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    • 专利摘要:
    The invention relates to compounds having the general formula (I) <CHEM> wherein X represents an oxygen atom or a -S(O)n-group, wherein n is zero, 1 or 2; R1 represents C1-C6 alkyl, benzyl, pyridyl, or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, nitro, amino, formylamino and C2-C8 alkanoylamino; each of R2 and R3 is independently: a) hydrogen, halogen or C1-C6 alkyl; b) hydrogen, C1-C6 alkoxy or C3-C4 alkenyloxy; or c) nitro, amino, formylamino or C2-C8 alkanoylamino; R4 represents hydrogen or C1-C6 alkyl; and Q represents hydrogen, carboxy, CONH2, C2-C7 alkoxycarbonyl <CHEM> wherein Ra represents hydrogen or C1-C20 alkyl and Rb represents C1-C20 alkyl or a -(CH2)m-R5 group, wherein m is zero, 1 or 2 and R5 is: a') C5-C8 cycloalkyl; b') pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, C1-C6 alkyl and C1-C6 alkoxy; or c') phenyl, unsubstituted or substituted by one or two substituents independently chosen from halogen, CF3, C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, formylamino, C2-C8 alkanoylamino, di (C1-C6 alkyl) amino, hydroxy, formyloxy and C2-C8 alkanoyloxy, and the pharmaceutically acceptable salts thereof, which possess immunodulating activity and are useful e.g. in the treatment of neoplastic diseases and acute and chronic infections of both bacterial and viral origin in mammals.
    公开号:SU1695826A3
    申请号:SU884355070
    申请日:1988-01-08
    公开日:1991-11-30
    发明作者:Дориа Джанфедерико；Мария Изетта Анна；Феррари Марио；Трицио Доменико
    申请人:Фармиталиа Карло Эрба С.П.А.(Фирма)；
    IPC主号:
    专利说明:

    The present invention relates to a method for producing new derivatives of heterogeneous 3-oxopropane-nitriles possessing immunomodulatory activity, which allows them to be used in the treatment of acute and chronic infections of both bacterial and viral origin.
    The purpose of the invention is the synthesis of new juridical derivatives of heteroaryl 3-oxopropano-nitriles, which are superior in activity to a structural analogue possessing the same type of activity.
    The method is carried out as follows: J5 ase.
    Example 1. Tiochroman-4-one (5 g) was reacted with oxalic acid triethyl ester (4.44 g) in anhydrous ethanol (25 ml) IQ in the presence of sodium ethylate (2.07 g) with stirring for one hour at 10 ° C and then 4 hours at 35 ° C. The precipitate was filtered and washed with cold ethanol, then dissolved 5 in water. Acidification with citric acid gave an oily residue, which was extracted with ethyl acetate. By evaporation of the solvent in vacuo, 3-ethoxalylthiochroman-4-one was obtained in the form of oil 0 (5.65 g), which was reacted with phenylhydrazine (2.54 g) in acetic acid (35 ml) in a temperature range varying from 25 to 40 ° C in 30 minutes The reaction mixture was diluted with ice water and then neutralized with 30% ammonium hydroxide. The precipitate was filtered, dissolved in ethyl acetate and washed with water. After evaporation of the solvent, -, in vacuo, the residue was crystallized from a mixture of dichromethane-isopropyl ether to obtain 1,4-dihydro-1-phenyl-1-benzothiopyrano (4,3-cj-pyrazole-3-carboxylic acid ethyl ester (t mp 139-141 ° C (4.2 g), which was reacted with acetonitrile (16.5 g) in dioxane (25 ml) in the presence of 50% sodium hydride (1.2 g) with stirring 60 ° C 30 min0 After cooling, the reaction mixture was diluted with ice water and acidified to pH 4.0 with citric acid. The precipitate was filtered, washed with water and cream was purified on a column. nezem using hexane-ethyl acetate in the ratio of 80:20 as eluent. Crystallization from dichloromethane-isopropyl ether gave
    35
    50
    55
    0, -,
    five
    0
    five
    3- (1,4 dihydro-1-phenyl-p-benzothio-pyrano-4,3-e-pyrazol-3-yl) -3-oxo-propanenitrile, m.p. 151-153 C (3.45 g), which was reacted with isocyanic acid phenyl ester (1.3 g) in the presence of triethylamine (1.15 g) in dimethylformamide (30 ml) with stirring for 30 minutes at 25-30 °;. The reaction mixture was diluted with ice water, the precipitate was filtered and washed with water. Crystallization from dichloromethane-, methanol gave 4 g of 2-cyano-3- (1,4 dihydro-1-phenyl-1-benzothiopyrano-4,3-cl pyrazol-3-yl) -3-oxo-M-phenyl propanamide,. / 128-230 S.
    NQR (LMSO-dg) § ppm, 6.50-7.80 (m, 14H, phenyl.protons), 10.90 (s, W, CON1I-).
    Similarly, the following compounds can be obtained:
    2-cyano-3- (1,4-dihydro-1 (4 methylphenyl) -Y-benzothiopyrano, 3-cl-pyrazol-3 yl) 3-oxo-m-phenylpropanamide: t. Pl. 262-265 ° C;
    3- (1- (4-chlorophenyl) 1,4-dihydro-GL-benzothiopyrano 4,3-e-pyrazol-3-yl; 2-cyano-3-oxo-phenylpropanamide; mp. 235-240 ° C with decomposition;
    3- (1- (3-chlorophenyl) -1,4 dihydroЈL-benzothiopyrano, 3-e-pyrazol-3-yl) -2-cyaco-3-oxo-phenylpropanamide; m.p. 224-226 ° C;
    2-cyano-3- (1,4-dihydro-1- (4-fluorophenyl) - {j-benzothiopyrano-A, 3-cj-pyrazol-3-yl) -3-oxo-c-phenylpropanamide ; mp 217-218c;
    2-cyano-3- (1,4-dihydro-1- (3-methylphenyl) -1-11-benzothiopyrano-4,3-cj - pyrazol-3-yl) -3-oxo-no. Phenylpropan-f amide;
    2-cyano-3- (1,4-dihydro-1- (4-methoxyphenyl) CO, yenzothiopiH1ano C3-pyrazol-3-yl) -3-oxo-n-phenylpropanam d; m.p. 2600 (1 with decomposition;
    2 cyano- (3-1,4-dihydro-1 (3-fluorophenyl) -r3 beisotiopyrano-4, pyrazol-3-yl) -3-oxb-N-fekylpropanamide.
    Example 2. By the method described in Example 1, using suitable substituted hydrazines, the following compounds can be obtained:
    2-cyano-3- (1,4-dihydr o-1-methyl-flj-benzothiopyrano-4,3-cj-pyrazol-3-yl) -3-oxo-K-phenylpropanamide; m.p. 240-242 ° C;
    3- (1-tert-butyl-1,4-dihydro (j J-benzothiopyrano-4, 3-e-pyrazol-3 yl) 2-cyano-3-oxo-N-phenylpropanamide; mp. "211 -212 ° C.5
    Example 30 By the methods of examples and 2, using suitable isocyanates, the following compounds can be obtained:
    M- (3-chlorophenyl) -2-cyano 3 (1,4-10 dihydro-1-phenyl-L-benzothiopyrano-G4,3-c-pyrazol-3-yl) -3-oxo-propane-amide; m.p. 238-240 ° C;
    No. (4-chlorophenyl) -2-cyano-3- (1,4-dihydr o-1-phenyl-IJ-b enz otiopyr ano-15 4, 3-cJ-pyrazol-3-yl) -3-oxo- propane-amide; m.p. 247-249 ° C;
    .-cyano-3- (1,4-dihydro-1-phenyl-LL-benzothiopyrano-4,3-cj-pyrazol-3-yl) -K- (4-methoxyphenyl) -3-oxo-propane-20 amide ; m.p. 219-220 ° C;
    2-cyano-3- (1,4-dihydro-1-phenyl) -LI-benzothiopyrano-4,3-c-pyrazol-3-yl) -N- (4-methylphenyl) -3-oxo-propanamide ; m.p. 217-219 ° C, 25
    2-cyano-3- (1,4-dihydro-.1-phenyl-Ll j-benzothiopyrano-4,3-e-pyrazole-) -3 oxo-no. (3-trifluoromethylphenyl) -propanamide; m.p. 273-277 ° 0,
    2-cyano-3- (1,4-dihydro-1-phenyl-30
    B-benzothiopyrano-4,3-c -pyrazole-3-N- (4-fluorophenyl) -3-oxo-propanamide; m.p. 260-263 ° C;
    3-I- (4-fluorophenyl) -1,4-dihydro-G-benzothiopyrano-4,3-e-pyrazole-3-yl-1-2-cyano-N- (4-fluorophenyl) -3-oxo - propanamide; m.p. 272 ° C;
    2-cyano-3- (1,4-dihydro-1-phenyl. P-benzothiopyranose, 4-c-pyrazol-3-yl) -N- (3-methylphenyl) -3-oxo-propan-40 amide; m.p. 198-200 ° C;
    2-cyano-3- (1,4-dihydro-1-phenyl-U-benzothiopyrano-4,3-e-pyrazole-) -M- (3-nitrophenyl) -3-oxo-propane-amide; m.p. 258-2 (1 ° С; 45
    2-cyano-K- (3-fluorophenyl) -3- (1,4-dihydro-1-phenyl-ij-benzothiopyrano-4,3-cj-pyrazol-3-yl) -3-oxo-propanamide; TogSho 215-217 ° C; .
    K-butyl-2-cyano-3- (1,4 dihydro-1-0 phenyl-p-benzothiopyrano, 3-e-pyrazol-3-yl) -3-oxo-propane mid, m.p. 208-20 ° C;
    N-benzyl-2-cyano-3- (1,4-dihydro-1-phenyl-benzothiopyrano-p, 3-e -, -, - pyrazol-3-yl) -3-oxo-propanamide m.p. 268-Z71 ° C.
    PRI me R 4. The methods in examples 1, 2 and 3, using as
    starting compounds suitable oxides thiochroman-4-one, the following compounds can be obtained:
    2-cyano-3- (1,4-dihydro-1-phenyl-GL-benzothiopyrano-4,3-e-pyrazole-3-, 5-dioxy) -3-oxo-M-phenylpropan-amide, m.p. 273-275 ° C.
    EXAMPLE 5 1,4-Dihydro-1-phenyl / G benzothiopyra-HO-J4,3-c-pyrazole-3-carboxylic acid ethyl ester (3.36 g) was suspended in dioxac (60 ml ) and processed 1 n. sodium hydroxide (30 ml) with stirring at room temperature for 5 hours, the reaction mixture was diluted with ice-water vodka and acidified to pH 3.0 with 37% hydrochloric acid, the precipitate was filtered, washed with water, dried in vacuum at 50 ° C and prepared , 4-dihydro-1-phenyl-ЈG benzothiopyra-, 3-cl-pyrazole 3-carboxylic acid (2.8 g), which was reacted with oxalyl chloride (17 g) with stirring at room temperature for 8 h.
    The reaction mixture was evaporated to dryness in vacuo, the residue of 1,4-dihydro-1-phenyl-Јlj benzothiopyran-4,3-cj-pyrazole-3-carbonyl chloride (2.9 g) was dissolved in dimethylformamide (Yu ml) and added at stirring to a suspension obtained by treating no-acetylaminopyridine (1.62 g) with 50% sodium hydride (0.5 g) in dimethylformamide (5 ml). The reaction mixture was kept at room temperature for 20 hours. The basic aqueous solution was washed with ethyl ether and then acidified to pH 5.0 with 37% hydrochloric acid. The precipitate was filtered off, washed with water, then crystallized from ethanol and 2.7 g of 2-cyano-3- (1,4-dihydro-1-phenyl-pl-benzothiopyramine-4,3-e-pyrazole-3- yl) -3-oxo-N- (2-pkridil) - propanamide, so pl. 258 ° C 260 ° C.
    In a manner similar to that described above, the following compounds can be prepared:
    2-cyaco-3- (1,4-dihydro-1-phenyl-L1J-benzothiopyrano-4,3-c-pyrazol-3-yl) -3-oxo-K-phenylpropan mid, m.p. 280-282 ° C;
    2-cyano-3- (1,4-dihydro-1-phenyl G benzothiopyran-4,3-e-pyrachol-3-yl) -3-oxo-N-methyl-fenshshropanamid, mp 183-184 ° WITH;
    ten
    2-cyano-3- (1,4-dihydro 1-phenyl-jj-bencho-thiopyrano-4,3-cj-pyrazole-) -N- (1, b-dimethylphenyl-3-oxo-propanamide, mp 215 -21b;
    N-benzyl-2-cyano-3- (1,4 dihydro 1 phenyl-jjQ-benzothiopyrano 4, -piazol-3-yl) -3-oxopropanamide, e.g. 2-8-271 ° C;
    2-cyano-3- (1,4-dihydro 1-phenyl-jjn-b-benzothiopyrano-4,3 -c-pyrazole-) 3 oxo-N-phenylpropanamide, T.sh. 228-230 ° C.
    II p and me 6, Cyanoacetic acid ethyl ester (1.4 g) was treated with sodium hydride (0.58 g) in cimethylformamide (10 ml) while stirring at room temperature to | stopping violent gas evolution. To this solution, with stirring., "At-room temperature, add-1,4-dihydro 1-phenyl-benzotirpyro-4,3-c-pyrazole-3-carbonyl chloride (3.2b g) prepared by the method , described in example 5, and dissolved in dimethylformamide (10 ml). The reaction mixture was allowed to react for 20 hours, then diluted with ice with ice and acidified to pI 3.0 with 37% hydrochloric acid. The precipitate was extracted with ethyl acetate, the organic solution was washed with water and then evaporated to dryness in vacuo. The residue was purified on a silica column using a mixture of hexane-ethyl acetate in the ratio 80:20 as the eluent, and 2-cyano-3- (1, 4-dihydro-1-phenyl-TJ-benzothiopyran-4,3- e-pyrazol-3-yl) -3-oxopropanoic acid ethyl ester (2.4 g), “so pl. 176-178 ° C.
    2-Cyano-3- (1,4-di-hydro-1-phenyl-Јl J-benzothiopyrano-4,3-e-pyrazol-3-yl) -3-oxopropanoic acid ethyl ester was reacted with aniline ( 1.7 g) in xylene (100 MIL) with heating under reflux for 48 hours. After cooling, the precipitate was filtered and washed with xi
    thirty
    35
    45
    lol, then crystallized from a mixture of dichloromethane-methanol to obtain 1.5 g of 2 cyano-3- (1,4-dihydro-1-phenyl-ЈP -benzothiopyrano-JJ4,3-e-pyrazole-Zylo-3-oxo- L-phenylprolanamide, so pl „228 230 ° C.
    In a manner similar to that described above, the following compounds were prepared:
    K- (Z-chlorophenyl) -2-cyano 3- (1,4
    16458268
    G4,3-gL-pyrazol-3-yl) -3-oxo-propane-amide, m.p. 238-240 C.
    Example 7. Using the methods of Examples 1 and 3, using respectively substituted thiochroman-4-ones as starting compounds, the following compounds can be obtained:
    2-cyano-3- (1,4-dihydro-8-methoxy-1 phenyl-T-benzothiopyrano 4,3-e-pyrazol-3-yl) -3-oxo-N-phenylpropan-amide, m.p. 205-210 ° C;
    3- (8-chloro-1,4-dihydro-1-phenyl-ЈL-benzothiopyrano-4,3-cJ-pyrazol-3-yl, - 2-cyano-3-oxo-N-trenilpropanamid, so pl. 235-236 °,
    2-cyano-3- (1,4 dihydro-8-methyl 1-phenyl- {jj-benzothiopyrano, pyrazol-3-yl) -3-oxo-M-phenylpropanamide, Topl. 224-22 ° C;
    N-6eH3im-3- (8-Tcnop-1,4-dihydro-1-phenyl-A-benzothiopyrano-G4,3-e-pyrazol-3-yl) -2-cyano-3-oxopropanamide, m.p. . 216-218 ° C
    PRI me R 8. A solution of 4-chloro-amine (11.2 g) and oxalic acid diethyl ester (13.3 g) in anhydrous dioxane (75 ml) was added with stirring at room temperature to a suspension of 50% - sodium hydride (4 g) in anhydrous dioxane (150 ml). The mixture was allowed to react for 3.5 hours while stirring at 80 ° C. After cooling, the reaction mixture was diluted with ice water and acidified to pH 4.0 with 40% citric acid (aqueous solution). The oily precipitate was extracted with ethyl acetate, then the organic was washed with 40% citric acid and water until neutral. After evaporation of the solvent in vacuo, the residue was purified on a silica column using a mixture of hexane-ethyl acetate in the ratio 80:20 as the solvent. Crystallization from isopropyl alcohol gave 3-ethoxylyl-chroman-4th, mp 73-75 ° C (7.7 g), which was reacted with phenylhydrazine (3.68 g) in acetic acid (80 ml) in the range of temperatures ranging from 2B to 40 ° (; for 30 minutes. The reaction mixture was diluted with ice water and then neutralized with 30% ammonium hydroxide. The precipitate was filtered and washed with water. Crystallization from propyl alcohol was obtained 1,4-dihydro-1-
    50
    55
    dihydro-1-phenyl-jjQ-benzothiopyran-phenyl-r 3-benzothiopyran-4,3-c
    pyrazole-3-carboxylic acid ethyl ester, so pl. 154-156 ° C (7.4 g), which were reacted with acetonitrile (74 ml) in dioxane (45 ml) in the presence of 50% sodium hydride (2.2 g) while stirring B) ° C for 30 min. After cooling (the reaction mixture was diluted with ice-water and acidified to pH 4.0 with a mono acid. The precipitate was filtered, washed and washed with water, then purified on a silica column using chloroform as eluent.
    By crystallization from a mixture of dichloro-J5 methane-isopropyl ether, 4.3-3- (1,4-dihydro-1-phenyl- (VI-benzopyrano-4,3-e-pyrazole 3-yl) -3-oxo was obtained. - propane nitrile, mp 155-158 C).
    NQR (C1) C13), § ppm: 4.19 (s, 20 2H, -СНгСМ); 5.54 (s, 2H OCH2-); 6.65-7.35 (m ,: protons of benzopyran) ;, 7.58 (m, 5H, protons of phenyl).
    In a manner similar to that described above, the following compounds can be obtained:
    3- (1,4-dihydro-4-methyl-1-phenyl-pJ-bezopyrano-4,3-e-pyrazol-3-yl) -3-oxo-propanenitrile, m.p. 162- .164 ° C; - 30
    3- (8-chloro-1,4-dihydro-1-phenyl- (benzopyran-4,3-e-pyrazole 3 yl) -3-oxo-propanenitrile, m.p. 1b3-1b5 ° C.
    Example 9. Following the process described in Example 10 and using suitable thiochroman-4-ones as starting compounds, the following compounds can be obtained:
    3- (1,4-dihydro-1- (4-methylphenyl) - 40 Ј L-benzothiopyrano-4,3-e-pyrazol-3-yl) -3 oxo-propanenitrile, m.p. 183-184 ° C;
    3- (1- (4-chlorophenyl) -1,4-dkgidro-
    35
    3- (1,4-dihydro-1-methyl) -j j-benz thiopyrano-G4, -pyrazol-3-yl) -3-and oxo-propanenitrile, i.e. 188-190 ° C;
    3- (1-tert-butyl-1,4-dihydro-jQ-benzothiopyrano, 3-e-pyrazol-3-yl-3-oxo-propanenitrile, mp, 150-
    152 ° C;
    3- (8-chloro-1,4-dihydro-1-phenyl-бензl benzothioprano-j 4,3-c -pyr ol-3-yl 3-oxo-propanenitrile, mp 151-153 ° C
    3- (1,4-dihydro-1-1-phenyl-Q-benzothiopyrano, 3-e-pyrazol-3-yl) -3-oxo-propac-nitrile, m.p. 151-153 ° C.
    Example 10. 3- (1,4-Dihydro-1-phenyl-rz benzopyrano-4,3-e-pyrazol-3-yl) -3-oxo-propanquitrnl (2.1 g was reacted with phenyl isocyanate ester ( 0.8 g) in the presence of triethylamine (0.75 g) in dimethylformamide (20 ml) with stirring for 30 minutes at a temperature of 25-30 ° C. The reaction mixture was diluted with water with ice, acidified to pH 2.0 The hydrochloric acid precipitate was filtered off and washed with water. Crystallization from dichloromethane-methanol gave 2.5 g of 2-cyano-3- (1,4-digcd o-1-phenyl-bcc opa no-4.3,3 -e -pira z ol-3-yl) -3- oxo-no.-pheny propanamide, m.p. 280- 282 ° C.
    NMR (CDC13) & ppm: 5.54 (s, 2H,); 6.7-7.7 (m, 14H, protons of phenyl), 8.94 (s, 1H, CONH-), 16.4 (brs, 1H, phenol).
    In a manner similar to that described, the following compounds can be obtained
    3- (8-chloro-1,4-dihydro-1-phenyl-l3 benzopyran-4,3-e-pyrazod-3-yl) -2-cyano-3-oxo-N-phenylpropanamide, mp 270- 273 ° C;
    2-cyano-3- (7, H-dichloride 1,4-di-gcd p o-1-f enyl-L1J-b ene base, 3-
    03 benzothiopyrano-4,3-e-pyrazol-3- 45 with -pyrazol-3-yl) -3-oxo-N-phenylpro
    il) -3-oxo-propanenitrile, so pl. 194-1U "° С;
    3- (1- (3-chlorophenyl) -1,4-dihydro-benzothiopyrano-4, 3x-pyrazol-3-yl) -3-oxo-propanenitrile, mp. 187-JQ 188 C;
    3- (1,4-dihydro-1- (4-fluorophenyl) - t lj-benzothiopyrano-4,3-e-pyrazol-3-yl) -3-oxo-propanenitrile, m.p. 190-192 ° C .;
     3- (1,4-d hydro-1- (4-methoxyphenyl) - fl-benzothiopyrano-4,3-e-pyrazol-3-yl) -3-oxo-propanenitrile, t „pl. 157-159 ° C .;
    panamid;
    2-cyaco-3- (1,4 dihydro-3 methyl-1-phenyl-Q-benzopyrano-4,3-e-pyrazol-3-yl) -3-oxo-N-phenylpropanamide.
    Example 11. By the method of Example 12, using suitable isocyanates, the following compounds can be obtained:
    N-beksyl-3- (8-chloro-1,4-dihydro-1-, g phenyl-p-benzopyran-4,3-cTj-nHpa-sol-3-yl) -2-cyano-3-oxopropacamide m.p. 281-284 ° C.
    Example 12. 3- (2,4 Dihydro-1-phenyl- (33-benzothiopyrano-4,3-cj-
    - about
    five
    0
    five
    0
    0
    five
    3- (1,4-dihydro-1-methyl) -j j-benz o-thiopyrano-G4, -pyrazol-3-yl) -3-yl-oxo-propanenitrile, i.e. 188-190 ° C;
    3- (1-tert-butyl-1,4-dihydro-jQ-benzothiopyrano, 3-e-pyrazol-3-yl-3-oxo-propanenitrile, mp, 150-
    152 ° C;
    3- (8-chloro-1,4-dihydro-1-phenyl-бензl benzothioprano-j 4,3-c -pyr ol-3-yl) -3-oxo-propanenitrile, so pl. 151-153 ° Cj
    3- (1,4-dihydro-1-1-phenyl-Q-benzothiopyrano, 3-e-pyrazol-3-yl) -3-oxo-propac-nitrile, m.p. 151-153 ° C.
    Example 10. 3- (1,4-Dihydro-1-phenyl-rZ benzopyrano-4,3-e-pyrazol-3-yl) -3-oxo-propanquitrnl (2.1 g) was reacted with isocyanic acid phenyl ester (0.8 g) in the presence of triethylamine (0.75 g) in dimethylformamide (20 ml) with stirring for 30 minutes at a temperature of 25-30 ° C. The reaction mixture was diluted with ice-water, acidified to pH 2.0 with hydrochloric acid, the precipitate was filtered and washed with water. Crystallization from a mixture of dichloromethane-methanol yielded 2.5 g of 2-cyano-3- (1,4-digcd o-1-phenyl-bcc ospa but-4,3-e-pyrazol-3 -yl) -3- oxo-№-phenylpropanamide, so pl. 280-282 ° C.
    NMR (CDC13) & ppm: 5.54 (s, 2H,); 6.7-7.7 (m, 14H, protons of phenyl), 8.94 (s, 1H, CONH-), 16.4 (brs, 1H, phenol).
    In a manner similar to that described, the following compounds can be obtained:
    3- (8-chloro-1,4-dihydro-1-phenyl-l3 benzopyran-4,3-e-pyrazod-3-yl) -2-cyano-3-oxo-N-phenylpropanamide, mp 270- 273 ° C;
    2-cyano-3- (7, H-dichloride 1,4-di-gcd p o-1-f enyl-L1J-b ene base, 3-
    5 with -pyrazol-3-yl) - 3-oxo-N-phenylpro
    Q
    panamid;
    2-cyaco-3- (1,4 dihydro-3 methyl-1-phenyl-Q-benzopyrano-4,3-e-pyrazol-3-yl) -3-oxo-N-phenylpropanamide.
    Example 11. The method of Example 12, using suitable isocyanates, can be used to obtain the following compounds:
    N-beksyl-3- (8-chloro-1,4-dihydro-1-g phenyl-p-benzopyran-4,3-cTj-nHpa-sol-3-yl) -2-cyano-3-oxopropacamide, m.p. 281-284 ° C.
    Example 12. 3- (2,4 Dihydro-1-phenyl- (33-benzothiopyrano-4,3-cj-
    pyrazol-3 yl) 3-oxo propanenitrile (1.6b g) was reacted with isothiocyanovic acid phenyl ester (1.0 g) in the presence of triethylamine (0.56 g) in dimethylformamide (15 ml) with stirring for one hours at 50 ° C. After cooling, the reaction mixture was diluted with water with jibflOM and acidified to pH 2.0 with chlorohydrochloric acid. The precipitate (extracted with chloroform, the organic solution was washed with 1N hydrochloric acid, then with water until the solution was neutralized. After evaporation of the solvent in vacuum, the estatok was crystallized from dichloromethane-isopropyl alcohol to obtain 1.55 g of 2-cyano-3 (1.4 -dihydro- (1 phenyl-jjj-benzothiopyrano-4,3-cj- | shrazol 3-yl) -3-oxo-M phenyl thiopropanamide, mp 167-170 ° C.
    II p and mep 13. Ethyl ester of 2- 2-cyano-3- (1, 4-dihydro-1-phenyl-L enenzopyran-4,3-cj-pyrazol-3-yl) -3-oxo-propane acids (1.2 g) were reacted with anilium (1.1 g) in xylene (100 ml) with heating under reflux for 48 h. After cooling, the rcipitate was filtered and washed with xylene, then crystallized from dichloromethane-methanol and 0.7 g of 2-cyano-3- (1,4-dihydro 1phenyl 3 benzopyrans {/ 3-cj-pyrazol-3-yl) -3-OKCO-N-phenylpropanamide was obtained, mp. 280 ° C 282 ° C.
    Example 14. 2 Cyano 3- (1,4-t Dihydro-1-phenyl-{L-benzopyrano-4 s 3-e-pyrazol-3-yl) -3-oxo-n-phenyl propanamide was dissolved by treatment with an equivalent amount ethylate chatri in ethanol. The solution was evaporated to dryness, the residue was treated with isopropyl ether, then filtered and the sodium salt of 2-cyano-3-C 1,4-dihydro-1-phenyl Vj-benopyrano 4,3-cj-pyrazol-3 yl) -3-oxo was obtained phenyl propanamide, so pl. about .
    -.
    In a manner similar to that described,
    received the sodium salt of the following compounds:
    2-tsnano-3- (1,4-dihydro-1 phenyl- and -benzothiopyrano-4.3 s {pyrazole 3 1; 3-oxo-L-tbenyl propacamide, mp, about 300 ° C;
    N-benzyl-2-cyano-3- (154-dihydro-I phenyl-13-benzothiopyran-4,3-c
    five
    Q 5 0
    Q
    0
    0
    five
    45
    pyrazol-3-yl) -3-oxopropanamide, and so pl. 290 ° (; (decomposition).
    The compounds of formula (I) possess immunomodulatory activity and can be used, in particular, as immunostimulating agents, for example, in the treatment of acute and chronic infections of both bacterial and viral origin, alone or in combination with antibiotic agents, and in the treatment of neoplasms alone or in combination with antitumor agents in mammals.
    The immunomodulatory activity of the compounds according to the invention is confirmed, for example, by the fact that they are effective in maintaining the cytotoxic activity of macrophages against tumor cells in vitro.
    The experimental method for evaluating this activity is the following: groups of mice, each with 4 animals each, was treated intraperitoneally with test compounds and then, after 7 days, peritoneal cells were harvested and grown for two hours at 37 ° C. After that, the walls were washed to remove the cells adhering to the walls of the dish, and the tumor target cells were added, continuing to grow for another 48 hours. By the end of this time period, the viability of the target cells was measured by the colorimetric method and quantified at 570 nm.
    Table 1 presents the data of the immunostimulating activity of a representative group of compounds of the invention in accordance with the procedure described above with respect to tumor
    cells.
    i
    FCE code number 25477 defines the compound 1,4-dihydro-1-phenyl-V | -benzothiopyrano-4,3-gL-pyrazole-3-carboxylic acid.
    FCE 25477 is a known compound having a similar chemical structure, tour.
    In the above experiment, the ratio of macrophages: TU5 tumor cells is 5: 1.
    Cytotoxic activity is calculated as% growth inhibition of TU5 tumor cells using the following formula:
    % gtppa, ptsts ", - HOHT..A .-). D.V.) -. (. C .-). D.L.)
    (ODA.AH). D.V.)
    de Oh, D.A. ABOUT. D.V. - О.Д.С. O.D.D. CE 42578 CE 25158 CE 25159
    thirty
    CE 25160 CE 25177 CE 25178 CE 25242 CE 25247 CE 25318 optical density from macroscopically grown TUS and macrochage-treated macrochages; optical density from one mile-treated macrophage; optical density from co-grown TU5 and FCE-coupled macrophages; 15 optical density from one macroscopic FCE-treated compound; 2-cyano-3- (1,4-dihydro-1-phenyl-ЈG | -benzothiopi-20-ra-4,3-e-pyrazol-Zyl) -3-oxo-N-phenylpropanamide;
    2-cyano-3 (1,4-dihydro-1-phenyl- (jQ-benzopyrano-25 4, 3-e-pyrazol-3-yl) -3-OKCo-N-phenylpropanamide; 2-cyano-H- ( 1,4-dihydro-1-methyl-and-benzothiopirano-4, 3-e-pyrazol-3-yl) -3-oxo-K-phenylpropanamide ;;
    3- (1,4-dihydro-1-phenyl-E13-bekozothiopyrano-4,3-e-pyrazol-3-yl) -3-oxo propanenitrile; 2-cyano-3- (1,4-dihydro-1-phenyl-tO-benzothiopirano-A, 3-e-pyrazole-Zyl) -3-oxo-K- (2-pyridyl) 40 lropanamide;
    2-and; iano-3- (1,4-dihydro-1-phenyl- (33 benzothiopyrano-f, 3-e-pyrazol-3-yl) -N- (4-methylphenyl) -3-ds oxo -propanamide; 2-cyano-Z- (1,4-dihydro-1-phenyl-p3-benzothiopyrano-J4,3-c3; pyrazol-3-yl) 3 oxo-K- (3-trifluoro-, - 0 methyl-phenyl) -propanamide; N-butyl-2-cyano-3- (1,4-dihydro-1-phenyl-J-benzothiopyran-4,3-c-pyrazol-3-yl-3-oxo-propanamide ;
    2-cyano-3- (1,4-dihydro-1-phenyl-p-benzothiopyrano-Qt, 3-e-pyrazole-335
    55
    thirty
    from 15 to 20
    25
    40
    ds, -0
    35
    five
    yl) -3-oxo-N-phenylthiopropanamide;
    FCE 25320 - 2-cyano-3 (1,4-dihydro-1- (ynyl-P1-benzothiopi
    early 4,3-cJ-pyrazol-3-yl) N- (4-methoxy-phenyl) -3-oxo-propanamide;
    FCE 25321 - LT- (3-chloro-phenyl) -2-.
    1shchano-3- (1,4-dihydro-1-phenyl-I-benzothiopyrano-4,3-e-pyrazol-3-yl) -3-oxo-lopanamide;
    FCE 25323 - 3- (8 chloro-1,4-dihydro-1-phenyl-LiJ-benzothiopyrano, 3-e-pyrazol-3-yl) -2-cyano-3-oxo-N-phenylpropanamide;
    FCE 25324 - K-benzyl-2-cyano 3- (1,4-dihydro-1-phenyl-I-benz o teplo-ft, 3-cJ - pyrazol-3-yl) -3-oxo-propanamide ;
    FCE 25432-2-cyano-3- (1,4-dihydro-1-phenyl-Q-benzothiopyrano-4, jj-cj-pyrazol-3-yl) -b, 3-dioxide) -3-oxo- N-phenyl-propanamide;
    FCE 25433 -2-cyaco-3- (1,4-dihydro-1-phenyl-pj-Benzothiopyrano-0, 3-e-pyrazol-3-yl) -N- (4-fluoro-phenyl) -3 - oxo-propane;
    FCE 25438-2 cyano-3- (1,4-dihydro-1-4-methoxy-phenyl-P0 benzothiopyrano-4,3-c-pyrazol-3-yl) -3-oxo-N-phenyl-propanamide;
    FCE 25478, 2-cyano-3- (1,4-dihydro-1- (4-fluoro-chienyl) benzothiopyrano-4,3-e - pyrazol-3-yl) -3-oxo-N-phenylpropanamide;
    FCE 25483 - 3- (1- (3-chloro-phenyl) -1,4-dihydro-1 J-benzothiopyran-4,3-rj-pyrazol-3-yl) -3-oxo-N-Lenyl-propanamide ;
    FCE 25564-2-cyano-3- (1,4-dihydro-8-methoxy-1-chien pj-benzothiopyrano, 3-cj-pyrazol-3-yl) -3-oxo-N-phenylpropanamide;
    FCE 25609 - 2-cyano-3 (1,4 dihydro) -1-phenyl-3-benzothiopyra, az ol-3-
    yl) -No (3-nitrophenyl) 3-oxo-propanamide; k FCE 25611 - 3- (1- (4-fluoro-phenyl) -1,4 dihydro T - benzothiopyran- 4, 3-сГ -pyrazole -Zyl) -3-cyano-N- (4 fluorophenyl) -3-ocean-propanamide;
    FCE 25612-2 cyano 3- (1,4 dihydro-1- (3-methyl-phenyl) -benzothiopyrano-4,3-cJ-pyrazol-3-yl) -3-oKco N-phenylpropanamide;
    FCE 25614 - N-benzyl-3- (8-chloro 1,4-dihydro-1-phenyl {TJ-benzothiopyrano-4,3-f) -pyrazol-3-yl) -2-cyano-3-oxo-propanamide .
    | By virtue of their immunomodulatory activity, the compounds of the invention have also been found to be active in mouse rushes moduli. -3-oxo-N-fenshg-propanamid (internal code FCE 24578), for example, was tested according to a known method.
    In tab. 2, 3 and 4 presents the results:
    Infectious Disease (FMD) was administered intraperitoneally
    Treatments using FCE 2457 or vehicle were performed at 3.2.2 and 0 days before infection.
    Treatments with FCE or Sitel were performed 3, 2, 1 and O the day before infection with OvSchCHO, administered intravenously.
    Cyclophosphamide (200 mg / kg) was administered Enetribriuginno for 4 days before infection
    Treatment with FCE 24578 or carrier was carried out on 3.2,2 and 0 days before infection (2 x LED5 and 1 x BD, administered intravenously.
    Preferred compounds of formula (I) with immunomodulating activity are the following compounds:
    2-cyano-3- (1,4-zdihydro-1-enyl-PQ-benzopyrano-4,3-c-pyrazole-3-1ch) -3-oxo-no. Phenylpropanamide (internal code FCE 25158);
    2-cyano 3- (1,4-dihydro-1-phenyl- | L-benzothiopyrano-4,3-cG -pyrazole-yl-3-oxo-N-phenylpropanamide (internal code FCE 24578).
    Due to their high therapeutic index, they can be safely used in medicine. For example, the approximate acute toxicity (50%) is the lethal dose (LD "3 In mice, caused by the compounds 2-cyano-3- (1,4-dihydro-1 phenyl-Ј fj-benopyopyran-4,3-e-pyrazole -3-yl) -3-ox oN-phenylpropanamide and 2-cyano-3- (1,4-dihydro-1-phenyl-1-benzothiopyrano-4, pyrazol-3-yl) -3-oxo -M-phenylpropan-amide, determined by single oral administration of increasing doses and measured on the seventh day of treatment, was higher than 800 mg / kg. Similar toxicity data was found for other compounds of the invention, for example, the compounds described in Table 1 .
    The therapeutic regimen for various clinical syndromes can be selected depending on the type of pathology taken into account, as well as the route of administration, the form in which the compounds are administered, the age, weight and overall health of the patient involved in the infection.
    权利要求:
    Claims (1)
    [1]
    1. A method for preparing derivatives of heteroaryl 3-oxopropane-nitriles of general formula I
    к4-и1-ы7
    I
    pine:
    XN
    ъ
    de X oxygen or the group —S (0) —n (n O or 2);
    R. - C — C alkyl or phenyl, while phenyl is unsubstituted or substituted by one or two substituents selected from halogen, C — O alkyl, and C — C4 alkoxy;
     and each independently of one another is hydrogen, halogen, C-C-alkyl, or C4-lux-hydroxy;
    (J is hydrogen, (-Cg is alkyloxycarbonyl or a group
    RQ. .
    sleep
    s
    or
    CSN
    s
    where Cd is hydrogen or C, -C-alkyl; I (-6 or group - (where, 1 or 2;
    RS - unsubstituted pyridyl or
    phenyl or substituted with one or two substituents independently selected from helogen, CF, C-SC-Pk, C-C alkoxy or nitro or their pharmaceutically acceptable salts, characterized in that the compound of formula II is reacted
    Rt-n
     R3
    have indicated
    where X, R (, meaning
    Y is a reactive derivative of a carboxy group, with a compound of formula III
    / CN
    CH2CQ
    where Q has the indicated values in an inert solvent in the presence of a basic agent at 0-100 ° C and, if necessary, reacting the obtained compound of the formula .1, where (I is hydrogen, with the compound of the formula V or Va.,
    de KL has the indicated values, thus obtaining the compounds of the formula I, where Q is the -CONKR group or the group is CSNHR, respectively, where R, has the indicated values, or the interaction of the compound of the formula I thus obtained, where ()
    C2 Cc is an alkoxycarbonyl group, g is a compound of formula VII
    / Rn
    Hl a
    p
    where Ra and R have the indicated meanings to obtain a compound of the formula, where Q is a group
    Ra TRb
    five
    0
    five
    0
    five
    where RQ and Ri have the indicated meanings, with the desired product being isolated in free form or in the form of a pharmaceutically acceptable salt.
    Priority featured:
    01/09/87 when X is a group - S (0) h, where or 2; K is C —C-alkyl or phenyl, wherein phenyl is unsubstituted or substituted by one or two substituents selected from halogen, Cj is C, alkyl and C — C alkoxy.
    .Ј and R - each independently of one another hydrogen, halogen, .- alkyl or (-Sf-alkokgi; Q - (HLCL, where R is C, -C, is alkyl or a group - (where, 1 or 2 ; Rr is unsubstituted with pyridyl or phenyl, or substituted with one or two substituents independently selected from halogen, CFj, C -CH-alkyl, (-CH-alkoxy, or nitro.
    07.22.87 with X - oxygen; O is hydrogen; C-Cg is alkoxycarbonyl or a group
    CON;
    RQ
    or CSN:
    H
    45
    where R0 is C-SL-alkyl. The remaining radicals have the above values .-,
    Table 1
    nineteen
    1695826Y
    Continuation of table 1
    Table 2
    t
    FCE activity against SJflexheri and D infections. pneumoniae in mice
    I T a, b l and c a 3
    FCE 24578 Activity Against Infection of L. raonocytogenes in Mice
    FCE 24578
    50 mg / kg
    (in nutribryushinno)
    10 mg / kg
    (intraperitoneally) Control FCE 24578
    250 mg / kg (orally)
    50 mg / kg
    f.
    Table
    FCE 24578 Activity Against P. Aeruginosa Infection in Immunosuppressed Mice
    FCE 24578 50 mg / kg 10 mg / kg
    Control
    169382622
    Continuation of table 3
    Oh oh
    Oh oh
    90 80
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    同族专利:
    公开号 | 公开日
    AU598893B2|1990-07-05|
    KR880008987A|1988-09-13|
    IE880002L|1988-07-09|
    EP0274443A1|1988-07-13|
    PT86516A|1988-02-01|
    NO165841B|1991-01-07|
    IL85004D0|1988-06-30|
    NO165841C|1991-04-17|
    ES2029003T3|1992-07-16|
    NZ223113A|1989-07-27|
    JPS63174988A|1988-07-19|
    FI880078A|1988-07-10|
    YU46787B|1994-06-10|
    NO880068L|1988-07-11|
    DE3862937D1|1991-07-04|
    CN1025500C|1994-07-20|
    FI880078A0|1988-01-08|
    IE60620B1|1994-07-27|
    GR3002032T3|1992-12-30|
    YU79489A|1989-10-31|
    EP0274443B1|1991-05-29|
    HU198722B|1989-11-28|
    CN88100153A|1988-07-27|
    JP2672312B2|1997-11-05|
    PH27000A|1993-02-01|
    FI89489C|1993-10-11|
    CZ17988A3|1993-02-17|
    IL85004A|1991-11-21|
    NO880068D0|1988-01-08|
    PT86516B|1991-12-31|
    CA1310647C|1992-11-24|
    MY103348A|1993-06-30|
    DK8088A|1988-07-10|
    CZ277972B6|1993-07-14|
    FI89489B|1993-06-30|
    DK8088D0|1988-01-08|
    YU1088A|1989-08-31|
    US4816467A|1989-03-28|
    AU1003788A|1988-07-14|
    HUT47113A|1989-01-30|
    KR960002852B1|1996-02-27|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB878700477A|GB8700477D0|1987-01-09|1987-01-09|Heteroaryl 2-cyano-3-oxo-propanamide derivatives|
    GB878717282A|GB8717282D0|1987-07-22|1987-07-22|Heteroaryl 3-oxo-propanenitrile derivatives|
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