction again behind myocardial infarction, stenocardia, angioplasty or the aortocoronary bypass and restenosis, apoplexy, of short duration local asphyxia outbreak, peripheral arterial occlusive disease, pulmonary infarction or dvt.
Positive progressive effect of the present invention is: of the present invention have good anti-thrombosis function or avoided deficiency well known in the prior art at least to a certain extent suc as formula the thiophene derivant shown in (I) and at pharmacy acceptable salt, optical isomer, as activity, toxicity etc.
Embodiment
Mode below by embodiment further specifies the present invention, but therefore invention is not limited among the described scope of embodiments.
Among the following method embodiment, the fusing point of compound is measured with the capillary melting point determination instrument, and thermometer is not proofreaied and correct;
1HNMR is interior mark by VarianAM-400 type nmr determination with TMS, and chemical shift is represented with δ (ppm); Ultimate analysis is measured by PerKin-240C elemental analyser (U.S. PerKin); Mass spectrum is measured with Q-TOF type mass spectrograph; Specific rotatory power is measured by Perkin Elmer P-341 polarimeter.
The column chromatography used silica gel is that Haiyang Chemical Plant, Qingdao produces.
The comparative example 1: alpha-brominated o-chlorobenzene acetic acid (2a)
56.4g o-chlorobenzaldehyde, 101g methenyl bromide are added in the 120ml isopropyl ether, add the aqueous solution (350ml) of 100g potassium hydroxide and 10g chlorinating benzyl triethylamine, cooling,-5 ℃ of-0 ℃ of insulation reaction 25 hours add 320ml water and 200ml isopropyl ether, stir 30 minute hands, leave standstill, tell organic phase, water layer divides three extractions with the 60ml isopropyl ether, water layer concentrated hydrochloric acid acidifying, divide three extractions with 600ml toluene, the combining methylbenzene layer washes with water 3 times, 3 * 40ml, anhydrous sodium sulfate drying.Solvent is to the greatest extent steamed in decompression, promptly gets solid 62.9g, yield 50.3%.The gained crude product need not purifying, is directly used in the next step.
The synthetic method of 2b-2c only is that o-chlorobenzaldehyde is changed into successively: adjacent fluorobenzaldehyde, phenyl aldehyde with comparative example's 1 described method.
2b: alpha-brominated o-fluoro-acid, yield 61.8%.
2c: alpha-brominated toluylic acid, yield 54.5%.
The comparative example 2: alpha-brominated o-chlorobenzene acetic acid methyl esters (IVa)
Alpha-brominated o-chlorobenzene acetic acid 50g is dissolved in 190ml methyl alcohol, add the 30g vitriol oil, back flow reaction 4 hours, reaction is finished, solvent is to the greatest extent steamed in decompression, add 100ml isopropyl ether and 100ml water, tell organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure, get alpha-brominated o-chlorobenzene acetic acid methyl esters (IVa) 47g, yield 89%
1HNMR (DMSO) δ ppm 7.71 (d, 1H), 7.19-7.22 (m, 3H), 5.58 (s, 1H), 3.69 (s, 3H).IVc, the synthetic method of IVe only is that alpha-brominated o-chlorobenzene acetic acid is changed into successively with comparative example's 2 described methods: alpha-brominated o-fluoro-acid, alpha-brominated toluylic acid.
The synthetic method of IVb only is that methyl alcohol is changed into ethanol with comparative example's 2 described methods.
IVd, the synthetic method of IVf only is that alpha-brominated o-chlorobenzene acetic acid is changed into successively with comparative example's 2 described methods: alpha-brominated o-fluoro-acid, alpha-brominated toluylic acid, and methyl alcohol changed into ethanol.
IV b: alpha-brominated o-chlorobenzene acetic acid ethyl ester, yield 88.5%.
1HNMR(DMSO)δppm7.70(d，1H)，7.18-7.23(m，3H)，5.56(s，1H)，4.23(m，2H)，1.32(t，3H)。
IV c: alpha-brominated o-fluoro-acid methyl esters, yield 91.7%.
1HNMR(DMSO)δppm7.60(m，1H)，7.49(d，1H)，7.24(d，1H)，7.08(s，1H)，5.59(s，1H)，3.70(s，3H)。。
IV d: alpha-brominated o-fluoro-acid ethyl ester, yield 90.2%.
1HNMR(DMSO)δppm7.60(m，1H)，7.49(d，1H)，7.24(d，1H)，7.08(s，1H)，5.59(s，1H)，4.25(m，2H)，1.35(t，3H)。
IV e: alpha-brominated methyl phenylacetate, yield 87.1%.
1HNMR(DMSO)δppm7.28-7.34(m，3H)，7.26(m，2H)，5.52(s，1H)，3.61(s，3H)。
IV f: alpha-brominated Phenylacetic acid ethylester, yield 89.3%.
1HNMR(DMSO)δppm7.28-7.34(m，3H)，7.26(m，2H)，5.52(s，1H)，4.19(m，2H)，1.26(t，3H)。
The comparative example 3: α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-(II is a) for the o-chlorobenzene acetic acid methyl esters
With 30g2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridines (III) are dissolved in 300ml methyl alcohol, and the high pure nitrogen protection down; add alpha-brominated o-chlorobenzene acetic acid methyl esters of 53g (IIIa) and 24g sodium bicarbonate, be heated to 80 ℃, reacted 6 hours; cool to room temperature, remove by filter inorganic salt, decompression steams solvent; add 450ml ethyl acetate and 250ml water, tell organic layer, organic layer is washed twice with 100ml; anhydrous sodium sulfate drying; decompression steams solvent, gets faint yellow oily thing 52g, yield 64.6%.EI-MS(m/z)：337.1(M
+)。
The above-mentioned faint yellow oily thing that takes a morsel is dissolved in the acetone, transfers PH2 with ethanol solution hydrochloride, white solid, M.P130 ℃-131.5 ℃.
II c, the synthetic method of II e is changed into alpha-brominated o-chlorobenzene acetic acid methyl esters successively with comparative example's 3 described methods: alpha-brominated o-fluoro-acid methyl esters, alpha-brominated methyl phenylacetate.
II c: α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-the o-fluoro-acid methyl esters.Yield 56.4%, EI-MS (m/z): 321.1 (M
+).
II e: α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-methyl phenylacetate.Yield 61.8%, EI-MS (m/z): 303.1 (M
+).
II b, II d, the synthetic method of II f is changed into alpha-brominated o-chlorobenzene acetic acid methyl esters successively with comparative example's 3 described methods: alpha-brominated o-fluoro-acid methyl esters, alpha-brominated methyl phenylacetate; Simultaneously, methyl alcohol is changed to ethanol.
II b: α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-the o-chlorobenzene acetic acid ethyl ester.Yield 58.2%, EI-MS (m/z): 351.1 (M
+).
II d: α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-the o-fluoro-acid ethyl ester.Yield 60.1%, EI-MS (m/z): 335.1 (M
+).
II f: α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-Phenylacetic acid ethylester.Yield 66.7%, EI-MS (m/z): 317.1 (M
+).
Embodiment 1: α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-chlorobenzene acetic acid methyl esters (compound 1)
With 3.4g α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-o-chlorobenzene acetic acid methyl esters (II
a) be dissolved in the 80ml methylene dichloride, high pure nitrogen is protected down, adds the 2g triethylamine, adds diacetyl oxide 1.6g under room temperature, stirs 6 hours, separates eluent then with silica gel column chromatography: methylene dichloride-ethyl acetate 9: 2 (volume ratio) gets the 1.6g product.
Ultimate analysis, C
18H
18ClNO
4S:
Calculated value C, 56.91; H, 4.78; C1,9.33; N, 3.69;
Measured value C, 56.79; H, 4.70; C1,9.23; N, 3.51.
EI-MS(m/z)：379.1(M
+)。
With the oily matter of gained be dissolved in 5 times of amount acetone (the mass/volume ratio, g/ml) in, stir to drip in 5 ℃-10 ℃ down and wait a mole vitriol oil, promptly get its vitriol.
Embodiment 2: α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-chlorobenzene acetic acid ethyl ester (compound 2)
With α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3; 2-c] pyridine-5-yl]-o-chlorobenzene acetic acid ethyl ester (II b) 1.8 grams; be dissolved in the 50ml trichloromethane; the high pure nitrogen protection adds 1 gram 4-Dimethylamino pyridine down, adds diacetyl oxide 1.2ml down in 40 ℃; stirred 7.5 hours; separate eluent then with silica gel column chromatography: methylene dichloride-ethyl acetate 9: 2 (volume ratio) gets product 0.75g.
Ultimate analysis, C
19H
20ClNO
4S:
Calculated value C, 57.94; H, 5.12; C1,9.00; N, 3.56;
Measured value C, 57.76; H, 5.13; C1,9.09; N, 3.43.
EI-MS(m/z)：393.1(M
+)。
With the oily matter of gained be dissolved in 5.5 times of amount acetone (the mass/volume ratio, g/ml) in, stir to drip in 5 ℃-10 ℃ down and wait a mole methylsulfonic acid, promptly get its mesylate.
Embodiment 3: α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid methyl esters (compound 3)
With α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3; 2-c] pyridine-5-yl]-o-fluoro-acid methyl esters (II c) 1.6 grams; be dissolved in the 50ml methylene dichloride; the high pure nitrogen protection adds 0.9 gram 4-Dimethylamino pyridine down, adds diacetyl oxide 2ml down in 10 ℃; stirred 7 hours; separate eluent then with silica gel column chromatography: methylene dichloride-ethyl acetate 9: 2 (volume ratio) gets product 0.81g.
The HNMR spectrum:
1HNMRδppm?2.14(s，3H)，2.64(t，2H)，2.75(t，2H)，3.47(dd，2H)，3.61(s，3H)，4.79(s，1H)，6.15(s，1H)，7.15(m，2H)，7.28(m，1H)，7.56(m，1H)。
Ultimate analysis, C
18H
18FNO
4S:
Calculated value C, 59.49; H, 4.99; F, 5.23; N, 3.85;
Measured value C, 59.35; H, 5.00; F, 5.16; N, 3.72.
EI-MS(m/z)：363.1(M
+)。
Split: with the oily matter of gained be dissolved in 6 times of amount acetone (the mass/volume ratio, g/ml) in, stir down and heat up, at 40 ℃-45 ℃ (+)-camphorsulfonic acids that add 0.5 mole, continue to stir 3.5 hours, then 25 ℃ of-30 ℃ of placements, separate out crystallization.Filter, get crystalline solid and filtrate two portions, handle respectively.
The Virahol of above-mentioned crystalline solid and equimolar sodium bicarbonate and 9 times of amounts was stirred 2.5 hours at 45 ℃-50 ℃, filter the filtering insolubles.Steam solvent under the filtrate decompression, get oily matter.This oily matter is dissolved in the ethyl acetate, stirs down, drip at 5 ℃-10 ℃ and wait the mole vitriol oil, at room temperature continue after adding to stir 12 hours, obtain white solid, i.e. (+)-α-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid methyl esters vitriol.[α]
25 D=+59.1 (c=1, methyl alcohol).
With above-mentioned filtrate part,, can get (-)-α-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid methyl esters through chiral column separation, purifying.
Embodiment 4: α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid ethyl ester (compound 4)
The method that provides by embodiment 3 is with α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-o-fluoro-acid methyl esters (II c) is changed to α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-o-fluoro-acid ethyl ester (II d) gets final product.
Ultimate analysis, C
19H
20FNO
4S:
Calculated value C, 60.46; H, 5.34; F, 5.03; N, 3.71;
Measured value C, 60.35; H, 5.21; F, 5.16; N, 3.72.
EI-MS(m/z)：377.1(M
+)。
Embodiment 5: α-(2-propionyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-methyl phenylacetate (compound 5)
The method that provides by embodiment 1 is with α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-(II a) is changed to α-[2-oxo-2,4,5,6,7,7 to the o-chlorobenzene acetic acid methyl esters
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-methyl phenylacetate (II e), diacetyl oxide is changed to propionic anhydride and gets final product.
Ultimate analysis, C
19H
21NO
4S:
Calculated value C, 63.49; H, 5.89; N, 3.90;
Measured value C, 63.45; H, 5.80; N, 3.82.
EI-MS(m/z)：359.1(M
+)。
Embodiment 6: α-(2-isobutyl acyl-oxygen-4,5,6,7-tetramethylene sulfide be [3,2-c] pyridine-5-yl also)-Phenylacetic acid ethylester (compound 5)
The method that provides by embodiment 2 is with α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-o-chlorobenzene acetic acid ethyl ester (II b) is changed to α-[2-oxo-2,4,5,6,7,7
a-six hydrogen thieno-s [3,2-c] pyridine-5-yl]-Phenylacetic acid ethylester (II f), diacetyl oxide is changed to isobutyric anhydride and gets final product.
Ultimate analysis, C
21H
25NO
4S:
Calculated value C, 65.09; H, 6.50; N, 3.61;
Measured value C, 65.15; H, 6.42; N, 3.71.
EI-MS(m/z)：387.2(M
+)。
Effect embodiment 1: the test of rat arteriovenous shut thrombus model
Positive control drug: compd A, i.e. clopidogrel.
Healthy on an empty stomach male SD rat (the The 2nd Army Medical College Experimental Animal Center provides, conformity certification number: SCXK (Shanghai) 2002-0006), body weight 220g～300g, random packet.Every group of 8 rats are established the blank group, positive controls, test-compound group.Gavage administration respectively, dosage is 30mg/kg, and the administration volume is 0.8ml/100g, and the blank group gives 1.0% Xylo-Mucine of equivalent.After the administration 2 hours, with vetanarcol 40mg/kg anesthesia, dorsal position was fixed, and separates left jugular vein and right carotid.One external shunt device is connected two blood vessels through the long polyethylene tube (internal diameter 1.5mm) of a 10cm.In the middle of this polyethylene tube, be connected with the thrombotic shaggy nylon rope that is used for of another root 3cm.From decontroling blood flow writing time, keep this extracorporeal circulation 15 minutes, remove described shunting then, and weighing contains the nylon wire (weight of nylon wire itself is measured) of thrombus before on-test as early as possible, obtains wet weight of thrombus (mg).Thrombus gets its dry weight (mg) in placing 8 hours under the normal temperature in vacuum drying oven.
To the influence of rat experiment thrombus (X ± SD, n=8)
| Specimen | Wet weight of thrombus (mg) | Thrombus dry weight (mg) |
| Blank group compd A compound 1 compound 2 | 31.3±7.9 14.8±5.5 *** 12.9±5.0 *** 13.3±4.9 *** | 10.1±2.2 5.6±1.2 *** 4.9±1.2 *** 5.0±1.3 *** |
| Compound 3 compounds 4 compounds 5 compounds 6 | 12.6±4.6 *** 13.1±5.1 *** 13.6±4.7 *** 14.0±5.0 *** | 4.7±1.2 *** 4.9±1.1 *** 5.0±1.0 *** 5.1±1.1 *** |
***P＜0.001。
Effect embodiment 2: toxicity test
Acute toxicity test is the most ancient toxicity test method, continues to use in drug evaluation for a long time, is the important content of new drug safety evaluation.The governing principle general provision of new drug preclinical study is observed 7～14d continuously behind the animals administer, reaction of record animal toxicity and dead animal distribute.
Sample: compound 1, compound 2, compound 3, compound 4, compound 5, compound 6 and contrast drug compound A (being clopidogrel), content 99.7%.
Laboratory animal: Kunming mouse, cleaning level, age all around, male and female half and half, body weight 20g ± 2g is provided by the The 2nd Army Medical College Experimental Animal Center, conformity certification number: SCXK (Shanghai) 2002-0006.
Laboratory condition: temperature ℃ 22 ± 2 ℃, relative temperature 50%-70%.
After trial test finishes, test by the following method.
Method: get 60 of mouse, be divided into 6 groups at random by body weight, 10 every group, male and female half and half.With 6000mg/kg is maximum dose level, successively decrease in 1: 0.7 ratio, give compound 16000.0mg/kg for respectively 6 groups of disposable filling stomaches of mouse, 4200.0mg/kg, 2940.0mg/kg, 2058mg/kg, 1440.6mg/kg, 1008.4mg/kg, test compound is mixed with different concns with 1%CMCNa, administration capacity 0.2ml/10g, fasting be can't help water 12 hours, fasting in 3 hours after the administration, breeding observing 14 days before the administration, reaction of record mouse toxicity and death condition adopt the improvement karber's method to calculate medium lethal dose (LD
50).
The appearance activity reduces after the medication, manic subsequently uneasiness, and whole body is twitched, and sticks up tail, and belly pastes ground, and hydrostomia appears in dysequilibrium then, and one's eyes became bloodshot, shed tears, symptoms such as diarrhoea, expiratory dyspnea and dead, dead preceding no tangible struggle phenomenon.The animal subject of anti-mistake, 6h～10h recovers the diet desire after the general administration, is also recovered normal gradually by hair and activity.
Cut open the inspection pathological change: dead animal is carried out part cut open inspection, as seen by the dry unrest of hair, lip, four limbs, tail are livid purple; The blutpunkte that liver has tip-like to be dispersed in; Spleen darkens, and volume increases; Stomach, duodenum, even whole little enteremia, hemorrhage, intestines wall oedema; The lungs wind-puff is covered with the blutpunkte of tip-like.
Compound 2, compound 3, compound 4, compound 5, compound 6 and compd A carry out acute toxicity test by above-mentioned identical method.
Test-results
| Compound | LD 50(mg/kg) |
| Compound 1 | 3840 |
| Compound 2 | 3790 |
| Compound 3 | 3880 |
| Compound 4 | 3670 |
| Compound 5 | 3780 |
| Compound 6 | 3750 |
| Compd A | 3100 |
Conclusion: the LD of 6 compounds
50All greater than 3000mg/kg; And toxicity is lower than compd A.
Application Example 1: tablet
Prescription: 50 digest compound 1, lactose 110 grams, and 15 gram PEG-4000, Magnesium Stearate 6 grams, starch 12 grams, croscarmellose sodium 16 grams, lime carbonate 6 grams, distilled water is an amount of, makes 1000.
Method preparation according to this area routine becomes tablet.
Application Example 2: capsule
Prescription: 25 digest compound 3, starch 58 grams, and lactose 38 grams, sucrose 15 grams, Microcrystalline Cellulose 29 grams, 10% polyvinylpyrrolidone ethanolic soln is an amount of, and Magnesium Stearate 2 grams are made 1000.
Method preparation according to this area routine becomes capsule.
Claims (12)
1. thiophene derivant is characterized in that: the structural compounds shown in (I) formula or its pharmacologically acceptable salts, optical isomer,
Wherein, R
1For: C
1-C
3Alkyl;
R
2For: hydrogen, chlorine, fluorine;
R
3For: C
1-C
4Alkyl.
2. thiophene derivant as claimed in claim 1 or its pharmacologically acceptable salts, optical isomer is characterized in that: described thiophene derivative compound is:
α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-chlorobenzene acetic acid methyl esters,
α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-chlorobenzene acetic acid ethyl ester,
α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid methyl esters,
α-(2-acetyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-o-fluoro-acid ethyl ester,
α-(2-propionyl oxygen-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)-methyl phenylacetate or
α-[2-isobutyl acyl-oxygen-4,5,6,7-tetramethylene sulfide be [3,2-c] pyridine-5-yl also]-Phenylacetic acid ethylester.
3. as the described thiophene derivative compound of claim 1-2 or its pharmacologically acceptable salts, it is characterized in that: described pharmacy acceptable salt is the salt of the compound shown in (I) formula and mineral acid or organic acid formation.
4. thiophene derivative compound as claimed in claim 3 or its pharmacologically acceptable salts, it is characterized in that: described mineral acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid, and organic acid is acetate, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid.
5. the application of thiophene derivant on medicine is characterized in that: the medicinal compositions that contains each described thiophene derivative compound among the claim 1-3 that treats significant quantity or its pharmacologically acceptable salts, optical isomer.
6. as the application of thiophene derivant on medicine as described in the claim 5, it is characterized in that: described pharmaceutical composition comprises various solids and liquid oral medicine.
7. the preparation method of the described thiophene derivant compound of claim 1-3 or its pharmacologically acceptable salts, optical isomer is characterized in that:
In organic solvent, basic catalyst exists down, and the compound reaction of the compound of general formula (II) and general formula (III) makes suc as formula the compound shown in (IV);
In organic solvent, basic catalyst exists down, the compound of general formula (IV) and different acid anhydrides (R
1CO-O-COR
1) reaction make suc as formula the compound shown in (I);
Compound shown in the formula (I) with mineral acid or organic acid in organic solvent, react formation salt.
Compound shown in the formula (I) is split as optical isomer through acid resolving agent.
In the said structure formula, R
1, R
2, R
3With the definition in the claim 1.
8. the preparation method of thiophene derivant compound as claimed in claim 7 or its pharmacologically acceptable salts, optical isomer is characterized in that: described basic catalyst is one or both in organic bases triethylamine, the 4-Dimethylamino pyridine.
9. the preparation method of thiophene derivant compound as claimed in claim 7 or its pharmacologically acceptable salts, optical isomer is characterised in that: described temperature of reaction is 10 ℃-40 ℃.
10. the preparation method of thiophene derivant compound as claimed in claim 7 or its pharmacologically acceptable salts, optical isomer is characterized in that: described organic solvent is a kind of of methylene dichloride, trichloromethane, dimethyl formamide.
11. the compound shown in each described (I) formula among the claim 1-3 or its pharmacy acceptable salt, optical isomer is characterized in that: the application in preparation treatment thrombotic diseases medicine.
12. thiophene derivant compound as claimed in claim 11 or its pharmacologically acceptable salts, the application of optical isomer in treatment thrombotic diseases medicine is characterized in that: described treatment thrombotic diseases medicine is meant that obstruction again and restenosis, apoplexy, of short duration local asphyxia outbreak, peripheral arterial occlusive disease, pulmonary infarction or the dvt behind preparation treatment myocardial infarction, stenocardia, angioplasty or aortocoronary bypass forms the application in the medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101393921A CN102212068A (en) | 2010-04-06 | 2010-04-06 | Thiofuran derivative, preparation method thereof and application thereof in medicaments |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101393921A CN102212068A (en) | 2010-04-06 | 2010-04-06 | Thiofuran derivative, preparation method thereof and application thereof in medicaments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102212068A true CN102212068A (en) | 2011-10-12 |
Family
ID=44743634
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101393921A Pending CN102212068A (en) | 2010-04-06 | 2010-04-06 | Thiofuran derivative, preparation method thereof and application thereof in medicaments |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102212068A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8772489B2 (en) | 2010-02-02 | 2014-07-08 | Jiangsu Vcare PharmaTech Co. Ltd. | Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereof |
| JP2014518260A (en) * | 2011-06-27 | 2014-07-28 | アイピーシーエー ラボラトリーズ リミテッド | Antithrombotic compounds |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6693115B2 (en) * | 2000-07-06 | 2004-02-17 | Sankyo Company, Limited | Acid addition salts of hydropyridine derivatives |
| CN101591344A (en) * | 2008-05-27 | 2009-12-02 | 连云港恒邦医药科技有限公司 | Antithrombotic compound, preparation method and application thereof |
| CN102120744A (en) * | 2010-02-02 | 2011-07-13 | 江苏威凯尔医药科技有限公司 | Optical-activity 2-hydroxytetrahydrothienopyridine derivative, preparation method and application thereof in pharmacy |
-
2010
- 2010-04-06 CN CN2010101393921A patent/CN102212068A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6693115B2 (en) * | 2000-07-06 | 2004-02-17 | Sankyo Company, Limited | Acid addition salts of hydropyridine derivatives |
| CN101591344A (en) * | 2008-05-27 | 2009-12-02 | 连云港恒邦医药科技有限公司 | Antithrombotic compound, preparation method and application thereof |
| CN102120744A (en) * | 2010-02-02 | 2011-07-13 | 江苏威凯尔医药科技有限公司 | Optical-activity 2-hydroxytetrahydrothienopyridine derivative, preparation method and application thereof in pharmacy |
Non-Patent Citations (1)
| Title |
|---|
| 周林芳: "氯吡格雷的合成路线研究", 《安徽医药》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8772489B2 (en) | 2010-02-02 | 2014-07-08 | Jiangsu Vcare PharmaTech Co. Ltd. | Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereof |
| US10000506B2 (en) | 2010-02-02 | 2018-06-19 | Jiangsu Vcare Pharmatech Co., Ltd. | Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereof |
| JP2014518260A (en) * | 2011-06-27 | 2014-07-28 | アイピーシーエー ラボラトリーズ リミテッド | Antithrombotic compounds |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5200198A (en) | Medicament and its production and use in the treatment of pain, inflammation and fever in man and animals | |
| JP4068802B2 (en) | (Methylsulfonyl) phenyl-2- (5H) -furanones as COX-2 inhibitors | |
| JP6324956B2 (en) | Substituted aminoindane- and aminotetralin carboxylic acids and uses thereof | |
| WO2013168022A1 (en) | Compositions and methods for treating atherothrombosis | |
| ES2733353T3 (en) | Lipid compounds for use in cosmetic products, as a food supplement or as a medicine | |
| SI8810231A8 (en) | Dextro-rotatory enantiomer of methyl alpha-(4,5,6,7-tetrahydro-thieno(3,2-c)pyrid-5-yl)-(2-chlorophenyl)- acetate, its salts and a process for its preparation | |
| ES2375082T3 (en) | COMPOSITION FOR THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM. | |
| JPS6267081A (en) | Novel 2,5 diaryltetrahydrothiphenes as paf antagonist and analogue of same | |
| BRPI0719187A2 (en) | Heterocyclic Compounds Useful as Anabolic Agents for Breeding Animals | |
| JP2022503890A (en) | A salt formed by 2- (1-acyloxy-N-pentyl) benzoic acid and a basic amino acid or aminoguanidine, and a method and use thereof. | |
| JP4662690B2 (en) | Coumarin derivatives used as anticoagulants | |
| CN101684124B (en) | Novel compound with blood coagulation resisting function | |
| JPH04502462A (en) | Therapeutically active substituted benzimidazoles and their preparation | |
| JP2009527461A (en) | Natural agents for the treatment of gastrointestinal toxicity, related symptoms and ulcers | |
| US5292771A (en) | Substituted β-diketones and their use | |
| US4694018A (en) | Substituted 1,5-diphenyl-2-pyrrolepropionic acids and derivatives | |
| CN102212068A (en) | Thiofuran derivative, preparation method thereof and application thereof in medicaments | |
| JPH08505362A (en) | 2,4-diaryl-1,3-dithiolane, 2,4-diaryl-1,3-dioxolane, 2,4-diaryl-1,3-oxathiolane, as PAF receptor antagonists and 5-lipoxygenase inhibitors 2,5-diaryl-1,3-oxathiolane | |
| IE58958B1 (en) | Leukotriene antagonists | |
| Samhoun et al. | Actions and interactions of lipoxygenase and cyclo-oxygenase products in respiratory and vascular tissues | |
| WO2012060387A1 (en) | Novel dihydroxybenzene derivatives and antiprotozoal agent comprising same as active ingredient | |
| WO2006007794A1 (en) | Cis-1,2-substituted stilbene derivates and the use thererof for manufacturing medicaments for treating medicaments for treating and/or preventing diabetes | |
| CN102212069A (en) | Cycloalkane derivative, preparation method thereof and application thereof in medicaments for cardiovascular and cerebrovascular diseases | |
| DD283602A5 (en) | PROCESS FOR PREPARING COMPOUNDS AND THEIR USE | |
| CN105418596A (en) | 1-[3-butyl-1(3H)-isobenzofuranone-6-yl]-1H-pyrazol-5(4H)-one derivative as well as preparation method and pharmaceutical application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20111012 |