Method of producing derivatives of vinylcarboxylic acids

专利摘要:
NEW MATERIAL:The substituted vinylcarboxylic acid derivative of formula I [R<1> is pyridyl; R<2> is phenyl, thienyl, furyl, etc. which may have lower alkoxy, lower alkyl, halogen, trifluoromethyl, lower alkenyl, or methylenedioxy as substituent group; Y is S, methylene or group of formula II (R<4> is H or acetyl; m is 0 or 1); R<3> is H or lower alkyl; n is 0-6]. EXAMPLE:7-Phenyl-7-(3-pyridyl)-6-heptenoic acid. USE:The compound inhibits specifically the activity of thromboxan A2 synthetase without much affecting the activities of prostaglandin I2 synthetase or prostaglandin synthetase (cyclooxygenase), and is useful as a preventive and remedy of e.g. cardiac infarction, apoplexy, etc. PROCESS:The compound of formula I is prepared by reacting the compound of formula III with the compound of formula IV (X is halogen).
公开号:SU1266470A3
申请号:SU833605554
申请日:1983-06-10
公开日:1986-10-23
发明作者:Текао Синьи；Нисикава Кохеи
申请人:Такеда Кемикал Индастриз,Лтд (Фирма)；
IPC主号:

专利说明:

This invention relates to vinylcarboxylic acid derivatives of the general formula
HK
/ С СН-СН2 Ш2 {СН2) p-СSO2
Ri
where R is pyridyl;
R is phenyl, Tienkle, furyl, naphthyl, benothienyl or pg RDSh1, containing HHsjnyro alkoxy or alkyl, halogen atom, tr1 fluoromethyl group, lower alkenyl group or methyleneDioxy group; RJ - hydrogen atom or lower
alkyl;
n is an integer from O to 6. The chain of the invention 11 is the development, on the basis of a well-known method, of a method of producing novel compounds having a high inhibitory activity in relation to thromboxane synthetase Aj and, thus, a pronounced anti-thrombotic effect. Example 1. To 40 ml of dimethyl sulphoxane, 1.0 g of sodium hydride is added in portions, and the mixture is heated at 80 ° C for 30 minutes. The reaction mixture is cooled to room temperature, 9.5 g of 5-carboxypentipriphenylphosphonium bromide (mmol) is added to it and stirred for 5 minutes, then 10 ml of a tetrahydrofuran solution is added 3.7 g
(0.02 mol) 3-benzoylpyridine. The mixture was stirred for 30 minutes at room temperature, water (100 ml) was added, then extracted (twice) with ethyl acetate (50 ml) to remove neutral products. The aqueous layers are combined and acidified to pH 6-2 and. hydrochloric acid, then they are extracted with ethyl acetate. The organic layers are combined, washed with water and dried over magnesium sulfate. The solvent was then stripped, the residue was subjected to chromatography on silica gel using a mixture of ethanol and ethyl acetate (1: 5) as an element, and 4.5 g (79%) of (E) + (g) -7-3-pi idyl) - were obtained. 7-fensh-1-6-heptenoic acid (Table 1, compounds).
Isomer separation is carried out by fractional crystallization or liquid chromatography using a Lobra Lichroprep R-P-8 instrument (40-63 µm, manufactured by Merck and Co).
In tab. Figures 1-6 show the physicochemical characteristics of the compounds obtained (where E are isomers in which the pyridine nucleus at one carbon atom and a hydrogen atom at the other carbon atom are on one side of the tri-substituted olefin bond; Z is the isomer in which they are located TC in opposite directions A and B - two types of geometric isomers, and A-4-B - their mixture).
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Table 4
Yield, 11.80 (1H, COOH); 8.53 (2H, t); 7.62 (1H, t); 62 7.30 (2H, t); 6.85 (1H, in); 6.83 and 6.48 (1H, t); 6.22 and 6.04 (1H, t, 7 Hz); 2.30 (4H, t) 1.46 (6H, ffl)
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8.50 (2H, m); 7.30 {2H, m); 7.09 7.0682
2H, d, 8 Hz); 6.88 n 6.78 (2H, d, 8 Hz); 6.05 and 6.02 (and, 6); 3.82 and 3.78 (ЗН, в); 3.64 (ЗН, в); 2.26 R 2.13 (2H, m); 1.55 4H, m)
6., OO; 8.40 (fH, ta); 7.46 (fH, d, 76 t, 7 m 2 Hz); 7.12 1H, d, d, 7 n 4 Hz);
6.90 (3H, m); 6.15 {lH, t, 7; 3,84 (ЗН, .в); 3.67 (ЗН, в); 3.64 (2H, m); 2.27 n
2.05 (2H, m); 1.51 (BYA.Sh); 0.78 (3H, t, 8 Hz)
8.46 8.53 (1H, w); 7.40 (3N, 1c); 6.72 (ЗН, t); 67
6.06 6.04 (1H, s, 7 Hz); 3.94 and 4.00 (2H, t, 7 Hz); 3.18 and 3.64 (ЗН,); 2.25 2.05 (2H, a); 1.80 (6H, t); 1.04 and 1.00 (3H, t, m)
8.49 (2H, c); 7.49 7.30 1H, w); 6.37 (2H, 8); 78 6.10 6.08 (W, s, 7 Hz); 3.82 (ЗН,);
3.80 (ЗН, в); 3.77 (ЗН, в); 3.65 (ЗН, в); 2.27 and 2.15); 1.59 (4H, 1c)
8.47 (2I, t); 7.64 (W, c); 7.25 (5H, t); 72 6.24 (1H, s, 7 Hz); 3.62 (3H, s); 2.25 (2H, s); 2.02 (2H, in); 1.56 4H, t)
8.50 (2H, i); 7.30 (6H, w); 6.14 6.1060 IH, t, 7 Hz); 3.63 (ЗН, в); 2.26 and 2.10 (2H, t);
1.55 (4H, s)
81
8.50 (2H, w); 7.30. (6H, t); 6.14 6.10 (1H, t, 7 Hz); 2.26 2.09 (2H, t); 1.55 (4H, t)
8.48 (2H, t); 7.31 (7H, t); 3.65 (3H, s);
6.16 6.07 (1H, t, 7 Hz); 2.28 (2H, t, 7 Hz); 2.11 (2H, and); 1.58 2H,); 1.30 (10K, iii)
8.4.6 (2H, w); 7.44 (1H, d, 5 Hz); 7.32
(ZN, t); 7.15 (ЗН, t); 6.09 (lH, t, 7 Hz); 3.66 (ЗН, в, Ме); 2.26 (2H, t, 7 Hz); 2, TK (2H, t, 7 Hz); 1.55 (4H,)
H, 50 2H, w); 7.48 (tH, d, 6 Hz); 7.23 (6H, t); 6, t6 (1H, t, 7 Hz); 3.66 (ЗН, в); 2.27 2H, t,
7 Hz); 2.09 (2H, t, 7 Hz); 1.56 (4H, w)
8.60 (tH.iO; 8.48 (ЗН, ш); 7.45 (4H, iE) i
6.21 1H, t, 7 Hz); 3.64 (3.A.); 2.28 (2H, w); 2.21 (2H, w); 1.57 (“H, w)
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S × y: e) H II p and m ep 2. (E.) - 7- {3-Pyridyl) 7-phenyl-6-heptenoic acid (Ia-4) 300 mg are dissolved in 5 ml of 2N hydrochloric acid. acid. The solution is concentrated under reduced pressure. Re-installation of the remaining crystals from a mixture of ethanol and isopropyl ether gives 285 mg of (E) -7- (3-pyrcdyl) -7-phenyl-6-heptenoic acid hydrochloride (If-1) with mp. 163-165С (tab. 6). EXAMPLE 3. (E) -7- (3-Pyridyl) 7-fensch-1-heptenoic acid (1a-4) 500 mg and 160 mg of sodium bicarbonate are added to 5 ml of water to obtain a homogeneous solution. which is concentrated under reduced pressure. The concentrate is sprayed using a mixture of ethanol and isopropyl ether and the sodium salt of (E) -7- (3-pyryl) -7-phenyl-6-heptenoic acid is obtained (rf-2, Table 6). EXAMPLE 4 31 t (0.79 mol) of sodium amide was added to 350 ml of dimethyl sulfoxide under a nitrogen atmosphere, and the mixture was stirred at room temperature for 10 minutes. Then, while maintaining the temperature or below, 140 g (0.306 mol) of 5-carboxypentyltriphenylphosphonium bromide is added, the mixture is stirred for 1 hour. A solution of 55 g of 3-benzoylpyridine (0.301 mol) and 50 ml of dimethyl sulfoxide at room temperature are added dropwise to this mixture. temperature and stirring. At the end of the addition, the reaction proceeds at room temperature for an additional 30 minutes. 700 ml of water are added, the neutral substance is extracted twice with toluene. The aqueous layer is acidified to pH 5.5 with 6 n. hydrochloric acid solution and extracted twice with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to obtain an equimolar mixture of 71.0 g of (E) - and (Z) 7-phenyl-7- (3-pyridyl) -6-heptenoic acid. This mixture is dissolved in a mixture of 47% hydrobromic acid (300 ml) and 300 ml of water. The resulting mixture is heated at, for. 18 hours, after cooling, it is basified to pH 5.5 with a 50% aqueous solution of sodium hydroxide and extracted twice with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The resulting oily product is dissolved in 100 ml of ethyl acetate, the solution is held at room temperature for 24 hours, to obtain a crystalline product, which is collected by filtration to obtain 28.6 g (33.8%) (E) of 7-phenyl-7- (3 -pyridyl) -6-heptenoic acid. When the filtrate is concentrated, a mixture of 40.4 g of (E) - and (g) -7-phenyl7- (3-pyridyl) -6-heptenoic acid is obtained (form ratio E / Z 17:23). This mixture is repeatedly subjected to acid isomerization as described and an additional 16.7 g (19.7% yield) of (E) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid are obtained. Acid isomerization is repeated twice as described and 12.3 g (14.5%) of (E) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid are obtained. The whole crystalline product (57.6 g), obtained by the described method of acid isomerization and crystallization, was recrystallized twice from 120 ml of ethyl acetate and 52.3 g (61.7%) of (E) -7-phenyl 7- (3-pyridyl) were obtained -6-heptenoic acid having a purity of not less than 99. So pl. 114-115s. Calculated,%: C, 76.84; H, 6.81; N 4.98. C, 8 H19 N02 Found,%: C 76.76; H 6.69; N 4.68. NMR spectrum (chemical shift, b, ppm, internal standard TMS, the same in all the following examples): 11.8 (1H, COOH); 8.55 (2H, multiplet); 7.46 (1H, doublet, 7 Hz); 7.31 (ZN, m); 7.16 (ЗН, m); 6.13 (1H, triplet, 7 Hz); 2.29 (2H, triplet, 7 Hz); 2.13 (2H, triplet, 7 Hz); 1.58 (4H, multiplet), Pr меm p 5. In a nitrogen atmosphere, add 1 g of sodium hydride (60% in oil) to 25 ml of dimethyl sulfoxide), the mixture is heated at 85 ° C and stirred for 1 hour. the mixture is cooled to room temperature, 5.2 g (11 mmol) of 5-carboxypentyltriphenylphosphonium bromide are gradually added. The mixture was stirred for 10 minutes, a solution of 2.5 g (0.11 mol) of (3,4-methylenedioxybenzene) pyridine in tetrahydrofuran (10 ml) was added dropwise to it. After the addition is complete, the mixture is stirred at ambient temperature for 30 1 "h. Upon completion of the reaction, 100 ml of water are added, the neutral substance is extracted twice with toluene (50 ml each). The aqueous layer is acidified to pH 5.5 with 2n. with hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is chromatographed on a silica gel column using ethyl acetate as eluant. The eluent is concentrated, the residue is crystallized from a mixture of ethyl acetate and isopropyl ether, to obtain 0.4 g (24.6%) (g) -7- (3,4-methylenedioxyphenyl) -7- (3-pyridyl) -6-heptaic acids, so pl. 90-91 C. NMR spectrum: 9.20 (COOH) j8.46 (2H, multiplet); 7.50 (1H, m); 7.30 (1H, m) j 6.68 (1H, d, 2 Hz); 6.68 (1H, doublet, 8 Hz); 6.53 (1H, doublets, 8 and 2 Hz) 6.06 (1H, triplet, 7 Hz); 5.92 (2H, singlet); 2.28 (2H, m); 2.03 (2H, m); 1.57 (4H, m). The obtained (Z) -isomer (0.3 g) is dissolved in 18% hydrochloric acid, the solution is heated at 110 ° C for 20 hours. After completion of the reaction, the reaction mixture is alkalinized to aqueous solution of ammonia and extracted with ethyl acetate. In the high-resolution liquid chromatography of this product, it was determined that the E-isomer: Z-isomer ratio is 51:21. By liquid chromatography with 0.26 g of this mixture using a Lobar Lichropren RP-8 instrument (40-60 nm, Merck, Darmstadt), the mixture is divided into Z-isomer, which is eluted first, and E-isomer, which is eluted later . When the fraction of the E-isomer is concentrated, (E) -7- (3,4 methylenedioxyfenyl) -7- (3-pyridyl) 6-heptenoic acid (0.14 g) is obtained. NMR spectrum: 10.30 (1H, COOH); 8.50 (2H, multiplet); 7.47 (2I, m); .6,80 (1H, doublet, 8 Hz); 6.60 (1H, doublets, 8 and 2 Hz); 6.57 (1H, d ,, 2 Hz) 6.06 (1H, triplet, 7 Hz); 5.96 (2H, singlet); 2.31 (2H, m); 2.16 (2H, m); 1.58 (4H, m). In an argon atmosphere, 10 g (0.25 mol, 60% in oil) of sodium hydride are added to 250 ml of dimethyl sulfoxide, the mixture is stirred for 1 hour at 85 ° C, then cooled to
at room temperature, 52 g of 5-carboxypentyltriphenylphosphonium bromide (0.11 mol) is gradually added, keeping the temperature at the same level. The resulting mixture is stirred for 10 minutes, a solution of 20 g (0.11 mol) of 2-nicotinoylthiophene in 60 mp of tetrahydrofuran is added dropwise. After the addition, the mixture was stirred at room temperature. The mixture was stirred for 30 minutes and 300 ml of water was added. The aqueous solution is extracted twice with toluene (300 ml) to remove the neutron. coolant. The aqueous layer was acidified to pH 5.5 with a clear acid (2N) and extracted with et1-saacetate. The ethyl acetate layer is washed with water, dried -. magnesium sulfate and concentrate under reduced pressure. The residue is chromatographed on a silica gel column using ethyl acetate as the eluent. The eluate is concentrated. The resulting oily product was dissolved in ethtacetate, the solution was incubated overnight, yielding 9 g (29%) of (Z) -7- (3-pyridyl) 7- (2-thienyl) -6-heptenoic acid, m.p. 93-94 ° C. . NMR spectrum: 11.9 (1H, COOH); 8.53 (2H, m); 7.62 (1H, m); 7.20 (1H, m); 7.15 (1H, m); 6.85 (1H, m); 6.48 (1H, m) .-, 6.22 (1H, triplet, 7 Hz); 2.35 (4H, m); 1.63 (4H, m). The Z-isomer obtained in the described reaction (1j, O g) is dissolved in 10 ml of a 50% aqueous solution of phosphoric acid, the solution is heated at 100 ° C for 16 hours. Upon completion of the reaction, the reaction mixture is alkalized with dd pc 5.5 of aqueous ammonia with subsequent extraction and separation in a known manner. The high resolution liquid chromatography method of this crude product has determined that the ratio of ErZ 76 isomers, 14. The crude product (0.92 g) is recrystallized from ethyl acetate to obtain 0.65 g of (E) -7- (3-pyridyl) -7 (2 -thienyl) -6-heptenoic acid, so pl. Y4-85 C. NMR spectrum: 10.50 (1H, COOH); 3.59 (1H, doublet, 2 Hz); 8.48 (1H, D, D. 2 and 4 Hz); 7.58 (1H, triplet, 7 and 2 Hz); 7.29 (1H, m); 7.24 (1H, D, D 4 and 7 Hz); 7.04 (1H, m); 6.85 (1H, m); 6.04 (1H, triplet, 8 Hz); 2.34 (4H, m); -1.64 (4H, m). Example 7. 11-Phenyl-11- (3-pyridyl) -10-ynedecenoic acid. In a gas stream of argon, sodium hydride (treated by washing 3.8 g of its 60% oily product with hexane) is added to 200 ml of dimethyl sulfoxide, the mixture is stirred at 85 ° C, the reaction is continued for 1 hour, then the reaction mixture is cooled to room temperature, 21 g (0.041 mol) of 9-carboxin nitrite, and 40 ° C are gradually added to the reaction mixture, the reaction temperature is maintained at 40 ° C. Reaction , continue for 10 minutes with stirring, then into the re-mix until 7.5 g (0.04 mol) of a solution of 3-benzoylpyridine in dimethyl sulfoxide (20 ml) was added and stirred for 30 minutes. To the reaction mixture, 200 ml of water was added and the neutral substance (triphenylphosphine oxide) was removed by extraction toluene; pH of the aqueous layer was adjusted to 4 by the addition of 2N. Chlorides of Prenatal Acid. The product thus obtained is extracted with ethyl acetate, then the organic layer is washed with water, dried with magnesium sulfate and concentrated under reduced pressure. The precipitate thus obtained is treated by chromatography on a silica gel column and eluted with isopropylether ethyl acetate (to obtain a mixture of (E) - and (Z) isomers (8 g, yield 86%). Part of this mixture is processed by high-speed liquid chromatography with the purpose of isolation, respectively, of (E) - and (d) -isomers. (E) -11-Phenyl-11- (3-pyridyl) -10 undecensoic acid, melting point 90-9. Elemental analysis. Calculated,%: C 78, 30} H 8.06; N 4.15. Found:% C 78.51; H 9.12; N 4.03. NMR spectrum (in CDC t, TMS internal standard): 1.27 (12H, t ); 2.07 (2H, t); 2.31 (2H, t); 6.11 (1H, t, 7H Z); (7H, t); 8.44 (W, d, d, 2H Z); 8.51 (lll, d, 1H.Z). (G) -11 -Fensh1-11- (3-pyridyl) -10undecenoic acid. PIC spectrum (in CDCEj, TMS internal standard): 1.27 (12H, t); 2.06 (2H, t); 2.32 (2H, t , 8H Z); 6.16 (1H, t, 7H Z); 7.21 (6H, m, t); 7.50 (1H, d, d); 7H Z, 2H Z); 8.46 (1H, d, 2H Z); 8.54 (1H, d, d, 2H Z, 4H Z). P p and m e p 8. 7- (3-Pyridyl) -7phenyl-6-heptenoic acid. Potassium tertiary butylate (2.6 g, 23 mM) was added to dimethyl sulfoxide (40 ni), 5-carboxypentyltriphenylphenylsulfonium bromide (4.25 g, 10.5 tM) was added to this solution gradually and the reaction temperature was kept below 40 ° C . Then a solution (3-benzoylpyridine, 1.85 g, 10 mmol) in tetrahydrofuran (5 ml) is added to this reaction mixture with stirring and the reaction is continued for 30 minutes. 200 mp of water is added to the reaction mixture, a neutral substance (triphenylphosphinic oxide) is removed by extraction with toluene, the pH of the Aqueous layer is adjusted to 5.5 by addition of 2N. hydrochloric acid, then the product thus obtained is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue thus obtained was worked up by chromatography on a silica gel column, and ethanol was eluted with ethyl acetate (1: 5) to obtain a mixture of (E) - and (Z) -isomers of 7- (3-pyridyl) -7-phenyl-6-heptenoic acid. (2.3 g, yield 80%). The (E) -isomer is isolated by recrystallization from ethyl acetate. At the same time, the (Z) isomer is isolated from the oily substance during the uxification of the (E) -isomer by means of high resolution liquid phase chromatography. Example 9. 7- (3-Pyridyl) -7 (2-thienyl) -6-heptenoic acid. To a mixed mixture of sodium methylsulfinylmethyl, which is obtained by adding powdered sodium hydride (500 mg) to excess dimethylsulfoxide with stirring in a nitrogen atmosphere at 65-70 seconds before the evolution of hydrogen ceases, in dimethylsulfoxide and tetrahydrofuran (1: 1.40 ml), 5-carboxypentyltriphenylphosphonium bromide (4.75 g) and 3-pyridyl2-thienyl ketone (1.89 g) are added at -10 ° C. After addition under the same conditions for 2 hours, the reaction mixture is allowed to stand at room temperature for 1 hour. The mixture is treated with 2n; the hydrochloric acid (150 ml) and the neutral component are extracted with toluene. The aqueous layer is adjusted to pH 5.5 with sodium carbonate and the product is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on silica gel using a mixture of isopropyl ether and ethyl acetate (1: 4) as eluent to give 7- (3-pyridyl 7- (2-thienyl) -6-heptenoic acid (2, 2g, 82%). The toxicity test in mice was carried out as follows: ICP at the age of five weeks was used in groups of five animals. Each animal was given a stomatological test compound at the rate of 200 mg / kg of live weight. Then count the number of dead animals for the next One week of typical weeks. Typical examples of test results are given in Table 6. T: Table 7 47030 To 60 µl of Tris buffer solution (pH 7.5, concentration 50 mM) of IPM containing 140 tgg in the form of protein, add 60 µl of a buffer solution or a solution containing the test compounds at various concentrations. These mixtures were incubated for 5 minutes at room temperature. Then 1 O 3 C to a portion of the mixture with a volume of too µl was added 200 µl of a buffer solution containing 30 mg of prostaglandin H (nPHj). This mixture was incubated for 5 minutes at OS to cause the formation of thromboxane A (fXAj). The reaction of TXA formation is stopped when 500 µl of Tris buffer is added to this mixture. Using 50 µl of the mixtures, the stable metabolite TXA ,, (thromboxane Bj) was quantitated using radioimmunoassay (Shibouta et al. Biochem. Pharmaco. 1979, 28, 3601). The inhibitory activity of the compound in relation to TXAj synthetase is determined by the difference in the accumulations of TXBj in the test and control groups. The results for typical compounds are shown in Table. 8. Table В

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING VINYL CARBOXYLIC ACID DERIVATIVES OF THE GENERAL FORMULA
C = CH — CH ₂ —CHg (CH _g ) _p —COOH ₃ where R ₍ - pyridyl;
- phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl containing a lower alkoxy or alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group or a methylene dioxo group;
R ₃ is a hydrogen atom or lower alkyl;
η is an integer from 0 to .6, characterized in that, a ketone of the general formula c = o where R ₍ and Rj have the indicated meanings _; are reacted with a compound of the general formula [(with ₆ n,), -p-cn ₄ sn ₂ cn ₂ - (cn ₁ ) _n -coorJ ^
where is r and η have the indicated meanings, · 'X-halogen atom, preferably in the presence of a base, for example sodium hydride, sodium amide or potassium tert-butylate, in the presence of an organic solvent, mainly tetrahydrofuran, dimethyl sulfoxide or a mixture of these two solvents at a temperature of from -10 to + 40 ° C.
SU "> 1266470 AZ

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CA1319698C|1993-06-29|3-alkoxy-4-thioacetoxy-2e-butenoic acid alkyl esters

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US4429129A|1984-01-31|1α-Ethyl-1β-|-10-methoxy 1,2,3,4,6,7,12,12β-octahydroindolo|quinolizines

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US4454336A|1984-06-12|Derivatives of 3-|-propanoate

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SU959622A3|1982-09-15|Process for producing derivatives of benzocycloheptene or their salts

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KR900006683B1|1990-09-17|Process for preparing cinyl carboxylic acid derivatives

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EP0426253B1|1995-02-22|Process for the separation of R and S-2,2R1, R2-1,3-dioxolane-4-carboxylic acid

同族专利:

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公开号 | 公开日

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ZA834094B|1984-02-29|

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JPS58219162A|1983-12-20|

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JPS6347707B2|1988-09-26|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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JPH0720935B2|1988-04-04|1995-03-08|武田薬品工業株式会社|Process for producing substituted vinyl pyridines|

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US5977125A|1994-10-31|1999-11-02|Eisai Co., Ltd.|Mono-or polyenic carboxylic acid derivatives|

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JP3964478B2|1995-06-30|2007-08-22|エーザイ・アール・アンド・ディー・マネジメント株式会社|Heterocycle-containing carboxylic acid derivative and pharmaceutical containing the same|

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US5849766A|1996-05-31|1998-12-15|Eli Lilly And Company|Carbamoyl substituted heterocycles|

---

CA2206466A1|1996-05-31|1997-11-30|Joseph Anthony Jakubowski|Carbamoyl substituted heterocycles|

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JP4546589B2|1998-04-23|2010-09-15|武田薬品工業株式会社|Naphthalene derivatives|

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KR101057546B1|2007-06-05|2011-08-17|주식회사 엘지화학|Optically anisotropic compound and resin composition containing same|

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ES2525748T3|2009-11-13|2014-12-29|Toray Industries, Inc.|Therapeutic or prophylactic agent for diabetes|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP10248882A|JPS6347707B2|1982-06-14|1982-06-14|

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