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    • 专利摘要:
    The method of producing 6,6-oxazinebthiazine diazoxide formula I .., where R is C — C-alkyl as methyl or ETHIL, X is an oxygen or sulfur atom Het is 2-isridazyl substituted by methyl, or 2-isoxazolyl or 2-pyrimidinyl substituted by methyl, characterized in that the compound of the formula II Het-lH-cf OHi where Het has the indicated values R-phenyl or tert-butyl, is subjected to thermal decomposition in the melt or in an inert non-polar solvent such as dimethyl ether, distillen glycol or 1-methylnaphthalene, and the resulting compound of formula III, Het - N C O where Het has the indicated meanings, directly reacts with the compound of the formula IV O) directly in the reaction medium; about SP with where R has the indicated values of Rj -. -alkyl, such as methyl or ethyl, with thermal decomposition and subsequent interaction with the compound of the formula IV is carried out at 160-2TO C, and, if necessary, a compound of formula I, where X is an oxygen atom, is reacted with a tilating agent, such as 2,4-bis-. - (2-methoxyphenyl) -2,4-dithiaphosphetane, in xylene at the boiling point of the reaction mixture to obtain the compound of formula 1, where X is an atom of sulfur.
    公开号:SU1195910A3
    申请号:SU833602726
    申请日:1983-06-14
    公开日:1985-11-30
    发明作者:Эстев Солер Хосе
    申请人:Провезан С.А. (Фирма)；
    IPC主号:
    专利说明:

    I
    This invention relates to a process for the preparation of HOBbix chemical biologically active compounds, namely, to a method for producing 6,6-oxazine benzthiazinedioxide, having anti-inflammatory and analgesic activity and the ability to inhibit prostaglandin synthetase.
    The aim of the invention is to obtain novel derivatives of the benzithizinedioxide, which have a high anti-inflammatory activity with low toxicity.
    Example 1. Preparation of 5-ethyl-3- (2-pyridyl) -2H, 5H-1,3-oxazin-5, 6-s3-C1,2 benzothiazin-2,4- (ZN) -dione-6, 6 - dioxide.
    When heated under reflux under nitrogen for 30 minutes .4.4 g (0.015 mol) of 2-ethyl-4-oxy-2H-1,2-benzothiazin-1, 1-dioxide-3-carboxyl ethyl and 3.5 g (0,016 mol) of 2-phenoxycarbonylaminopyridine in 40 ml of diethylene glycol dimethyl ether. The mixture is cooled at ambient temperature and poured into 150 ml of water. The precipitate formed is filtered and washed with water. By recrystallization in acetone, 3.0 g (54%) of 5-ethyl-3- (2-pyridyl) -2H, 5H-1, 3-oxazine C5, 6-c 1.2 b of zothiazin-2,4- (3N a) -dione-6,6-dioxide
    Melting point 268-270 C.
    Data spectroscopic analysis.
    IR (KBG), cm: 1185, 1355, 1415 1635, 1705, 1795.
    1H NMR, cr DMSO / dfe3: 1.08 (t, 3N) -, 3.75 (q, 2H) -, 7.43 (e; 2H); 7.86 (e, 5H); 8.4 (d, 1H).
    Example 2. Preparation of 5-methyl-3- (2-pyridyl) -2H, 5H-1, 3-oxazine 5, 1.2 benzothiazin-2,4- (3N) -dione-6,6-dioxide.
    Option A. 14.1 g (0.05 mol) of 2-methyl-4-hydroxy-2H-1, 2-benzothiazin-1, 1-dioxide-3-carboxyl ethyl is heated to melt in a silicone bath at 210 ° C in a nitrogen atmosphere. and 11.8 g (0.055 mol) of 2-phenoxycarbonylaminopyridine. The phenol is distilled off under 10 minutes under reduced pressure (25 mm Hg). The precipitate was dissolved in acetone and 12.1 g (68%) of 5-methyl 3- (2-pi959102) crystallized out.
    Ridyl) -2H, 5H-1,3-oxazine C5,6-s -:. , 2 benzothiazin-2,4- (3N) -dione-6,6 dioxide.
    Melting point 259-261 C.
    5 Data spectroscopic analysis.
     IR (KBG), cm-H 1185, 1355, 1410, 1640, 1710, 1790.
    1H NMR, crCDMSO / dj: 3.02 (s,
    10 MH) -, 7.52 (e, 2H); 7.92 (e, 5H); 8.52 (d, 1H).
    Option B. Heated to 200 ° C for 15 minutes in a nitrogen atmosphere 2.7 g (0.01 mol) of 2-methyl-4-oxy15 -2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate methyl and 2.1 g (0.011 mol) of 2-tert-butrxycarbonylaminopyridine in 30 ml of 1-methylnaphthalene, cooled and precipitated using petroleum ether. By recrystallization from acetone, 1.9 g (55%) of 5-methyl-3- (2-pyridyl) -2H, 5H, 1,3-oxazine 5, 23benzothiazin-2, 4- (3N) -dione-6 is obtained , 6-dioxide.
    25 Melting point 257-259 0. Spectroscopic data.
    IR (KBG), cm-h: 1185, 1355, 1410, 1640, 1710, 1790.
    30 1H NMR, cTLDMSO / dJ: 3.0 (S, 3N); 7.52 (e, 2H); 7.92 (ej 5H) -, 8.52 (d, 1H).
    Example 3. Obtaining 5-methyl-3- (2-pyridyl) -2H, 5H-1,3-oxazine (5, 6-s-0, 2 benzothiazin-2 (ZN) TION-4-OH-6, 6 - dioxide.
    Under reflux, the temperature is 140 ° C for 36 hours with 8.1 g (0.02 mol) of 2.4i-bis (2-methoxyphenyl) -2,4-dithiadi-, phosphetane and 3.6 g (0.01 mol) 5-methyl-3- (2-pyridyl) -2H, 5H-1,3-oxazine t5, 6-c} 1.23 benzothiazin-2,4- (ZN) -dione-6, 6-dioxide in 80 ml of xylene. Chromatography was performed on a silica gel column, taken as the stationary phase, washing first with xylene and then with chloroform. 1.4 g (38%) of 5-methyl-3- (2-pyridsh1) -2H, 5H-1,3-oxazine 5, 6-with 1,2 benzothiazin-2- (ZN) -THION are extracted from the chloroform solution. -4-OH-6, 6-dioxide.
    After recrystallization from acetone, the obtained derivative has a melting point of 269-27I C.
    Data spectroscopic analysis.
    IR (KBr), CM: 1190, 1320, 1355, 1400, 1640, 1712.
    1H NMR, cf OMSO / d: 3.05 (S, 3H); 7.54 (; 2H); 7.92 (ei 5H); 8.48 (d, 1H).
    Example 4. Preparation of 5-methyl-3- (3-3- (5-methylisoxazolyl) -2H, 5H-1,3-oxazin 5, 2 benzothiazin-2, 4- (3N) -dione-6,6-dioxide.
    2.8 g (0.01 mol) of 2-methyl-4-hydroxy-2H, 1,2-benzothiazine-1, 1-dioxide-3-ethylcarboxylate and 2.4 are heated to nitrogen for 15 minutes under a nitrogen atmosphere. g (0,011 mol) of 3-phenoxycarbonylamine-5-methylisoxazole in 40 ml of 1-methylnaphthalene. Cooling and precipitation are carried out using petrlay ether.
    Recrystallization is carried out in acetone and 2.2 g (61%) of 5-methyl-3- 3- (5-methylisoxazolyl) -2H, 5H-1,3-oxazine 5,6-s, 2 benzothiazin-2, 4 are obtained. - (3N) -dione-6,6-dioxide.
    Melting point 268-269 ° C.
    Data spectroscopic analysis.
    IR (KBG), CM-l: 1185, 1360, 1400, 1640, 1715, 1788.
    1 H NMR, “rCDMSO / d j: 2.5 (S, 3N) 3.08 (S, 3N); 6.44 (S, 1H) i 7.98 (e, 4H).
    Example 5. Preparation of 5-methyl-3- (2-pyrimidinyl) -2H, 5H-1,3oxazine C5,6-s3 1,2 benzothiazin-2, 4- (3N) -dione-6,6-dioxide.
    2.8 g (0.01 mol) of 2-methyl-4-hydroxy-2H-1,2-bvnsotiazin-1, 1-dioxide-3-carboxyl ethyl is heated under reflux to 160 ° C for 30 minutes under a nitrogen atmosphere. and 2.4 g (0.011 mol) of 2-phenoxycarbonylaminopyrimidine in 30 ml of diethylene glycol dimethyl ether. The mixture is cooled at ambient temperature and poured into 100 m of water. The resulting precipitate is filtered off, washed with water, stirred with acetone at boiling and filtered off again. Obtain 1.8 g (50%) of 5-methyl-3- (2-pyrimidinyl) -2H, 5H-1,3-oxazin 5, 2 benzothiazin-2, 4- (ZN) -dione-6,6- dioxide.
    Melting point 282-284 C.
    Data spectroscopic analysis.
    IR (KBG), 1180, 1355/1400, 1632, 1710, 1787.
    959104
    1H NMR, DMSO / d J: 3.05 (S, 3N); 7.93 (e; 5H) 8.85 (d, 2H).
    Example 6. Obtaining 5-megyl-3- 2- (4-methylpyridyl) -2H, 5H-1, 3-oxazin 5, 2 benzothiazin-2, 4- (ZN) -dione-6,6-dioxide.
    2.7 g (0.01 mol) of 2-methyl-410-OXI-2H-1,2-benzothiazine-1,1-dioxide-3-methylcarboxylate and 2.3 g are heated to melt in a silicone bath under a nitrogen atmosphere. (0.011 mol) 2-tert-butoxycarbonylamin-4-methylpyridine. Maintain melting for 5 minutes. The residue is dissolved in acetone and 2.3 g (62%) of 5-methyl-3-2- (4-methylpyridyl) -2 -2H, 5H-1,3-oxazine 5,6-c 1,2 benzothiazin-2 are crystallized out , 4- (3N) t -dione-6,6-dioxide.
    Melting point 259-26l C.
    Data spectroscopic analysis.
    IR (KBr), cm-b: 1195, 1360, 1415, 1640, 1720, 1795.
    1H NMR, cTLDMSO / d /: 2.42 (S, 3N); 3.1 (S, ЗН) -, 7.4 (e; 2H); 7.98 (e-, 4H) -; 8.4 (d, W).
    Example 7. Obtaining 5-methyl-3- 2- (6-methylpyridyl) -2H, 5H-1,3-oxazin 5, 6-c l, 23benzothiazin-2,4- (ZN) -dione-6,6- dioxide.
    Heated to melt in a silicone bath while in the atmosphere
    nitrogen 2.8 g (0.01 mol) of 2-methyl-4-OXY-2H-1, 2-benzothiazine-1,1-dioxide-3-ethylcarboxylate and 2.3 g (0.011 mol) of 2-tert-butoxycarbonsh1 amine-6-methylpyridine. Support
    melting for 5 min. Dissolve the residue in acetone and crystallize from a solution of 1.5 g (41%) 3-methyl-3-2- (6-methylpyridyl) -2H, 5H-1,3-oxazine 5,6-c j p, 2 benzothiazine -2, 4- (3N) -dione-6,6-dioxide.
    Melting point 248-250 C.
    Data spectroscopic analysis.
    IR (KBG), cm: 1190, 1360, 1410, 1715, 1790.
    1H NMR, crLDMSO / d, .l: 2.43 (S, 3N); 3.0 (S, 3N); 7.4 (e, 2H) ;, 7.97 (e, 5H).
    The anti-inflammatory activity (inhibition of edema caused by corragenin) of new derivatives of 6,6-oxazinbenzthiazinedioxide is examined as follows.
    Vinter's method. Male Sprague-DawJPey HC-CEU rats weighing 90-110 were used. Compounds were administered orally as a 5% suspension in gum arabic using an esophageal probe, 1 hour before that was sub-primed by the injection of 0.1 ml of the animal’s right paw. 1% corragenine suspension in physiological transmigration (NaC 0.9%). Experimental animals get 5% gum arabic, the total volume used in all cases being 10 ml / kg. The volume of each paw is measured immediately prior to the injection of corragenin, then 3 or 5 hours after the injection with a mercury plethysmograph. For each animal, the inflammation index is calculated after 3 hours (1) and 5 hours (Ij-) after administration of corragenin, using the following formulas for this: 1s 100; 0 I, x 100, where V. is the volume of the foot just before the introduction of the corgenic cortex, V, is the volume of the foot after 3 h after the administration of corragenin, V is the volume of the foot after 5 h after the administration of corragenin. The rate of inflammation, average for experimental animals, is calculated after 3 hours (It) and 5 hours (it). The percentage of inhibition of edema (anti-inflammatory activity) is calculated for each animal using the formulas: d - It, - IJ (It; - 100) D (Its - 15). Oll S - (ity - 100) where AZ is the anti-inflammatory activity,%, at the end of tert its 4acaj AC is the anti-inflammatory activity,%, at the end of the first hour. 10 Anti-inflammatory activity is proportional to the logarithm of the dose administered. The curve obtained in the coordinates of the logarithm of the dose -% effect, determines the dose, which reduces the volume of edema by 25%. Equate this dose to DE-50, since the maximum effect achieved in reducing edema is 50%. In tab. Figure 1 shows the anti-inflammatory activity of 6,6-oxazine benzthiazine dioxide derivatives. The analgesic activity of the new 6,6-oxazinbenzthiazinedioxide derivatives with respect to pain caused by acetylcholine was investigated as follows. Collier method. Male Swiss mice weighing 20–25 g were used. Mice were placed in individual cages. Each animal is administered an intraperitoneal solution of acetylcholine bromide with a concentration of 0.32 mg / ml in an amount of 0.2 ml per 20 g of mouse weight. Thus, the dose of acetylcholine bromide administered is 3.2 g / kg. Within 5 minutes, record the number of contortion, which is observed in each mouse. After 5 min, the proposed compounds are introduced using 5% gum arabic as an excipient. After the AO has expired and 120 minutes after the administration of the proposed compounds, repeat the acetylcholine injection and record the number of contracts observed in mice for 5 minutes. For each animal, the percentage of inhibition of the lactation number after 40 and 120 minutes is calculated using the following formulas: NO - N40 X 100-, A.,., 110 where Ln is the number of hormones before the administration of the proposed compounds, is the number of hormones 40 minutes after the administration of the proposed compounds, N ,, 0 - The number of contracts after 120 min after the administration of the proposed compounds. The percentage of inhibition of contortion is directly proportional to the logarithm of the dose administered. Using the curve plotted in coordinates of the logarithm of the dose -% effect, the dose is calculated, which reduces the number of contortions to half the original value (DE-50). In tab. 2 presentation: analgesic activity of the proposed compounds. The inhibition of the prostaglandin syntheses of the seminal vesicle of the bull by new compounds is investigated as follows. Yashimoto method. The determination of prostaglandin synthetase activity (1.14.-99.1) is carried out by measuring the increase in adsorption by 278 nm, which occurs when prostaglandin B is formed from prostaglandin E in an alkaline medium. The incubation temperature is in all cases 37 + 0.10 s. The method is carried out as follows. To 1.5 ml of a solution of a concomitant factor (0.55 mg of hydroquinone +0.5 m hemoglobin +7.7 mg glutathione in 12 ml of Tris-HC- buffer, 0.2 M, pH 8, containing 10 mg of enzyme, add 0.5 ml of substrate solution (0.6 m of arachidonic acid in 10 ml of buffer) and 0.5 ml of buffer and incubate at 37 ° C for 10 min. Disrupt the enzymatic reaction by adding 1.5 ml of 0.2 M citric acid and pGE, extracted with 2x5 ml of ethyl acetate. The organic phase is evaporated under a stream of nitrogen at and the residue is dissolved in 2 ml of methanol and 0.5 ml of ZM of potassium hydroxide. Finally, the absorption of n is measured. and 278 nm with respect to the white pigment, to which 0.5 ml of buffer was added instead of 0.5 ml of substrate solution. The enzymatic activity is expressed through an increase in optical density during a 10 min reaction. Inhibition caused by the action of phenylbutazone and, for example, Example 2 for prostaglandin synthetase is determined by contacting the enzyme with compounds for 5 minutes. The following method is used: 0.5 ml of various solutions of phenylbutazone are added to 1.5 ml of a solution of a concomitant factor containing 10 mg of enzyme. or prod -stand as in Example 2, and the resulting mixture was kept at 37 ° C for 5 minutes, after which was added 0.5 ml of substrate solution and stored for 10 minutes further incubation at this temperature. Subsequent steps are similar to the above. The ratio between the increase in optical density in the presence or in the absence of inhibitors is the inhibition value. Concentrations that result in 50% inhibition are as follows: Clyo (M) Compound 3-10 Phenylbutazone Prize-winning compound Acute toxicity was investigated by the method of Litshfield and Wilcoxon. The compound is administered orally as a suspension in 5% gum arabic. The volume injected is 25 mg / kg for mice and 10 mg / kg for rats. The results obtained when using derivatives of example 2 are presented in table. 3. New derivatives of 6,6-oxazi; nbenzthiazinedioxide of example 2 were compared by acute and cumulative toxicity with piroxicam (N- (2-pyrrh; yl) -3,4-dihydrr-2-methyl-4-OXO-2H- 1, 2-benzthiazine-3-carboxamide), which is a close structural analogue of the proposed compounds and is currently the most common among nonsteroidal anti-inflammatory drugs. . The data presented in Table. 4 and 5. Test compounds were orally administered. From tab. 4 and 5, it follows that the new derivatives of 6,6-oxazinbenzthiazine dioxide are less toxic than piroxicam, with the same anti-inflammatory activity. New derivatives of 6,6-oxazinenzthiazine dioxides can be used in human and animal therapies, in particular in the treatment of acute or chronic diseases, which require a combination of anti-inflammatory and analgesic agents, for example, in deforming arthritis, osteoarthritis, spondylitis, acute musculoskeletal changes and acute gout. In human therapy, the recommended za depends on the disease. Basically, it is 100 mg per day. Derivatives of 6,6-oxazinbenztiazine dioxide can be administered in the form of tablets, gelatin capsules or suppositories. Below are the three galenic forms of derivatives of 6,6-oxazinbenzthiazine Dioxide, gelatin capsules have the following composition, g:. 5-Metsh1-3 -. (2-pyridyl) -2H, 5H-1, 3-oxazine C5, Lbenzothiazin-2, 4- (ZN) -dione-6, 6-dioxide 0.020 Lactose-0.136 Talc, 0.0016 Magnesium stearate O, 0016 Aerosil-2000,008 Tablets have the following composition 5-Methid-3- (2-pyri. Deyl) -2H, 5H-1,3-oxazine 5, 23benzothiazin-2, 4 (ЗН) dione- 6, 6-dioxide 0.020 Avitsel pH 1b2 0.016 Lactose .0.055 Primozel0.003 Polyvinylpyr Magnesium Stearate
    0,100
    Suppositories have the following remaining, g:
    5-Methyl-3- (2-pyridyl) -2H, 5H-1,3-okasazin 5, bs 1, 2 benzothyazin-2, 4- (3) -dione-6, 6-dioxide 0,050
    Monolen1,950
    2,000 T a b l and c a
    T a b l and c a 3

    6192 8841
    f 1434
    1994, Table 1, mk / kg, orally treating time, h Table 2 0, mg / kg, orally over time,
    eleven
    fl959102
    t a (b l and c a 4
    (6,191.6
    (2342.0-16368.7) 8840.9
    (2378.9-32856.5) 1434.2
    (742.8-2769.3) 1994.4
    (1015.0-3918.8) i Control Example 2 290.65 + 6 41roxycam
    141.4
    (75.7-264.4)
    118.0
    (18.0-771.6)
    226.6
    (132.9-386.6)
    50.2
    (15.6-162.2)
    Table 5 tf 0/6 0/60/60/6 3/60/60/60/6 cG 0/6 0/6 o / b 0/6 0/6 o / b 0/6 6/6. 3/6 5/6
    37.5 290.65 + 7S, 06
    150.0
    0/6 1/6 3/6 4/6
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 6,6-OXAZINBENZTHIAZINDIOXIDE DERIVATIVES where R is C ^ -C ^ -alkyl as methyl or ethyl ·,
    X is an oxygen or sulfur atom
    Het-NH-C * 0 *
    0R1 where Het has the indicated meanings ·; R 7 - phenyl or tert-butyl, is thermally decomposed in a melt or in an inert non-polar solvent such as dimethyl ether, diethylene glycol or 1-methylnaphthalene, and the resulting compound of formula III
    Het - N = C = O, where Het has the indicated meanings, is reacted directly with the compound of formula IV ’in the reaction medium, where R has the indicated meanings}
    R 2 is C 1 -C 4 ~ alkyl, such as methyl or ethyl, with thermal decomposition and subsequent reaction with a compound of formula IV being carried out at 160-210 ° C, and, if necessary, a compound of formula I, where X is an oxygen atom, is subjected interaction with a tylating agent ', such as 2,4-bis ···.
    y - (2-methoxyphenyl) -2,4-dithiophosphetane in xylene at the boiling point of the reaction mixture to obtain a compound of formula I ,. where X is an atom of sulfur. · ·>
    I
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    同族专利:
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    引用文献:
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    US3492298A|1968-02-21|1970-01-27|Mcneilab Inc|Oxazino-benzothiazine-6,6-dioxides|
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    US3923801A|1974-09-23|1975-12-02|Mcneilab Inc|Oxazinobenzothiazine 6,6-dioxides|
    EP0043961A1|1980-07-14|1982-01-20|MEDIOLANUM FARMACEUTICI s.r.l.|1,2-Benzothiazinopyrazoles having pharmacological activity|US4656265A|1984-06-21|1987-04-07|Pfizer Inc.|Cyclic prodrugs of antiinflammatory oxicams|
    FR2597103B1|1986-04-15|1988-12-16|Provesan Sa|PROCESS FOR THE PREPARATION OF OXAZINOBENZOTHIAZINE 6,6-DIOXIDE DERIVATIVES|
    US5196410A|1986-10-31|1993-03-23|Pfizer Inc.|Transdermal flux enhancing compositions|
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    WO2002076463A1|2001-03-23|2002-10-03|Smithkline Beecham Corporation|Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8210409A|FR2528433B1|1982-06-15|1982-06-15|
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