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    • 专利摘要:
    A compound of the formula:- …<CHEM>… or a pharmaceutically acceptable acid addition salt thereof, wherein… R is 2-pyridyl, 6-methyl-2-pyridyl, 6-fluoro-2-pyridyl, 6-chloro-2-pyridyl, 5-methyl-3-isoxazolyl or 2-thiazolyl;… Y is N,N-dialkylamino having up to three carbon atoms in each alkyl moiety, N-methyl-N-benzylamino, N-ethyl-N-benzylamino, N-methyl-N-( beta -phenylethyl)-amino, N-ethyl-N-( beta -phenylethyl)amino, N-methyl-N-cycloalkylamino and N-ethyl-N-cycloalkylamino each having up to six carbon atoms in the cycloalkyl moiety, N-methyl-N- phenylamino, N-ethyl-N-phenylamino, N-methyl-N- (p-chlorophenyl)amino, N-ethyl-N- (p-chlorophenyl) amino, N-methyl-N- (N min ,N min -dimethylcarbamylmethyl) amino, N-methyl-N- (N min ,N min -diethylcarbamylmethyl) -amino, pyrrolidino, piperidino, 2-methylpiperidino, 2-ethylpiperidino, homopiperidino, 1-azacyclooctyl, N-methylpiperazino, morpholino or thiomorpholino;… Z is pyridinium, 2-methylpyridinium, 3-methylpyridinium, 4-methylpyridinium, 2,6-dimethylpyridinium, 2,4,6-trimethylpyridinium, 3-ethylpyridinium, 4-ethylpyridinium, 3-ethyl-4-methylpyridinium, 4-ethyl-2-methyl-pyridinium or 5-ethyl-2-methylpyridinium; and… A is pharmacologically acceptable anion. …<??>The compounds are anti-inflammatory agents.
    公开号:SU1538896A3
    申请号:SU864027578
    申请日:1986-05-28
    公开日:1990-01-23
    发明作者:Джордж Ломбардино Джозеф
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    The beam as a result of the product is white, waxy, containing a small amount of oil. Remainder
    after removing the insoluble sodium chloride, the filtrate is then concentrated in vacuo and a white crude product is obtained (yield 33.5 g). The latter material is recrystallized from about 50 ml of isopropanol and filtered, yielding 15.0 g of material melting at 140-100C (fraction A). An additional 1.8 g of product was isolated from the mother liquor, and this material was melted at (fraction B). Fractions A and B are pooled into 175 ml of isopropanol, then the alcohol solution is concentrated to 125 ml. The resulting crystalline product is filtered off, yielding
    (0.117 mol) ei-chloro-para-toluic acid in 150 ml of absolute alcohol (ethanol) in a nitrogen atmosphere at a natal temperature (20 ° C) is added dropwise a solution consisting of 27.7 g (0 mol) N-methyl-M-cyclic hexylamine dissolved in 50 m of absolute ethanol. The resulting p mixture is heated under reflux for 20 h and cooled to room temperature. The cooled reaction mixture is concentrated in vacuo and the residue is separated.
    the result of 13.0 () pure hydro-15 between 100 ml of diethyl ether and
    chloride - (m, K-diethylaminomethyl) benzoic acid, etc. 191-193 ° C (according to literature data, mp. 185 ° C. A pure product is characterized by measuring 100 ml of a 3N aqueous solution of sodium hydroxide. The main aqueous layer is separated and extracted three times with diethyl ether, after which it is cooled
    (0.117 mol) ei-chloro-para-toluic acid in 150 ml of absolute alcohol (ethanol) in a nitrogen atmosphere at room temperature (20 ° C) is added dropwise a solution consisting of 27.7 g (0 mol) N-methyl-M-cyclohexylamine dissolved in 50 ml of absolute ethanol. The resulting reaction mixture is heated under reflux for 20 h and then cooled to room temperature. The cooled reaction mixture is concentrated in vacuo and the residue is separated
     between 100 ml of diethyl ether and
    100 ml 3 n. an aqueous solution of sodium hydroxide. The main aqueous layer is then separated and extracted three times with diethyl ether, after which it is cooled.
    house mass spectroscopy, nuclear mag-20 is given in an ice bath, then gently
    resonance, thin layer chromatography and infrared absorption spectra.
    Preparation N. To a well stirred mixture consisting of 1.3 g (0.08 mol) of d-chloro-para-toluic acid in a nitrogen atmosphere, 25 g (0.185 mol) are added at room temperature (20 ° C). -methyl-I - (/ N is acidified with concentrated hydrochloric acid to pH 1. This leads to the formation of an oil, and the resulting oil / water system is vigorously stirred 25 with 200 ml of methylene chloride. As a result, a thin strip of oil is formed between two layers of aqueous of the organic phase, this oil layer is separated and then thoroughly triturated from diethilonylethyl) -amine, dissolved th 50 ml zo vym ether to give ultimately
    absolute ethanol. The resulting reaction mixture is heated under reflux for 18 h, then cooled to room temperature. The cooled reaction mixture was concentrated in vacuo, divided into three parts between 100 ml of 3N. an aqueous solution of sodium hydroxide and 100 ml of diethyl ether. The basic aqueous layer was cooled in an ice bath, carefully acidified with concentrated hydrochloric acid and a white solid was obtained. The last product is filtered off and then vigorously stirred in acetonitrile for 30 minutes. After filtering the mixture and drying, 20.26 g (79%) of C- (N-methyl) -N- (p-phenyl ethyl) aminomethylbenzoic acid hydrochloride are obtained in the final result, m.p. 2b8-2b9is in the form of white crystalline powder. The product is characterized by thin layer chromatography and infrared absorption spectra. As such, it was used in the next stage without further purification.
    Preparation I. For a well-stirred mixture of 20.0 g
    35
    40
    solid white product. The last product is collected by filtering off the filter, then triturated with hot isopropanol and filtered again, dried, and 13.5 g (kl%) of pure k- (M-methyl-N-cyclohexylamino-methyl) benzoic acid hydrochloride are obtained. hydrate, m.p. 266-26f ° C. The pure product is characterized by thin layer chromatography and infrared spectroscopy.
    Calculated,%: C 59; H 7.37; N, 66.
    45
    HC1-CgO
    c, ngokog
    Found,%: C 59.67; H 7
    50
    55
    N M5.
    Preparation J. To a well stirred mixture consisting of 15, g (0.095 mol) -chloro-para-toluic acid in 150 ml of absolute ethanol at room temperature (20 ° C) under nitrogen atmosphere, is added dropwise of 30 g (0.2125 mol) -chloro-L-methylaniline, dissolved in 50 ml of absolute ethanol. The resulting mixture is heated under reflux for 20 hours and then cooled to room temperature.
    acidified with concentrated hydrochloric acid to pH 1. This results in the formation of an oil, and the resulting oil / water system is vigorously stirred with 200 ml of methylene chloride. As a result, a thin strip of oil is formed between the two layers of the aqueous organic phase, this oil layer is separated and then thoroughly triturated with diethyl ether, ultimately producing
    five
    0
    solid white product. The last product is collected by filtering off the filter, then triturated with hot isopropanol and filtered again, dried, and 13.5 g (kl%) of pure k- (M-methyl-N-cyclohexylamino-methyl) benzoic acid hydrochloride are obtained. hydrate, m.p. 266-26f ° C. The pure product is characterized by thin layer chromatography and infrared spectroscopy.
    Calculated,%: C 59; H 7.37; N, 66.
    45
    HC1-CgO
    c, ngokog
    Found,%: C 59.67; H 7
    0
    five
    N M5.
    Preparation J. To a well stirred mixture consisting of 15, g (0.095 mol) -chloro-para-toluic acid in 150 ml of absolute ethanol at room temperature (20 ° C) under nitrogen atmosphere, is added dropwise of 30 g (0.2125 mol) -chloro-L-methylaniline, dissolved in 50 ml of absolute ethanol. The resulting mixture is heated under reflux for 20 hours and then cooled to room temperature.
    P
    temperature The cooled reaction mixture is concentrated in vacuo and the residue is partitioned between 100 ml of diethyl ether and 100 ml of 3N. an aqueous solution of sodium hydroxide. The basic aqueous layer was separated and extracted three times with diethyl ether, then cooled in an ice bath, carefully acidified with concentrated hydrochloric acid to pH 1, and a yellowish-white precipitate was obtained. The last product is filtered on a suction filter, triturated with hot isopropanol, filtered off again and dried and finally 16.0 g (64%) of pure 4-p-methyl-N-N (p-chlorophenyl) -amipomethyl benzoic is obtained. acids, mp. 183-1910C. The pure product is characterized by chromatography and infrared absorption spectra.
    Calculated 5 N 5.08.
    C, 5HWC1N04
    Found,%: N 4.98.
    Drug k,
    c 65.34; n 5.12;
    C 65.28; H 5.11;
    AT
    A four-necked round bottom flask equipped with a reflux condenser, mechanical stirrer, separatory funnel and thermometer with a volume of 300 ml was placed in a% water solution (61 ml) of methylamine (24.18 g, 0.78 mol), which was cooled to 5 ° C in a bath containing an ice-water-salt mixture. M, M-dimethylchloroacetam (24.3 g, 0.20 mol) is then added dropwise to the solution over 30 minutes while the temperature in the reaction vessel is maintained in the range from 0 to 10 ° C over the entire stage. After the addition was complete, the reaction mixture was stirred at 0-5 ° C for 7 hours and then placed in a refrigerator, where it was left overnight (16 hours). Water and excess methylamine are removed by evaporation under reduced pressure to give the residue in the form of a pale yellow oil, which is subjected to vacuum distillation. After distillation, 3.4 g of the fraction boiling at 25–30 ° C under a pressure of 20 mm Hg is distilled. the product remaining in the flask solidifies to form a waxy product of an off-white color, which is then recrystallized from 125 ml of isopropanol. This product (yield 19.5 g) is then recrystallized

     from 50 ml of ethanol. The resulting white crystals are filtered and dried, resulting in 10, A g (34%) of pure HMH-dimethyl-2-methylaminoacetamide hydrochloride as a quarter of the hydrate, m.p. 171-173 ° C. The pure product is characterized by mass spectroscopy, 1Q nuclear magnetic resonance, thin layer chromatography, and infrared absorption spectra.
    Calculated,%: C 38, H 8.66; 17.83.
    N

    five
    C5H O-HC1-0.25HgO Found;%: C 38.31; H 8.38; N 18.01.
    Preparation L. A solution consisting of 9.16 g (0.06 mol) N, K-dimethyl-2-methylaminoacetamide hydrochloride (obtained as a quarter of the hydrate of preparation K), dissolved in 24 ml of 3N. an aqueous solution of sodium hydroxide is stirred at room temperature (20 ° C) for 20 minutes. The solution is concentrated in vacuo to remove water, and the residue is washed three times with about 30 ml of ethanol, to give an oily white solid. Then 40 ml of ethanol is added to the residue, and the mixture is heated to boiling, after which it is filtered off to remove insoluble sodium chloride.

    The ethanol filtrate obtained in
    for five minutes, a well stirred suspension of 4.43 g (0.026 mol) of oЈ-chloro-p-toluic acid in 40 ml of ethanol is added dropwise in a nitrogen atmosphere at room temperature (20 ° C). The resulting reaction mixture is stirred at room temperature for 10 minutes and then heated under reflux, then 20 ml of ethanol is added and refluxing is continued for 18.5 hours. The final reaction mixture is filtered while hot and then cooled. then concentrated in vacuo to give an oily solid residue. This residue is then dissolved in 50 ml of 3N. an aqueous solution of sodium hydroxide and extracted twice with 40 ml of diethyl ether. The main aqueous layer is poured into 17.5 ml of concentrated hydrochloric acid containing approximately
    13 1
    35 ml of ice water. After the mixture was cooled in an ice bath, it was filtered to remove white solids, the filtrate was concentrated in vacuo, and the resulting residue was washed with about 30 ml of ethanol and then the solvent was distilled off. The white product thus obtained is then dissolved in about 150 ml of hot ethanol, filtered to remove inorganic substances, and the resulting filtrate is evaporated under reduced pressure to obtain a white solid. The crude product is then triturated in about 175 ml of hot isopropanol and filtered to obtain 2.55 g (34%) of pure 4-N-methyl-M- (K, N-dimethylcarbamyl-methylaminomethyl benzoic acid hydrochloride as a hemihydrate, mp 230 ° C (decomp.). An additional amount of pure product (yield 1.98 g) was later isolated from the isopropanol stock solution, resulting in a total yield of the final product of 4.53 g (61%). The pure product was characterized nuclear magnetic resonance thin layer chromatography data and spectra and frakrasnogo absorption.
    Calculated,% C 52.79, H 6.82,
    N 9.7.


    C, 5H) g HC1-0,5H20
    C 52.97; H 6.37;
    K mix wellFound%
    N 9.35.
    Drug Suspension consisting of 8.5 g (0.05 mol) of oЈ-chloro-para-toluic acid in 100 ml of ethanol in a nitrogen atmosphere at room temperature (20 ° C) is added over 15 minutes to 7.9 g (0,, 10 mol) pyridine. The resulting reaction mixture is heated under reflux for, then cooled to room temperature. The cooled reaction mixture is filtered and the isolated product is dried, ultimately 9.72 g () of pure 1- (4-carboxybenzyl) pyridium chloride are obtained, m.p. 252-253 ° C. The pure product is characterized by mass spectroscopy methods, data of nuclear magnetic
    35
    40
    45
    Preparation O, To 1.8 g (0.007 mol) of 4- (morpholinomethyl) benzoic acid hydrochloride, preparation B is added under nitrogen atmosphere with 10 ml of thionyl chloride (16.3 g, 0.137 mol), which leads to the formation of a mixture of pale yellow one that is then heated under reflux for 22 hours. The resulting yellow-cloudy solution is concentrated in vacuo to remove excess thionyl chloride, and the crude solid thus obtained is washed with about 10 ml of methylene chloride and then about 10 ml of benzene ( twice), resulting in a crystalline esky white product. Thus, 1.88 g (99%) of essentially pure 4- (morpholomethyl) benzoyl chloride hydrochloride, m.p. 227 230 ° C (decomp.). The latter product is used in the further reaction step without any purification. The yield of the product is quantitative.
    Preparation R. To 20 g (0.0b5 mol) of dihydrochloride - (- methylpiperazino-methyl) -benzoic acid (obtained ka hemihydrate, preparation C), under nitrogen atmosphere, add 119 ml of thionyl chloride (194 g, 1.625 mol), which leads to
    ,., ... f f- j - 7 fi - - i
    resonance, thin layer chromatography, the formation of a suspension of beige-white and infrared absorption spectra.
    Calculated,%: C 62.53; H 4.84; N 5.61.
    color, the reaction mixture is heated for 24 hours and then cooled to room temperature (C &amp; C). By
    14
    0
    N 5 0
    five
    0
    five
    0
    five
    C, eNg, C1N02 Found: C, 5.66. Drug N.
    62.60; n 4.87;
    To 9.21 g (0.035 mol) of 4- (piperidinomethyl) benzoic acid hydrochloride (preparation A), 55 ml of thionyl chloride (89.65 g, 0.753 mol) are added under a nitrogen atmosphere, which results in the formation of a white suspension. The reaction mixture is heated under reflux for 2.75 h, then cooled to room temperature (20 ° C). The resulting yellow solution is concentrated in vacuo to remove excess thionyl chloride, and the residue is washed with about 30 ml of benzene and then about 30 ml of methylene chloride, resulting in an off-white solid product. Crude hydrochloride - (piperidinomethyl) benzoyl chloride is used in the next reaction step without further purification. The yield of the product is quantitative.
    Preparation O, To 1.8 g (0.007 mol) of 4- (morpholinomethyl) benzoic acid hydrochloride, preparation B is added under nitrogen atmosphere with 10 ml of thionyl chloride (16.3 g, 0.137 mol), which results in the formation of a pale yellow color which is then heated under reflux for 22 hours. The resulting yellow-cloudy solution is concentrated in vacuo to remove excess thionyl chloride, and the crude white solid thus obtained is washed with about 10 ml of methylene chloride and then about 10 ml of benzene (twice) resulting in a crystal The usual product is white. Thus, 1.88 g (99%) of essentially pure 4- (morpholinomethyl) benzoyl chloride hydrochloride, m.p. 227 230 ° C (decomp.). The latter product is used in the further reaction step without any purification. The yield of the product is quantitative.
    Preparation R. To 20 g (0.0b5 mol) of dihydrochloride - (- methylpiperazino-methyl) -benzoic acid (obtained as hemihydrate, preparation C), 119 ml of thionyl chloride (194 g, 1.625 mol) is added under nitrogen atmosphere, which leads to
    f- j - 7 fi - - i
     the formation of a suspension of beige-white
    color, the reaction mixture is heated for 24 hours and then cooled to room temperature (C &amp; C). Po15
    the resulting suspension is filtered off, the separated solids are washed with diethyl ether and dried, and finally 17.0 g (81%) of pure dihydrochloride - (A-methyl-piperazinomethyl) benzoyl chloride are obtained, mp. 260-263 S.
    Preparation Q. To a well-stirred suspension consisting of 1.4 g (5.0 mmol) of 4- (2-ethyl-piperidine-aminomethyl) benzoic acid hydrochloride (preparation D) in 25 ml of methylene chloride under a nitrogen atmosphere dropwise over 10 The solution consisting of 1.1 g (11.0 mol) of oxalyl chloride, dissolved in 10 ml of methylene chloride, is added. The resulting reaction mixture is heated under reflux to heat procedures to obtain 2.26 g of essentially pure 4- (1-azacyclo-octylmethyl) benzoyl chloride hydrochloride, m.p. 173-175 ° C. The resulting product is used in the further reaction step without any purification. The yield is quantitative.
    The drug S. K well mixed
    A suspension of 2.2 g (0.01 mol) of a quarter of 4- (M, N-dimethylaminomethyl) benzoic acid hydrochloride hydrate (preparation F) in 70 ml of methylene chloride in a nitrogen atmosphere to
    15 Bavly 2.8 g (0.022 mol) of oxalyl chloride. The resulting reaction mixture was heated under reflux for 3.5 hours, then cooled to room temperature (20 ° C). By
    three hours, after which the colorless
    to room temperature (20 ° C). The cooled colorless solution was evaporated under reduced pressure, the obtained residue was washed twice with about 30 ml of benzene, after which the solvent was distilled off to obtain a white solid. After milling this product with about 50 ml of isopropyl ether, filtering and drying, 1.55 g of essentially pure 4- (2-α-ethylpiperidipomethyl) benzoyl chloride, mp, 1b -1b6 ° C, are obtained. The latter product is used in the next reaction stage without any purification. The yield of the product is quantitative.
    Preparation R. To a well stirred suspension consisting of 2.0 g (7.0 mmol) and a quarter of the hydrate solution is evaporated under reduced pressure, the resulting residue is washed twice with approximately k0 ml of a mixture of benzene: methylene chloride (1: 1 by volume
    25 mu), the solvent is distilled off, resulting in a white-colored solid product. After rubbing this product with about 30 ml of diethyl ether, followed by filtration and
    30 ki in the end get 2.15 g of (921) hydrochloride - (N.N-d methylaminomethyl) -benzoyl chloride, m.p., 187 &amp; C. This product is used in the subsequent reaction stage b for further purification.
    35
    Preparation T. K is well mixed with a suspension consisting of 1.3 g (5.0 mmol) of 4- (M, M-diethylaminomethyl chloride M1-azacyclooctylmethyl) ben-40 thyl) benzoic acid (preparation F)
    zoic acid (preparation E) in 35 ml of methylene chloride under a nitrogen atmosphere, a solution consisting of 1.9 g ((0.015 mol) of oxalyl chloride, dissolved in 15 ml of methylene chloride) is added dropwise over 10 minutes. The resulting reaction mixture is heated under reflux for three hours, then cooled to room temperature (20 ° C). The solution of this color thus obtained is evaporated under reduced pressure, the resulting residue is washed twice with about 30 ml of benzene and after distillation the solvent is obtained the solid residue is not combined. White color. This residue is triturated with about 50 ml of isopropyl ether, a solution consisting of 1.5 g (0.0188 mol) of oxalyl chloride, diluted in 5 ml of methylene chloride, is filtered off with 25 ml of methylene chloride under a nitrogen atmosphere over 5 minutes. The resulting reaction mixture is heated under reflux for l17 h, after which the reaction mixture is cooled to room temperature (% -20 ° C). The 50 colorless solution thus obtained is evaporated under reduced pressure, the residue
    the current is washed twice with methylene chloride and then the solvent is distilled off and a white solid is added. T - "In this way, essentially pure hydrochloride 4- (H, N-diethyl nomethyl) benzoyl chloride is easily obtained, which is used in the following reaction mixture
    dry and dry after these


    896 16
    procedures for the preparation of 2.26 g of essentially pure 4- (1-azacyclo-octylmethyl) benzoyl chloride hydrochloride, m.p. 173-175 ° C. The resulting product is used in the further reaction stage without any purification. The yield of the product is quantitative.
    Preparation S. A well mixed suspension consisting of 2.2 g (0.01 mol) a quarter of 4- (M, N-dimethylaminomethyl) benzoic acid hydrochloride hydrate (preparation F) in 70 ml of methylene chloride is added under nitrogen atmosphere 2.8 g (0.022 mol) of oxalyl chloride. The resulting reaction mixture is heated under reflux for 3.5 h, then cooled to room temperature (20 ° C). The solution is evaporated under reduced pressure, the resulting residue is washed twice with about k0 ml of a mixture of benzene: methylene chloride (1: 1 by volume).
    ), the solvent is distilled off, resulting in a white solid. After trituration of this product with about 30 ml of diethyl ether, followed by filtration and drying, the final result is 2.15 g of (921) hydrochloride - (N.N-Dimethylaminomethyl) -benzoyl chloride, mp 187 &amp; C. This product is used in the subsequent reaction stage without further purification.
    Preparation T. K of a well-stirred suspension consisting of 1.3 g (5.0 mmol) of 4- (M, M-diethylaminomethyl) benzoic acid (preparation F)
    thyl) benzoic acid (preparation F)
    in 25 ml of methylene chloride under a nitrogen atmosphere, a solution consisting of 1.5 g (0.0118 mol) of oxalyl chloride, dissolved in 5 ml of methylene chloride, is added over 5 minutes. The resulting reaction mixture is heated under reflux for l17 h, after which the reaction mixture is cooled to room temperature (% -20 ° C). The colorless solution thus obtained is evaporated under reduced pressure, the residue remaining
    the current is washed twice with methylene chloride with ohm, after which the solvent is distilled off and a white solid is obtained. Ta- - “imgly, essentially pure 4- (H, H-diethylaminomethyl) benzoyl chloride hydrochloride is easily obtained, which is used in the next reaction unit without any purification. The yield of the product is quantitative.
    Preparation U. K of a well-stirred suspension consisting of k, 0 g 5 (0.0131 mol) of 4-n-m hydrochloride "§1 til-N - (- phenylethyl) aminomethyl benzoic acid (preparation I) in 100 ml of methylene chloride under a nitrogen atmosphere, 3.9 g (0.0275 mol) of oxalyl chloride (2, ml) are added and a white suspension is obtained. This mixture is heated under reflux for two hours, after which an additional 7.28 g (0.057 mol) of ox-is salyl chloride (5 ml) is added and heating is continued for another 5 hours. The suspension thus obtained is concentrated under reduced pressure until dryness, after which the resulting residue is azeroped with benzene twice, triturated with diethyl ether and filtered to obtain a white solid. In this way, essentially pure hydrochloride-25 REED - m-methyl-K- (|: -phenylethyl) aminomethyl benzoyl chloride is taught. This product t j „
    used in the subsequent reaction
    stage with virtually no further purification. The product yield is quantitative.
    Preparation V. To 2.83 g (0.01 mol) of k- (s-methyl-M-cyclohexyl-aminomethyl) benzoic acid hydrochloride (hydrate, drug, and) in an atmosphere of azo-35 add 10.25 g (0.10 mol) thionyl chloride (7.3 ml). The yellow solution is heated under reflux for three hours, then cooled to room temperature 40 (20 ° C). The cooled reaction mixture was concentrated in vacuo, after which the resulting residue was azeotroped twice with benzene, then triturated with diethyl ether and a white solid was obtained. After filtration, the collected material is washed well with diethyl ether and dried, and 2, kg (80%) of pure M- (M-methyl-M-cyclohexylaminomethyl) benzoyl chloride hydrochloride is obtained. The latter product is used as such in the subsequent reaction step without any purification.
    Preparation W. To 3.12 g (0.011 mol) of 1 -Gl-methyl-H- (para-chlorophenyl) amino-methyl} benzoic acid (preparation Y) in a nitrogen atmosphere add 10.25 g
    (0.10 mol) of thionyl chloride (7.3 ml) to obtain a yellow solution. The resulting mixture is heated under reflux for 2.5 h, then cooled to room temperature (). The reaction mixture thus obtained is concentrated in vacuo to almost dryness, the resulting residue is azeotroped twice with benzene, and an oil is obtained. The oil is triturated with diethyl ether, then filtered on a filter with a vacuum and dried in vacuum to constant weight, to obtain 1.3 g (36%) of 4-m-methyl-I- (p-chlorophenyl) hydrochloride aminomethyl benzoyl chloride as a beige crystalline product. This product is used in the subsequent reaction stage as such without any subsequent purification.
    Preparation X. To 1.3 g (0.005 mol) of hydrochloride — M-methyl-M- (S, and -dimethylcarbamylmethylamipomethyl) benzoic acid (hemihydrate, preparation L) under a nitrogen atmosphere was added 15 ml of thionyl chloride (24.5 g, 0.205 mol), a yellow suspension is obtained. The resulting mixture is heated under reflux for 1.5 hours and then cooled to room temperature (20a C). The yellow solution thus obtained is concentrated in vacuo, distilling off the excess thionyl chloride, the residue obtained is azeotroped twice with 10 ml of methylene chloride, after which an off-white foamy product is obtained. In this way, essentially pure hydrochloride, N-methyl-L- (k, M-dimethylcarbamylmethyl) -aminomethyl benzoyl chloride, which is used in the subsequent reaction stage as such without any purification, is easily obtained. The yield of the product is quantitative.
    Preparation Y. To 1.37 g (0.05 mol) of 1- (4-carboxybenzyl pyridinium chloride) (preparation M), 10 ml of thionyl chloride (16.3 g, 0.137 mol) are added under a nitrogen atmosphere and a partially mixed solution is obtained. This mixture is heated under reflux for 23.5 hours and then cooled to room temperature (). The clear yellow solution thus obtained is concentrated in vacuo to remove
    an excess of thionyl chloride, and the residue obtained (yellow resin) is washed twice with about 50 ml of benzene, then the solvent is distilled off and a white solid is obtained. In this way, essentially pure 1- (C-chlorocarbonylbenzyl) pyridinium chloride) is easily obtained; 201-203 C, with decomposition, which is then used in the subsequent reaction stage without any purification. The yield of the product is quantitative.
    Example 1. A stirring solution consisting of 9.9 g (0.03 mol) of 4-hydroxy-2-methyl-H (2-pyridinyl - 2H- -1,2-benzothiazine 3 carboxamide-1,1- -dioxide), dissolved in 500 ml of methylene chloride under a dry nitrogen atmosphere, cooled in an ice bath and treated with 10.93 g (0.036 mol) of triethylamine (15.1 ml), after which 9.87 g (0.036 mol) was added. ) 4- (piperidinomethyl) benzoyl chloride hydrochloride (preparation N) in portions for five minutes. The mixture was then stirred in the cold for 15 minutes and then at room temperature () for 19.5 hours. The stirred mixture was extracted successively twice with water (250 ml), twice with 250 ml of saturated sodium bicarbonate aqueous solution and once with 250 ml of saturated an aqueous solution of sodium chloride. The total organic layer is then dried over anhydrous sodium sulfate for five hours. After removing the drying agent by filtration and evaporation of the solvent under reduced pressure, a yellowish-brown solid is obtained as a crude residue. The residue is triturated with about 100 ml of ethyl acetate and left to stand for 2.5 hours before filtering. The crude product is dissolved in 250 ml of ethyl acetate, filtered, and the resulting filtrate is concentrated to a volume of about 175 ml and left to settle in air at room temperature, the result is a solid white product, which is sequentially filtered and dried, then 6.45 g (44%) of pure 2-methyl-4- 4- (piperidipomethyl) benzoyloxy -K- (2-pyridinyl) -2H-1,2-benz-eothiazine-3-carboxamide 1,1-dioxide, tons. square 171 ° C (decomp.). Pure product
    characterized by thin layer chromatography and infrared absorption spectra.
    Calculated,% with 63,14; n 5.30; N 10.52.
    five
    0
    five
    0
    five
    0
    five
    0
    five
     about s
    Found,%: C 63.08; H 5.18;
    N
    10.45.
    Example 2 A stirred solution consisting of 17.3 g (0.05 mol) of 4-hydroxy-2-methyl-M- (6-methyl-2-pyridinyl) -2N-1, 2-benzothiazine-3-carboxamide 1,1-dioxide, dissolved in 850 ml of methylene chloride, is treated with 18.21 g (0.18 mol) of triethylamine in a dry nitrogen atmosphere. This solution is cooled in an ice bath and then treated with 17.82 g (0.065 mol) of K- (piperidinomethyl) benzoyl hydrochloride, which is added in portions over five minutes. The resulting solution was stirred at 5 ° C for 20 minutes and then at room temperature (20 ° C) for one hour. The reaction mixture is sequentially extracted twice with 250 ml of water, twice with a saturated aqueous solution of sodium bicarbonate and once with a saturated aqueous solution of sodium chloride. The total organic layer was then dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure. The resulting residue was triturated with 150 ml of ethyl acetate and filtered, giving 23.85 g of crude product. The last product is recrystallized from 200 ml of a mixture of chloroform: hexane, taken in a 1: 1 volume ratio, to obtain 9.07 g (33%) of pure 2-methyl-N- (6-methyl-2-pyridinyl) (pipa -, Ridinomethyl) benzoyloxy -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, m.p. 178 ° C (decomp.). Additionally, 7.4 g of product from the filtrate (2%) was isolated. The pure product is characterized by thin layer chromatography, infrared absorption spectra.
    Calculated,%: C 63.72, H 5.53; N 10.25,
    C23H3oN405S
    Found: C 63.95; H 5.6G; N 10.47.
    Example A stirred solution consisting of 6.0 g
    (0.018 mol) 4-hydroxy-2-methyl-N- (2-pyridinyl) -2H-1,2-benzothiazine 3 carboxamide 1,1-dioxide, dissolved in 150 ml of methylene chloride, in an atmosphere of 5 icyxoro nitrogen treated with 6.07 g (0.06 mol) of triethylamine (8.1 ml). The resulting yellow solution is cooled in an ice bath and 5.52 g of u are added in portions over 15 minutes.
    (0.02 mol) 4- (morpholinomethyl) benzoyl chloride hydrochloride (preparation D). An additional 50 ml portion of methylene chloride is added to the reaction mixture, stirred in the cold for 15
    30 minutes and then at room temperature (20 ° C) for 19 hours. The stirred solution is sequentially extracted with twice 200 ml of a saturated solution of sodium bicarbonate and one 20 times with a saturated aqueous solution of sodium chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo to a foamy 25 residue of a light yellow color. The foam is triturated with 100 ml of ethyl acetate and then filtered to obtain a pale yellowish white solid (yield 4.7 g), which melts at 30 177 ° C (with decomposition). The last product is dissolved in 200 ml of ethyl acetate, filtered and the filtrate is concentrated to a volume of about 100 ml and allowed to stand at. 35 room temperature. The crystalline product which separated out was filtered off to obtain a solid beige-colored product (yield 2.65 g), which melted at 180 ° C (decomp.). After further purification of the product by recrystallization from approximately 50 ml of benzene, filtration and drying, 1.45 g (15%) of pure 2-methyl-4-4- (morpholipomethyl) benzoyloxide (2 -pyridinyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide), mp. 178 ° C (decomp.). The pure product is characterized by thin layer chromatography, by the spectra of the in-5Q fraction of red absorption, in addition to the elementary analysis.
    Calculated,%: C 60.66; H 4.90i N 10.48.
    C27H N408S55
    Found,%: C 60.52; H 4.9V, N 10, 5.
    Example 4: Mixable solution consisting of 2.07 g
    (0.006 mol) 4-hydroxy-2-methyl- (6-methyl-2-pyridinyl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, dissolved in 20 ml of methylene chloride, in an atmosphere dry nitrogen is treated with 2.0 g (0.0198 mol) of triethylamine (2.8 ml). The resulting solution was cooled in an ice bath, and a solution consisting of 1.82 g (0.0066 mol) of 4- (morpholinomethyl) benzoyl chloride hydrochloride in 30 ml of methylene chloride was added over 15 minutes. The resulting reaction mixture was then stirred at room temperature () for 23 hours. The stirred solution was sequentially extracted with twice 50 ml of water, twice 50 ml of a saturated aqueous solution of sodium bicarbonate and once with 50 ml of a saturated aqueous solution of sodium chloride. The organic layer is then dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo to give a yellow foam which is triturated with about 20 ml of ethyl acetate and left to stand overnight. After the slurry is filtered off, an off-white solid is obtained (yield 2.56 g), which is recrystallized, and 150 ml of hot ethyl acetate is filtered and dried, eventually giving 1.20 g (37%) of pure 2-methyl -M- - (6-methyl-2-pyridinyl) -4- (4-morpholinomethyl) benzoyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide in the form of white crystals, melt at 197 ° C (decomp.). The pure product is characterized by mass spectroscopy, thin layer chromatography and infrared absorption spectra.
    Calculated,%: C 61.30; H 5.14; N 10.21.
    C2BHMN + 06S
    Found,%: C H 5.10; N 10.09.
    Example 5: Mixable solution consisting of 13.3 g (0.040 mol of 4-hydroxy-2-methyl-M- (2-pyridinyl) -2H--1,2-benzothiazine-3-carboxamide 1 , 1-dioxide, dissolved in 1000 ml of methylene chloride, is treated with 18.4 g (0.183 mol) of triethylamine (25.5 ml) in a dry nitrogen atmosphere. The resulting solution is then treated with a suspension consisting of 17 g (0,) |
    - (4-methylpiperazinomethyl) beisoyl chloride hydrochloride (preparation P) in 500 ml of methylene chloride, which is added in portions. The resulting reaction mixture was then stirred at room temperature for 18 hours. The stirred mixture was sequentially extracted three times with a saturated aqueous solution of sodium bicarbonate and once with a saturated aqueous solution of sodium chloride, after which the organic layer was dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, a foam-like product is obtained, which is then transferred to 2 liters of boiling ethyl acetate. After removing the insoluble impurities by filtration, the resulting clear filtrate is concentrated in vacuo to a volume of about 100 ml. The resulting yellow solid was filtered off and dried, yielding 6.0 g (27%) of pure 2-methyl-4-4-methyl-piperazinomethyl-benzoyl- (2-pyridinyl) -2H-1,2 in the final result. -benzothiazine-3-carboxamide 1,1-dioxide as a quarter of the hydrate, so pl. 170-173 ° C (decomp.). The pure product is characterized by nuclear magnetic resonance, thin layer chromatography and infrared absorption spectra.
    Calculated,%: C 60.91i H 5.39, N 12.69.
    SgbNg3K5065 0.25Hg. Found;%: C 60.83; H 5.38; N 12.34.
    EXAMPLE 6 A stirred solution consisting of 2.65 g (0.0077 mol) of 4-hydroxy-2-methyl-N- (6-methyl-2-pyridinyl) -2H-1, 2-benzothiazine-3-carboxamide 1,1-dioxide dissolved in 150 ml of methylene chloride is treated with 2.48 g (0, -0-246 mol) of triethylamine (3.44 ml) in a dry nitrogen atmosphere. The resulting solution is then treated with a suspension of 3.0 g (0.0092 mol) of 4- (4-α-methyl piperazinomethyl) benzoyl chloride hydrochloride in 50 ml of methylene chloride, which is added in portions. The resulting reaction mixture is stirred at room temperature for about 18 hours. The stirred mixture is subsequently extracted twice with a saturated aqueous solution of sodium bicarbonate and once with a saturated aqueous solution
    0 5 0
    0
    5 Q
    five
    rum sodium chloride, after which the organic layer was dried over anhydrous sodium sulfate. After removing the drying agent by filtration and evaporation of the solvent under reduced pressure, an orange foamy residue is obtained. This foamy residue is dissolved in 500 ml of ethyl acetate, filtered, and concentrated to a volume of about 50 ml, then left to stand at room temperature. The resulting white solid was filtered and dried, eventually giving 800 mg (19%) of pure 2-methyl-4-4-methyl-piperazinomethyl-benzoyloxy-N- (6-methyl--2-pyridinyl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide as a quarter of the hydrate, so pl. 17b-177C. The pure product is characterized by thin layer chromatography and infrared absorption spectra. Calculated,%: C, 61.52; H 5.61,
    N 12.47.
    Cr.9H ,, Нр053-0,25НгО, Found,%: C 61.37; H 5.63; N 12.28.
    PRI me R 7. A stirred solution consisting of 1.32 g (0.004 mol) of 4-hydroxy-2-methyl-M- (2-pyridinyl) -2N- -1,2-benzothiazine-3-carboxamide 1,1-dioxide, dissolved in 25 ml of methylene chloride, in a dry nitrogen atmosphere is treated with 1.33 g (0.0123 mol) of triethylamine - 1.84 ml. The resulting yellow solution is cooled in an ice bath, and a solution consisting of 1.45 g (0.0048 mol) of 4- (2-ethyl-piperidinomethyl) -benzoyl chloride hydrochloride (preparation Q ) dissolved in 10 ml of methylene chloride. The resulting reaction mixture is stirred at room temperature () for 18 hours, then heated under reflux for 24 hours. This mixture is cooled to room temperature and subsequently extracted twice with 40 ml of water, twice with 40 ml of an aqueous solution of sodium bicarbonate and once ml of a saturated aqueous solution of sodium chloride. The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo to a yellow foamy residue, which is then triturated with about 50 ml of diethyl ether. The mixture was allowed to stand overnight and then filtered to obtain a pale-yellow solid (yield 1.7 g). The latter material is recrystallized from 30 ml of ethyl acetate, the resulting product is filtered off, the result is a solid product of yellow jle-lexane and filtered to remove (yield 60 mg). According to the data of insoluble impurities, after which thin-layer chromatography this material is the resulting filter. Concentrated to
    The rial is the desired product with traces of impurities. Further purification is carried out by recrystallization from ethyl acetate (approximately 10 ml). The resulting yellow crystalline product is filtered and dried, ultimately obtaining
    100 mg of pure (2-ethyl-piperidinomethyl) benzoyloxy -2-methyl-L- - (2-pyridinyl) -2H-1,2-enzothiazine-3-carboxamide 1,1-dioxide as a hemihydrate with t .pl. (different).
    20
    volume about 75 ml. After the concentrated filtrate is at room temperature, a pale yellow solid is obtained, which is filtered and dried, which ultimately results in 80 mg (16%) of pure (1-azacycloooctyl-methyl) benzoyl-oxy ) -2-methyl-G - (2-pyridinyl) -2H -1,2-benzooxythiazine-3-carboxamide 1,1-dioxide in the form of a monohydrate, put in at (decomp.). Clean
    The pure product is characterized by the method; 25 the product is characterized by 4 methods.
    Mass spectroscopy, thin layer chromatography and infrared absorption spectra,
    Calculated,% C 63.25i H 5.8V, N 9.8.
    CJOH N4OffS.O, 5H20
    Found,%: C 62.91; n 5.73, N 9.70.
    mass spectroscopy, thin layer chromatography and infrared absorption spectra.
    t
    Calculated, 30 N 9.68.
    C, 62.27; H 5,
    C30H, tN40
    5 Ng.o
    C, 61.82; H, 5.77;
    Found,% N, 9.35.
    PRI me R 8. Mixed ras-PRI me R 9. Mixed
    a creator consisting of 1.82 g (0.0055 mol) 35 Solution consisting of 2, b5g
    4-hydroxy-2-methyl-M- (2-pyridinyl) -2H-. -1,2-Benzothiazin-3 carboxamide 1,1-dioxide dissolved in 35 ml of methylene chloride is treated with 1.82 g (0.018 mol) of triethylamine (2.5 ml) under nitrogen atmosphere. The resulting yellow solution is cooled in an ice bath, a solution consisting of 2.2 g (0.0066 mol) of hydrochloride - (2-aza-cyclooctylmethyl) benzoyl chloride (preparation R) dissolved in 15 ml of methylene chloride, the resulting reaction solution is stirred at room temperature (20 ° C) for 40 hours. The stirred mixture is sequentially extracted with twice 50 ml of water, twice with 50 ml of a saturated aqueous solution of sodium bicarbonate and one
    (0.008 mol) -oxy-2-methyl-M- (2-pyridinyl) -2H-1,2-benzothiazine-3-carboamide of 1,1-dioxide dissolved in 35 ml of methylene chloride in the atmosphere
    40 dry nitrogen is treated with 2.67 g (0.02bA mol) of triethylene (3.7 ml). The resulting light yellow solution is cooled in an ice bath, adding the suspension for 10 minutes,
    45 consisting of 2.15 g (0.0092 mol) of 4- (s, Ј} -dimethylaminomethyl) benzoyl chloride hydrochloride (preparation S), in 40 ml of methylene chloride. The resulting reaction solution is stirred to
    50 at room temperature (20 ° C) for 1 hour. The stirred reaction mixture is sequentially extracted once with 60 ml of water, twice with 60 ml of a saturated aqueous solution of bicarb
    once with 50 ml of a saturated aqueous solution of sodium nata-sodium and once with 60 ml of sodium chloride solution. The organic layer is then dried over anhydrous sodium sulfate, filtered and the resulting filtrate is concentrated in a saturated aqueous solution of sodium chloride. The organic layer is then dried over anhydrous sodium sulfate and filtered, and the resulting filter
    until a foamy yellow residue is obtained, which is then triturated with about 75 ml of diethyl ether. The mixture was allowed to stand overnight and then filtered to obtain a yellow solid (yield 2.25 g). This product is dissolved in 150 ml cycl.
    volume about 75 ml. After the concentrated filtrate is at room temperature, a pale yellow solid is obtained which is filtered and dried, which ultimately results in 80 mg (16%) of pure (1-azacycloooctyl-methyl) benzoyl oxy) -2-methyl-G - (2-pyridinyl) -2H- -1,2-benzooxythiazine-3-carboxamide 1,1-dioxide as a monohydrate, melted at (decomp.). Clean
    product is characterized by 4 methods
    mass spectroscopy; thin layer chromatography; and infrared absorption spectra.
    t
    Calculated N 9.68.
    C, 62.27; H 5,
    C30H, tN40
    5 Ng.o
    C 61.82,
    Found, 35%.
    Solution consisting of 2, b5g
    (0.008 mol) -oxy-2-methyl-M- (2-pyridinyl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, dissolved in 35 ml of methylene chloride, in an atmosphere
    dry nitrogen is treated with 2.67 g (0.02bA mol) of triethylene (3.7 ml). The resulting light yellow solution is cooled in an ice bath, adding the suspension for 10 minutes,
    consisting of 2.15 g (0.0092 mol) of 4- (s, Ј} -dimethylaminomethyl) benzoyl chloride hydrochloride (preparation S), in 40 ml of methylene chloride. The resulting reaction solution is stirred at
    at room temperature (20 ° C) for 1 hour. The stirred reaction mixture was successively extracted once with 60 ml of water, twice with 60 ml of a saturated aqueous solution of bicarbonated aqueous solution of sodium chloride. Then the organic layer is dried over anhydrous sodium sulfate, filtered and the resulting filtrate
    concentrate in vacuo to give non-. yellowish yellow residue. This residue is triturated with 30 ml of ethyl acetate and allowed to stand for three hours, after which it is filtered and a pale yellow solid is obtained (yield 1.6 g). This product is recrystallized from 75 ml of ethyl acetate. The resulting off-white crystalline product is filtered off and dried, eventually yielding 600 ml (15%) of pure (N, N10
    volume of about 150 ml. The organic concentrate is then left to stand at room temperature overnight, the resulting crystalline precipitate is filtered off and dried, and the final result is 410 mg (14Ј) of pure -Ј (NjN-diethylaminomethyl) benzoyloxy -2-methyl-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide hydrochloride as a hemihydrate, melting at 181-183 C (decomp.). The pure product is characterized by the methods of mass spectroscopy,
    -dimethylaminomethyl) benzoyloxy -2-methanol chromatography and spectral-2H-1, 2-benzothiazine-3-carboxamide 1,1-dioxide, m.p. 173-C (decomp.). The pure product is characterized by mass spectroscopy using infrared absorption spectra.
    Calculated,%: C 60.96; H 4.91) IN 11.37. Ci5Hi4N405S
    Found,%: C 60.40; H 4.91J
    N 11.28.
    i
    Example 10. A stirred solution consisting of 1.7 g (0.005 mol) of 4-hydroxy-2-methyl-I- (2-pyridinyl) -2H- -1,2-benzothiazine-3-carboxamide 1.1 1, 1-dioxide, dissolved in 20 ml of methylene chloride, is treated with 556 mg (0.0055 mol) of triethylamine (0.40 ml) in a dry nitrogen atmosphere. The resulting yellow solution is cooled in ice water, adding dropwise to a solution consisting of 1.44 g (0.0055 mol) of 4- (and M-diethyl-aminomethyl) benzoyl chloride hydrochloride ( preparation T) dissolved in 20 ml of methylene chloride. The resulting reaction mixture was stirred at room temperature (20 ° C) for 120 hours and then concentrated in vacuo to give a foamy yellow product. This residue is triturated with about 25 ml of ethyl acetate and left to stand overnight (16 hours), then filtered and a solid product of an off-white color is obtained (yield 5.2 g). This solid is recrystallized from 30 ml of ethanol. The resulting off-white crystalline product is filtered off and dried, yielding 1.1 g of product melting at 128-133 ° C. (decomp.). This product is then dissolved in EzZOOML ethyl acetate, after which the resulting filtrate is concentrated in vacuo to
    5.34;
    20
    mi infrared absorption.
    Calculated,%: C 57.29; H N 9.90.
    Cr7NgvM405 HC1-0.5N., 0
    Found,%: C 57.45; H 5.25; N 9.82.
    Oxycam-based prodrugs of the invention can be readily adapted for use in the therapeutic treatment of arthritis. For example, 2-methyl-4- 4- (piperidino-methylmethyl) -benzoyloxy-3- (2) -pyridinyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is typical and preferred. body drug that shows anti-inflammatory activity in the standard test-swelling of the paws in rats, caused by an algal diet. Oral administration of the drug in the amount of 32 mg / kg leads to a decrease in the tumor by 7%. The described para-amino-benzoyl derivatives show additional advantages, for example, 2-methyl-A- C- (piperioid-methyl) - .-, -benzoyl-oxy -N- (2-pyridinyl) -2H- -1,2-benzothiazine-3-carboxamide 1,1-dioxide has a bioavailability value in the case of rats 84%, soluble in dilute acid and stable in dilute acid at 37 ° C more than 24 h, moreover, exhibit high efficacy as an anti-inflammatory analgesic when administered once m animals receiving the daily dose. Other prodrugs of the invention present the same results.
    The described hydroxycam prodrugs of the invention can be administered orally, parenterally, or used as a means of local action (ointment, etc.). In general, the dosage of these compounds is desirable to be from about 5.0 mg to about 1000 mg.
    45
    50
    55
    volume of about 150 ml. The organic concentrate is then left to stand at room temperature overnight, the resulting crystalline precipitate is filtered off and dried, and the final result is 410 mg (14Ј) of pure -Ј (NjN-diethylaminomethyl) benzoyloxy -2-methyl-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide hydrochloride as a hemihydrate, melting at 181-183 C (decomp.). The pure product is characterized by the methods of mass spectroscopy,
    thin layer chromatography and spectrum5, 34;
    0
    mi infrared absorption.
    Calculated,%: C 57.29; H N 9.90.
    Cr7NgvM405 HC1-0.5N., 0
    Found,%: C 57.45; H 5.25; N 9.82.
    Oxycam-based prodrugs of the invention can be readily adapted for use in the therapeutic treatment of arthritis. For example, 2-methyl-4- 4- (piperidino-methylmethyl) - benzoyloxy-3- (2) -pyridinyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is typical and preferred body drug that shows anti-inflammatory activity in the standard test-swelling of the paws in rats, caused by an algal diet. Oral administration of the drug in the amount of 32 mg / kg leads to a reduction of the tumor by 7%. The described para-amino-methylbenzoyl derivatives show additional advantages, for example, 2-methyl-A- C- (piperioid-methyl) - -, -benzoyloxy - N- (2-pyridinyl) -2H- -1,2-benzothiazine-3-carboxamide 1,1-dioxide has a bioavailability value in the case of rats 84%, soluble in dilute acid and stable in dilute acid at 37 ° C for more than 24 hours in addition, they show high efficacy as an anti-inflammatory analgesic with a single m taking a daily dose of animals. Other prodrugs of the invention present the same results.
    The described hydroxycam prodrugs of the invention can be administered orally, parenterally, or used as a means of local action (ointment, etc.). In general, the dosage of these compounds is desirable to be from about 5.0 mg to about 1000 mg.
    five
    0
    five
    per day, although variations are possible, depending on the weight and conditions of the subject to be treated, and on the particular mode of administration. However, the most desirable dose for daily use is from about 0.08 to 16 mg per kg of body weight, variations are possible, however, depending on the type of animal being treated and on its individual response to the indicated drug, as well as from the selected type of pharmaceutical composition, time period and
    the interval at which the production is made. When for oral ingestion30
    taking the drug. In some cases, dosages below the lower limit of the indicated dosage area may be more than adequate, while in other cases even more than 20 higher dosages may be used, without causing any harmful side effects. This is due to the fact that a large dose is broken up into several small portions, 25 taken in a day.
    The hydroxycam prodrugs of the invention can be administered alone or in combination with pharmaceutically acceptable carriers in one of the three indicated ways. More specifically, the novel therapeutic formulations of the invention can be administered in the form of a wide variety of different dosage forms, i.e. they can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, solid suppositories, suppositories, powders, aerosols, creams, ointments, jellies, pastes, 40 ointments, lotions, aqueous suspensions, solutions for injections, elixirs, syrups , balms, etc. Moreover, pharmaceutical compositions for oral administration can be sweetened or flavored. In general, the therapeutically effective compounds of the invention in such dosage forms are from about 0.5 to about 90% by weight.
    For oral administration, tablets containing various constituents, such as microcrystalline cellulose, cy35 can be used.
    45
    50
    whether it is desirable to use aqueous suspensions and / or elixirs, the active ingredient can be combined with various sweetening and flavoring agents, coloring agents and coloring agents, and, if desired, emulsifying and / or suspending agents, such diluents as water, ethanol, propylene, glycol, glycerin, and various combinations thereof may be used.
    For parenteral administration, solutions of these hydroxyl prodrugs in sesame (sesame) oil or peanut oil or aqueous propylene glycol can be used. If necessary, the aqueous solutions should be buffered (pH 8) and the liquid diluent must first be converted to an isotonic state. These aqueous solutions can be used for intravenous injection. In addition, these hydroxycamic prodrugs can be administered as topical preparations for the treatment of inflammatory processes in the skin or eyes, and in this case they are preferably used in the form of ointments, creams, lotions, jellies, pastes, solutions, etc. in accordance with standard pharmaceutical practice.
    The anti-inflammatory activity of the compounds of the invention is tested according to a standard test — on paw edema in rats caused by an algal diet. According to this test, anti-inflammatory activity is defined as the percent inhibition of swelling on the hind paws of sodium rat, calcium carbonate, secondary albino males (weight: 150
    Before
    Calcium phosphate and klitsin, along with various disintegrators, such as starch, preferably corn, potato or tapioca,
    190 g) caused by the injection of algae under the sole of the paws. The algae is injected in the form of a 1X aqueous suspension (0.05 ml) after ne
    alginic acid and various complex silicates together with granulating binders such as polyvinylpyrrolidone, gelatin, and gum. Very often, laboratory agents such as sodium lauryl sulphate, magnesium stearate and talc are used for tabletting. Solid formulations of this type may also be used as a filler for gelatin capsules: preferred materials also include lactose or milk sugar along with high molecular weight polyethylene glycol.
    0 5
    0
    five
    five
    0
    whether it is desirable to use aqueous suspensions and / or elixirs, the active ingredient can be combined with various sweetening and flavoring agents, coloring agents and coloring agents, and, if desired, emulsifying and / or suspending agents, such diluents as water, ethanol, propylene, glycol, glycerin, and various combinations thereof may be used.
    For parenteral administration, solutions of these hydroxyl prodrugs in sesame (sesame) oil or peanut oil or aqueous propylene glycol can be used. If necessary, the aqueous solutions should be buffered (pH 8) and the liquid diluent must first be converted to an isotonic state. These aqueous solutions can be used for intravenous injection. In addition, these hydroxycamic prodrugs can be administered as topical preparations for the treatment of inflammatory processes in the skin or eyes, and in this case they are preferably used in the form of ointments, creams, lotions, jellies, pastes, solutions, etc. in accordance with standard pharmaceutical practice.
    The anti-inflammatory activity of the compounds of the invention is tested according to a standard test — on paw edema in rats caused by an algal diet. According to this test, anti-inflammatory activity is defined as the percent inhibition of edema formation on rat hind paws.
    albino males (weight from 150
    190 g) caused by the injection of algae under the sole of the paws. The algae is injected in the form of a 1X aqueous suspension (0.05 ml) after oral administration of the drug, which is usually given in the form of an aqueous solution. The formation of edema is assessed by measuring the volume immediately after the injection and three hours after the injection of algae. Increased in volume three hours after the injection of the algae represents an individual response. Compounds are considered active if the difference in the individual reaction of rats (a group of six rats) treated with the drug and the control group — the 5th group that received only an injection — is significant compared to the results obtained using a standard compound like phenylbutazone in an amount 33 mg / kg, administered by the oral route
    The following n-aminomethylbenzoyl derivatives are α-hydroxy-2 methyl-K- (2-pyridinyl) -2H-1,2-benzothiazine 3 carboxamide 1,1-dioxide and-hydroxy-2-methyl-M - (6-methyl-2-pyridinyl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxid in examples 1-3, and accordingly were tested for anti-inflammatory activity in rats using the standard method Carrantin-induced swelling of a rat's paw in accordance with the conventional procedure.
    The compounds were administered orally in the indicated doses and obtained results in% inhibition of edema for each
    compared with the control (i.e., without entering the compound), as shown in the table.
    one
    2
    3
    five
    6
    7
    9
    ten
    famous
    65 60 61 60
    55 k2
    69 53 2/33
    58 32 9 50
    &
    38 23 34
    kO
    50
     The known compound (according to US patent No.) -benzoyloxy-2-methyl-N- (2-pyridinyl) -2H-1,2-benzothiazine 3 carboxamide 1,1-dioxide.
    Derivatives according to examples 1-3, and respectively, and benzoyl derivative-hydroxy-2-methyl-I- (2-pyridinyl) -2H-1,2-benzothiazine 3 carboxamide 1,1-dioxide example 3 "(patent USA) were tested for solubility in dilute aqueous acid simply by adding 10 mg of the compound used to 2.0 ml (N hydrochloric acid at room temperature 20 ° C). Under these identical conditions, it was found that the compounds of the invention have excellent solubility (5.0 mg / 1.0 ml), while the known compound (as per US Patent No.) is practically insoluble.
    Thus, the proposed compounds have an improved anti-inflammatory activity as compared to the known.
    权利要求:
    Claims (1)
    [1]
    1. A process for the preparation of p-aminomethyl-benzoyl derivatives of the general formula
    CH2Y
    rT CONHR WAxNCH
    where R is 2-pyridyl, 6-methyl-2-pyridyl, Y - S, M-dimethylamino, NjN-diethylamino, piperidine,
    2-ethyl-piperidino, 1-azacyclooctyl, N-methylpiperazino or morpholino,
    their pharmaceutically acceptable acid addition salts with an inorganic acid, characterized in that
    or myh
    HE
    CONHR CH3
    Og
    where R has the indicated meanings, is reacted with an acyl halide of the formula
    ABOUT
    where Y has the indicated meanings, X is chlorine or bromine,
    33 1538896 34
    or its hydrochloric additive2. Method pop. 1, distinguished by salt in an inert organic solution and with the fact that, as an inertizer in the presence of a base with a true organic solvent using an equimolar amount, the halogenated lower initial reagents are used at 0–20 ° C in those - hydrocarbon, and as base 1-120 part of tertiary amine.
    类似技术:
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    同族专利:
    公开号 | 公开日
    IL78912A|1990-07-12|
    FI862252A|1986-11-30|
    YU90686A|1987-10-31|
    ZA863986B|1988-01-27|
    HUT43597A|1987-11-30|
    KR870000913B1|1987-05-06|
    DD247451A5|1987-07-08|
    FI86065B|1992-03-31|
    ES8707211A1|1987-07-16|
    PT82649A|1986-06-01|
    PH23146A|1989-05-11|
    DK249086D0|1986-05-28|
    NO165240C|1991-01-16|
    AT56010T|1990-09-15|
    DE3673710D1|1990-10-04|
    JPH0575754B2|1993-10-21|
    NO165240B|1990-10-08|
    EP0208404A2|1987-01-14|
    PL147843B1|1989-08-31|
    HU200178B|1990-04-28|
    US4623486A|1986-11-18|
    EP0208404B1|1990-08-29|
    YU44576B|1990-10-31|
    EG17811A|1990-08-30|
    EP0208404A3|1987-04-15|
    JPS61277683A|1986-12-08|
    CA1270485A|1990-06-19|
    AU557396B1|1986-12-18|
    FI862252A0|1986-05-28|
    KR860009012A|1986-12-19|
    CN86103603A|1987-01-21|
    DK249086A|1986-11-30|
    NO862124L|1986-12-01|
    NZ216310A|1988-10-28|
    CN1004628B|1989-06-28|
    PT82649B|1988-08-17|
    SU1531855A3|1989-12-23|
    HU199839B|1990-03-28|
    ES555374A0|1987-07-16|
    FI86065C|1992-07-10|
    GR861389B|1986-09-17|
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    法律状态:
    优先权:
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    US06/738,805|US4623486A|1985-05-29|1985-05-29|[4-substituted benzoyloxy]-N-substituted-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides having anti-arthritic activity|
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