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    • 专利摘要:
    N-{4-[2-(Pyrazole-1-carbonamide)-ethyl]-benzenesulphonyl}-ureas of the formula 1 <IMAGE> wherein R, R2 are a hydrogen atom or lower alkyl of up to 4 carbon atoms, R1 is a hydrogen, chlorine or lower alkyl atom containing up to 4 carbon atoms and R3 is an alkyl of 2 to 5 carbon atoms or cycloalkyl of 5 to 6 carbon atoms, and their method of preparation is described, said compounds possessing biological properties, capable of decreasing the sugar level in blood.
    公开号:SU816398A3
    申请号:SU782688156
    申请日:1978-11-24
    公开日:1981-03-23
    发明作者:Бжозовски Здзислав；Магелка Станислав；Ангельски Стэфан；Яницки Станислав；Вуйциковски Чэслав；Якубовски Зэнон
    申请人:Старогардзке Заклады Фармацэутычнэ"Польфа"；Акадэмия Мэдычна (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new Ν- 2 - {(pyrazol-1 == V
    uh ~ nnsn £ sn ; and·
    where R and R 2 are hydrogen or alkyl c ^ -c 4 ; 10
    Rj is hydrogen, chloro, alkyl with 4 -C 4 ;
    R is alkyl C ^ -Cg, cycloalkyl Cj.-C (which have a strong effect, 15 lowering the blood glucose concentration, low toxicity and are well tolerated by people when administered orally, so they can be used in pharmaceutical arthritis and as oral hypoglycemic agents for the treatment of sugar disease.
    The proposed method is based on the well-known chemical reaction for the production of 25 carboxylic acid amides by the interaction of acid chlorides with the corresponding amines [1].
    However, the use of Y- as one of the starting compounds [4–30
    -carbonamide) -ethyl] -benzenesulfonyl · -urea of the general formula
    - (2-aminoethyl) -benzenesulfonyl] urea of the general formula
    where - has the above meanings, allows to obtain new compounds with improved hypoglycemic properties.
    The purpose of the invention is to obtain new useful compounds of General formula I, which allow to expand the arsenal of means of exposure to a living organism.
    This goal is achieved in that the preparation of sulfonylurea derivatives of the general formula I, the distinguishing feature of which is that the N- [4- (2-aminoethyl) -beneolsulfonyl) urea of the general formula II, are reacted with pyrazole-1-car hydride with chloran 816398. of bronic acids of the general formula · / GDO R, R ^ HR 2 have the above values at 15-25 ° C in a medium of dipole aprotic solvents in the presence of acid binding agents.
    Example 1. To a suspension of 16.3 g of 1 (0.05 mol) of I- [4- (2-aminoethyl) ben / zolsulfonyl] -I-cyclohexylurea in 120 ml of dimethyl sulfoxide is added 6.55 g (0.065 mol) three ' ethylamine and, while stirring for 30 minutes at 18-20 ° C, a solution of 7.9 g (0.055 mol) of 3-methyl-pyrazole-1-carboxylic acid chloride in 30 cm of methylene chloride is added dropwise, and then everything is stirred for 2 h at room temperature. Sludge, unreacted I- [4- (2-aminoethyl) -
    - benzenesulfonyl J-N'-cyclohexylurea, filtered and the filtrate introduced into a solution of 8 g of sodium carbonate in 500 ml of water, preheated to 50 ° C. The resulting solution was decolorized with activated carbon and, stirring at a temperature of 20 ° C, 8% hydrochloric acid was added dropwise to pH 1. The precipitate formed was filtered off, washed with water and dried, and then it was purified from crystallization by crystallization. 9.9 g of N- $ 4- are obtained [2-
    - (3-Methylpira.zol-1-carbonamide) -ethyl] -benzenesulfonyl} -I-cyclohexylurea with so pl. 149-150 ° C. Yield • *, 5.8% ·
    Found,%: C 55.40) H 6.29)
    N, 16.26.
    c 2o h 27 n 5 o s.
    Calculatedί,%: C 55.40; H 6.27;
    I am 16.15.
    Similarly, from 7.18 g (0.055 mol) of pyrazole-1-carboxylic acid chloride and 16.3 g (0.05 mol) of N- [4-, - (2-aminoethyl) -benzenesulfonyl] -I-cyclohexylurea is obtained by crystallization from hydrated methanol, 9.4 g of Я-} 4- [2- (pyrazole-1-carbonamide) ethyl] benzene sulfonyl} -I * cyclohexylurea with mp 166167 ° С. Yield 44.8%.
    Found,%: C 54.26) H 6.29)
    N, 16.88.
    C 49 N 25 N 5 ° 4 S
    Calculated,%: C 54.39, H 6.00,
    N, 16.69.
    Of 8.72 g (0.055 mol) of 3, 5-dimethylpyrazole-1-carboxylic acid chloride and 16.3 g (0.05 mol) of M- [4- (2-aminoethyl) benzenesulfonyl]. -I * -cyclohexylurea is obtained after crystallization from hydrated methanol, 7.8 g of N- [4- [2- (3,5-dimethylpyrazole-1-carbonamide) ethyl]
    - benzenesulfonyl] -I f -cyclohexylurea with so pl. 159-160 s, with a yield of 34.8%.
    Found,%: C 55.92) H 6.25, ’
    N, 15.58.
    Calculated,%: C 56.35) H 6.53, I 15.64.
    From 8.72 g (0.055 mol) of 3,4-dimethylpyrazole-1-carboxylic acid chloride and 16.3 g (0.05 mol) of I- [4- (2-aminoethyl) -benzenesulfonyl, J-I'-cyclohexylurea is obtained after crystallization from methanol 11.65 g I - [4- [2- (3,4-dimethylpyrazole-1-carbonamide) -ethyl] -benzenesulfonyl} -I'-cyclohexylurea with so pl. 163-164 ° C. Yield 52.1%.
    Found,%: C 56.43) H 6.57, 'I 15.69.
    C 24 N 2E ° 4 S
    Calculated,%: C 56.35) H 6.53,
    I am 15.64.
    Of 9.49 g (0.055 mol) of the acid chloride of 3,4,5-trimethylpyrazole-1 ~ carboxylic acid and 16.3 g (0.05 mol) of N- [4- (2-aminoethyl) -benzenesulfonyl] -N * - cyclohexylurea is obtained after crystallization from hydrated methanol 9 g of I- [4- [2- (3,4,5-trimethylpyrazole-1-carbonamide) ethyl] · benz olsulfonyl] -I 1 -cyclohexylurea with so pl. 146-147 ° C. Yield 38.9%.
    Found,%: C 57.32) H 6.57)
    N15.46.
    S 22. N 34 M 4 S '
    Calculated,%: C 57.24) H 6.76) I 15.17.
    From 9.49 g (0.055 mol) of 3-ethyl-4-methylpyrazole-1-carboxylic acid chloride and N [-4- (2-aminoethyl) -benzenesulfonyl] -I 1 -cyclohexylurea, 15.8 g are obtained after crystallization from hydrated methanol I - (4- [2- (3-ethyl-4-methylpyrazole-1-carbonamide) ethyl] benzene sulfonyl-i'-cyclohexylurea with a mp of 150-150 ° C, in 68.4% yield.
    Found,%: C 57.48) H 6.78) I 15.07.
    C N 5Ό4 S. ·
    Calculated,%: С 57.24) Н 6.76, Я 15.17.
    Example 2. In 50 ml of water, successively, 0.6 g (0 .015 mol) of sodium hydroxide and 4.85 g (0.015 mol) of I- [4- (2-aminoethyl) benzenesulfonyl] —I * cyclohexylurea are dissolved. Then, a solution of 2.6 g (0.018 mol) of 3-methylpyrazole-1-carboxylic acid chloride in 20 ml of acetone is introduced dropwise at 18-20 ° C. over 2 hours, maintaining the pH of the mixture within 8-9 ways of gradually adding 20% solution of sodium hydroxide in water. After the next 4 hours of stirring at room temperature, 50 ml of water are poured, ___ discolored with activated charcoal and, introducing dropwise 8% hydrochloric acid to pH 1, a precipitate is formed, which is filtered off, washed with water and dried, and then crystallized from methanol. 3.3 g of N- ς - | 4- [2- (3-methylpyrazole-1-carbonamide) -ethyl] -benzenesulfonyl] -m'-cyclohexylurea are obtained with so pl. 149-150 ° C. Yield 50.76%.
    In the same way, starting from 3.35 g (0.018 mol) of 3,5-dimethyl-4-ethylpyrazole-1-carboxylic acid chloride and 4.85 g (0.015 mol) of N-f4- (2-aminoethyl) -benzenesulfonyl] -N-cyclohexylureas, 4.3 g of N- {4 - (2- (3,5-diMetyl-4-ethylpyrazole-1-carbonamide) ethyl] benzene sulfonyl} -N 1 are obtained after crystallization from hydrated 15 methanol -cyclohexylurea with mp 143-144's.
    60.8%. 20
    Found,%: C 58.09, ’H 6.73) N 14.73.
    H 33 ^ 5 θ4 ‘
    Calculated,%: C 58.08, H 6.99, N14.72. 25
    Of 3.22 g (0.018 mol) of 3-methyl-4-chloropyrazole-1-carboxylic acid chloride and 4.85 g (0.015 mol) of Ν- (4- (2-aminoethyl) benzene sulfonyl] -Ν 1 -cyclohexylurea after jq crystallization from hydrated methanol, 3.6 g of N - [2 - (3-methyl-4-chloropyrazol-1-c-carbonyl amide) -ethyl] -benzenesulfonyl] -Ν'-cyclohexylmene evine are obtained with t mp 176-177 ° С and s.vykho ,, house 51.3%. *
    Found,%: C 51.38; H, 5.45; ‘N, 15.16.
    Cho "26 M 4 SC1.
    Calculated,%: C 51.32) H 5.60;
    N14.96. 40
    In the same way, from 2.6 g (0.018 mol) of 3-methylpyrazole-1-carboxylic acid chloride and 4.49 g (0.015 mol) of N- [4- (2-aminoethyl) benzene sulfonyl] -M'-p- butyl-45 chevins are obtained after crystallization from hydrated methanol 3.49 g of N- ^ 4- [2- (3-methyl-pyraeol-1-carbonamide) -ethyl] -benzenesulfonyl} -and'-p-butylurea with so pl. 145-147’s jq Yield 57.2%.
    Found,%: C 5 3.31 ', H 6.42) N 17.39.
    H 25 N y 0 4 S.
    Calculated,%: C 53.05 H 6.18, N17.18. ''
    Example 3. 0.6 g (0.015 mol) of sodium hydroxide and 4.28 g (0.015 mol) of N- [4- (2-aminoethyl) benzosulfonyl] -№-p-propylurea are alternately dissolved in 50 mp of water. 6 © us. Then, a solution of 2.6 g (0.018 mol) of 3-methylpyrazole-1-carboxylic acid chloride in 20 ml of acetone is introduced dropwise at 20-25 ° C. over 2 hours; The pH of the mixture is maintained at 65 level 8-9 by the gradual addition of a 20% solution of sodium hydroxide in water. After the next 4 hours of stirring at room temperature, 50 ml of water are poured, decolorized with activated charcoal and, dropwise added, 8% hydrochloric acid acid to pH 1, a precipitate is formed, which is filtered off, washed with water and dried, and then crystallized from methanol.
    Obtain 3.04 g of N- | 4- [2- (3-methylpyrazole-1-carbonamide) ethyl] beneolsulfonyl ^ -H * -p-pfopylurea with so pl. 14b-148 ° C. Yield 51.6%.
    Found,%: C 52.07; H, 6.03; N, 18.01.
    C 47 "23 M 4 S
    Calculated,%: С 51.89) Н 5.89, ’N 17.80.
    Example 4. 0.6 g (0.015 mol) of sodium hydroxide and 4.67 g (0.015 mol) of N- (2-aminoethyl-benzenesulfonyl) -8-cyclopentylurea are alternately dissolved in 50 ml of water. Then, a solution of 2.6 g (0.018 mol) of 3-methylpyrazole-1-carboxylic acid chloride in 20 ml of acetone is introduced dropwise at 18-20 ° C. over 2 hours, maintaining the pH of the mixture within 8-9 by gradually adding 20% aqueous solution of sodium hydroxide.
    After the next 4 hours of stirring at normal temperature, add 50 ml of water, decolorize with activated charcoal and, dropwise adding 8% hydrochloric acid to pH 1, precipitate, which, after filtering, washing with water and drying,. 'subjected to crystallization from hydrated methanol.
    Obtain 3.06 g of N- | 4- [2- (3-methylpyrazole-1-carbonamide) ethyl] benzene sulfonyl] -N '-cyclopentylurea with so pl. 148-149’s, and its yield is 47.0%.
    Found,%: C 54.23, H 6.20, N 16.80.
    Calculated,%: C 54.39; H, 6.00; N, 16.69.
    From 3.10 g (0.018 mol) of 3,4,5-trimethylpyrazole-1-carboxylic acid chloride and 4.67 g (0,015 mol) of Ν- (4- (2-aminoethyl) benzodsulfonyl] ~ -Ν-cyclopentylurea obtained after crystallization From hydrated methanol, 2.96 g of Ν- | 4- (2- (3,4,5-trimethylpyrazole-1-carbonamide) -ethyl] -benzenesulfonyl ^ -N'-cyclopentylurea with a melting point of 166-167 'C, with a yield of 44.2%.
    Found,%: C 56.46, H 6.15, N 15.66.
    Nj-O ^ S.
    Calculated,%: C 56.35 ', H 6.53',
    N, 15.64.
    Example 5. 6.36 g (0.06 mol) of anhydrous sodium carbonate and 4.85 g (0.015 mol) of N- [4 • - (2-aminoethyl) -benzenesulfonyl] are successively dissolved in 100 mp water. b-cyclohexylurea. Then, a solution of 2.6 g (0.018 mol) of 4-methylpyrazole-1-carboxylic acid chloride in 20 mp acetone is added dropwise at 18-22 ° C. over 2 hours.
    After the next 4 hours of stirring at ordinary temperature, 50 ml of water are added, decolorized with activated carbon, and, dropwise adding 8% hydrochloric acid to pH 1, a precipitate precipitates, which, after filtration, washing with water and drying, is crystallized from methanol. 3.51 g of N- ^ 4- (2- (5-methylpyr-15 .zol-1-carbonamide) -ethyl] -benzenesulfonyl | -m'-cyclohexylurea are obtained with a melting point of 168-169 ° C, at the exit 54.1%.
    Found,%: C 55.81 *, H 6.22; N, 16.43.
    ^ 2o ^ 27 N5Q4
    Calculated,%: C 55.40; H 6.27;
    N, 16.15.
    Similarly, from 3.86 g (0.018 mol) of 3,5-dimethyl-4-C-butylpyrazole-1-carboxylic acid acid chloride and 4.85 g (0.015 mol) of N- [4t- (2-a ”“ noethyl ) - benzenesulfonyl-N'cyclohexylurea is obtained after crystallization from hydrated methanol 3.36 g of N- | 4- [2- (3,5-dimethyl-n-butylpyrazole-1-carbonamide) -ethyl] -benzenesulfonyl ^ -N-cyclohexylurea with mp 134-135 ° C, with a yield of 44.5%.
    Found,%: C 59.50; H, 7.34; N, 14.01. Cu r H 0, S.
    Calculated,%: C 59.61; H, 7.40; N, 13.90.
    The hypoglycemic effect of N- | 4-C2- (pyrazole-1-carbonamide) -ethyl] -benzenesulfonyl-urea obtained by this method can be observed by oral administration of these drugs to mice, rats, rabbits or humans, then determining the concentration of glucose in the blood of known enzymatic method using glucose oxidase.
    Using the method, it was found that these compounds have a very high ability to lower the concentration of glucose in the blood, many times higher than what can be observed in the case of Glibornuride or Glibenclamide, which are currently considered the most active and effective antidiabetic sulfonylureas.
    - (2-endo-hydroxy-3-endo-bornyl) -, urea (Glibornuride) in three different animal species, it was found that the activity of the new compound both by oral and parenteral administration is approximately two times higher than Glibornuride activity.
    A single oral administration of the new compound causes longer hypoglycemia than the use of Gliboryuride. After another 9 hours from the administration of a single dose to rats, a reduced level of glucose in the blood is detected, while after the use of Glibornuride, after 6 hours, the normal level of glucose concentration is restored.
    Pharmaceutical preparations containing a new active substance, such as tablets, coated tablets, extended-release tablets, dragees, or powders, which include known carriers and excipients, such as talc, starch, lactose, magnesium stearate, gelatin, avitel, film formers , skeletal substances, as well as other additional or hypoglycemic agents can be produced in a convenient form for use, providing action at a certain time. A single dose of a new biologically active agent is due to its biological effectiveness and the desired effect of its action and ranges from 0.5 to 50 mg; optimal. naya dose - 1-10 mg.
    权利要求:
    Claims (5)
    [1]
    This invention relates to a process for the preparation of new N- | 4- 2 - {(pioazop-1y-e-NHCH CH -carreonamide) -ethyl-benzalsulfonyl-ureas of the general formula SOgHH-C-NHfly f with pyrazole-1-carboxylic acid with the total formulas / where Rn have superior injections, at 15-25 ° C in a medium of dipole aprotic solvents in the presence of an acid binder. Example 1. To a slurry of 16.3 g {0.05 mol) (2-aminoethyl) ben / zolsulfonyl-M-cyclohexyl urea in 120 ml of dimethyl sulfoxide were added 6.55 g (0.965 mol) of triethylamine and stirring for 30 minutes at .18-20 0, a solution of 7.9 g (0.055 mol) of 3-methyl-pyrazole-1-carboxylic acid chloride in 30 cm of methylene chloride is added dropwise, and then everything is stirred for 2 hours at room temperature. The precipitate of unreacted (2-aminoethyl) -benzenesulfonyl J-N-cyclohexylmobenum is filtered and the filtrate is introduced into a solution of 8 g of sodium carbonate in 500 ml of water, preheated to 50 ° C. The resulting solution is decolorized with activated carbon and, by stirring at a temperature of 20 ° C, introducing dropwise 8% hydrochloric acid to pH 1. 1. The precipitate is filtered off, washed with water and dried and then purified by crystallization from methanol. 9.9 g of N-i4- 2- (3-methylpyrazole-1-carbonamide) -ethyl-benolesulfonyl | -M-cyclohexyl urea with m.p. 149-150 ° C. Yield: 3.8%.: Found,%: C 55.40; H 6.29) H 16.26 .., 5 ° 4 Calculated,%: C 55.40; H 6.27; I am 16.15. Similarly, from 7.18 g (mol of pyrazole-1-carboxylic acid chloride and 16.3 g (0.05 mol) of M-4-. - (2-amino-ethyl) -benzenesulfonyl -N-cyclohexyl urea) is obtained by crystallization from hydrated metaiol 9 , 4 g (pyrazole-1-carbonamide) -ethyl-benzenesulfonyl-N-cyclohexyl urea with mp.166IGT C. Yield 44.8%. Found: C 54.26, H 6.29; N 16.88 H N 04 S ... Calculated,%: C 54.39, H 6.00, N 16.69. From 8.72 g (0.055 mol) of acid chloride 3, 5-dimethylpyrazole-1-carboxylic acid and 16, 3 g (0.05 mol) of 2-aminoethyl) -benzenesulfonyl. -H-cyclohexyl urea, after crystallization from hydrated methanol, 7.8 g (3, 5-dimethylpyrazole-1-carbonamide) -ethyl-benzenesulfonyl-N-cyclohexyl urea with m.p. 159-160s, with an output of 34.8%. Found,%: C 55.92; H b, 25, N 15.58, C, H .. Calculated,%: C 56.35) H 6.53, M 15.64. From 8.72 g (0.055 mol) of 3,4-dimethylpyrazole-1-carboxylic acid halogenide and 3,3-dimethylpyrazole-1-carboxylic acid and 16.3 g (0.05 mol) of M-It - (2-amnoethyl) -benzol PhiMyl-N-cyclohexylurea is obtained after crystallization from methanol 11.65 g of N - | 4- 2- (3,4-dimethylpyrazole-1-carbonamide) -ethyl-benzenesulfonyl 5-N-cyclohexyl urea with m.p. 163-164 C. The yield is 52.1%. Found,%: With 56,43; H 6.57 / N 15.69. . Calculated,%: C 56.35; H 6.53, H 15.64. From 9.49 g (0.055 mol) of hlcэ | anhydride of 3,4,5-trimethylpyrazole-1-carboxylic acid and 16.3 g (0.05 mol) of N —C 4- (2-aminoethyl) -benzenesulfonyl —N - cyclohexyl urea after crystallization from hydrated methanol 9 g (3,4, 5-trimethylpirazol-l-carboxamide) -ethyl-benzosulphonyl-N-cyclohexylurea with m.p. 146-147 ° C. The yield of 38.9%. Found,%: C 57.32; H 6.57; 1P5.46. C22 .. Calculated,%: C 57.24; H 6.76; N 15.17. From 9.49 g (0.055 mol) of 3-ethyl-4-m-methylpyrazole-1-carboxylic acid chloride and N f-4- (2-amino-ethyl) -benzenesulfonyl-J-N-cyclohexyl urea, after crystallization from hydrated methanol, 15.8 g are obtained. 4- 2- (3-ethyl-4-methylpyrazole-1-carbonamide) -ethyl-benzenesulfonyl-N-cyclohexyl urea with m.p. 150151 ° C, with the release of 68.4%. Found,%: C 57.48; H 6.78; N 15.07. .p04S. . Calculated,%: C 57.24; H 6.76, N 15, -17. Example
    [2]
    2. 0.6 g (0, .015 mol) of latry hydroxide and 4.65 g (0.015 mol) of (2-aminoethyl) -benzenesulfonyl 3-N -cyclohexylurea are alternately dissolved in 50 mp of water. A solution of 2.6 g (0.018 mol) of 3-methylpyrazole-1-carboxylic acid chloranhydride in 20 ml of acetone is then added dropwise with 18-20s over 2 hours, maintaining the pH of the mixture within 8-9 ways of gradually adding sodium hydroxide solution in water. After the next 4 hours of rinsing at room temperature, 50 ml of water are added. 8% hydrochloric acid is added dropwise with activated carbon to a pH of 1, a precipitate is formed, which is filtered, washed with water and dried, and then crystallized from methanol. 3.3 g (3-methylpyrazole-1-carbonamide) -ethyl-benzene-sulfonyl-J-N-cyclohex of urea with m.p. 149-150 pp. 9 output 50.76%. In the same way, starting from 3.35 g (0.018 mol) of 3,5-dimethyl-4-ethylpyrazole-1-carbonic acid chloride and 4.85 g (0.015 mol) of (2-aminoethyl) benzenesulfonyl-M-cyclohexyl urea after crystallization from hydrated iridated methanol, 4.3 g of N- {4 (3,5-dil4ethyl-4-ethylpyrazole-1-carbonamide-ethyl-benzene sulfonyl 5-N-1 × cyclohec of urea with mp. 143-144s is obtained. , 8%. Found,%: C 58.09, H 6.73; N 14.73. Calculated,%: C 58, Ob, H 6.99, N14.72 Out of 3.22 g (0.018 mol ) 3-methyl-4-chloropyraz-ol-1-arboxylic acid chloride and 4.85 g (0.015 mol) of N-f4- (2-aminoethyl) -benzenesulfonyl -N-cyclohexylureas after crystallization from hydrated methanol, 3.6 g of (3-methyl-4-chloropyrazole-1-carbonamide) -ethyl-benzenesulfonyl -N-cyclohexylmolyne with m.p. and c are obtained in a yield of 51.3%. Found, %: C 51.38; H 5.45 / N 15.16. Cho 2bM504 C1. Calculated: C 51.32; H 5.60, N 14.96. Similarly, from 2.6 g (O , 018 mol) 3-methyl-nitrazap-1-carboxylic acid chloride and 4.49 g (0.015 mol) of (2-aminoethyl) -benoenesulfonyl-n -n-butyl-chevine are obtained after crystallization from hydrated methanol: 3.49 g (3 methylpyrazole-1-carbonamide) -ethyl-benzenesulfonyl} -m-butylurea with m.p. 145-147C. Yield 57.2%. C 53.31; H 6.42; Found,%: N 17.39. Sd N „Ny 0. S. Calculated,%: G 53.05; H 6.18, N17.18. Example
    [3]
    3. Into 50 ml of water alternately add 0.6 g (0.015 mol of sodium hydroxide and 4.28 g (0.015 mol) of (2-aminoethyl) benzosulfonyl-N-p-propyl moiety. Then, in 2 hours, at 20-25 ° C, a solution of 2.6 g (0.018 mol) of 3-methylpyrazole-1-carboxylic acid chloride in 20 m of acetone is kept; the pH of the mixture is maintained at 8-9 by gradually adding 20% sodium hydroxide solution in water . After expulsions for 4 hours, at 50 ° C, they are poured at room temperature, 50 ml of water are poured, they are decolorized with activated carbon and, drop by drop, 8% hydrochloric acid to a pH of 1 ok, which is filtered off, washed with water and dried, and then crystallized from methanol to give 3.04 g of N- | 4-G2- (3-methylpyrazole-1 carbonamide) -ethyl-benzenesulfonyl -M-nn |) opilurea with m.p. 146-148 ° C. Yield 51.6%. Found,%: C 52.07; H 6.03, N 18.01. . Calculated,%: C, 51.89; H 5.89; N 17.80. Example
    [4]
    4. Into 50 ml of water alternately dissolve 0.6 g (0.015 m) of sodium hydroxide and 4.67 g (0.015 mol) of M- {2-aminoethyl gbenzalsulfonyl) - M-Cyclopentyl urea. A solution of 2.6 g (0.018 mules) of 3-methylpyrazole-1-carboxylic acid chloride in 20 ml of acetone is then added dropwise at 18-20 ° C over 2 hours while maintaining the pH of the mixture within 8-9 by gradually adding 20 % aqueous solution of sodium hydroxide. After the next 4 hours of stirring at normal temperature, a fraction of -. 50 ml of Veda are decanted, the carbon is decolorized with activated carbon and, dropwise injecting 8% hydrochloric acid to pH 1, a precipitate is precipitated, which after filtration, washing with water and drying,. subjected to crystallization from hydrated methanol. 3.06 g of M- | 4- 2- (3-methylpirazol-l-carbonamide) -ethyl-benzenesulfonyl-M-cyclopentyl urea with m.p. 148-149 ° C, and its yield is 47.0%. Found,%: C 54.23; H 6.20, N 16.80. Cj. HjyNj-G.S. Calculated,%: C 54.39; H 6.00; N 16.69. From 3.10 g (0.018 mol) of 3,4,5-trimethylpyrazole-1-carboxylic acid chloride and 4.67 g (0.015 mol) of (2-amino-ethyl) -benzenesulfonyl-N -cryclopentyl urea, is obtained after crystallization from hydrated methanol 2 , 96 g of tsJ- | 4-.2- (3,4,5-trimethylpirazol-l-carbonamide) -ethyl-benzenesulfonyl-N-cyclopentyl urea with m.p. 166-167 0, with an exit of 44.2%. Found,%: C 56.46, H 6.75 H, 15.66. Cai%) “r04S С S6.35, H 6.53, Calculated,% N, 15.64.
    [5]
    5. In an example, 6.36 g (0.06 mol) of anhydrous sodium carbonate and 4.85 g (0.015 mol) are dissolved in 100 mg of water. - 2-g1 inoethyl) -benzenesulfonyl-M.-cyclohexylurea. A solution of 2.6 g (0.018 mol) of 4-methylpyrazole-1-carboxylic acid chlorine solution in 20 ml of acetone is then added dropwise at 18-22 over 2 hours. After the next 4 hours, at a usual temperature, 50 ml of water are added at ambient temperature, decolorized with activated charcoal and, by adding dropwise 8% hydrochloric acid to pH 1, precipitation gives a precipitate, which after filtering off; washing with water and drying are crystallization from methanol. 3.51 g of (5-methylpyr. Sol-1-carbonamide) -ethylJ-benzenesulfyl-N-N-cyclohexylurea are obtained, m.p. 168-169 ° C, with a yield of 54.1%. C 55.81; H 6.22; Found,%: N 16.43. C20 "27 NyO S from 55.40, - H 6.27; Calculated% N 16.15. Similarly, from 3.86 g of 10.018 mol of 3,5-dimethyl-4-H-butylpyrazole-1-carboxylic acid chloride and 4.85 g (0.015 mol) of - (2-ai “noethyl) -benylsulfonyl-N-cyclohexylurea after crystallization from hydrated methanol, 3.36 g of (3,5-dimethyl-p-butylpyrazole-1-carbonamide) -ethyl f-benzylsulfonyl-N-cyclohexyl urea with m.p. 134-135 With, with an exit -. Found,%: C 59.50; H 7.34: N 14.0 C, jH, NO, S. Vimisleno,%: C 59.61; H 7.40; And 13.90. 1H1Poglycemizing the effect of N- | 4-C2- (pyrazole-1-carbonamide) -ethyl-benzenesulfonyl-urea, obtained by this method, can be observed by oral administration of these funds to mice, rats, rabbits or lms, then determined the concentration of glucose in the blood known enzymatic method using gluco 3 oxidase. With the help of the method, it has been established that these compounds have a very high ability to lower the concentration of glucose in the blood, which is several times higher than that observed with the use of GlyOornurid or Glibenclamide, which are currently considered to be the most active and effective anti-diabetic sulfonylureas. In the study of the hypoglycemic effect of one of the compounds obtained, i.e. (3-methylpirazol-l-carbonamide) -ethyl-benzolfonyl-N -cyclohexyl urea and compounds of the N- (p-toluenesulfonyl) -n- (2-endo-hydroxy-3-endo-6-urrnyl) urethyne nomerichesous n-cyclohexyl) in three different animal species, it was established that the activity of the new compound, both by oral and parenteral administration, is about twice as high as that of Gliborbornuride. A single oral administration of a new compound causes more prolonged hypoglycemia than the use of Gliburyurid. After a further 9 hours from the time of administration of the single dose to the rats, a reduced level of glucose in the blood is detected, while after the use of Gliborne after 6 hours, the normal level of glucose termination is restored. Pharmaceutical preparations containing a new active ingredient, such as tablets, film-coated tablets, prolonged-release tablets, dragees, or porosity, which include well-known carriers and auxiliaries, such as talc, starch, lactose, magnesium stearate, gelatin, avicel, film-forming agents, skeletal substances, as well as other additional or hypoglycemic agents can be produced in a (convenient for use form that provides action at a certain time. Single dose of a new biol of a physically active agent due to its biological efficacy and the desired effect of its action and ranges from 0.5 to 50 mg, optimally at a dose of 1-10 mg. Formula of the invention The method of obtaining N-} 4- 2- (pyrazole- 1- carbbnamide) -ethyl-benz olulfonyl urea of the general formula X H - HHCHgCHf-L i O NH-CrNH-K t where R and ftj mean hydrogen or alkyl, hydrogen, chlorine, alkyl R. - alkyl C1-O, cycloalkyl different in that and that the (2-aminoethyl) -benzenesulfonyl} -urea in the general formula NCH ... H C-NH-K, where Rj is as defined above, undergoes the interaction staying true with chlorides pyrazole-1-carboxylic acids of general formula ft- c ce
    981639810
    where R, R have indicated sources of information,
    Eiacheni, at a temperature of 15-25 C taken into account during the examination
    in the medium of dipole aprotic solutions - / 1. Bühler K. Pearson D. Organizers in the presence of means, their syntheses. M., Mir, Part 2, 1973,
    zanyu an acid. with, ZM.
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    同族专利:
    公开号 | 公开日
    DE2759241B2|1980-07-24|
    JPS5633391B2|1981-08-03|
    PL106114B1|1979-11-30|
    PL195000A1|1978-11-20|
    JPS53149974A|1978-12-27|
    DE2759241C3|1981-05-21|
    DE2759241A1|1978-07-06|
    SU789520A1|1980-12-23|
    US4153710A|1979-05-08|
    GB1592380A|1981-07-08|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CH516578A|1967-11-02|1971-12-15|Bayer Ag|Process for the preparation of arylsulfonylureas containing heterocyclic acylamino groups and having an antihypertensive effect|
    US3668215A|1967-11-25|1972-06-06|Bayer Ag|Aryl-sulphonyl-semicarbazides containing heterocyclic acylamino groups|
    US3887709A|1971-09-16|1975-06-03|Zdzislaw Brzozowski|2-Pyrazoline-1-carboxamide sulfonamide derivatives useful as hypoglycemic agents|
    CH593263A5|1974-02-22|1977-11-30|Hoffmann La Roche|
    GB1505518A|1975-05-30|1978-03-30|Kyorin Seiyaku Kk|Pyrazole derivatives|UA84390C2|2001-12-21|2008-10-27|Ново Нордиск А/Я|Amide derivatives as glucokinase activators|
    EP1531815B1|2002-06-27|2014-09-24|Novo Nordisk A/S|Glucokinase activators|
    MXPA06007667A|2004-01-06|2006-09-01|Novo Nordisk As|Heteroaryl-ureas and their use as glucokinase activators.|
    EP1904438B1|2005-07-08|2012-02-29|Novo Nordisk A/S|Dicycloalkylcarbamoyl ureas as glucokinase activators|
    AU2006268708A1|2005-07-08|2007-01-18|Transtech Pharma Inc.|Dicycloalkyl urea glucokinase activators|
    AU2006268589B2|2005-07-14|2011-09-29|Vtv Therapeutics Llc|Urea glucokinase activators|
    EP2118083A1|2007-01-09|2009-11-18|Novo Nordisk A/S|Urea glucokinase activators|
    AU2008204530B2|2007-01-11|2013-08-01|Vtv Therapeutics Llc|Urea glucokinase activators|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    PL1976195000A|PL106114B1|1976-12-31|1976-12-31|METHOD OF MAKING NEW N--Urea|
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