• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Neue Sulfonamide der allgemeinen Formel 1 in welcher R Wasserstoff oder eine niedere Alkylgruppe, R eine Alkylgruppe oder eine Aryl-, Aralkyl- oder Aralkenylgruppe, deren Aryl-Rest jeweils gegebenenfalls ein-oder mehrfach durch Hydroxyl, Halogen, Trifluormethyl, niedere Alkyl-oder Alkoxy-Gruppen oder durch Acyl, Carboxy-oder Alkoxycarbonyl-Gruppen substituiert sein kann, n die Zahlen 1 - 3 bedeuten, W eine Bindung oder eine unverzweigte oder verzweigte Alkylenkette darstellt, die entweder gesättigt ist oder eine Doppelbindung enthält, sowie deren physiologisch unbedenklichen Salze, Ester und Amide, ihre Herstellung, ihre Verwendung zur Lipidsenkung und zur Hemmung der Thrombozytenaggregation sowie diese Verbindungen enthaltende Arzneimittel.
    公开号:SU1088664A3
    申请号:SU813223600
    申请日:1981-01-04
    公开日:1984-04-23
    发明作者:Витте Эрнст-Кристиан；Петер Вольфф Ханс；Штегмайер Карлхайнц；Роеш Эгон
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new chemical compounds, specifically alkylphenylcarboxylic acid sulfonamides, which are given by the region with an action that reduces lipids and inhibits platelet aggregation in the blood. The derivatives of alkylphenylalkanoic acids 15i of the general formula A- € K-Tx-ion I ш are known, where A represents a hydroxy, halogen trifluoromethyl group, alkyl sh or apoxy radical; X, Y - alkylenyl radical; R is an alkyl radical; Also known are derivatives of alkyl phenylcarboxylic acids 2 of the general formula C-coon ACN-r Ё 1 (W O H where A is halogen; trifluoromethyl group, alkyl, alkoxy radical, alkylamino group; -alkyl radical. Pointer. 1e compounds have an action, lowering lipid content and blood sugar. The purpose of the invention is to develop a method for producing sulfonamide alkylphenylcarboxylic acids, which have an effect that lowers the content of lipids and inhibits the aggregation of thrombiocytes in the blood. Alkylphenylcarboxylic acid sulfonamides of the general formula R, S02y (CH2) fj: where R is hydrogen, or a lower alkyl radical; Rf, is an alkyl radical with 1-16 carbon atoms, unsubstituted phenyl or substituted by one or two halogen atoms or one apical radical with 1 to 2 carbon atoms, sludge of trifluoromethyl, acetyl, hydroxy, methoxy, carboxy or ethoxycarbyl group, on (tyl group, unsubstituted phenylethyl group or substituted with halogen or unsubstituted phenylethylene group; . n 1-3; W means a bond to either an unbranched or branched lower alkyl or alkenyl radical, as well as their esters and amides, based on the known condensation reaction of the halogen-substituted compounds with C3 amines which implies that the amine of the general formula lAT-iJ is CHS2) a p and W. have indicated R, neither; Y denotes the group -COOR2, where R2 is hydrogen or a lower alkyl radical,. condense with sulfonic acid chloride with a compound of the formula R, S02C1 (V) where R.J. has the indicated values, in an organic solvent or water medium in the presence of a hydrohalic acid acceptor and isolate the desired product in free form or as an ester or as an amine acid. The reaction of sulfonic acid halides with compounds of general formula (IV) should be carried out with the addition of an acid binding agent, for example, alkali metal acetate, sodium bicarbonate, sodium carbonate, sodium phosphorus, calcium oxide, calcium carbonate or magnesium carbonate. However, organic bases, such as pyridine or triethylamine, can also take on this function, with ester, benzene, methylene chloride, dioxane or an excess of tertiary amine being, for example, an inert solvent. When using inorganic substances, binding acids, the reaction medium is, for example, water, aqueous ethanol or aqueous dioxane. The resulting compounds of formula (III), in which Y represents an ester group, immediately after condensation. Sulfurise into the corresponding carboxylic acids with mineral acids
    acids or alkali metal hydroxides in a polar solvent (for example, water, methanol, ethanol, diokean or acetone); -. The washing is preferred by a strong 5 base (for example, sodium or potassium hydroxide) in a mixture of methanol and water at room temperature or at moderately elevated temperatures. And, on the contrary, it is also possible to esterify carbonaceous slots in an ordinary way.
    The esterification of carboxylic acids is advisable to be carried out in the presence of an acid catalyst, for example, 15 hydrogen chloride, sulfuric acid, p-toluenesulfonic acid or a strongly acidic ion-exchange resin.
    Essentially all are suitable for the esterification of the carboxyl group20
    alcohols. Preferred are lower monohydric alcohols, for example methanol, ethanol or propanol, as well as polyhydric alcohols, for example glycol, or alcohols with other 5 functional groups, for example ethanolamine or glycol ether.
    Amides derived from carboxylic acids of general formula (III) are preferably prepared using well-known 30 methods from carboxylic acids or their reactive derivatives (for example, carboxylic acid halides, esters, azides, carboxylic anhydrides or mixed anhydrides / 55 in reaction with amines. As amino components, for example, ammonia, alkyl, diapkylamines, as well as amino alcohols, such as ethanolamine and 2-aminopropanol, and amino acids, for example / 3-alanine, etc. are used. Other valuable amino components are alkyl, aralk silt and arylpiperazines.
    Complexes produced from carboxylic acids of the general formula (III) contain lower monohydric alcohols as the alcohol component, of which methanol, ethanol and n-butanol are preferred, as well as 50 polyhydric alcohols, for example glycol or glycerol or alcohols with other functional groups, such as ethanolamine or glycol ether.
    Amides derived from carboxylic 51. acids of general formula (III) contain, for example, ammonia, p-aminobenzoic acid as the amino component.
    acid, / 5 -apanine, ethanolamine or 2-aminopropanol (all of which should be preferred, however, alkylamines can also be used, for example iso-propylamine or tert-butylamine, dialkylamines, for example diethylamine, as well as cyclic amines, for example morpholine or 4-alkyl- or 4-aralkyl- or 4-aryl-piperazines, for example 4-methylpiperazine, 4- (4-chlorobenzyl) -piperazine or 4- (3-methoxyphenyl) -piperazine.
    Example 1. 4-G2- (2-phenylethanesulfonamide) ethylbenzoic acid.
    To an ice-cooled solution of 14.3 g (70 mmol) of 4- (2-amino-ethyl) benzoic acid ethyl ester hydrochloride in 150 ml of absolute pyridine, 16.1 g (70 mmol) of 2- is added dropwise over 1 hour with stirring. phenylethanesulfonyl chloride. The cooling bath is then removed and stirred for 2 hours at room temperature. After that, it is poured into ice water and acidified with concentrated hydrochloric acid, whereby the ectc oil is absorbed by the ether. The aqueous phase is again extracted with ether, the combined ether phases are dried with sodium sulfate and finally evaporated. The residue is recrystallized From a mixture of ethyl acetate and ligroin. 18.4 g (73% of theoretical) ethyl ester of (2-phenylethyl sulphonamide) ethyl benzoic acid with a mp. 8386С.
    I
    A mixture of 12.5 g (35 mmol) of ethyl ester (2-phenylethanesulfonamido) ethyl benzoic acid, 70 ml of 1N. potassium hydroxide and 200 ml of methanol are incubated for 2 hours at 35 ° C. Then acidified with 2N. salt acid The methanol is evaporated and the remaining aqueous phase is extracted several times with methylene chloride. The combined methylene chloride phases are washed with water, dried over sulfate and evaporated. The residue after evaporation is dissolved in sodium bicarbonate and precipitated by evaporation. hydrochloric acid. The crystals are sucked off and dried. The result is 9.3 g (88% of theory), 4-C2 (2-feshethanesulfonamido) ethyl benzoic acid with so pl. 183-186 C. In a similar way, a) ethyl ester of (4-chlorobenzenesulfonamido) ethyl} benzoic acid is obtained from 4- (2-aminoethyl) benzoic acid ethyl ester hydrochloride and 4-chlorobenzenesulfonyl chloride (mp. 87-89 C , 84% yield from theory) and from the first by hydrolysis of 4- | 2- (4-chloro-benzene sulfonamido) ethyl 3 benzoic acid with m.p. 199-201 C and the release of 91% of theory. b) 4- {2-C2- (4-chloryl-nyl) ethanesulfonamido} ethyl phenylacetic acid ethyl ester from 4- (2-aminoethyl) -phenylacetic acid ethyl ester hydrochloride and 2- (4-chlorophenyl) tansulfonyl chloride with mp, 69-70 ° C, aqueous ethanol) and 76% yield from theory, and from the first by hydrolysis with 4 {-2-G2- (4-chlorophenyl) ethanesulfones to ethyl-phenylacetic acid, c. 155-156®С (aqueous ethanol) and yield 67% of theory. c) 4 - {- 2-f2- (4-chloro-phenyl) ethenesulfonamido} ethyl j-phenylacetic acid ethyl ester from ethyl 4- (2-amino-ethyl) -phenylacetic acid hydrochloride and 2- (4-chlorophenyl) ethenesulfonic chloride with m.p. . 101-102 C, 65% ethanol (yield 70% of theory) and from the first by hydrolysis 4- {2- | 2- (4-hporpenyl) eten sulfonamido ethyl phenylacetic acid with T.Sh1. 175-176 C (water ethanol) and the release of 87% of theory. d) (4-chlorobenzenesulfonamido) ethyl phenylacetic acid ethyl ester from ethyl 4- (2-aminoethyl) phenylacetic hydrochloride and 4-x-benzene sulfonic chloride with T.Sh1. 88-80 C (acetic ester-t lig roin) and with a yield of 96% of theory, and from the first by hydrolysis of (4-chlorobenzenesulfonamido) ethyl phenylacetic acid with so pl. 138140®C (ligroin acetate) and. yield 93% of theory. d7 Ethyl ester of (4-carbox benzenesulfonamido) ethyl 3-phenylacetic acid from 4- (2-amino-ethyl) -phenylacetic acid ethyl ester hydrochloride and 4-carboxybenzenesulfide chloride with mp, (sodium salt) and yield 94% of theory, and first by hydrodolysis (4-carboxybenzenesulfonamido) ethyl phenyl oxus 340 C and yield of an acid with mp. 85% of theory. 46 Example 2. 4- (2-Methanesulfonamidoethyl) benzoic acid. To a mixture of 150 ml of absolute pyridine, 12.8 g (92) of powdered anhydrous carbonate K-Ali, and 21.25 g (92 mmol) of 4- (2-aminoethyl) benzoic acid ethyl ester hydrochloride are added dropwise at 1015 ° C. 10.6 g (92 mmol) of methanesulfonyl chloride. Then it is stirred for 30 minutes at 20 ° C and 5 minutes at 80 ° C, after which it is cooled and poured into ice water. The mixture is acidified with concentrated hydrochloric acid and the precipitated substance is extracted with methylene chloride. After drying over sodium sulfate, the methylene-phase phase is evaporated. 24.8 g (98% of theory) of 4- (2-methanesulfon-amidoethyl) benzoic acid ethyl ester are obtained, mp 96-99 C. By hydrolysis of ethyl ether, analogously to Example 1, 96% of theory are obtained. 4- (2-methanesulfonamidoethyl / benzoic acid, tons of pieces 173174p. In a similar way, a) 4-(2-methanesulfonamidoethyl) phenylacetic acid ethyl ester from 4- (2-aminoethyl) phenylacetic acid ethyl ester hydrochloride (colorless oil, yield 81% of theory) and from the first by hydrolysis of 4- (2-methanesulfonamidoethyl) phenylacetic acid with m.p. 170-172 C (ethyl acetate + ethanol) and 79% yield of theory. b) Ethyl ester of (2-Lenylethanesulfonamido) ethanesphenyl} propionic acid from (2-aminoethyl) phenyl propionic acid ethyl ester hydrochloride and 2-phenyl ethanesulfonyl chloride (colorless oil, 77% yield from theory) and from the first by hydrolysis of 2- | 4 -12- (2-phenylethanesulfonamido) ethyl phenyl propionic acid with so pl. 94-97 C (ether + ligroin) and a yield of 69% of theory. c) 2- {4- 2- (2-Phenylethane sulfonamido) ethyl-J phenyl V-2-methylpropionic acid ethyl ester from (2-amino-ethyl) phenyl -2-methyl-1-propionic acid ethyl ester hydrochloride and 2-phenylethane sulfonyl chloride (colorless oil, yield 52% from theory) and from the first by hydrolysis of (2-phenylethanesulfonamido) ethyl phenyl 1-2-methylpropionic acid with so pl. 109-110 ° C (ethanol-water) and a yield of 62% of theory. d) (2- 2- (4-Chlorophenyl) ethanesulfonamyl) DoZethyl fensh-1-propionic acid ethyl ester from 3-H4- (2-am ethyl-ethyl-felyl-hophopionic acid ethyl ester hydrochloride and 2- (4-chlorophenyl) ethanesulfonyl chloride with t. 70-71 C (ethanol) and a yield of 66% of theory from the first by hydrolysis - 3 ((A-chlorophenyl) ethanesulfonic amide 3 ethyl phenyl propionic acid with mp 157-158 C (ethanol + water) and yield 76 % of theory. d) Ethyl ester ((-chloro-benzenesulfonamido) ethyl 3 peNIL propionic acid from ethyl ester hydrochloride (2-aminoethyl) fensh propionic acid and 4-chlorobenzenesulfonyl Ida with mp 61–62 ° C (ethanol) and 65% yield from the theory and from the first by hydrolysis with (4-chlorobenzenesulfonamido) ethyl acetate Nile PROPIONOVOH) acid with Т.1Ш 129-1ЭОС (ethanol + water a) and a yield of 87% of theory. e) Ethyl ester (n-hexadecylsulfonamido) ethyl cinnamic acid from 4- (2-aminoethyl) cinnamic acid ethyl ester hydrochloride and n-hexadecan sulfonyl chloride, m.p. 104®C (ethanol) and 71% yield from theory and from the first by hydrolysis of - - (n-hexadecylsulfonamido) ethyl short cinnamon with so pl. 164-165 ° C (etSH1ol + water) and a yield of 76% of theory. g) Ethyl ester (2-phenyl sulfonamido) ethyl cinnamic acid from 4- (2-aminoethyl) cinnamic acid ethyl ester hydrochloride and 2-phenyl ethanesulfonyl chloride (mp 98-99 C, 77% yield from theory) and from the first by hydrolysis. (2-Phenyl et Anul 4) it1 "1do) ethyl j-cinnamon kis from with so pl. 187-188c and a yield of 76% of theory. h) 4 - ((4-chlorophenyl) ethanesulfonayidoz ethyl cinnamic acid ethyl ester from ethyl hydrochloride E (ailra 4- (2-aminoethi1) cinnamic acid and 2- (4-chlorophenyl) ethanesulfonyl chloride, so pl. 91-92 0 (ethanol + water) and a yield of 63% of theory, and from the first by hydrolysis of 4- {2-C2- (4-chloro sh1) ethanesulfonamido ethyl cinnamic acid e 4 and so on. 212-2GsS Tethanol + water) and yield 94% of theories. i) Ethyl ester (4-chlorobenzenesul4; onamido) ethanolic acid from 4- (2-aminoethyl) cinnamic acid ethyl ester hydrochloride and 1-naphthylsulfonyl chloride, m.p. 9798 ° C (ethanol) and output 92% of the theory, and from the first by hydrolysis - 4- 2- (4-chlorobenzenesulfonamid6) ethyl cinnamic acid with so pl. 173-175 С and vii: odom 93% of theory. j) Ethyl ester (1-naphthylsulfonamido) ethyl Zcinnamic acid from 4- (2-aminoethyl) cinnamic acid ethyl ester hydrochloride and 1-naphthylsulfonyl chloride, m.p. 85-86 C (ethanol) and yield 88% of theory, and from the first by hydrolysis of (1-naphthylsulfonamido) ethyl dictic acid with so pl. (ethanol + water) and yield 93% of theory. l). Ethyl ester of 4-C2- (2-Fensh ethenesulfonamido) ethyl cinnamic acid from ethyl ester hydrochloride of 4- (2-aminoethyl) cinnamic acid and 2-phenylethanesulfonyl chloride (mp 102104c, 63% of theory) and from the first by hydrolysis of - (2-phenylethenesulfonamido | ethyl cortical acidic acid with a melting point of 190-191 ° C and a yield of 94% of theory. m) Ethyl ester of (4-kp6phenyl) ethenesulfonamido} ethyl cinnamic acid from ethyl ester hydrochloride 4- (p- aminoethyl) cinnamic acid and 2- (47 chloroform) this "nsulfonyl chloride, so pl. 131-132 0 (ethanol) and the yield of 83% of theory, and from the first by hydrolysis 4- {2- | 2- (4-chlorofesh) ethenesulfonamido ethyl cinnamic acid e so pl. 2P-212 C (ethanol + water) and a yield of 78% of theory. Example 3 4-C2- (4-Toluenesulfonamido) ethyl phenylacetic acid. To a solution of 14.6 g (60 MMOLB) 4- (2-amioethyl) phenylacetic acid ethyl ester hydrochloride in 120 ml of absolute pyridine at -10 ° C a mixture of 12.0 g (63 mmol) toluenesulfonyl chloride and 50 mp of pyridium are left to room temperature and then kept at. Then evaporated in vacuum to half the volume.
    poured into ice water and acidified with hydrochloric acid. The precipitated viscous mass is placed in ethyl acetate and the solution is dried over sodium sulfate. It is evaporated in vacuo and the residue is recrystallized from a mixture of ethyl acetate and ligroin. 18.0 g (B2% of theory (ethyl 4-toluenesulfonamido) ethyl} phenylacetic acid) are obtained.
    na-ns c.
    To a solution of 13.3 g (37 mmol) of ethyl ester (4-toluenesulfonamido) ethyl phenylacetic acid in 220 ml of ethanol is added dropwise PO 1 ml of 1N. potassium hydroxide and then maintained for 2 hours at 3540 ° C. The ethanol is then distilled off in vacuo and the aqueous phase is extracted with ether. Addition of 55 ml 2 n. hydrochloric acid solution precipitates a colorless precipitate, which is sucked off and recrystallized from a mixture of ethyl acetate and ligroin. Output 10.8 g (88% of theory) (4-toluensulfonamido) ethyl phenyl acetic acid with so pl. 141-145 C.
    In a similar way receive:
    a) 2-Phenylethenesulfonamido) ethyl benzoic acid ethyl ester from ethyl ester hydrochloride
    4- (2-aminoethyl) benzoic acid and 2-phenylethanesulfonyl chloride, m.p. 59-61c (ethanol + water) and a yield of 66% of theory, and from the first by hydrolysis of 4-C2- (2-phenyl ethenesulfonamido) ethyl Zb. Benzoic acid with m. Pl. 169.5170s (acetic acid z4mr) and yield 81% of theory. .
    b) 4-C2- (2-phenylethanesulfonamido) ethyl phenylacetic acid ethyl ester from 4- (2-amino ethyl) phenylacetic acid hydrochloride and 2-phenylethanol sulfonic acid (colorless oil, yield 61% of theory) and from the first by hydrolysis.a .4-C2- (2-phenylethan-. Sflone aIdo) ethylSphenyl cyclic acid with m.p., 50-g152 C (ethyl acetate) and a yield of 69% of theory.
    c) (2-Phenylethenesulfonamido) ethyl phenylacetic acid ethyl ester from 4- (2-aminoethyl) phenyl acetic acid ethyl ester hydrochloride and 2-phenylethenesulfonic chloride as a colorless oil with the yield
    78% of theory and of the first by hydrolysis of (2-phenylethanesulfonamido) ethyl jfcnylcyclic acid with so pl. 146-149 with (ethyl acetate + + naphtha) and the release of 81% of the theory.
    d) 3- {4- 2- (2-chlorobenzenesulfonamido) ethylSphenylIpropionic acid ethyl ester of (2-amino-ethyesh1) ethyl ester hydrochloride phenyl 3-propionic acid and 2-chlorobenzenesulfonyl chloride (mp. 57-60 0, yield 94% of theory ) and from the first by hydrolysis 3- {4- 2- (2-chlorobenzenesulfonamido) etyl phenyl | propionic acid with so pl. 136-139 C (acetic ether + naphtha) and the output of 82% of theory
    d) 3- {4- 2- (3-methoxybenzenesulfonamido) ethylSphenyl propionic acid ethyl ester from (2-aminoethyl) phenyl3 propionic acid ethyl ester hydrochloride and 2-methoxybenzenesulfonyl chloride (colorless oil, yield 92% of theory) and from the first by hydrolysis (3-methoxybenzylsulfonamido) ethyl 3-phenyl 1-propionic acid with m.p. IOO-10Z C (with ether) and a yield of 65% of theory.
    e 3- {4- 2- (3-trifluoromethylbenzenesulfone-ShDo) ethylSphenyl propionic acid ethyl ester from (2-aminoethyl) phenyl propionic acid ethyl ester hydrochloride and 3-trifluoromethylbenzenesulfonyl chloride (colorless oil, yield 99% of theory) and from the first by hydrolysis 3 - {4- 2- (3-trifluoromethyl-benzenesulfonamido) ethyl phenoxy | propionic acid with m.p. 119-121 С- (toluene) and yield 74% of theory.
    g) Ethyl ester of 3- 4- 2- (4-chlorophenylSethenylsulfone p to ethyl) NILE propionic acid from 3-H4- (2-amino- ethyl) phenyl-propionic acid hydrochloride and 2- (4-chlorophenyl) ethanesulfonylchloride ethyl ester, 2- (4-chlorofenyl) propyl acid and 2- (4-chlorophenyl) ethanesulfonylchloride mp 94-96 C (acetic ester + + LIGROIN) and 86% of the theoretical yield, and of the first, by hydrolysis of 3-4- {2- (4-chlorophenyl) ethenesulfonamido3 ethylSphenyl propionic acid with mp 165 C (kcycHbrii ether + menthol) and 73% yield of theory.
    PRI me R 4. (4-Fluorobenzenesulfonamido) ethyl} phenylacetic acid.
    A mixture of 11.0 g (51 mmol) of 4- (2-aminoethyl) -phenylacetic acid hydrochloride, 8.3 g (60 mmol) of potassium carbonate and 200 mp of water is heated to and 9.5 g is added at this temperature. (49 mmol) 4-fluorobenzenesulfrhlord. Then it is kept for another 2 h, cooled, and using 2 n. the hydrochloric acid is adjusted to pH 2. The precipitate is filtered off with suction, dried and recrystallized from 66% ethanol. 10.2 g (66% of theory) (4-fluoro-benzenesulfonamido) ethylZhonyl acetic acid are obtained from T.Sh1. 121-122C. In a similar way, one obtains: a) (2-Benzenesulfonamidoethyl) phenyl propionic acid from (2-aMinoethyl) phenyl propionic acid and benzenesulfonic. chloride with t.sht. 102.5-103 ° C (ethyl acetate + naphtha) and yield 63% of those; Orii. b) 4- (2-Benzenesulfonamidoethyl) benzoic acid from 4- (2-aminoethyl) benzoic acid hydrochloride and benzenesulfonyl chloride. M.p. 144.5145 C (prominent ethanol), yield 74% of theory. c) (4-Methoxy-benzenesulfonamido) ethyl benzoic acid from 4- (2-aminoethyl) benzoic acid hydrochloride and 4-methoxybenzenesulfonyl chloride. M.p. 177-178 s (aqueous ethanol), EXIT 68% of theory. d) 4- (2-Benzenesulfonamidoethsh1) o phenylacetic acid from 4- (2-aminoethyl) phenylacetic acid hydrochloride and benzenesulfonyl chloride. M.p. 127-128 with (ligroin + isopropanol), yield 92% of theory. d (4-methoxybenzenesulfonate amido) ethyl phenylacetic acid from 4- (2-aminoethyl) phenylacetic acid hydrochloride and 4-methoxybenzene sulfonyl chloride. M.p. 160-162 C (aqueous ethanol), the output of 72% of theory. (e) (4-Acesh1benzenesulfonone before) phenyl acetic acid from 4- (2-aminoethyl) phenylacetic acid hydrochloride and 4-acetylbenzenesulfonyl chloride. M.p. 193-194 C (this NOL was taken), yield 82% of theory. g) (2-Naphthalenesulfonamido) ethyl phenylacetic acid from 4- (2-amino-ethyes1) hydrochloride of phenyl acetic acid and 2-naphthapine sulfonic chloride, m.p. 135-136 ° C (aqueous ethanol), 68% of the theory. h) 4- (2-Benzenesulfonamidostil) cinnamic acid from 4- (2-aminoethan1) cinnamic acid hydrochloride and B 10 4 eolsulfonyl chloride. M.p. 164-166 ° U (aqueous ethanol), yield 73% of theory. i) 4- (3-Benzene sulfo-Namidopropsh1) benzoic acid from 4- (3-aminopropyl) benzoic acid hydrochloride and benzene sulfate. M.p. 207.5209С (acetone + water), yield 63% of theory. k) 4- (Benzenesulfonamidomethyl) phenylacetic acid from 4-aminomethylphenylacetic acid hydrochloride and benzenesulfonyl chloride. M.p. 144.5145, 5c (ethyl acetate), yield 76% of theory. l) 4- (3-Benzenesulfonamido) phenylacetic acid from 4- (3-aminopropyl) phenylacetic acid hydrochloride and benzenesulfonic chloride. M.p. 128-129 ° С (vinegar ester + ligroin), yield 84% of theory. m) (2-Benzenesulfonamidoethyl) phenyl-2-methylpropionic acid from (2-aminoethyl) phenyl 2-methylpropioic acid hydrochloride and benzenesulfonyl chloride. M.p. 86-88 0 (ethyl acetate), yield 80% of theory. and (2,5-Dichlorobenzenesulfonamido) ethyl phenylacetic acid from (2-aminoethyl) acetic acid hydrochloride and 2,5-dichlorobenzenesulfonyl chloride. M.p. 163-164 0 (aqueous ethanol), yield 65% of theory. . , o) 4tC (2-Benzenesulfonamidoethyl) phenyl butyric acid from (2-aminoethyl) phenyl butyric acid hydrochloride and benzenesulfonyl chloride. M.p. 70-71 0 (aqueous ethanol), yield 67% of theory. (p) (2-Benzenesulfonamidoethyl) phenyl propionic acid from (2-a 0 0 noethyl) hydrochloride of propionic acid and benzenesulfonyl chloride. M.p. (sodium salt) 236-239 C, injection of 83% of theory. p) 2-Benzenesulfonamidoethyl1 phenyl} -2-metsh1Pro1shonic acid from 3-C4- (2-aminoethyl) phenyl -2-methylpropionic acid hydrochloride and benzenesulfonic chloride. M.p. 1,13115 6 (ethyl acetate + naphtha), yield 85% of theory. c) 4- (2-Benzenesulfonamidoethn1) ot-methylcinnamic Kisloto from 4- (2-aminoethyl) -methyl chloride; hydrochloride and benzenesulfonyl chloride. M.p. 147-148 ° C; yield 62% of theory. t) (2-Naphthylsulfonamido) ethyl cinnamic acid from 4- (2-aminoethyl) cinnamic acid hydrochloride and 2-naphthylsulfonyl chloride. T, pl. 192193 C (ethanol + water), yield 96% of theory. In a similar way, y) - (L-Methylbenzene sulfoiamidomethyl j cinnamic acid, mp 21221A C (isopropanol + water). F) (H-Methylbenzene sulphonamidetophenyl) phenyl acetic acid, r.g. 159-160 C (ethyl acetate). PRI me R 5. (n-Hexadecan sulfonamido) ethyl-benzoic acid. To a mixture of 11.5 g (50 mmol) of 4- (2-amine etuta) ethyl ester hydrochloride of benzoic acid, 150 ml of benzene and 20 g (200 mmol) of triethylamine with OC with strong stirring. 16 g, 50 mmol of n-hexadecanesulfonyl chloride are added dropwise, continue to stir in an ice bath for another 2 hours and quenched overnight at 20 ° C. Then poured onto ice, acidified with hydrochloric acid and extracted with ether . The ether phase is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from aqueous ethanol. 17.0 g (69% of the terum) of 4- (2- (n-hexane cansulfonamido) ethyl 3-phenylacetic ethyl) are obtained, mp: 82-83 ° C (aqueous this acid is nol). The hydrolysis of the ester is carried out as in Example 1 c. using an aqueous solution of caustic potash in methanol .. You move (86% of theory) 4-C2- (n-hexade cansulfonamido) ethyl Zenzoic acid, mp 168-169s (aqueous ethanol. Example 6, (n-Octanesulo-fonamido) ethyl phenylacetic acid, 9.9 g (43 mmol) of 4-2-aminoethyl) phenyl acetic acid ethylchloride and 9.2 g (43 mmol) of p-octanesulfonyl chloride — are suspended in 175 MP of benzene, with very While stirring, a solution of 11.9 g (86 mmol) of potassium carbonate in 400 ml of water is added dropwise, stirred for another 10 minutes, and then the phases are separated. The benzene phase is washed with water, dried over sodium sulfate and evaporated in vacuo. After recrystallization 12.6 g (79% of theory) of this 6414 4-H2-2-ester (n-octanesulfonam-to-d) ethyl2-phenyl acetic acid with mp 59-60 ° C (aqueous ethanol) are obtained from aqueous ethanol. A mixture of 10.7 g (29 mmol) of ethyl ether, 29 ml 2 n. potassium hydroxide and 29 ml of ethanol are held at 40 ° C for 3 hours. Then the ethanol is distilled off in vacuo, acidified with hydrochloric acid, sucked off and recrystallized from aqueous ethanol. 9.0 g (91% of theory) of (n-octane sulfonamido) ethyl 3-phenylacetic acid are obtained with a m.p. 156-157 C. In a similar way, ethyl ester (2-n-octylsulfonamidoethyl) fensh1 propionic acid is obtained from ethyl ester hydrochloride (2-amino-Hegyl) phenyl hydrochloric acid and n-octanesulfonyl chloride, m.p. 66-68 ° C (in the case of the sausage ester + lig roin) and the yield of 69% of the theory, and from the first by hydrolysis of (2-n-octylsulfonamidoethyl) phenyl Zapropic acid with m. 146-148 ° C (ethyl acetate) and the release of 83% of theory. Example 7. n-Butilovy E4 1p 4- (benolsulfonaminoesh1) fs1pshacetic acid. A mixture of 6.11 g (20 mmol) of 4-benzenesulfonamidomethyl phenylacetic acid (Example 4k), 2.83 g (20 mmol) of boron trifluoride etherate and 40 ml of i-butanol is heated to boiling point for 3 hours while stirring, most of the excess n The α-butanol is evaporated in vacuo and the residue is diluted with 100 MP of ice water. The mixture is extracted with ether, the combined extracts are washed with 2N, respectively. hydrochloric acid, water and sodium bicarbonate solution, dried over sodium sulfate and evaporated. Remaining the current is recrystallized from a mixture of ether with ligroin. This gives 6.1 g of 84% of the theory of 4- (benzenesulfonamicdomethyl) phenylacetic acid butyl ester with TP. 60.5-61 ° C. Example 8. 4-Methylpiglérazide 4- (2-benzenesulfonic amide 1) phenylacetic acid. A mixture of g (0.05 mmol) of 4- (2-benzalsulfonamidoethyl) phenylacetic acid, 100 ml of benzene and 17.9 g (0.15 mol) of thionyl chloride was heated to boiling point for 5 hours. Then benzene and excess thionyl chloride are distilled off in vacuo. the crude product is quantitative. After recrystallization from toluene
    14.9 g (88% of theory) of 4- (2-benzenesulfonamidoethyl) phenylacetyl chloride are obtained with t. tech. (decomposes with).
    To an ice-cooled solution of 3.0 g (30 mmol) of N-methylpiperazn and 100 ml of absolute pyridine, 10.1 g (30 mmol) of 4- (2-benzenesulfonic amidoethyl) phenylacetylene chloride are added in portions with stirring in an hour. It is then brought up to 20 ° C, heated for 5 hours, cooled, and drunk in (approximately) 500 ml of ice water. This mixture is extracted with methylene chloride and the methylene chloride phase is evaporated after drying over sodium sulfate. The residue is dissolved in ether and the hydrochloride is precipitated with ether saturated with hydrogen chloride. After recrystallization from ethanol, 8.7 g (66% of theory) of A-methyl. Piperazide hydrochloride with 4- (2-benzenesulfonamidoethyl) phenylacetic acid, m.p. 168 S.
    PRI me R 9. 4-G2- (4-HydroxyphenylsulfonamidoI ethylSphenylacetic acid.
    Prepare a mixture of 8.75 g (36 mol) of ethyl complex 4- (2-aminoethyl) -phenesyl acetic acid hydrochloride and 90 MP of methylene chloride with 7.3 g (72 mol) of triethnlamine, stir the mixture for 1 hour at room temperature, then cooled in an ice bath and a solution of 9.5 g (36 mol) of 4-ethoxygfbonyloxybenzenesulfonyl chloride in 10 ml of methylene chloride are slowly added dropwise. The reaction mixture is allowed to stand for 1 hour at then 3 hours at room temperature. Then the organic phase is washed with dilute hydrochloric acid and water, dried and evaporated.
    15.0 (96% of theory) of ethyl ester (4-ethoxycarbonyloxyphenylsulfonamido) ethyl 3-phenan acetic acid, colorless oil (Wy1-184) are obtained as a residue.
    14.8 g (34 mol) of crude ester is heated with 100 ml 2 n. After cooling, the formed solution is clarified with activated charcoal and precipitated with hydrochloric acid 4-C2- (4-hydroxyphenylsulfonamido) ethyl feshchuk hydrochloric acid. T. pl. 157-159 C (acetic ether + toluene), yield 67% of theory.
    For the preparation of medicinal media, the compounds of the general formula (III) are mixed by a well-known method with appropriate pharmaceutical excipients, flavoring and coloring agents and prepared as tablets or dragees, or by adding appropriate auxiliary substances, suspended or dissolved in water or oil, for example olive oil.
    The substances of general formula (III) can be used orally and parenterally in liquid or solid form. Preferably, water is used as the injection medium, which contains conventional stabilizers, dissolution agents and / or buffers in the injection solutions. Such additives are, for example, tartrate or borate buffers, ethanol, dimethylsulfonic sulfate, complexing agents, such as ethylene diamine tetraacetic acid, high molecular weight polymers, such as liquid polyethylene oxide, which are used to adjust viscosity, or derivatives of polyethylene from sorbitanhydratose.
    Solid excipients are, for example, starch, lactose, mannitol, methanol cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids, such as stearic acid, gelatin, agargar, calcium phosphate, magnesium stearate, animal and vegetable fat, or high carbon. for example polyethylene glycol. Formulations suitable for oral administration may, if necessary, contain flavoring and sweet substances. The dose used depends on the patient's growth, the health and weight of the patient, the degree of development of the disease, the type, if necessary, other treatments that are simultaneously given, the frequency of treatment and the desired effect. Typically, the daily dose of the active compound is 0.150 mg / kg body weight. As a rule, 0.5–40, preferably 1.0–20 mg / kg per day is sufficient with one or several administrations per day to obtain the desired results.
    A more effective effect of the compounds of formula (III) in comparison with the trade preparation, acetylsalicylic acid, is shown in the results of the following tests. Lipid reduction. 10 male rats who do not suffer from a metabolic disorder, the test substance is given orally for 7 di at a dose of 50 mg / kg as a suspension in methylcellulose. At the end of the test, 3 hours after the last probing, the content of cholesterol and triglyceride in the Serum is determined. Changes are determined by comparison with control animals. Inhibitory effect on aggregation. The effect on thromobite aggregation was tested using the Born test. Venous blood of probands not suffering from metabolic disorder is mixed with sodium citrate (9: 1 /. Centrifuging about O g of the mixture cools erythrocytes. Platelets are concentrated in the supernatant. This supernatant is not called plasma platelet-rich (TOT). Top part POT is placed in an aggregometer cuvette (Brown Melsugen Universal Aggregometer) and mixed with a small magnet. The test substance is placed in an aqueous solution (pH approx. 7). Changes in light transmission in suspension Zia are continuously recorded using a recorder. At the end of self-aggregation, further aggregation is caused by the addition of 5-10 mol / l of adrenaline .. Significantly greater concentrations of thrombocytes are formed, due to which the suspension transmits more light. Induction of adrenaline aggregation occurs in two phases, t fb light transmission first increases, then stays unchanged for a short time and increases again. By means of an action that inhibits aggregation, the test substance has 5C aggregation varied only in the second phase. To evaluate the results, the angle of the second phase of aggregation relative to the horizontal for aggregation induced by adrenaline is determined, and the latter is taken as zero percent inhibition (control experiment). Isolation of the mountains of the second 100 10 51 price for the same PRP after the addition of the substance to be removed, the aggregation is induced by adrenaline. And again, the angle of the second phase relative to isontal will be determined, while the ratio of their angles gives the percentage of inhibition of the platelet aggregation phase. For a comparative preparation, acesalicylic acid, the inhibition% is at a mol / L concentration. At a concentration of 0 mol / l, it is 0%. All substances have a concentration of 5-10 mol / l. The data on the physiological activity of the compounds obtained are given in the table ..
    Table continuation
    In addition to the compounds presented in the examples, and the compounds obtained
    as a result of a combination of all specified-. values of substituents, the following compounds are preferred: 4- (2-benzenesulfonamidoethyl) phenylacetamide; 3-p4- 2- (4-phenylsulfonamido) ethyl phenyl-propionic acid.: Ta; 3- {4- 2- (4-phenylsulfonamido) ethyl phenyl-propionamide, 3- {4- 2- (4-feshsulfonamido) ethyl ester
    ethyl propane acid.
    Example 10. Preparing tablets. Each tablet contains 10 ml of 3- 4- (2-benzenesulfonamidoethyl) phenyl / propionic acid, according to the following recipe: (2-benzenesulfonamidoethyl) fensh1 propionic acid 10 g.
    lactose 80 g, starch 29 g, magnesium stearate 1g.
    The specified compound is finely ground into powder and cured with lactose and starch. The mixture is granulated in the usual manner. Py magnesium stearate is added to the granulate and this mixture is convened in 1000 tablets weighing 0.12 grams.
    Thus, the proposed method allows obtaining new substances with a high effect, which reduces lipids and inhibits platelet aggregation in the blood.
    权利要求:
    Claims (1)
    [1]
    . METHOD FOR PRODUCING Sulfonamides of Alkylphenylcarboxylic Acids of the General Formula RlSO 2 y- (CH 2 ) ^^> - W-C00H
    R where R is hydrogen or a lower alkyl radical;
    t is an alkyl radical with 1-16 carbon atoms, unsubstituted phenyl or substituted with one or two halogen atoms or one alkyl radical with 1-2 carbon atoms, or a trifluoromethyl, acetyl, indroxy-methoxy, carboxy-group or ^ toxycarbonyl group,; a naphthyl group or an unsubstituted phenylethyl group or substituted with a halogen or unsubstituted phenylethylene group;
    . n = 1-3;
    W - means a bond or unbranched or branched lower alkyl or alkenyl radical.
    as well as their esters and amides, characterized in that the amine of the general formula
    HN- (CHzk - ^ - ’W-a R where R, η and N have the indicated meanings,
    - Υ means a group -000¾, where R 2 is hydrogen or a lower alkyl radical, are subjected to condensation with chloride “sulfonic acids of the general formula
    R ^ SOjCl where R ^ has the indicated meanings, in an organic solvent or water in the presence of an acceptor of hydrohalic acid, and the desired product is isolated in a free form either as an ester or as a zmin acid.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1088664A3|1984-04-23|Process for preparing alkylphenylcarboxylic acid sulfonamides
    US4258058A|1981-03-24|Phenoxyalkylcarboxylic acid compounds and thrombocyte-aggregation inhibition
    EP0901466B1|2001-10-31|Biphenylsulfonamide matrix metalloproteinase inhibitors
    EP0239907B1|1991-09-18|Phenoxyalkanecarboxylic-acid derivatives, process for their preparation and medicines containing these compounds
    CA1212380A|1986-10-07|Process for the preparation of new thieno| pyrrole derivatives
    US5756545A|1998-05-26|Biphenysulfonamide matrix metal alloproteinase inhibitors
    HU204029B|1991-11-28|Process for producing sulfonamide derivatives and pharmaceutical compositions comprising same
    US4153728A|1979-05-08|Phenoxyalkylcarboxylic acid compounds and therapeutic compositions
    US4134991A|1979-01-16|Derivatives of 2-|-acetic acid
    EP0149419B1|1988-08-17|Acylindole derivatives and pharmaceutical compositions containing them
    RU1837765C|1993-08-30|Emulsifiable fungicide concentrate
    PL105799B1|1979-10-31|METHOD OF MAKING NEW DERIVATIVES / ALPHA-AMINOACETYL / BENZENE
    PT87162B|1992-07-31|PREPARATION PROCESS OF COMPOSITE OF PYRIDILLOIC ACID CONTAINING A SULFONAMIDE GROUP AND PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH COMPOUNDS
    US4152456A|1979-05-01|Tropone derivatives
    US4628083A|1986-12-09|2-hydroxy-5-|-benzene alkanoic acids
    BE779775A|1972-08-24|DERIVATIVES OF UREA, METHOD FOR PREPARING THEM AND THEIR APPLICATIONS
    WO1983000146A1|1983-01-20|New derivatives of dipeptides, method for the preparation thereof and utilization thereof as drugs
    US3758546A|1973-09-11|Methoxy amine derivatives and process for preparing them
    SU385443A1|Method of producing indol derivatives or their salts
    US4788198A|1988-11-29|Diazine-ethyenylphenyl oxamic acids and esters and salts thereof
    EP0576349A1|1993-12-29|Indolizine derivatives, process of preparation and use for the preparation of aminoalkyloxybenzenesulfonylindolizine compounds with pharmaceutical activity
    US4103029A|1978-07-25|Amino substituted arylthio-alkanoic acids having hypolipidemic activity
    SU1158041A3|1985-05-23|Method of obtaining sulfimine derivatives
    SU526285A3|1976-08-25|The method of obtaining derivatives of 3-and / or 2-butenoic acid
    HU198928B|1989-12-28|Process for producing tetrahydro-beta-carboline derivatives and pharmaceutical compositions comprising same
    同族专利:
    公开号 | 公开日
    FI73667C|1987-11-09|
    YU42995B|1989-02-28|
    DE3000377A1|1981-07-09|
    JPS56100757A|1981-08-12|
    FI73667B|1987-07-31|
    DE3067068D1|1984-04-19|
    PL229072A1|1982-04-26|
    DD157190A5|1982-10-20|
    EP0031954A3|1981-11-11|
    PH18739A|1985-09-16|
    EP0031954A2|1981-07-15|
    GR72486B|1983-11-14|
    IE50657B1|1986-06-11|
    HK68887A|1987-10-02|
    CA1241341A|1988-08-30|
    ES8200655A1|1981-12-01|
    AU538993B2|1984-09-06|
    YU881A|1983-10-31|
    FI804085L|1981-07-08|
    PL127050B1|1983-09-30|
    IE810006L|1981-07-07|
    ES498308A0|1981-12-01|
    AU6597481A|1981-07-16|
    EP0031954B1|1984-03-14|
    ZA8132B|1982-02-24|
    PT72305A|1981-02-01|
    IL61834A|1984-06-29|
    PT72305B|1981-12-17|
    US4443477A|1984-04-17|
    SG2387G|1987-11-13|
    JPS6352625B2|1988-10-19|
    CS238611B2|1985-12-16|
    AT6641T|1984-03-15|
    IL61834D0|1981-01-30|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE542184A|1954-10-21|
    US3027405A|1959-07-29|1962-03-27|Geigy Chem Corp|Nu--amino acids and salts thereof|
    US3991106A|1974-09-13|1976-11-09|Merck & Co., Inc.|16-Ethers of 8-aza-9-dioxothia-11,12-seco-prostaglandins|
    DK148576A|1975-04-18|1976-10-19|Boehringer Mannheim Gmbh|PHENYLALCANCARBONIC ACID DERIVATIVES AND PROCEDURE FOR THEIR PREPARATION|
    GB1572201A|1977-04-05|1980-07-23|Bristol Myers Co|Cephalosporins|
    US4112236A|1977-04-04|1978-09-05|Merck & Co., Inc.|Interphenylene 8-aza-9-dioxothia-11,12-secoprostaglandins|
    DE2809377A1|1978-03-04|1979-09-13|Boehringer Mannheim Gmbh|PHENOXYALKYL CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    DE3000519A1|1979-02-01|1980-08-14|Byk Gulden Lomberg Chem Fab|Omega-Benzene-sulphonamido:phenyl-alkanoic acid derivs. - useful as hypoglycaemics and inhibitors of hepatic glucose synthesis to treat e.g. pre-diabetic states and circulatory disorders|US4401663A|1981-06-30|1983-08-30|The Procter & Gamble Company|Novel sulfonamide derivatives|
    AU567140B2|1984-01-06|1987-11-12|Shionogi & Co., Ltd.|Sulphonamido-benzamide derivatives|
    EP0194548A3|1985-03-12|1988-08-17|Dr. Karl Thomae GmbH|Sulfonylaminoethyl compounds, medicines containing these compounds and process for their preparation|
    DE3535167A1|1985-10-02|1987-04-09|Boehringer Mannheim Gmbh|NEW SULFONYL-PHENYLAMINES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS|
    US4689182A|1985-12-20|1987-08-25|Warner-Lambert Company|Benzoic acid and benzoic acid ester derivatives having anti-inflammatory and analgesic activity|
    FR2598412B1|1986-03-12|1988-10-21|Sanofi Sa|NOVEL DIARYLCETON DERIVATIVES AND PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    IL83230A|1986-08-06|1992-06-21|Tanabe Seiyaku Co|Phenoxyacetic acid derivatives,their preparation and pharmaceutical compositions containing them|
    DE3629929A1|1986-09-03|1988-03-10|Thomae Gmbh Dr K|NEW SULFONAMIDO-AETHYL COMPOUNDS, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF|
    JPH01503233A|1986-10-28|1989-11-02|
    GB8708233D0|1987-04-07|1987-05-13|Smith Kline French Lab|Pharmaceutically active compounds|
    KR880012221A|1987-04-13|1988-11-26|사노 가즈오|Pharmaceutical compositions containing esters or amides as active ingredients|
    CA1294974C|1987-05-08|1992-01-28|Sanji Hagishita|Bicyclic sulfonamide derivatives and process therefor|
    US4752616A|1987-06-29|1988-06-21|E. R. Squibb & Sons, Inc.|Arylthioalkylphenyl carboxylic acids, compositions containing same and method of use|
    GB8717374D0|1987-07-22|1987-08-26|Smith Kline French Lab|Pharmaceutically active compounds|
    US4752613A|1987-08-03|1988-06-21|E. R. Squibb & Sons, Inc.|Sulphonamidothienylcarboxylic acid compounds|
    US4783473A|1987-09-02|1988-11-08|E. R. Squibb & Sons, Inc.|Geminally substituted cyclic ether carboxylic acids, derivatives thereof, compositions containing same and method of use|
    US4931460A|1987-09-17|1990-06-05|E. R. Squibb & Sons, Inc.|Post-ischemic myocardial dysfunction using thromboxane A2 antagonists|
    JPH0523257B2|1987-12-28|1993-04-02|Tanabe Seiyaku Co|
    DE68909958D1|1988-01-19|1993-11-25|Tanabe Seiyaku Co|Phenoxyacetic acid derivatives, their preparation, pharmaceutical compositions containing them and their use.|
    US5066480A|1988-04-11|1991-11-19|E. R. Squibb & Sons, Inc.|Method of preventing or reducing adverse reactions to protamine using a thromboxane a2 receptor antagonist|
    DE3819052A1|1988-06-04|1989-12-07|Basf Ag|NEW SULFONAMIDE DERIVATIVES, THEIR PRODUCTION AND USE|
    DE3829455A1|1988-08-31|1990-03-15|Boehringer Mannheim Gmbh|SULFONAMIDOALKYL-CYCLOHEXAN COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS|
    US4925873A|1988-09-01|1990-05-15|E. R. Squibb & Sons, Inc.|Method of treating skin injuries using thromboxane A2 receptor antagonists|
    GB8823731D0|1988-10-10|1988-11-16|Smith Kline French Lab|Biologically active compounds|
    US5280043A|1988-10-10|1994-01-18|Smith Kline & French Laboratories Ltd.|Sulphonamido containing phenylalkanoic acids as thromboxane A2 antagonists|
    US5070099A|1988-10-31|1991-12-03|E. R. Squibb & Sons, Inc.|Arylthioalkylphenyl carboxylic acids, derivatives thereof, compositions containing same method of use|
    US4959383A|1988-10-31|1990-09-25|E. R. Squibb & Sons, Inc.|Phenylsulfone alkenoic acids, derivatives thereof, compositions containing same and method of use|
    US5006542A|1988-10-31|1991-04-09|E. R. Squibb & Sons, Inc.|Arylthioalkylphenyl carboxylic acids, derivatives thereof, compositions containing same and method of use|
    US4975452A|1989-06-02|1990-12-04|E. R. Squibb & Sons, Inc.|Geminally substituted thiaheterocyclic carboxylic acids and derivatives thereof|
    US5106991A|1989-06-02|1992-04-21|E. R. Squibb & Sons, Inc.|Geminally substituted thiaheterocyclic carboxylic acids and derivatives thereof|
    US5025025A|1989-06-28|1991-06-18|Ciba-Geigy Corporation|-substituted carboxylic acids and derivatives thereof and use for suppressing thromboxane activity|
    US5153214A|1989-06-28|1992-10-06|Ciba-Geigy Corporation|Certain -substituted carboxylic acids and derivatives thereof and use for suppressing thromboxane activity|
    DE4010536C2|1990-04-02|1992-05-07|Boehringer Mannheim Gmbh, 6800 Mannheim, De|
    FR2665440B1|1990-07-31|1994-02-04|Lipha|NOVEL SUBSTITUTED CYCLOALKYLSULFONAMIDES, METHODS OF PREPARATION AND MEDICAMENTS CONTAINING THEM.|
    US5189211A|1990-08-01|1993-02-23|Taisho Pharmaceutical Co., Ltd.|Sulfonamide derivatives|
    US5409959A|1991-01-29|1995-04-25|Genelabs Incorporated|Antithrombotic treatment with calixarene compounds|
    DE4109735A1|1991-03-25|1992-10-01|Boehringer Mannheim Gmbh|NEW SULPHONAMIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    US5280034A|1991-08-23|1994-01-18|E. R. Squibb & Sons, Inc.|Bis-heterocyclic prostaglandin analogs|
    US5827868A|1991-10-07|1998-10-27|E. R. Squibb & Sons, Inc.|Prostaglandin analogs|
    TW219358B|1991-12-20|1994-01-21|Hokuriku Pharmaceutical|
    GB9220137D0|1992-09-23|1992-11-04|Pfizer Ltd|Therapeutic agents|
    JPH0753505A|1992-10-01|1995-02-28|Hokuriku Seiyaku Co Ltd|Benzensulfonamide derivative and use thereof|
    DK0896533T3|1996-02-22|2004-01-26|Tularik Inc|Pentafluorobenzene sulfonamides and analogues|
    DK0939627T3|1996-07-19|2003-10-13|Tularik Inc|Pentaflourobenzene sulfonamides and analogues|
    GB9702194D0|1997-02-04|1997-03-26|Lilly Co Eli|Sulphonide derivatives|
    FR2760235B1|1997-02-28|1999-04-09|Adir|NOVEL BENZENESULFONYLAMINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    UA67754C2|1997-10-10|2004-07-15|Пфайзер, Інк.|Prostaglandin agonists and use thereof for the treatment of bone disorders|
    US6693137B1|1998-07-31|2004-02-17|Eli Lilly And Company|Sulphonamide derivatives|
    MXPA02006322A|1999-12-22|2002-12-13|Pfizer Prod Inc|Ep4 receptor selective agonists in the treatment of osteoporosis.|
    US20050250854A1|2000-11-03|2005-11-10|Amgen Inc.|Combination therapy using pentafluorobenzenesulfonamides and antineoplastic agents|
    WO2002039958A2|2000-11-03|2002-05-23|Tularik Inc.|Combination therapy using pentafluorobenzenesulfonamides and antineoplastic agents|
    BRPI0517263A|2004-10-29|2008-10-07|Astrazeneca Ab|New Sulfonamide Derivatives as Glucocorticoid Receptor Modulators for the Treatment of Inflammatory Diseases|
    TW200829578A|2006-11-23|2008-07-16|Astrazeneca Ab|Chemical compounds 537|
    JO2754B1|2006-12-21|2014-03-15|استرازينكا ايه بي|Indazolyl amide derivatives for the treatment of glucocorticoid receptor mediated disorders|
    WO2008132154A1|2007-04-27|2008-11-06|Tibotec Pharmaceuticals Ltd.|Methods for the preparation of n-isobutyl-n--p-nitrobenzenesulfonylamide derivatives|
    UY31831A|2008-05-20|2010-01-05|Astrazeneca Ab|DERIVATIVES OF INDAZOLS REPLACED WITH PHENYLL OR PIRIDINYL|
    CA2729767A1|2008-07-07|2010-01-14|Fasgen, Inc.|Novel compounds, pharmaceutical compositions containing same, methods of use for same, and methods for preparing same|
    KR101992929B1|2012-09-20|2019-06-25|템플 유니버시티-오브 더 커먼웰쓰 시스템 오브 하이어에듀케이션|Substituted alkyl diaryl derivatives, methods of preparation and uses|
    AU2015258805B2|2014-05-16|2018-05-10|Cumberland Pharmaceuticals, Inc.|Compositions and methods of treating cardiac fibrosis with ifetroban|
    WO2017023912A1|2015-08-03|2017-02-09|Temple University - Of The Commonwealth System Of Higher Education|2,4,6-trialkoxystryl aryl sulfones, sulfonamides and carboxamides, and methods of preparation and use|
    EP3454850A4|2016-05-11|2019-11-20|Cumberland Pharmaceuticals Inc.|Compositions and methods of treating muscular dystrophy with thromboxane-a2 receptor antagonists|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19803000377|DE3000377A1|1980-01-07|1980-01-07|NEW SULPHONAMIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    [返回顶部]