• 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:
    Compounds of formula (I): <IMAGE> in which X at 5, 6, 7 or 8 is H, halogen, (C1-5) alkyl, (C1-4) alkoxy, -CF3, -SCF3, -OCF3, R1 is phenyl optionally substituted by at least OH, (C1-5) alkyl, (C1-4) alkoxy, CF3, NO2, halogen or a heterocyclic radical optionally substituted by a (C1-4) alkyl radical, R2 and R3 which are identical or different are H, (C1-4) alkyl, aryl, -C(:O)-R5, R5 being (C1-4) alkyl or aryl. R4 is H, (C1-4) alkyl or aryl, and their addition salts with acids and bases.
    公开号:SU1584749A3
    申请号:SU864027833
    申请日:1986-07-23
    公开日:1990-08-07
    发明作者:Клеменс Франсуа；Ле Мартре Одиль；Дельвалле Франсуаз
    申请人:Руссель-Юклаф (Фирма)；
    IPC主号:
    专利说明:


    s
    This invention relates to a process for the preparation of novel 4-hydroxyquinolinecarboxylic acid derivatives, possessing analgesic and anti-inflammatory properties in chronic inflammations.
    The purpose of the invention is the synthesis of new compounds of the 4-hydroxyquinoline carboxylic acid series, which in their anti-inflammatory properties are superior to the use of the drug indomethacin.
    Example K 4-Hydroxy-2 (1-hydroxy-2-methoxyethyl) -N- (2-thiazolyl) -8- (trifluoromethyl) -3-quinolinecarboxamide.
    Stage A: 2- C (2-chloro-3-methoxy-1-oxopropyl) amino-L-OKCO-N (2-thiazolyl) -3-t rifluoromethylbenzenepropane mid.
    At 0 ° C, 350 cm-5 n-butyl lithium in solution in hexane are introduced into a suspension of 34 g of 2-acetylaminothiazole in 1100 cm 5 of tetrahydrofuran. The mixture is cooled to -70-75 ° C and a solution of 36.78 g of 2- (1-chloro-2-methoxyethyl) 8-trifluoromethyl-4H-3,1-benzoxazin-4-one, a product obtained from 2-chloro-3-methoxypropanoic acid and 2-am-but-3-trifluoromethylbenzoic acid in 250 tetrahydrofuran.
    The resulting solution is drunk in aqueous hydrochloric acid solution, extracted with ether, washed with 1N hydrochloric acid,, dried, concentrated under reduced pressure.
    The residue obtained is taken up in dough in ether, sucked off, washed with ether, dried under reduced pressure, and 33.35 g of the expected product are obtained, melting at.
    Found,%: С 45.6; H 3.4; N 9.0; F 12.4; C1 7.8; S 7,8.
     (449,845)
    Calculated,%: C 45.39, H 3.36, N 9.34; F 12.67; C1 7.88; S 7.13.
    Stage B: 2- (1-chloro-2-methoxyethyl) 4-hydroxy-M - (2-thiazolyl) -8--trifluoromethyl-3-quinolinecarboxamide.
    33.35 g of the product of stage A and 10 g of dimethylaminopyridine in 300 cm of tetrahydrofuran are heated with reflux for 30 minutes.
    The mixture is cooled to room temperature, poured into a mixture of water and 2N hydrochloric acid, extracted with ethyl acetate, washed, dried and concentrated under reduced pressure. The residue of cry-1 is sprinkled in ether, sucked off, washed, dried at 60 ° C under reduced pressure, and 28.2 g of the desired product are obtained, melting at 186 ° C.
    Q
    P
    five
    0
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    Stage B: 1,3-dihydro-3- (methoxy-megap) -1-G (2-thiazolyl) imino 1-5-trifluoromethylfuro- (3.4 b) -quinolin-9-ol.
    For 30 minutes, 23.9 g of the product of stage B and 7.7 g of potassium t-butoxide in 550 cm of dioxane are heated with reflux. Dioxane is removed under reduced pressure, the residue is taken up in a mixture of water and 2N. hydrochloric acid solution, the insoluble matter is extracted with a mixture of ethyl acetate and acetic acid and tetrahydrofuran (80-20) 0 The organic layer is washed with water and the aqueous layers are combined.
    The aqueous layer is neutralized by adding an aqueous solution of (saturated) sodium bicarbonate, extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. 22 g of the expected product are obtained.
    Stage G: 4-hydroxy-2- (1-hydroxy-3-methoxyethyl) -M- (2-thiazolyl) -8- (trifluoromethyl) -3-quinoline carboxamide.
    At room temperature, the solution containing 16 g of the product of stage B, 70 cm5 of water, and 130 cm of concentrated hydrochloric acid is stirred for 16 hours.
    The precipitate obtained is filtered off with suction, washed with water, taken in 200 cm3 of water, extracted with ethyl acetate and tetrahydrofuran (50-50), the organic layer is washed with water, dried, concentrated under reduced pressure, and 15 g of product is obtained which is purified chromatographic method on silica under pressure (eluant: ethyl acetate). 12.5 g of product are obtained, which is dried in ether, sucked off, washed with ether, dried under reduced pressure at 100 ° C.
    11.83 g of the chain product are obtained, melting at 216 - 218 ° C.
    Found,%: C 49.5; K 3,4; N 10 F 13.9; S 7.7.
    ) 4 04N3F3S (413,384)
    Calculated,%: C 49.39; H 3.41, N 10.16, F 13.76, S 7.76.
    Example 2. 2- (1,2-Dihydroxyethyl) -4-hydroxy-I- (2-thiazolyl) -8- trifluoromethyl-3-quinolinecarboxamide.
    In an inert atmosphere, 6.7 cm of trimethylsilane iodide was slowly introduced into the mixture containing 6.5 g of product at
    515
    measure 1 and 120 cmE of acetonitrile, mix for 16 hours at room temperature, drink 400 cmE of water containing 50 cm3 of sodium bisulfate.
    The resulting suspension is stirred for 45 minutes at room temperature, 100 cmE of ethyl ether is added, stirred for 30 minutes, sucked off, washed with water and dried under reduced pressure at 75 ° C for 16 hours. 5.9 g of product are obtained, which is dissolved in 75 cm5 of dimethylformamide, filtered, ether is added to the filtrate, ice nt, the resulting crystals are filtered off with suction, washed with ether, dried under reduced pressure, and 4.86 g of the expected product are obtained, melting at.
    Found,%: C 48, OJ H 3.0, N 10.4, F 14.1; S 8.0.
    С & Н «НзР3048 (339,356)
    Calculated,%: C 48.12; H 3.03, N 10.52; F 14.27, S 8.03.
    EXAMPLE 3. 2- (1,2-Dihydroxy-propyl) -4-hydroxy-M- (2-thiazolyl) -8--trifluoromethyl-3-quinoline-carboxamide.
    Step A: | 3-oxo-2G (1-oxo-2-butenyl) -amino-M- (2-thiazolyl) -3-trifluoromethyl benzene propanamide.
    The procedure is as described in stage A of Example 1, but starting from 19.44 g of 2-acetylaminothiazole and 17.3 g of 2- (1- -propencl) -8-trifluoromethyl-4H-3,1-benzoxazin-4- ono 19,03tr of the desired product is obtained, melting at 206 -.
    Stage B: 4-hydroxy-2- (1-propenyl-N- (2-thiazolyl) -8-trifluoromethyl-3-quinoline carboxamide.
    17.5 g of the product of stage A in a solution of 175 cm 5 of dimethylacetamide are added to a mixture containing 2.11 g of sodium hydride in a 50% dispersion in oil and 100 cm 3 of dimethyl acetamide. Heated to 120 ° C and kept at this temperature for 30 min.
    The solution is cooled, then it is poured onto a mixture of water and 2N hydrochloric acid. The resulting precipitate is sucked off, washed with water, dried at 80 ° C under reduced pressure, and 16.7 g of the expected product is obtained, melting at 2651.
    Stage B: 1- (1,2-dihydroxypropyl) -4-hydroxy-i- (2-thiazol) -8-trifluoromethyl-3-quinolinecarboxamide.
    In an inert atmosphere with stirring for 1 h a mixture containing 12.2 g
    0
    five
    five
    749
    ,
    product of stage B in 300 cm3 of methylene chloride, 9.16 g of methyl benzyl ammonium chloride and 6.32 g of potassium permanganate.
    150 cm3 of ice water is added, and then 150 cm3 of sodium bisulfide solution, the resulting insoluble material is sucked off, washed with water, and partially dissolved in tetrahydrofuran.
    The organic solution is dried, concentrated under reduced pressure, and 5.8 g of crude product is obtained, which is dissolved in warm dimethylformamide. The solution obtained is filtered, concentrated to 40 cm, 60 cm3 of ethyl ether are added, ice-nt, crystals are sucked off, washed with ether, dried at 100 ° C under reduced pressure. The resulting product is dissolved in tetrahydrofuran.
    It is filtered, concentrated under reduced pressure, the residue is concentrated in ethyl acetate, sucked off, washed, dried at 100 ° C under reduced pressure, and 3.04 g of the desired product are obtained, melting at 275 ° C.
    Found,%: C 49.3; H 3.3; N 10.1; F 14.1; S 7,8.
    With THrt (413,384)
    Calculated,%: C 49.39, H 3.41; N 10.16; F 13.79, s 7.76.
    Example 4, 2-Bis- (1-oxo-propoxy) ethyl 7 4-hydroxy-L- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide.
    At 20 ° C, 2.15 g of the product obtained in Example 2, 70 cm of methylene chloride and 0.96 cm3 of propionic acid are mixed. After 5 minutes, 2.9 g of dicyclohexylcarbodiimide was added, followed by 2.4 g of dimethylaminopiridine and kept under stirring for 1 hour and 30 minutes. Filter, wash the filtrate with a saturated aqueous solution of sodium carbonate, aqueous hydrochloric acid and then with water. It is dried, evaporated to dryness and the residue is recrystallized in acetonitrile. 1.34 g of the expected product is obtained. M.p. .
    Found,%: C 51.7; H 3.9; N 8.1, S 6.2; F 11.1.
    CQQHuoF3N3ObS (511,479)
    Calculated,%: C 51.66, H 3.94, N 8.22; g 6,27; F 11.14.
    0
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    0
    ITR and -Mer 5. 5-C2-Methoxy-1- (1- -oxopropoxy) ethyl-4-hydroxy-M- (2- -thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide.
    According to the method described in example 4, 2 g of the product obtained in example 1 was used at the end of the procedure. 0.4 cm of propionic acid, 1.2 g of dicyclohexylcarbodiimide and 0.3 g of dimethylaminopyridine. After crystallization in ethyl acetate, 1 g of the expected product is obtained. M.p. 190 ° C.
    Found,%: C 51.5; H 4.0; F 11.9; m 8.9, S 6.5.
    CieHieF N305S (469,442)
    Calculated,%: C 51.17; H 3.87, F 12.14; N 8.95, S 6.83.
    Example 6. 2- 0,2- (Dibenzoyl-oxy) ethyl D-4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide.
    The procedure is as described in Example 4, starting with 0.5 g of the product obtained in Example 2, 0.37 g of benzoic acid, 0.67 g of di- [cyclohexylcarbodiimide and 0.075 g of dimethylaminopyridine. 0.8 g of crude product is obtained, which is dissolved in 15 cm 5 of tetrahydrofuran. Add 0.3 cmE to 5.7 n. solution of hydrochloric acid in ethanol. The crystals formed are filtered off with suction and dissolved in a mixture of ethyl ether - water. Extracted with ethyl acetate, dried and concentrated to dryness. The residue is dissolved in tetrahydrofuran, ethyl ether is added, cooled to 0 ° C for 2 hours, the crystals are sucked off and dried. 0.33 g of the expected product is obtained. M.p. 240 ° C.
    Found,%: C 59.2, H 3.2; N 6.9,
    19.6, S 5.4.
    CteHeeF9N306S (607,563)
    Calculated,%: C 59.31, H 3.32, N 6.91, - F 9.38, g S S 5.28.
    Example. 2-l, 2- (Dietsetiloksi) ethyl-4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide.
    Act according to the method described in example 4, based on
    2 g of the product obtained in Example 2, 0.7 cm of acetic acid, 2.7 g of dicyclohexylcarbodiimide and 0.3 g of dimethylaminopyridine. 0.9 g of a crude product containing a small amount of dicyclohexylurea is obtained, which is removed by washing with tetrahydrofuran, by recrystallization in di
    five
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    methylformamide, and then the formation of hydrochloride in tetrahydrofuran, to which is added an ethanolic hydrochloric acid solution. After recrystallization in acetic acid, 0.38 g of the expected product is obtained. M.p. .
    Found,%: C 49.4; H 3.2; N 8.4; F 11.9, S 6.8.
    C H FsNgOeS (483.432) Calculated,%: C 49.69; H 3.34; N 8.69; F 11.79; S 6.63.
    Example 2- (2,2-Dimethyl-1,3-dioxolan-4-yl) -4-hydroxy-M- (2-thiazolyl) -8-trifluoromethyl-3-quinoline-carboxamide.
    3 g of the product obtained in Example 2 are introduced into a suspension in 80 cm of acetone. The mixture is heated with reflux, and then 0.3 g of para-toluenesulfonic acid is added and the reflux is maintained for 5 hours. It is cooled to 20 ° C, the crystals are sucked off and dried under reduced pressure. It is dissolved in 100 cm-5 of tetrahydrofuran, heated to 40 ° C, filtered, concentrated to half the volume, cooled to 20 ° C and ethyl ether is added. The crystals are sucked off, washed with ethyl ether and dried. 1.2 g of the expected product are obtained. M.p. 250 ° C.
    Found,%: C 51.8; H 3.5; N 9.4; F 12.8; S 7.1.
    CigH 6F3N304S (439.417) Calculated,%: C 51.94; H 3.67; N 9.56 ", F 12.97; S 7.30.
    EXAMPLE 9 4-Hydroxy-2- (1- -hydroxy-2-methoxyethyl) FM. (2-Thiazolyl) -7-chloro-3-quinoline-carboxamide. Step A:
    2- (2-chloro-3-methoxy-1-oxopropyl) -amino - & amphoxo-M- (2-thiazolyl) - -4-chlorobenzenepropanamide.
    Act as in stage A of Example 1, starting from 2- (1-chloro-2-methoxyethyl) -7-chloro-4H-3,1-benzoxazin-4-β-one. M.p. . The expected product is obtained melting at 180 ° C in a yield of 76%.
    Stage B: 2- (1-chloro-2-methoxy-ethyl) -4-hydroxy - (2-thiazolyl) -7-chloro-3-quinolinecarboxamide.
    Act as in stage B of Example 1. The product is consumed for the next stage without its isolation.
    Stage B: 1,3-dihydro-3- (methoxymethyl) -1- | (2-thiazolyl) -iminoZ-6-chlorofuro-Ez, 4-6 T-quinoline-9-ol.
    five
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    The procedure is the same as described in stage B of example 1 without intermediate isolation of quinoline of stage B, the reaction is carried out with reflux with tetrahydrofuran for 24 hours. The end product is obtained with a yield of 65%. M.p. 2706C.
    Stage G: 4-hydroxy-2- (1-hydroxy-2-methoxyethyl) -M- (2-thiazolyl) -7-chloro-3-quinolinecarboxamide.
    Act similarly to the method described in stage G of example 1, holding with stirring in 6 n. hydrochloric acid 36 hours. Obtain the desired product. M.p. 270 ° C.
    The proposed product is at least 40 times better tolerated than indomethacin, and 20 times better than piroxicam.
    Pharmacological study.
    Anti-inflammatory activity: induced chronic arthritis (prophylactic treatment).
    Injection of an arthritis-causing Freund-type adjuvant into the hind paw causes a rapid appearance of a primary inflammatory disease in the paw in the rat, then after a time period of 13-15 days, secondary arthritis develops, acquired by the other hind paw. The test was carried out on male rats aged 42-50 days who received intramuscular injection of Freund-type adjuvant a ml (suspension in vaseline oil 6 mg per ml of sacrificed My co-bacterium butyricum).
    Animals receive the test product orally, starting on day O (day of injection of the adjuvant) until the day before the animals are killed for experiments performed on day 17 Arthritis control animals, normal (healthy) control animals receive only excipient. Cree
    Degree X: Number of rats having a sound. pl
    ------------------------- l .--------- - jp e
    NUMBER CRYS
    The dose corresponding to the index of 100 or DI 100 is determined graphically (the maximum index of ulcer is 300)
    The product of example 2 DI 100 mg / kg
    200
    Indomethacin5
    Piroxicam9
    The compounds obtained are of low toxicity.
    0
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    The criteria for evaluating the activity of the studied substances are an increase in the volume of the hind, in which injection (primary and secondary inflammation) was made and in which the paw was not injected (secondary inflammation) in relation to the average volume of the corresponding paws of control animals.
    YES is defined. a dose that reduces by 50% the increase in the volume of the hind paws of treated animals compared to control animals.
    t
    The DA50 values found are about 2, 0.7, 3, 1, and 5 mg / kg, respectively, for the products of Examples 1-5.
    The DA5 & found values for indomethacin and piroxicam, respectively, are 0.6 and 0.8 mg / kg.
    Gastric ulcerogenic effect.
    The effect is investigated on female rats weighing 120-150 g with a water diet starting from 24 hours from the time of treatment and distributing them in blocks.
    Products are administered orally. After 7 hours, the animals are sacrificed, and their stomachs opened along the greater curvature are washed with an isotonic solution of sodium chloride and expanded by wiping with a cotton swab soaked in the same solution.
    The significance of ulcerative lesions according to the number and height is assessed according to a scale of 0–3 by two permanent observers of the treatments: grade 1 indicates the presence of a genuine ulcer or several pointlike expressions.
    In order to also take into account the percentage of rats with ulcers (the degree of seizure is above 0.5: an assessment which is attributed to hyperemia or petition, often occurring in the control, live, taken on an empty stomach, the index. each group according to the formula
    权利要求:
    Claims (1)
    [1]
    50 claims
    The method of obtaining 4-oxy-.-Quinoline-carboxylic acid derivatives of the general formula
    HE
    55x v- v-CONHRl
    N
    CH-CH-Rct OR2 OR3
    CD
    111584749
    e X - trifluoromethyl in position 8 or halogen in position 7, RJ - thiazolyl,
     and R-j is the same or different and means hydrogen, Cx-C4-alkyl or C - RS,
    h o
     where Rs is C, -C4 alkyl or aryl, or R.2. and Ra form the residue of acetonide R4 hydrogen or C-C4 alkyl, differing in that the combination of the general formula
    ABOUT
    Yu
    Yu
    (and)
    Y- CH-CH-OR115 g
    H
    R
    where X and R have the indicated meanings;
    R is Cr-C4 alkyl;
    X - halogen,
    Subject to the interaction with the compound-
    CH3 CONHR,
    (Iii)
    de R has the indicated meanings
    The resulting compound of the general form - 3Q by clenching into an ether or ester of one or two hydroxyl groups.
    for the preparation of compounds of formula (I), where R0 and / or Ra are the same or different and mean C-C4 alkyl, aryl or, the --C - group, with the selection of the intended product or, if necessary,
    The compound of formula (I), where Rg and R are hydrogen, is treated with acetone in the absence of an acidic agent in order to obtain the corresponding acetonide, or treated with an acid of the formula Rg – COOH to obtain compounds of formula (I), where X, R, R4 have the indicated values -45 nor Cs C (-C4 alkyl; RЈ-C-C-Rg,
    Oh with the release of the target product
    COClb-CONH-Rt (iv) II,
    xhhhhhhhhhhh
    t
    where X, R |, X), Rj, R4 have indicated
    meanings
    cyclized in the presence of an alkaline agent to form a compound of the general formula
    OH (V)
    1, CONH-RI
    N -r, H-i: N-UH, Xi U
    X
     2
    where X, Rj, Xf,., R 3 have the indicated
    meanings
    which are cyclized in the presence of potassium t-butoxide in organic solvent to form a compound of the general formula
    he is N-RI o
    (Vi)
    CH-OFU
    i 5
    where X {, RI, R3 R4 have the indicated
    meanings
    which are treated with either an acid to form a compound of formula (I), wherein X, R, and R4 are as defined; Rg is hydrogen; R is C-C4 alkyl, with isolation of the target product or with the conversion of a compound of formula (I), where Re is Cb-Cd-alkyl, into a compound of formula (I), where R3 is hydrogen, with isolation of the target product or with the conversion of a compound of formula ( I), where RS is 1,4-C4-alkyl, to a compound of formula (I), where RJ is hydrogen, with the release of the target product or with
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    FR2585356A1|1987-01-30|
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    DK351886D0|1986-07-24|
    PT83064A|1986-08-01|
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    AU3339797A|1996-06-20|1998-01-07|Smithkline Beecham Plc|4h-3,1-benzoxazin-4-one derivatives and analogs as antiviral agents|
    JP3337992B2|1997-11-04|2002-10-28|ファイザー製薬株式会社|5-Substituted picolinic acid compound and method for producing the same|
    JP4804590B1|2010-04-14|2011-11-02|帝人テクノプロダクツ株式会社|Meta-type wholly aromatic polyamide fiber|
    法律状态:
    2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20040724 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR8511389A|FR2585356B1|1985-07-25|1985-07-25|NOVEL DERIVATIVES OF 4-OH QUINOLEINE CARBOXYLIC ACID SUBSTITUTED IN 2 BY TWO POSSIBLE ETHERIFIED OR ESTERIFIED HYDROXYL FUNCTIONS, THEIR PREPARATION PROCESSES, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS|
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