• 专利附录
  • 专利说明
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    • 专利摘要:
    A method for producing pyridine derivatives of the general formula Nf3 CH2-S-9, OR where B is a hydrogen atom, methyl, is a C-C-alkanoyl, U. is propylene or ethylene, unsubstituted or substituted by one methyl group or phenyl, provided that a carbon atom bonded to an OR, -group V contains at most one substituent, or a -CH-i-CH group - where X is a nitro or methoxy group, provided that R is methyl, Y is different from propylene, in that that, a compound of the general formula X CH —SWC where V / is methylene, unsubstituted or substituted with one methyl or phenyl group up-Z-C ;, -C4-alkoxy, methyl, phenyl or - / 4U where X has the indicated values O is reduced with a hydride and, if it is necessary to obtain a compound, in the torus RI is different from hydrogen, the resulting product, where R is hydrogen , is acylated or alkylated.
    公开号:SU1144617A3
    申请号:SU813349450
    申请日:1981-11-04
    公开日:1985-03-07
    发明作者:Джордж Ломбардино Джозеф；Армон Харберт Чарльз
    申请人:Пфайзер Инк.(Фирма)；
    IPC主号:
    专利说明:

    I The invention relates to a process for the preparation of pyridium derivatives on o6inefi of the formula N CH -S-yf where R (is a hydrogen atom, methyl, C „H 5-alkanoyl; propylene or ethylene is unsubstituted or substituted by one methyl I.PI group with phenyl, with the proviso that at the carbon atom connected to the OK group there are not more than one substituent, or the group Sig-CH where the X is a nitro or methoxy group, provided that it is methyl, V (other than propylene, which have anti-inflammatory and immunoregulatory activity and can be used in chemical It is known that ketones or esters are reduced by hydrides to the corresponding alcohols, and sodium lithium aluminum hydride 5 sodium borohydride, sodium cyanoborohydride and others are used as hydrides, the reaction is carried out in an inert organic solution both during heating and during cooling. - ene is similar in structure to 3- (2-hydroxyethylthiomethyl) pyridine, 5 but its pharmacological activity has not been studied 2j. The purpose of the invention is the development, on the basis of a known method, of a method for the preparation of new pyridine derivatives with valuable pharmaceutical properties. The goal is achieved by the method of obtaining the pyridine derivatives of the general formula (t) concluding that the compound of the general formula / L-CH-i-S-W-C VJ is methylene, unsubstituted sludge substituted by one methyl or phenyl group; - C, - (: 4 alkoxy group, methyl, phenyl or the group - // y -) (where X has the indicated values, is reduced with a hydride and, if necessary, to obtain a compound in which K is different from hydrogen, the resulting product, where hydrogen, subjected to acylation or alkylation. Lithium aluminum hydride, lithium borohydride or sodium borohydride, or sodium cyanoborohydride, or a less reactive lithium aluminum hydride derivative, which is a 70% solution of g, can be used as a reducing agent. Bis (2-methoxyethoxy) aluminum in benzene or lithium aluminum hydride in the form of a 50% suspension in oil. The reduction of esters of compounds of general formula (II) is carried out in the presence of a strong hydride reducing agent (lithium aluminum hydride or sodium borohydride). This reduction is an aprotic solvent that does not contain reducing groups (any type of carbonyl functional, nitrile, nitro, aliphatic halogen, sulfonate, etc.). Preferred solvents are ethers, such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, bis-2-methoxyethyl ether, etc. Temperature and reaction time are not critical factors and vary from 0 to 100 ° C for up to 24 hours. Only lithium borohydride can also be used, but more severe conditions are required (for example, refluxing tetrahydrofuran). It is also very effective in reducing Red-El esters. Suitable solvents for use with Red El are toluene, benzene, diethyl ether, tetrahydrofuran, dimethoxyethane, etc. For the reduction of ketones, with the exception of ketone substituted with aromatic nitro, the same conditions can be used as for the reduction of esters, while borg can also be used. lithium under mild conditions (for example, a temperature of 25 ° C in tetrahydrofuran) using the same solvents as for lithium aluminum hydride. However, in the preferred embodiment, a milder reagent is used — sodium borohydride, used in a non-acidic proton solvent (water, 5-sec pies) at temperatures of 85 ° C or less (generally, at temperatures above 35 ° C in water). The reaction time is not critical and varies from 1 to 24 hours. Sodium borohydride can be used in ethers as a solvent, but in order to achieve a reasonable reduction reaction rate, the presence of a protic solvent is necessary. For the reduction of keto ton in the presence of a functional aromatic nitro group, an even milder hydride reducing agent, sodium cyanoborohydride, is preferred, with which acidified water or methanol can be used, although the pH is maintained at 3 in order to avoid undesirable decomposition of the reagent. The temperature is 0-40 ° C and the reaction time is up to 24 hours. The starting compounds of general formula (II) can be obtained by known methods, for example by reaction. 4-picolyl mercaptan or 2- (4-pyridyl) ethyl mercaptan with OC -halogen-substituted carboxylic ester or oC-halo-ketone or by the interaction of 4-picollyl halide or 2- (4-pyridyl) ethyl-hypopoid with about-mercaptocarboxylic acid ester or with mercaptokette; Example 1. 4- (1-6xy-2-propylthiomethyl) pyridine; Red-el (70% solution of bis (2methoxyethyl) sodium aluminum hydride in benzene, 1.2 g, 1.1 ml, 5.86 mmol) was cooled in a nitrogen atmosphere in an ice bath. a solution of ethyl 2- (4-pyridylmethylthio) propionate in 10 ml of dry tetrahydrofuran. The mixture is then heated and gently refluxed for 1 hour and then stirred at room temperature for approximately 16 hours. The reaction mixture is poured into 40 ml of cooled ice-cream IN Solution of HCE , the coagulum is removed by filtration. Sodium bicarbonate and extractant are added to the filtrate with ethyl acetate (four times in 50 ml each time). The combined ethyl acetate extracts are dried (by washing with a saturated solution of sodium chloride and then over anhydrous sodium sulfate) and concentrated to give 4- (1-hydroxy-2-propylthiomethyl a) pyridine in the form of oil, approximately 200 mg; YAPMR (CDCe, / TM5) C: 8.6 (d, 3N); 7.2 (s. wide, 1H), 6.3 (m, 5H), 2, 7 (d. 2H), 1.3 (d, 2H); m / e - calculated: 183, found: 183, 152, 118, 92, 65, IR (film): 3.1; 6.25; 7.1; 9.25 12.15 | 1). In order to further purify the product, it is placed in chloroform, treated with activated carbon and concentrated to an oil (194 mg). EXAMPLE 2. 4- (1-Phenyl-2-Oxyethylamine) pyridine. Crude methylphenyl (4-pyridyl-l methylthio) acetate (5 g; 0.018 mol) is dissolved in 30 ml of toluene and added dropwise to 7.4 ml of stirred cold Red-el (70% solution of bis (2-methoxyethoxy sodium sodium aluminate and benzene) previously cooled in an ice bath. After the foam is removed, the reaction mixture is heated to room temperature and stirred for approximately 16 hours. To isolate the product, the reaction mixture is poured into approximately 60 ml of cold Iff HCC solution, the precipitated salt is removed by filtration, the filtrate is weakly alkalized with sodium bicarbonate, is drained from the precipitated salts, and the product is extracted with an excess amount of toluene. Alkali salts are extracted with hot ethyl acetate. The toluene and ethyl acetate extracts are combined, dried over anhydrous magnesium sulfate and concentrated to an oil (2.05 g). The oil is chromatographed on 110 g of silica gel, using a 1: 1 mixture of hexane and ethyl acetate as eluent. Fractions of approximately 10 ml each are taken, which are then subjected to thin layer chromatography (silica gel, which is eluted with ethyl acetate). The product fractions (which are eluted after the first three fractions with impurities) have a thin layer in the system, 25. The product fractions are combined and evaporated.
    Found,%: C 67.57, H 6.30; N 5.32, m / e 245.
    , NOS0.25H20
    Calculated,%: C 67.39; H 6.21 | N 5.60, m / e 245.
    Other peaks of the mass spectrum: 214, 136, 121, 103, 92, 91, 77 and 45.
    Example 3. 4- (2-Hydroxy-1-propylthiomethyl) pyridine.
    Under nitrogen, 4-picolylthioacetone (9.10 g, 50 mmol) was dissolved in 130 ml of stirred isopropyl alcohol. Sodium borohydride (0.76 g, 20 mmol, 1.6 equiv.) Is added cautiously in portions. A small amount of foam is formed. The reaction mixture is placed under nitrogen and heated to reflux temperature, which is maintained for 1.5 hours. The reaction mixture is cooled and concentrated to an oil. 150 ml of 4N HCE solution is added to the oil in order to control the formation of foam. The solution is stirred for another 15 minutes and then strongly alkalinized by the addition of a YuM solution of sodium hydroxide. The oil that is formed upon alkalization is extracted with chloroform MOM (three 250 ml portions), the combined chloroform layers are washed with dilute sodium oxide solution. The chloroform solution is dried over anhydrous sodium sulfate and evaporated, to give 4- (2 hydroxy-1-propylthiomethyl) pyridine 8.71 g oil, YPMR (SZ) Sat, / TM5) s: 3.56 (m, 2H), 2.28 (m, 2H), 3.90 (sextet, 1H), 3.87 (s , 1H, exchanged with DO), 3.72 (s, 2H), 2.52 (d, 2H) and 1.23 (d, 3N).
    The hydrochloride salt is formed as a oil by dissolving 0.367 g (2 mmol) of the free base in 2 ml of 1) J HCP solution (2 mmol and evaporating the solvent.
    The phosphate salt is obtained by dissolving the free base (5.00 g, 27.3 mmol) in 11.6 ml of ethyl acetate, cooling the solution until 85.5% phosphoric acid (3.13 g, 27.3 mmol) is added. in 11.6 ml of ethyl acetate. The salt precipitates as a sticky liquid (methanol. Methanol (100 ml) is added to purify the salt, the mixture is heated so that the solution becomes clear and concentrated
    before oil, which crystallizes on standing. Recrystallization from isopropyl alcohol gives purified two-acid phosphate salt (3.78 g, 88 -, IR (KBr) 2.95, 3.55 6.10; 6.65 W, YGGMR (CT)) SO / TMS) / o: 8.57 (m, 2H), 8.33 (s, exchanged with), 3.80 (s, 2H), 3.77 (sextet, 1H), 2.44 (d, 2H) and 1.10 ( d, ZN).
    Found,%: C 38.6 N 5.3; N 5.2 t / e 183.
    Calculated,%: C 38.4; H 5.7; N 5.0 t / e 183.
    Example 4. 4- (2-Hydroxy-2-phenylethylthiomethyl) pyridine. "
    Under a nitrogen atmosphere, about - (4-picolylthio) acetophenone (852 mg, 3.5 mmol) was dissolved in 3.75 ml of isopropyl alcohol and sodium borohydride (54 mg, 1.4 mmol, 1.6 equiv.) Was added. After stirring for 0.5 h at room temperature, the reaction mixture is boiled for 1 h, then cooled and evaporated to an oil. While stirring, neb is slowly added to the oil (4N, 10 ml) so that heat release and foam formation can be controlled. After the addition is complete and there is no sign of gas evolution, the acidic solution is strongly alkalized with a 20% sodium hydroxide solution and the Oil that precipitates is extracted with chloroform. The chloroform is washed with a dilute solution of sodium hydroxide, dried over anhydrous sodium sulphate and concentrated to an oil (0.86 g) which crystallizes into waxy solids upon standing. The solid is triturated with ether and filtered to give the crude product (0.61 g). Recrystallization from ethyl acetate gives purified 4- (2-hydroxy-2-phenylethylthiomethyl) pyridine (0.42 g, mp. 116, 5-119 С, data are incomplete), IR (Kvr): 3.17; 5.2-1.8; 6.22; 6.88, 9.49; 12.25, 13.88 and 14.25 U, mass spectrum: t / e - calculated 245, found 245, NMR- (CD) o: 8.73-9.27 (m, 2H), 7.57-7 , 10 (m, 7H), 4.75 (t, 1H), 3.63 (s, 2H), 3.10 (s, 1H, exchanged with IgO) and 2.72 (d, 2H).
    .7
    PRI and e R 5. (A-Methoxyphenyl) -2-hydroxyethylthiomethyl pyridine,
    Under a nitrogen atmosphere, gt- (4-picolyl thio) -P-methoxy acetophenone (1.99 g, 7.3 mmol) is dissolved in 25 ml of mixed ethanol and sodium borohydride (0.45 g, 11.7 g) is added in portions. mmol), then boil gently for 30 minutes. The mixture is cooled and evaporated to dryness. Water (50 ml) is added to the residue, which is acidified by an excess of IN of the HC8 solution. The acidic solution is extracted with ethyl acetate. The ethyl acetate is dried over anhydrous sodium sulfate and concentrated to an oil, which crystallizes on aging. As a result of trituration in diethyl ether and filtration, purified (4-methoxyphenyl) -2-oxyethylthiomethyl-pyridine is formed, 1.50 g, mp. 72.5C, PPMR (WWTP, // TMS); : 7.2 (d, 2H), 6.4 (s, 2H), 6.3 (1H, cDjO exchange), 6.2 (d, 3N), 5.3 (t, 1H), 3.2 (broad doublet, 2H), 2.7 (d and s, 4H), 1.5 (d, 2H), IR (KBg): 3.25-6.25; 6.65; 8.05; 8.6-, 12.5 fU.
    Found,%: C 64.34; H 6.06; N 4.95.
    С, 5Н „М0 50 25Н О
    Calculated,%: C 64.34; H 6.12; N 5.00.
    PRI and, meer 6. 4- 2-Oxy-2- (4nitrophenyl) ethylthiomethyl pyridine.
    Under nitrogen, oi - (4-picolylthio) -P-nitroacetophenone (0.45 g 1.56 mmol) and sodium cyanoborohydride (0.10 g, 1.56 mmol) are dissolved in i 15 ml of dry methanol and added traces of bromcresol, green pH indicator (blue at pH 5.5, yellow at pH 3.8). Reaction mixture la green and blue color. A methanol solution of hydrogen chloride is added dropwise until the reaction mixture turns yellow (pH about 4). For about 4 hours, a small amount of methanol solution of hydrogen chloride is added whenever the reaction mixture becomes cloudy. The reaction mixture is stirred for another 16 hours, then concentrated to an oil, which is placed in 10 ml of water, and the product is extracted with ethyl acetate (3 times 20 ml). United ethyl extracts 446178
    acetate is laminated nashe; a sodium bicarbonate solution (2 times 15 ml) and then with a saturated solution of sodium chloride, dried over anhydrous
    5 sodium sulphate and evaporated to give 4-2-hydroxy-2 (4-nitrophenyl) ethylthiomethylZpyridine, 0.347 g, m.p. 135-137 ° C, IR (KBr): 3.25, 6.25, 6.6; 7.35 9.35 11.75; 10 13.75 (11, NMR (DMSO - d2 / TMS) S: 7.2 (d, 2H), 6.5 (broad s., 1H), 6.2 (s, 2H), 5.1 ( t, 1H), 2.6 (d, 2H), 2.3 (d 2H), 1.7 (d, 2H), 1.4 (d, 2H).
    15Found,%: C 56.50; H 5.87;
    H 9.50.
    C ,, S-0.5H20 Calculated,%: C, 56.23; H 5.05, and 9.36.
    2 ° Example 7. 4- (1-Oxy-1-fe1ish-2-propylthiomethyl) pyridine.
    Under nitrogen, alpha- (4-picolylthio) -propiophenone (2.0 g, 7.8 mmol) is dissolved in 20 ml of ethanol being stirred. Sodium borohydride (0.48 g, 12.4 mmol) is added in portions over 10 minutes and then the reaction mixture is boiled for 0.5 hours, cooled and evaporated to dryness. The residue is placed in water, a 1 M solution of HC is added in order to decompose the excess borgndride, then it is strongly alkalinized with a 20% sodium hydroxide solution, and the product is extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and concentrated to an oil. The oil is subjected to chromatography on 60 g of silica gel, and a 1: 1 mixture of hexane and ethyl acetate is used as eluent. The fractions containing the product are co5 combined and evaporated to give 4- (1-hydroxy-1-phenyl-2-propylthiomethyl) pyridine, 1.45 g, oil, 9 kD (CSC6 (TM5) 0: 8.8 (d, 3N), 7.0 (m, 2H, 1H exchange
    0), 6.4 (s, 2H), 5.5 (q. 1H), 2.7 (s, 5H), 2.7 (m, 2H), 15 (m, 2H), IR (SNSC) : 3.25-3.5, 5.80; 6.25; 6.95, 8-8.25; 10.05 (U. Found,%: C 69.00, H 6.54,
    5 N 5.14) frj / e 259.
    Calculated,%: C 69.48, H 6.61, .N 5.40, t / e 259..
    91
    Example 8. Methyl-3- (4-oligthio) propioiat.
    Under nitrogen atmosphere, sodium methoxide (3.7 g, 68 mmol) is dissolved in 45 ml of methanol and the solution is cooled in an ice bath. Then 4-picolyl chloride hydrochloride (5.0 g, 30 mmol), slowly suspended in
    7.5ml methanol. After 10 minutes, a solution of methyl 3-mercaptopropionate is added over the next 10 minutes.
    in 7.5 ml of methanol. The reaction mixture is heated to room temperature. and stirred for approximately 16 hours. The reaction mixture is filtered and the mother liquor is concentrated to an oil. The oil is chromatographed on 250 g of silica gel using a short but wide ethyl- column. acetate as eluent. The fractions containing the product are combined and extruded, resulting in 7 methyl 3- (4-picolylthio) acetate, 63 g oil, NMR (SYaSE, / TM5) s: 7.4 (d, 4H), 6.3 (s, 5H), 2.7 (d, 2H),
    1.6 (d, 2H), IR (film): 3.0; 3.5; 5.80; 6.25; 7.0-, 7.15-, 12.25 / c.
    Found,%: C 55.87, H 5.99; I 6.59, P) / e 211.
    C ,, H, .N023-0.25
    Calculated,%: C 55.74 H, 6.27; W 6.49, Ch / e 211.
    Example 9. 4- (3-Hydroxypropylthiomethyl) pyridine.
    Under a nitrogen atmosphere, the solution of Red-el (2.04 ml, 10.4 mmol) is stirred to O ° C, then a solution of methyl 3 (4-picolshTiO) propionate in 10 ml of dry tetrahydrofuran is slowly added. The reaction mixture is warmed to room temperature and stirred for 45 minutes, then slowly poured into
    25 ml of cold INB solution of NSB, the solids are removed by filtration and the mother solution is extracted with four portions of 25 ml of ethyl acetate. The combined extracts are dried over anhydrous sodium sulphate, filtered and concentrated, resulting in the formation of 4- (3-hydroxypropylthiometyp) pyridine, 1.40 g oil, NMR (C1) SC / TM5) 1) t 3.1 (k, 2H) , 7.4 (t, 2H), 6.4 (t, 2H), 6.3 (d,
    2H), 1.5 (d, 2H), IR (film): 3.1; 3.5, 5.25 i 7.1 i 9.51 12.25 / u.
    1710
    Found,%: C 58., 77 H 7.11 W 7.67.
    WITH
    Calculated,%: C 58.98i H /, 15; 7.64.
    Example 10. 4- (2-Acetoxyethylthiomethyl) pyridine.
    4- (2-hydroxyethylthiomethyl) pyridine (1.0 g) is boiled with 10 ml of acetic anhydride for 3 hours. After keeping overnight at room temperature, the acetic anhydride is distilled off, alkalized with sodium bicarbonate and the product is extracted with chloroform (four times on 50 ml). Chloroform is treated with charcoal, dried and concentrated to an oil (1.47 g). The oil is chromatographed on 60 g of silica gel using a mixture of 5% methanol and chloroform as eluent. The fractions containing only the product (HI 0.6 for thin-layer chromatography on a score gel, which is eluted with a mixture of chloroform and methanol 18: 1), are combined and concentrated to form 4- (2-acetoxyethylthiomethyl) pyridine, 300 mg, NMPR oil (SBS , (TM5) 1: 7.9 (s, 3N), 7.3 (t, 2H), 6.3 (s, 2H), 5.8 (t, 2H), 1.4 (d, 2H) .
    Example 11. 4- (2-Methoxyethylthiomethyl) pyridine.
    Sodium hydride sludge (170 mg, 7.1 mmol, from 340 ml of a 50% dispersion in oil, washed under nitrogen with hexane) in 5 ml of dry tetrahydrofuran is prepared. A solution of 4- (2-hydroxy-methylthiomethyl) pyridine (t, 0 g, 5.9 mmol) in 10 ml of dry tetrahydrofuran is added dropwise to the mixture over 5 minutes and stirred for 5 minutes. Methyl iodide (260 mg, C, 1 ml, 5.9 mmol) in 2 ml of tetrahydrofuran is then added and
    the mixture is stirred overnight. The reaction mass is purified by filtration and by blending to an oil (approximately 1.3 g), which is subjected to chromatography on silica gel.
    chloroform as eluent. The pure fractions of the product are combined and concentrated to give 4- (2-methoxyethylthiomethyl) pyridine, 210 mg, an oil; g / e 133, NMPR
    (CDCf, (TMS): 7.4 (t, 2H), 6.7 Ds, ZN), 6.5 (t, 2H), 6.3.
    Immunoregulatory activity of the proposed compounds is evaluated at 11,144 using the E-rosette procedure for mice. In mice, the presence of a thymus gland is a prerequisite for the complete realization of the formation of a normal outlet with red blood cells. Using this procedure, the ability of the drug to restore rosaceous cells that are sensitive to azathioprine in an adult mouse with a thymus removed to the level typical for normal animals is being investigated. In particular, the formation of the socket is analyzed in mice CD-I with a thymus gland removed at the age of 15 weeks, and the mouse is used to test compounds after at least 14 days after the operation (ATX). ATX mice are injected in a dental way with a dose of either a saline solution or a preparation. After 16 hours, suspensions containing a single cell are prepared in a balanced solution of the Hanks salt (HBSS) from 25 spleen extracted spleens. To each tube, 0.1 ml of lymphocytes (6-10 cells / mp) in HB3 and either O, 1 ml of HBSS, or 0.1 ml of azathioprine solution (40 U g / ml) in HBSS are added. After 90 min of incubation at 37 ° C, the cells are flushed twice with 5 ml of HBSS, the volume is adjusted to 0.2 ml and then 0.2 mb of sheep red blood cells (erythrocytes) with a concentration of 1.210 cells / ml are added. 10 ml is pipetted onto the hemagglutination slides and the number of rosettes is calculated. This determines the ability of the test compound to reduce the number of azathioprine-sensitive rosette cells to normal or higher levels. It was found that in normal mice, the sensitivity to azathioprine is 42-12%, in adult mice with a specific goiter 31: 3%.
    The ability of the proposed compounds to restore azathioprine-sensitive cell-forming cells to a normal and even higher level at various oral doses (mg / kg, i.e., mg preparation / kg of mouse weight) is presented in Table. 1 (the higher the percentage and the lower the effective dose, the more:
    Note. Untreated control group (baby with thymus gland removed); .
    P
    a) individual results were obtained in two tests;
    c) 60, 58 at 0.3 mg / kg; 42.53 at 0.3 mg / kg; 42.51 at 0.1 mg / kg, 21.33 at 0.03 mg / kg; 16 at. 0.01 mg / kg
    c) 50 at 10 mg / kg.
    The anti-inflammatory activity of the proposed compounds is determined by the standard carrageenin rat paw tumor test. In this test, the anti-inflammatory activity is determined by the inhibitory effect of the drug on the formation of a tumor on the hind paw of a male albino rat (weight 150-190 g) as a reaction to a subcutaneous injection in the rape paw area of the carragenin. Carragenin is administered in the form of a 1% aqueous suspension (0.05 ml) 1 hour after the oral administration of the drug. Tumor formation is then evaluated within 3 hours after administration of carragenin by measuring the volume of the paw, which was injected at the beginning of the experiment and after 3 hours. The increase in volume 3 hours after the injection of carrageenin reflects the individual response. Compounds are considered as active if the difference in the reactions between animals to which the drug was administered (six rats in a group) and the control group (i.e. animals to which only the diluent was administered) was considered significant compared with the results obtained. , when using standard compounds such as acetylsalicylic acid at a dose of 100 mg / kg or phenyl / batazone at a dose of 33 mg / kg, both of which are administered by a dental method. The activity of the test compound is expressed in the N percent of tumor suppression at
    prescribed dental dose. h
    The ability of compounds to suppress tumor development at various oral doses (mg / kg, i.e., mg drug / kg rat weight) is shown in Table. 2 (the higher the percent inhibition of tumor development and the lower the dose, the more active the compound is). In a similar test, 4- (2-hydroxyethylthiomethyl) pyridine
    I
    gives 11% inhibition of tumor development at a dose of 33 mg / kg.
    Table 2 Anti-inflammatory active-. 5 pyridine content in the rat paw tumor procedure (dental dose 33 mg / kg)

    I y
    N, (eH2) n-S-y-ORi
    29 for 10 mg / kg i 16 for 3.3 mg / kg
    The activity of 4- (2-hydroxyethylthiomethyl) pyr1adine (Y is, R, is H), both as an anti-inflammatory and immunoregulatory agent (Tables 1 and 2) is noteworthy. In addition, this connection is not. It has an effect on the synthesis of prostaglandin in the laboratory in MC5 cells ((U M) and, therefore, does not possess this known harmful side effect of many other nonsteroidal anti-inflammatory (NSAID) drugs, i.e. ulcerogenicity. That 4- ( 2 Oxyethylthiometyp) pyridine is easily distinguished from classical NSAID preparations, established due to its lack of activity in the procedure associated with erythema caused by ultraviolet radiation, when used at a dose of 33 mg / kg sp, in this procedure using ind metatsina, phenylbutazone and other NSAID drugs was observed suppression of erythema.
    4- (2-Oxyetch-Thiomethyl) pyridine at close doses provides protection against polyarthritis caused by administering a full dose of the Frend's adjuvant to Wistar-Lewis rats. This agent is active in this procedure in doses of 3.3-3.33 mg / kg cp, and the ED50 value for it is approximately 33 mg / kg. Its anti-arthritic effect is selective with slow commissioning, the secondary reaction is the formation of lymphoid cells (spread of the disease to the paw into which no injection was given). Whereas no effect was noted during rapid commissioning, acute inflammation of the paw developed, in which an auxiliary preparation was administered, either on the fourth or the sixteenth day. It does not affect the weight loss caused by the disease as a result of administering the same drug. On the other hand, piroxicam and phenylbutazone are potent in suppressing both primary and secondary reactions, and in particular, prevent weight loss. Such a structure against arthritic activity also removes 4- (2-hydroxyethylthiomethyl) pyridine from known NSAID drugs. Four daily oral doses of 4- (2-hydroxyethylthiomethyl) pyridine in an amount of 33 mg / kg do not affect the humoral immune response of the mouse to the sheep's red blood cells. Under the same conditions, immunosuppressive drugs (methotrexate, cyclophosphamide, azathioprine, and 6-mercaptopurine) are absolutely inhibitors. 4- (2-hydroxyethylthiomethyl) pyridine did not cause any significant 1716 ulcerogenic effects in rats at doses of approximately 100 mg / kg c. Although a weak ulcerogenic tendency was detected for levamisole in the 100 mg / kg cp zone, in a static sense this effect is insignificant. These results are in marked contrast with the results obtained for phenylbutazone, aspirin, and indomethacin, for which various ulcerogenic effects were noted at the oral doses of 100, 50, and 10 mg / kg, respectively. 4- (2-hydroxyethyl thiomethyl) pyridine is less toxic than levamisole, at least in rats and mice. Its dental LD value for mice and rats exceeds 1000 mg / kg. When used as a capsule (without additives) for 14 days in dogs at a dose of 30 mg / kg per day, he did not cause any abnormalities in the general pathology or histopathology. There were also no changes in clinical chemistry, hematology, or animal weight. I The proposed pyridine derivatives can be used in medicine as anti-inflammatory agents or as regulators of the immune response in warm-blooded animals. Such a combination of anti-inflammatory activity and activity as regulators of the immune response is particularly valuable in the treatment of diseases such as rheumatoid arthritis and other diseases associated with immune disorders and their accompanying inflammatory processes.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING PYRIDINE DERIVATIVES OF GENERAL FORMULA
    S-Mj-or.
    V / is methylene unsubstituted or substituted with a single methyl keel phenyl group; C 1 -C 4 ~ alkoxy group, methyl, phenyl or a group wherein R ( is a hydrogen atom, methyl, C ^ -C ^ alkanoyl;
    U ( - propylene or ethylene, unsubstituted or substituted by a single methyl group or phenyl, provided that where X has the indicated meanings, is reduced with hydride and, if necessary, to obtain a compound in which R (other than hydrogen, the product obtained, where R, is hydrogen, subjected to acylation or alkylation.
    1 144617 ί
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    DE2740836A1|1979-03-22|N-Acyl-fused ring indole derivs. - useful in human or veterinary medicine as antiphlogistics
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/085,011|US4246263A|1979-10-15|1979-10-15|Antiinflammatory and immunoregulatory pyrimidines, their method of use and pharmaceutical compositions|
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