• 专利附录
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    • 专利摘要:
    This invention relates to heterocyclic compounds, in particular to the preparation of substituted 3-phenyl-7H-thiazolo [3,2-B] [1,2,4] triazin-7-ones of the common formula @ where R 1 is direct or branched C 1 - C 4 -alkyl R 2 - H or C 1 - C 3 -alkyl R 3 is H, straight or branched C 1 -C 4 -alkyl or hydroxymethyl, which can be used in medicine. The goal is to develop a method for producing compounds with a new type of biological effect. Preparation of lead from 3-mercapto-2H-1,2,4-triazin-5-one and 2-halogen-1-phenyl-alkanone in a neutral or acidic medium to obtain the desired product, or in the basic medium with the formation of an intermediate S-alkylated 2H- 1,2,4-triazin-5-it, followed by its dehydration with the formation of the target product. The novel compounds are antirheumatic agents. 3 hp f-ly, 3 tab.
    公开号:SU1579462A3
    申请号:SU884355085
    申请日:1988-01-29
    公开日:1990-07-15
    发明作者:Торварт Вернер；Геберт Ульрих；Шлейербах Рудольф；Райдер Бартлетт Роберт
    申请人:Хехст Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new heterocyclic chemical compounds, namely, substituted 3-phenyl-7H-thiazolo (3, Јl, 2.4Dtriazin-7-ones, which can be used as active substances in drugs, especially for the treatment of rheumatic diseases.
    The aim of the invention is to obtain novel 7H-thiazolo derivatives of 3,2-bj i, 2,4} triazin-7-ones with a new type of biological effect in this series of compounds.
    The structure of all the compounds obtained was confirmed by elemental analysis, infrared spectrum and H-nuclear magnetic resonance.
    Example 1. 3- (3,5-Di-tert-butyl-4-hydroxyphenyl) -7H-thiazolo 3,2-З3-, 2,4-triazin-7-one.
    a) In an acidic environment.
    af) 2-Bromo-1- (3,5-di-tert-butyl-4-. -oxysyl) ethanone.
    sl 1
    with
    3 N

    cm
    asnz
    No. zs) 3s- (o
    H2C-Br
    206 g (0.83 mol) of 1- (3,5-di-tert-butyl-4-hydroxyphenyl) ethanone is dissolved with stirring in 415 ml of methylene chloride, heated to boiling and in the course of 30 minutes, drop by drop m mixed with 144 g (0.9 mol) of bromine. After that, it is heated for 2 hours under reflux, the mixture is cooled, mixed with 400 ml of water, the organic phase is separated and dried over sodium sulfate. After removal of the solvent under reduced pressure, the obtained solid crude product is recrystallized from 540 ml of methylcyclohexane hexane. Yield 191 g (67% of theory); m.p. 105-108 ° C; C vN23Vg0 (mol. Weight 327.3).
    a) 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -7H-thiazolo 3,2-b, 2,4 j triazin-7-one
    BUT
    (H3C) 3C
    c (w3b

    w °
    197 g (0.6 mol) of 2-bromo-1- (3,5-di-tert-butyl-4-hydroxyphenip) ethanol from step a and 80 g (0.62 mol) of 3-mercapto 2H-1,2,4-triazin-5-one is stirred in 700 ml of glacial acetic acid for 4 hours at 90 ° C. After that, the reaction mixture is left to cool slowly and the resulting crystalline precipitate is sucked off, which is then washed with water and stirred in 1000 ml of water for a maximum of 90 ° C for 30 minutes. The recrystallization of the still wet aggregate of crystals and mother liquor is carried out from 7000 ml of ethanol.
    Output: 171.6 g (80% of theory); m.p. 257 C (decomposition).
    Calculated,%: C 63.84; H 6, -49; N 11.75; S 8.99.
    C (mol. Weight 357.5)
    Found,%: C 63.55; H 6.44; N 12.03; S 9.00.
    b) In basic terms.
    B) p- (3,5-di-tert-butyl-4-hydroxyphenyl cycl) -2H-1,2,4-triazin-5-one
    but
    C (CH3) 3
    50
    five
    0
    35
    40 45
    five
    (NCS)
    Hl o
    To a suspension of 12.9 g (0.1 mol) of 3-mercapto-2H-1,2,4-triazin-5-one in 250 ml of water was added 5.3 g (0.04 mol) of sodium carbonate and stirred 30 minutes, then a solution of 32.6 g (0.1 mol) of 2-bromo-1- (3,5-di-tert-butyl-4-hydroxyphenyl) ethanone in 250 ml of methanol is added dropwise and the reaction mixture is kept for 1 hour at 75 ° C. After cooling, the precipitate is filtered and recrystallized from ethyl acetate.
    Yield: 26.6 g (71% of theory); m.p. 209-21 TOS.
    Calculated,%: C 60.78; H 6.71; N 11.19; S 8.54.
    C, qH25N303S (mol. Weight 375.5).
    Found,%: C 60.45; H 6.82; N 10.06; S 8.68.
    B) 3- (3,5-di-tert-butyl-4-hydroxy-phenyl) -7H-thiaool 3, 2.4 triazin-7-one.
    3.7 (0.01 mol) of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -thio -2H-1 2,4-triazine -one from step b, stirred in mixtures of 60 ml of tetrahydrofuran and 50 ml of 2N hydrochloric acid for 36 hours at room temperature. The slowly precipitated cyclocondensation product is filtered off and recrystallized one to three times from tetrahydrofuran / ethanol (3: 2).
    Output: 1.5 g (42% of theory), so pl. 256-257 ° (decomp.); C (() HZ3N302S (mol. Weight 357.5).
    Analytical and spectroscopic data confirm the identity of the product obtained to the compound prepared according to the list of a.
    Example 2. 3- (3-tert-Butyl-5- -methyl-4-hydroxyphenyl) -7H-thiazolo 3,2-L 1,2,4-triazin-7-one.
    al) 2-Bromo-1- (3-tert-butyl-5-methyl-4 hydroxyphenyl) ethanone
    sssvdz
    ch2-Vg
    179 g (0.8 mol) of copper (II) bromide heated to boiling
    A solution of 28.5 g (0.1 mol) of 2-bromo-1- (3-tert-butyl-5-methyl-4-ox-phenyl) ethanone from the af stage and 12.9 g (0.1 mol) 3-mercapto-2H-1,2,4-triazin-5-one is heated in 250 ml of ethanol for 8 hours under reflux. After removal of the solvent in vacuo, the solid residue is dissolved in 200 ml of boiling complex acetic acid effector and filtered while hot. By condensation of the filtrate, colorless crystals are obtained which are recrystallized once more from opropanol.
    Yield: 18.9 g (61% of theory);
    , pl. 225 - 226 ° С (decomp.)
    Calculated,%: C 59.23; H 3.08; N 12.95; S 9.88.
    Cfc NP NJ 0.7.7 (mol. Weight 315.4).
    Found,%: C 59.51; H 8.17; N 12.83; S 9.82.
    Example 3. 3- (3,5-Di-tert-butyl-4-hydroxyphenyl) -6 hydroxymethyl-7H-thiazolo-3,2-Ü 1,2,4-triazin-7-one.
    a) 6-Oxymethyl-3-mercapto-2H-1, 2,4-triazin-5-one
    N
    l
    N
    ABOUT
    I
    S (SNY
    JN L CHrOH
    sV °
    -g
    40
    14.4 g (0.044 mol) of 2-bromo-1- (3, 5- -di-tert-butyl-4-hydroxyphenyl) ethanone (Example 1af) and 7.0 g (0.044 mol) of 6-hydroxymethyl-3 -mercapto-2H-1,2,4-triazin-5-one from step a, is heated in
    300 ml of ethanol 4 hours before boiling. The reaction mixture, which was concentrated under reduced pressure, was dissolved in 300 ml of chloroform and treated with 100 ml of a saturated solution of sodium bicarbonate. The chloroform phase is separated, dried and concentrated. Raw product filtration
    0 on silica gel with ethyl acetate / methanol (99: 1) gives colorless needles as a solvent.
    Yield: 11.1 g (65% of theory); m.p. 215-217 ° C.
    5Calculated,%: C, 61.99; H 6.50;
    N 10.85; S 8.27.
    C-2oH25N303s (mol. Weight 387.5) Found,%: C 61.98; H 6.65; N 10.75; S 8.25.
    1579462
    L p, and me R 4. 3- (3,5-Di-tert-butyl-4-oxyLenyl) -2,6-dimethyl-7H-thia-, 2-b i, 2.4 triaine- 7-he
    a) 2-Bromo-1- (3,5-di-tert-butyl-4-oxyphenyl) propanone
    with (sn3) 3
    (H3C) 3C
    xp
    In a boiling suspension of 139.0 g (0.62 mol) of copper (II) bromide in 300 ml of ethyl acetate, a solution of 82.0 g (0.31 mol) of 1- (3,5-di- tert-butyl-4-hydroxyphenyl) -pro panopa in 300 ml of chloroform. Then it is heated until the release of hydrogen bromide is complete for 3 hours under reflux. After cooling to room temperature, the copper salts are filtered off with suction, the residue from filtration is further washed 2 times with ethyl acetate and the filtrate is concentrated under reduced pressure. The recrystallization of the solid residue is carried out from petroleum ether (40-60 ° C).
    Yield: 87.5 g (82% of theory); m.p. 130-132 ° C; C17 (mol. Weight
    341.3).
    a2) 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -2,6-dimethyl-7H-thiazolo 3,2-bJ
    i, 2, 4J triazin-7-one
    S1SVD3 BUT
    1n3s) gf
    aa-sleep
    S n and
    17.1 g (0.05 mol) of 2-bromo-1- (3,5- -di-tert-butyl-4-hydroxyphenyl) propanol from step a, and 792 g (0.05 mol) of 3-mercapto -5-methyl-2H-1,2,4-triazin-5-one is stirred in 60 ml of glacial acetic acid for 4 hours at 90 ° C. The reaction mixture evaporated under reduced pressure was dissolved in 30Q ml of chloroform and treated with 100 ml of a saturated solution of sodium bicarbonate. After separation, sugaki and condensation of the chloroform phase, recrystallization from isopropanol is carried out twice.
    Yield: 10.8 g (56% of theory); m.p. 256-257 ° C.
    eight
    C 65.42; H 7.06;
    Calculated,%: 10.90; S 8.32.
    C21H2 N: 07S (mol. Weight 385.5) Found,%: C 65.11; H 7.15;
    10.75; S 8.16.
    five
    0
    five
    0
    five
    0
    0
    5 5
    Analogously to Examples 1-4, the compounds of Examples 5-10 are prepared. The structure and characteristics of the compounds are given in Table. one.
    Pharmacological testing and results.
    The compounds obtained according to the proposed method were tested on the anti-inflammatory effect, the effect of immunopathological processes, the deactivating ability of oxygen radicals, ulcerogenic activity and acute toxicity. Comparison agent was naproxen-2- (6-methoxy-2-naphthyl) -propionic acid anti-inflammatory drug used in revotherapy.
    1. Additional arthritis. The research was carried out according to the method
    Pearson. Experimental animals - male Wistar-Lewis strain rats weighing 130–200 g. Test compounds were administered orally at doses of 50 mg per .1 kg of body weight once daily from day 1 to day 5. Animals of the control group received an indifferent basis of the drug. Each experimental group and control group included 8 animals. The effectiveness criterion was a decrease in paw volume increase compared to the untreated control group (in percent).
    2. Ostra gastralnaya calling.
    Studies were conducted respectively on 10 male Sprague-Dawley rats with a gastric mucosa sensitized with a hungry stress. The body weight of the animals was 200 - 300 g. 48 hours before prescribing the tested preparations, before killing the animals, they were deprived of food with free access to drinking water. The rats were killed 24 hours after oral ingestion of the substance, the contents of the stomachs were removed, cleaned with running water and inspected damage to the mucous membrane. All visible damage was considered an ulcer. The number of animals with a dose per dose was determined, and hence, according to Littfield and Wilcoxon, the LDgO- doses at which
    50% of the animals were caused by damage.
    3. Acute toxicity.
    Determination of LD,
    ru g after oral administration of 3.1 and 6.3 mg / kg caused a significant normalization of immune reactivity, while at doses up to 25 mg / k
    According to the standard (for mortality, we were tested, naproxen was ineffective for 7 days in NMRI (Naval Medical Research Institute) - mice (6 animals per dose) after a single intraperitoneal (I. p.) Technique. Q
    The results of these studies are given in Table. 2
    From the dose efficacy curve in the model of additional arthritis, for example, we obtained for
    50
    1 value (single dose) of 10.9 mg / kg, which is definitely more favorable than the corresponding comparative value of 17.5 mg / kg for the standard drug, naproxen. In terms of acute sounding of LD5o per ED§0, the therapeutic spectrum of action was 36.7 for the compound of Example 1, which is only 1.3 for the comparative drug naproxen, which characterizes the good gastric compatibility of the proposed compounds. The same data was obtained when calculating the therapeutic spectrum of action when certain LL5 основу / U was taken as the basis for the compound of Example 1 is above 110 and for naproxen 28.6).
    Thus, the tests showed a significant superiority of the compounds obtained by the proposed method over the standard drug, naproxen.
    4. Inhibition of immunopathological processes.
    The progressive course of inflammatory rheumatic diseases is mainly caused by disorders in the immune system, and causative therapy can be effective only in the case of the use of medicines that can interrupt these immunopathological processes.
    a) Advanced arthritis.
    In the model with rats described in paragraph 1, arthritis caused by the Freundsch supplement usually greatly reduces the immune activity of lymphocytes with respect to certain mitogens, such as concavenalin-A, phytohemagglutinin-A, and dextran sulfate. Therefore, we were looking for a stimulating effect on this strongly suppressed immune response. In this case, for example, the compound according to example 15
    20
    25
    thirty
    35
    40
    45
    50
    55
    veins.
    B) Collagen-induced arthritis type II.
    In this experiment, arthritis was induced on male Wistar rats using type II collagen, which was obtained using standard Miller and Rhodes methods from the calf nasal septum and was injected intradermally into animals mixed with incomplete Freindsch supplementation. The immunization process was repeated after 7 days. After 20 days after the first immunization, the rats were divided into groups of 7 animals, which in the subsequent 20-day treatment period received the relevant test substances once a day or a clean indifferent basis of the medicinal preparation (control group) orally. On the 41st day of the experiments, that is, one day after the last intake of the substance, the increase in the volume of the hind legs was determined.
    At the same time, the compound of Example 1 showed a dose-dependent inhibition of paw volume increase, which was statistically significant at doses of 25 mg / kg for oral administration, while for Naproxen, only small amounts of inhibition were obtained at the same dosage.
    In this model of arthritis with collagen, the immune state of lymphocytes is sensitively disturbed. Therefore, from the spleen, experimental animals received lymphocytes and investigated their immune activity relative to mitogens, and the compounds obtained according to the proposed method exert a dose-dependent therapeutic effect on a strongly weakened immune system, while naproxen has no effect. Thus, for example, at a dose of 12 mg / kg (oral administration), the compounds of example 1 completely normalized the immune function of both T and B lymphocytes.
    c) Arthus reaction is active.
    Sprague-Dawley was used as experimental animals - rats weighing 80-100 g, injected with 0.5 ml of pertussis and ovalbumin vaccine emulsion in vaseain oil under
    ru g after oral administration of 3.15 and 6.3 mg / kg caused a significant normalization of immune reactivity, while at doses up to 25 mg / kg
    - tested naproxen was not effective; a.Q
    ,

    15
    20
    25
    thirty
    35
    40
    45
    50
    55
    veins.
    B) Collagen-induced arthritis type II.
    In this experiment, arthritis was induced on male Wistar rats using type II collagen, which was obtained using standard Miller and Rhodes methods from the calf's nasal septum and injected intradermally into animals mixed with incomplete Freundsch supplementation. The immunization process was repeated after 7 days. Twenty days after the first immunization, the diseased rats were divided into groups of 7 animals, which in the subsequent 20-day treatment period received once a day the corresponding test substance or pure indifferent basis of the drug (control group) orally. On the 41st day of the experiments, i.e. one day after the last intake of the substance, an increase in the volume of the hind legs was determined.
    In addition, the compound of Example 1 showed dose-dependent inhibition of paw volume increase, which was statistically significant at doses of 25 mg / kg for oral administration, while for Naproxen, only small amounts of inhibition were obtained at the same dosage.
    And in this model of arthritis with collagen, the immune state of lymphocytes is sensitively disrupted. Therefore, lymphocytes were obtained from the spleen of experimental animals and their immune activity relative to mitogens was examined, and the compounds obtained by the proposed method exert a dose-dependent therapeutic effect on a strongly weakened immune system, while naproxen has no effect. For example, at a dose of 12 mg / kg (oral administration), the compounds of example 1 completely normalized the immune function of both T and B lymphocytes.
    c) Arthus reaction is active.
    Sprague-Dawley was used as experimental animals - rats weighing 80-100 g, injected with 0.5 ml of pertussis and ovalbumin vaccine emulsion in vaseain oil under
    Kotkno root coccyx. After two weeks, the rats were divided into groups of 8 animals. 24 hours and 1 hour before provoking the Arthus reaction, injection of 0.1 ml of a 0.4% ovapumin solution in the right hind paw gave the corresponding test substance orally or a pure indifferent basis of the drug (positive control). A solution of sodium chloride was injected into the left paw. A group of non-sensitized animals (negative control) was treated in the same way with OVAlbuMINOM TO EXCLUDE
    non-specific protein reactions.
    The criterion for evaluating the effect of the drug was inhibition of paw volume increase compared with inhibition of the sensitized but not treated control group (positive control) 4 hours after provocation of ovalbumin, when the swelling reaches its maximum value.
    Non-steroidal anti-inflammatory drugs, including naproxen, are ineffective with this formulation. On the contrary, the Arthus reaction can be successfully inhibited after oral administration, for example, the compounds of example 1 with an ED50 of 10-15 mg / kg.
    5. Antioxidant action. In many progressive factors caused by rheumatoid arthritis and other inflammatory diseases, aggressive oxygen radicals play a decisive role, which are formed in excess during the chronic inflammatory process and G continuously support the destruction of connective tissue that occurs through lipid peroxidation. Consequently, antioxidant-acting pharmaceuticals with the ability to deactivate these highly cytotoxic oxygen radicals should provide targeted intervention in the chronic course of inflammation. An animal model for this kind of oxygen-induced tissue destruction is inflammation induced in a rat by
    adriamycin (doxorubicin),
    a) Adriamycin-induced inflammation.
    The study was performed according to the method of Siegel on Sprague-Dawley rats.
    0
    ir
    n 5
    jQ
    d§, -. 55
    male with a body weight of 200–230 g (in groups of 7 animals), which received 0.1 mg of adriamycin dissolved in 0.1 ml of a 0.9% sodium chloride solution by subcutaneous injection of the left hind paw.
    After 72 hours, an increase in paw volume was determined as a measure of the degree of inflammation by measuring with a plethysmograph.
    Oral administration of the test preparations in a 1% aqueous suspension of carboxymethylcellulose was carried out once a day for four days following, starting on the day of adriamycin injection.
    The research results are summarized in table. 3
    As follows tab. 3, and in this test, the compound of Example 1 showed a strong dose-dependent protective effect against adriamycin-induced tissue damage. Both steroidal and non-steroidal anti-inflammatory drugs, including naproxen, are ineffective with this setting.
    b) Inhibition of in vitro lipid peroxidation.
    The protective effect of the compounds obtained by the proposed method, compared with aggressive oxygen radicals, is determined using a thiobarbituric acid test according to A.Ottolenyh. Using this method, it is possible to determine the effect of both microsomal and mitochondrial lipid peroxidation of the preparation with antioxidant action on the basis of the formation of malonic dialdehyde fatty acids formed by the oxidative cleavage of membrane-bound multiply unsaturated fatty acids.
    Research results have shown j that compounds of formula I have a strong inhibitory effect. For the compound of example 1, microsomes and mitochondria from rat liver were prepared, for example, 1C50-3-10 bmol / L.
    6. Inhibition of 5-lipoxygenase.
    The inhibitory effect of the compounds obtained by the proposed method on the arachidonic acid catalyzed by 5-lipoxygenase was found in experiments in vitro
    31579462
    isolated polymorpha-dermal humano- where R
    ten
    granulocytes. For this purpose, Calcium-ionophore-A 23 187 stimulated cells (Calbiochem GmbH, Frankfurt am Main, Germany) were incubated with 14C-labeled arachidonic acid and formed after 15 min at 37 ° C by biotransformation of radioactive products of the main arachidonic cleavage Acids - 5-hydroxyecoacetetraenoic acid (5-NETE) and having a particularly strong anti-inflammatory effect leukotriene B4 (LTB4) after separation are quantified by liquid chromatography at high pressure (HPLC).
    In this experimental setup, it is possible to significantly inhibit the formation of both LIB,}, and 5-HETH and, therefore, the arachidonic acid cleavage through 5-lipoxygenase as a result of 15 minutes pre-incubation of granulocytes using the compound of Example 1 at a concentration of-5 CG5-1SG mol / l.
    权利要求:
    Claims (4)
    [1]
    1. The method of obtaining substituted
    YU
    35
    3-phenyl-7H-thiazolo 3,2-Ь D 2,4 triazin-7-ones of the general formula I
    50
    five
    C (CH3b
    -N
    14
    R2R. straight or branched C, -C4 alkyl;
    hydrogen or C -Ce-alkyl; hydrogen, straight or branched.-alkyl or hydroxymethyl.
    characterized in that, 3-mercapto-2H-1,2,4-triazin-5 it of general formula II
    R3
    HN V IS V O
    HS
    wherein Rj has the indicated meanings, is reacted with 2-halo-1-phenyl-alkanone of the general formula III
    asn3

    where R. and R
    have the indicated meanings;
    X - halogen,
    in a neutral or acidic medium to obtain the desired product, or in the basic medium to form an intermediate S-alkylated 2H-1,2,4-triazin-5-one with the general formula IV
    up to 45
    35
    with (sn3) 3
    AL
    N
    ABOUT
    where R., Kr and R3 have the indicated meanings,
    with its subsequent dehydration with the formation of the target product.
    [2]
    2. A method according to claim 1, wherein a compound of the formula I is prepared, where R (is tert-butyl; K, and RS are independently of each other, hydrogen or methyl.
    [3]
    3. The method according to claim. Wherein a compound of formula I is prepared, wherein R is tert-butyl
    and R. and RJ are simultaneously hydrogen or methyl.
    [4]
    4. A method according to claim 3, characterized in that 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -7H-thiazo 3,2-b 1,2,43tRiazin-7- he.
    Table 1
    The maximum dose.
    table 2
    Spreadsheets
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    DK47988A|1988-07-31|
    EP0276805A2|1988-08-03|
    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19873702758|DE3702758A1|1987-01-30|1987-01-30|SUBSTITUTED 3-PHENYL-7H-THIAZOLO TRIAZINE-7-ONE, METHODS FOR THE PRODUCTION THEREOF, THE MEDICINAL PRODUCTS CONTAINING IT AND THEIR USE, AND SOME OF THE PRODUCTS FORMING THE SAME COMPOUNDS INTERMEDIATE PRODUCTS|
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