• 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:
    Novel enol ethers of 6-chloro-4-hydroxy-2-methyl-N-(2-pyridyl) -2H-thieno-[2,3-e]-1,2-thiazine-3-carboxylic acid amide-1,1-dioxide of the formula …<IMAGE>… in which R denotes (C1-C6)-alkyl, (C5-C7)-cycloalkyl or benzyl, and a process for their preparation. The novel compounds have antiinflammatory activity and are suitable for the treatment of rheumatism.
    公开号:SU1591813A3
    申请号:SU884356752
    申请日:1988-10-28
    公开日:1990-09-07
    发明作者:Diter Binder；Franz Rovenski；Hubert Peter Ferber
    申请人:Cl Pharma；
    IPC主号:
    专利说明:

    The invention relates to heterocyclic compounds, in particular the method of obtaining the enol esters of amides ’
    1,1-dioxo-6-chloro-4-hydroxy-2-methyl-y (2-pyridyl) -2H-thieno [2,3-e] thiazine-3carboxylic acid total f-ly
    _
    '0H = -CC1-5-C = C-8 (O) 2 -I (CH 3 ) -C2 = C0-CH (CH 3 ) -0-C (0) -0K, where Ζ is -C (0 ) -IN-C = CH-CH = CH-CH = CN ^ K - C 4 -C 6 -alkyl, which have anti-inflammatory effect, which can be used in medicine. The goal is to create new, more active compounds of the specified class. The process is carried out by the reaction of an alkali metal carbonate first. With a compound of f — ly II, and then with the so-called fusion of III: Χ-ΟΗ (ΙΙ),
    CH 3 SI (U) OS (O) 0K (111), where Υ - 'halogen; X and K, see above, when heated in an inert polar solvent. It is desirable to use acetone as a solvent, the process should be carried out at boiling with the addition of 1,5- £
    ; 2.0 mol Aa1 per 1 mole of ether III. New compounds cause a 50% newer retardation of inflammation caused by carrageen- 2 at a dose of 0.29 mg / kg (versus 0.46 mg / kg for chloro-pen-xycam) with almost the same toxicity as known (LP £ 0. In the range of 2496 mg / kg), 4 c.p. f-ly, 2 tab.
    1591813
    The invention relates to organic chemistry, in particular to a method for producing new compounds - enol esters of 1,1-dioxo-6-chloro-4-hydroxy-2-methyl-N- (2-pyridyl) -2H-thieno amides [2,3 -e] thiazin-3-carboxylic acid with anti-inflammatory activity, which suggests the possibility of their use in medicine.
    The purpose of the invention is to obtain new derivatives in the series of amides of 1,1-dioxo-6-chloro-4-hydroxy-2-methyl-L- (2-pyridyl) -2H-thieno [2,3-e] thiazin-3-carboxylic acids with stronger anti-inflammatory effects in this series of compounds.
    Example 1. Getting amide
    1 "1-dioxo-6-chloro-4- (1-ethoxycarbonyl3
    1591813 4
    20
    25
    hydroxy) -ztoxy-2-methyl-Ν- (2-pyridyl) 2H-thieno [2,3-e] -1,2-thiazine-3-carboxylic acid (compound I).
    10 g (26.9 mmol) amide is boiled
    1,1-dioxo-6-chloro-4-hydroxy-2-methyl-y (2-pyridyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxylic acid, 9.29 g (99.5 mmol) of potassium carbonate and 15.1 g (99.5 mmol) of 1-chloroethyl carbonate in 150 ml of acetone 20 and. Then add
    24.5 g (163.3 mmol) of sodium iodide and boil for another 5 hours. After that, the precipitated sodium chloride is sucked off, the filtrate is evaporated and 15 are distributed between 100 ml of methylene chloride and 100 ml of a saturated sodium bicarbonate solution. The phases are separated and the organic phase is washed with 100. ml of labor and 20 ml of 3% sodium bisulfite solution. Dry over sodium sulfate, filter, and evaporate. The resulting oily crude product (17.5 g) is filtered through silica gel (100 g silica gel-60, grain size 0.040.063 mm, solvent methylene chloride: ethyl acetate 9: 1). 10.1 g of light orange crystals are obtained. The latter are dissolved in 17 ml of dioxane at boiling point, the solution is mixed with 0.6 g of activated carbon and then filtered while hot. Cool and mix with 40 mp dietary ether. The precipitated colorless crystals are sucked off, washed with ether and dried at 50 ° C / 1 mbar. Output
    6.3 g of colorless crystals (48% of theory), so pl. 148 ^ 0 (decomposition).
    1 H-NMR (csGe) <P, ppm: 8.9 (p. Nir. 1Y, -ΝΗ-); 8.3 (m. 2H, Ru-N);
    7.8 (m. 1H, Ru-N); 7.2 (p. 1H, TH-H);
    7.1 (m. 1H. Ru-N); 6.5 (q, 1H, b-CH-O);
    4.1 (q, 2H, -CH 2 -); 3.2 (s., 3N, Ν-ΟΗ 3 );
    . 1.7 (d, OG, -CH-CH 3 ); 1.2 (t., 3N,
    g sc 2 -sn 3 ).
    1 * 13 С-NMR '(SPS1 E ) <G, ppm; ] 57.9
    153.1, 150.5, 147.9, 142.1, 137.9,
    135.9, 135.5, 134.9, Ί26.6, 121.1,
    120.1, 113.9, 100.1, 64.4, 36.7,
    19.0, 13.7 .. 50
    Example 2. The study of anti-inflammatory properties.
    Experience with swelling of a paw in a rat
    40
    45
    called carragenin.
    Reducing the intensity of the preg-.
    The effects of the test substances were checked by their inhibitory effect on the tumor, paw injection in the rat, caused by carrageenin.
    As a test substance used:
    hlrotenoksikam: a ^ id 1,1-dioxo-6-chloro-4-hydroxy-2-methyl-J- (2-pyridyl) -2Htieno [2,3-e] -1,2-thiazine-3-carboxylic acid; · '
    Chlorotenexy enol ester: 1,1-dioxo-6-chloro-4- [1- (ethoxycarb onyloxy) epoxy amide] -2-methyl-N- (2-pyridyl) -2H-thieno [2,3-e] -1,2-tiaein-Zcarboxylic acid (compound 1);
    piroxicam: 1,1-dioxo-2-methyl-Ν- (2-pyridyl) -4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid amide;
    Piroxicam enol ester: 1, 1-dioxo-4- [1- (ethoc-Cicarbonyloxy) ethoxy] -2-methyl-Ν- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxylic acid amide.
    Before the start of the experiment, the volume of the right hind paw of the rat was determined using a plethysmometer and the water was expelled in milliliters. The substances were administered as a suspension in 0.5% carboxymethyl cellulose by oral route using a gastric tube. The dosage was 0.3; 1.0; 3.0 and 10 mg / kg body weight. Eight animals tested one substance and one dose or control. After 1 hr, inflammation of the injections of 0.05 ml of a 2% solution of lambda-carrageenum in isotonic solution into the right hind paws of experimental animals was provoked. For 3 and 4 hours after the onset of inflammation, a second determination of the volume of the right hind paws of the rats was performed using a plethysmometer.
    The magnitude of doses of inhibition of inflammation (in percent) are given in table. 1. From these values, 80 and 50% of 1NB were calculated. (dose of inhibition); 80% 1NB indicates the dose of body weight that can inhibit inflammation by 80%.
    .P p. And me R 3. Determination of acute toxicity.
    To determine the acute toxicity of the rats injected orally tested substances. On the dose and sex of rats, 5 animals are tested and possible future deaths are recorded up to 2 weeks after treatment with the test substances.
    As the test substances are:
    chloroethenoxy: 1,1-dioxo-6-chloro-4-oxy-2-methyl-D- (2-pyridyl) -2Htieno [2,3-e] -1,2 amide; -thiazine-3-carbonoBoy,
    acids;
    55
    1591813
    Chlorotenexy enol ester: 1,1-dioxo-6-chloro-4- (1- (ethoxycarbonyloxy) ethoxy) -2-methyl-n- (2-pyridyl) -2H-thieno amide amide [2,3-eZ-1,2- tyazine 3-carboxylic acid.
    The results of the acute toxicity of compound 1 and chlorenoxime are presented in table. 2
    'From tab. 2 shows that the lethal dose of the studied substances is more than 24 mg / kg of body weight and less than 96 mg / kg of body weight.
    At a dose of 96 mg / kg of body weight, 6-10 animals die with the administration of chlorenoxime and 410 animals die with the administration of enol ester of chloroethyxam.
    И p and me R 4. Getting gel compounds 1.
    In the technological installation rast-. 8 g of 1,1-dioxo-6-chloro-4 [1- (ethoxycarbonyloxy) amide. ethoxy-2-methyl-L- (2-pyridyl) -2H-thieno [2,3-e] 1,2- thiazine-3-carboxylic acid in 4717 g of ethanol and 2082 g of water. 167 g of carbopol are introduced in parts with stirring into this solution. After the addition of 139 g of luvitol ENO, the initial mixture is neutralized with a solution prepared from 83 g of diisopropylamine, 833 g of ethanol and 833 g of water, and then adjusted to pH 7 using a solution consisting of 28 g of diisopropylamine, 555 g of ethanol and 555 g of water ,five. The gel is placed in tubes.
    Thus, new connections. in anti-inflammatory activity superior to chloroethenes with 'almost the same toxicity.
    权利要求:
    Claims (1)
    [1]
    Claim
    1. The method of obtaining the enol esters of amides of 1,1-dioxo-6-chloro-4-oxy2-methyl-Ν- (2-pyridyl) -2H-thieno about [2 ', 3-e] thiazin-3-carbon acids of general formula
    where K is C ^ -C 6 -alkyl,
    characterized in that the chlorotene formulas
    O 0 (i)
    ten
    15
    treated with alkali metal carbonate and the resulting salt hloretenok- .. Sikam Formula
    0 chh 0 (w>
    δ
    C1
    "" СНз 0 "М + Ν
    where M * is an alkali metal cation, directly in the reaction mixture, is reacted with ether of the general formula
    СН 3 .СНОСООК, (IV)
    25 X
    where K. has the specified value; 4 X - halogen,
    when heated in an inert polar solvent under reaction conditions.
    2. Method pop.1, characterized in that potassium carbonate is preferably taken 3-4 times as alkali metal carbonate. .
    in excess.
    35 .3, The method according to paragraphs. 1 and 2, which is based on the fact that acetone is taken as the polar solvent inert under the reaction conditions.
    40
    4. The method according to paragraphs. 1 - 3, about tl and - .. due to the fact that the interaction of the salt of chlorenoxime of the general formula (III) with the ether of the general formula (IV)
    45 lead at boiling, with reflux.
    5. The method according to claims 1-4, characterized in that, in order to accelerate the interaction of the salt of chlorenoxime of the formula (III) with the ether of the general formula (IV), sodium iodide is introduced in an amount of 1.5-2.0 mol per 1 mole ether of general formula (IV).
    7
    1591813
    eight
    Table 1
    with Substance The dose of inhibition of inflammation, ’% 3 h aftercarragenin,mg / kg Through '4 h after carragenin ,. mg / kg Geometric average, mg / kg 80% inhibition of inflammation Enol ether chloro- tenoxicam (compound Decision 1) 3.01. 3.03 3.02 Chlorteneksikam Not achieved Not achieved Not achieved Piroxicam - n - - n - - n - Enol ether pi roxicam -
    50% inhibition of inflammation
    Enol ether chloro- tenoxicam 6.23 0.36 0.29 (compound 1) Chlorteneksikam . 0.35 0.60 0.46 Piroxicam 3.88 5.06 4.43 Enol ether pyro- ' xikam ten Yu' ten
    Table 2
    Group Dose, mg / kg Number deaths / number of animals Chlorteneksikam Enolovy air chloro xikam (compound 1) Male Female Male Female one 0 0/5 0/5 0/5 0/5 2 1.5 .. 0/5 0/5 0/5 ' 0/5 3 6.0 0/5 6/5 0/5 0/5 four 24.0 0/5 0/5 0/5 0/5 five 96.0 2/5 4/5 3/5 ' 1/5
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