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    • 专利摘要:
    Compounds of the formula (I) <IMAGE> (1) wherein R1 is (a) hydrogen or halogen; (b) a C1-C6 alkyl group, unsubstituted or substituted by C1-C4 alkoxy or by halogen; (c) a phenyl ring unsubstituted or substituted by a group chosen from halogen, C1-C4 alkyl and C1-C4 alkoxy; (d) a C1-C6 alkylthio group; R2 is hydrogen or halogen; R3 is 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein each pyridyl group is unsubstituted or substituted by C1-C4 alkyl; and the pharmaceutically acceptable salts thereof. The compounds possess anti-ulcerogenic and gastric anti-secretory activity.
    公开号:SU1321377A3
    申请号:SU833550643
    申请日:1983-02-02
    公开日:1987-06-30
    发明作者:Дориа Джанфедерико；Пассаротти Карло；Буттинони Ада
    申请人:Фармиталия Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of 1,3,4-thiadiazo (3,2-a) pyrimidine-5-one derivatives or their pharmaceutically acceptable salts, which makes it possible to obtain biologically active compounds that can be used in medicine,
    The purpose of the invention is to obtain new 1,3,4-thiadiazolo (3,2-a) pyrimidin-5-one derivatives, which are characterized by low toxicity and higher anti-ulcer activity.
    Example 1. 2-Amino-1,3,4-thiadiazole (5 g) is reacted with 12.3 g of ethyl 4 - chloroacetate in 25 g of polyphosphoric acid with stirring at 2 hours.
    After cooling J, diluting with ice water and neutralizing with 35% NaOH, the resulting precipitate is filtered and injected with water until neutral, to give 7-chloromethane 1-5 H.-1, 3, 4-thiadiazole (3, 2-a) pyrimidine 5-one, mp 194-196 C (9 g), which is reacted with triphenylphosphine (12.6 g) in acetonitrile with stirring at reflux temperature for 30 hours. After cooling, the precipitate is filtered and washed with ethyl acetate to obtain 5-oxo-5H -1,3,4-thiadiazolo (3,2-a) pyrimidine-7-yl methyltriphenylphosphonium chloride, mp 230-240 with decomposition (20.5 gsuspended in dimethylsulfoxide (60 ml) and treated with potassium terbutylate dropwise (4.9 g). dissolved in dimethyl sulfoxide (40 ml) at 20 ° C. The solution of the ylid thus obtained is reacted with 5.5 g of benzaldehyde at room temperature for 30 minutes. After dilution with ice water, the precipitate is filtered off and washed with water. After crystallization, 4.4 g of 7-trans- (2-phenylethene-1) -5H-1, 3 are obtained from the CH 1 Cl-acetone mixture , 4-thiadiazolo (3, 2-a) -pyrimidin-5-one, so pl. 217-21 with „
    NMR (CDC1,), & nd. : 6.39 (1H, -proton); 6.90 (d, 1H, fi-ethenyl proton); 7.30-7.67 (m, 5H, phenyl protons), 7.80 (d, 1H, ethenyl protons), 8.73 (s, I1, C-2 protons), 16 Hz. In a similar way, when using pyridinaldehyde instead of benzaldehyde, 7-trans (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3,2-a) -pyrimidin-5-one was obtained, m.p. 245-253 C (with decomposition) about
    Example 2 of 2-amino-5-methyl-thio-1,3,4-thiadiazole (9.4 g) is reacted with ethyl 4-chloro acetate (15.8 g) in polyphosphoric acid (50 g) with stirring at 100 ° C for 1 h.
    After cooling, diluting with ice water and neutralizing with 35% NaOH, the precipitate is filtered and washed with water until neutral to obtain 7-chloromethyl-2-methylthio-5H-1,3,4-α-thiadiazole (3,2-a) pyrimidine -5-she, f m.p. 168-169 ° C (12.4 g), which is reacted with triphenylphosphorin (14.4 g) in acetonitrile (250 ml) with stirring at reflux temperature for 24 hours. After cooling, the precipitate is filtered and washed with isopropane. - sawing ether to produce 2-methyl-TIO-5-OXO-5H-1,3,4-thiadiazolo (3,2-a) pyrimidin-7-yl-methyl-triphenylphosphonium chloride (24 g), which is suspended in dimethyl sulfoxide (100 ml) and potassium terbutylate (5 g) dissolved in dimethyl sulfoxide (80 ml) at 20 is added dropwise with 20 Co The solution of ylide thus obtained is interact with benzdehyde (4.65 g) at room temperature for 60 minutes. After dilution with ice water, the precipitate is extracted with ethyl acetate and the organic solution is evaporated to dryness in vacuo. After purification on a column with SiO. Mixture of CHCl 3, hexane, and crystallization from a mixture of methanol, 3.8 g of 2-methylthio-7-trans- (2- -phengshetenyl) -5H-1,3,4-thiadiazolo are obtained (3, 2-a) -pyrimidin-5-she, so pl. 180 - 182 C.
    NMR (CDCl,), M.D .: (/ -ethylnyl proton), 7.2-7.7 (m, 5H, phenyl protons), 7.70 (d, 1H, OC -ethyl proton ), JHj / Hp, 16 Hz.
    Similarly, when using pyridylaldegnd, 2-benzylthio-7-trans-2- (3-pyridyl) -E-en-1 -5H-1,3,4-thiadiazolo- (3,2-a) -pyrimidin-5-one, ToPLo 179-181 ° C and 2-methylthio-7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3,2-a) - pyrimidin-5-one, t. square 179-181 ° C.
    EXAMPLE 3 5-Oxo-2-phenyl-5H--1,3,4-thiadiazolo (3,2-a) pyrimidine-7- -yl-methyltriphosphonium chloride, obtained in Example 5 (g), with They are spun in 20 ml of dimethyl sulfoxide and treated with potassium terbutylate (1.6 g), dissolved in 40 ml of dimethyl sulfoxide at. The solution of the ylide thus obtained is reacted with 1.5 g of 3-pyridinecarboxaldehyde at room temperature for 10 min „After dilution with ice-containing water, the precipitate is filtered and washed with water; after crystallization from methanol, 2 g of 2-phenesh-7-trans-2- (3-pyridyl) -ethenyl-3-5H-1,3,4-thiadiazolo (3,2-a) pyrimidine-5- are obtained. She, TopLo 279-282 ° C
    NMR spectrum (CDCL, -CF, GOOD), cG MOD: 7.02 (s, 1H, C-6-proton), 7.48 (d, 1H, A-ethenyl proton), 7.66 (m , ZN) and 7.95 (m, 2H, phenyl proons), 7.9-8.2 (m, ZN, pro-ethenyl proton, 1-4 and C-5 pyridic protons), 8.33 ( bd, 1H, Cb-pyridyl proton), 9.10 (1H, C-2-pyridine proton) o
    25 adiazolo (3,2-a) pyrimidin-5-one, so pl. 193-195 ° C, which is reacted with triphenylphosphine (9.1 g) in acetonitrile (125 ml) with stirring at the boiling point and in a similar way, the following compounds are obtained:
    2- (4-methylphenyl) -7-trans-2- (3-pi-30 rat condenser for 20 h. Ridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, After cooling, the precipitate is filtered and 2 -a) pyrimidine-5-one, so pl. 244-246 ° C; washed with ethyl acetate, get
    2- (4-methoxyphenyl) -7-trans-2- (3-6-chloro-5-oxo-5H-1,3,4-thiadiazolo (3, -pyridne) ethenyl-5H-1,3,4 -thiazolo (3, 2-a) pyrimidin-7-sh1) -methyltriphenylphos-2-a) pyrimidin-5-one, so pl. 258-2b1 ° C; 35 Phonium chloride (16 g), which is suspended 2- (4-Chlorophenyl) -7-trans-2- (3-pyrate in 60 ml of dimethyl sulfoxide and obridyl) ethenyl-5H-1,3,4-thiadiazolo (3 , working, adding on the terbutyla ca-2-a) pyrimidine-5-one, mp, 273-274 ° С; whether (8.6 g) dissolved in 30 ml of di2- (4-fluorophenyl) -7-trans-2- (3-pymethylsulfoxide at 20 ° C. The resulting one) -tenyl-5H-1,3,4 -thiadiazolo (3.40 ny thus a solution of ylide pod-2-a) pyrimidin-5-one, t.gsh. 272-273 C;
    2- (4-nitrofensh1) -7-trans-2- (3-pyriddsh1) -ethenylZ-5H-1,3,4-thiadiazolo (3, 2-a) -pyrimidin-5-one, mp . 175-178 ° C;
    2- (4-hydroxyphenyl) -7-trans-2- (3-pi-45 is washed with water. After crystallization of the ridyl) ethylene 13-5H-1,3,4-thiadiazolo (3, from a mixture of chloroform - ethanol, 2- a) pyrimidine-5-one;
    2- (3-hydroxyphenyl) -7-trans-2- (3-pyriddsh1) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimiding 5-one; 50 times).
    2- (2-thienyl) -7-trans-2- (3-pyri-NMR spectrum (CF, CCOU), S ppm: 7.45 dil) -ethenyl-5H-1,3,4- thiadiazolo (3, 2-a) pyrimidin-5-one, so pl. 308-310 ° C;
    2-phenyl-7-trans-2- (4-pyridyl) --ethenshG) -5H-1,3,4-thiadiazolo (3,2-a) pyrimidin-5-one, t.p. 245-246 ° C;
    2-phenyl-7-trans-2- (6-methyl-6-pyriddsh1) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one, so pl. 250-251 ° C; After cooling, the solution is diluted with ice water and the precipitate is filtered off and about 3 g, 4 g of 6-chloro-7-trans- (2-phenylethenyl) -5H- 1,3,4-thiadiazolo (3,2-a) pyrimidin-5-one, m.p. 265-270 C (with decomposition (m, 3N, C-3, C-4- and C-5- phenyl protons), 7.53 (d, 1H, | 3-ethenyl protons), 7.66 (dd, 2H, C-2- and C-6- 55 phenyl prototypes), 8.05 (d, 1H , oi- ethenyl protons), 9.02 (s, 1H, C-2 protons); 16 Hz.
    Similarly, using pyridylaldehyde, 6-chloro-72- (4-aminophenyl) -7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo is obtained (3, 2-a) pyrimidine -5-he, Topl. 322-325 С; 2- (4-acetylaminophenyl) -7-trans-C2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3,2-a) pyrimidin-5-one.
    Example 4. In example 1, starting from substituted 7-chloromethyl-5H-1, 3,4-thiadiazolo (3,2-a) pyrimidine-5-one
    2-methyl-7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one, ToPL. 2b1-264 ° C.
    PRI me R 5. 7-Chloromethyl-5H-1,3, 4-thiadiazolo (3,2-a) pyrimidine-5-one
    (10 g), prepared according to Example 1, is reacted with sulphuryl-. chloride (7.5 g) in dichloroethane (150 ml) with stirring at 60 ° C for 2 hours. After cooling,
    the dock is filtered off and then suspended in water (500 ml) and neutralized, treated with 35% NaOH. After filtration and washing with water, 7.5 g of 6-chloro-7-chloromethyl-5H-1,3,4-thiadiazolo (3,2-a) pyrimidin-5-one are obtained, m.p. 193-195 ° C, which is reacted with triphenylphosphine (9.1 g) in acetonitrile (125 ml) with stirring at reflux temperature for 20 hours. After cooling, the precipitate is filtered and washed with ethyl acetate, to give
    methyl sulfoxide at 20 ° C. The solution of the ylide obtained in this way is
    wash with water. After crystallization from a mixture of chloroform - ethanol receive
    After cooling, the solution is diluted with ice water and the precipitate is filtered and washed with water. After crystallization from a mixture of chloroform - ethanol receive
    zheniem).
    3.4 g of 6-chloro-7-trans- (2-phenylethenyl) -5H-1,3,4-thiadiazolo (3,2-a) pyrimidine-5-one, mp 265-270 ° C (with NMR spectrum (CF, CCOU), S ppm: 7.45
    (m, 3N, C-3, C-4- and C-5-phenyl protons), 7.53 (d, 1H, | 3-ethenyl protons), 7.66 (dd, 2H, C-2- and C-6-5 phenyl proto} 1s), 8.05 (d, 1H, oi-ethenyl protons), 9.02 (s, 1H, C-2-protons); 16 Hz.
    Similarly, using pyridylaldehyde, 6-chloro-7-trans 2- (3-pyridyl) -ethenyl 3-5H-1,3, 4-thiadiazolo- (3,2-a) pyrimi-5-one, t. square 225-230 ° С (with decomposition).
    EXAMPLE 6, 7-Sloromethyl-5H-1,3 4-thiadiazolo (3,2-a) pyrimidine-5-one (10 g) obtained in Example 1 is dissolved in dimethylforma 1ide (40 ml ) and subjected to interaction with anhydrous potassium acetate (10 g) with stirring at room temperature for 20 hours. After dilution with ice and water, the precipitate is filtered and washed with water, 9.7 g of 7-acetoxy-5H-1.3 are obtained, 4-thiadiazolo (3,2-a) -pyrimidin-5-one, which is hydrolyzed by treating with 37% HC1 (50: ml) in dioxane (100 ml) with stirring at room temperature for 2 hours The reaction mixture is diluted with acetone and the precipitate is filtered and then treated with aqueous NaHPO. After filtration and washing with water until neutral reaction, 6.2 g of 7-oxy-methyl-5H-1,3,4-thiadiazolo (3,2-a) pyrimidin-5-one are obtained, which are reacted with dicyclohexylcarbodiimide. (14.4 g) in 90 ml of benzene and 25 ml of dimethyl sulfoxide in the presence of 1 ml of trifluoroacetic acid and 1.71 ml of pyridine with stirring at room temperature for 20 Cho After treatment with oxalic acid dihydrate (8.1 g) at room temperature precipitate dicyclohexyl urea is filtered off and the organic solution is evaporated to dryness in vacuo. The residue is purified on a SiOj column, using jcMecb chloroform-ethyl acetate 95: 5 as eluent, 2.5 g of the 7-formyl-5H-1,3,4-thiadiazolo (3,2-a) pyrimidine-5- obtained in such a way it is reacted with a ylide obtained by treating triphenylphosphonium benzyl chloride (2.94 g) with 50% NaOH (0.43 g) in 40 ml of dimethyl sulfoxide at room temperature for 22 hours. After dilution with ice water, the precipitate is filtered and washed with water; after crystallization from a mixture of etayl, 2.1 g of 7-trans- (2-phenyl-ethenyl) -5H-1,3,4-thiadiazolo (3,2-a) pyrimidine-5-one are obtained, t. pl, 216-218 C.
    Similarly, the following compounds are obtained:
    2-phenyl-7-trans-iZ- (3-pyridyl) - -ethenylZ-5H-1,3,4-thiadiazolo- (3,2-a) pyrimidine-5-0n, so pl. 279-282 ° C;
    2- (4-fluorophenyl) -7-trans-2- (Ridyl)-ethensh1 -5N-1,3,4-thiadiazolo (3, 2-a) gshrimidin-5-one, t „pl. 272-273 ° C;
    7-trans-2- (3-pyridsh1) -ethenyl-5H- -1j 3,4-thiadiazolo (3,2-a) pyrimidine-5- -one, m.p., 245-253 C with decomposition; -
    2-benzylthio-7-trans-2- (3-pyridine1) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one,, 179-18l C;
    2- (4-methylphenyl) -7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one,. 244-246 C}
    2- (4-methoxyphenyl) -7-trans-2- (3- -pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyri imidin-5-one, m.p. 258-261 ° C;
    2- (4-chlorophenyl) -7-trans-2- (3-pyrid, yl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one, t. pl, 273-274 C;
    2- (4-nitrophenyl) -7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one, m.p. 175-178 ° C;
    2- (4-hydroxy-fvnil) -7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one;
    2- (3-hydroxyphenyl) -7-trans-2- (3- -pyridyl) -ethenyl-5H-1,3,4-thiadiazo (3,2-a) pyrimidin-5-one;
    2- (2-thienyl) -7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one, t „PL, 308 -3 ° C;
    2-phenyl-7-trans-2- (6-methyl-2-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one, mp, 250-251 ° C;
    2- (4-aminophenyl) -7-trans-2- (3-pyridyl) -ethenylZ-5H-1, 3,4-thiadiazolo (3, 2-a) pyrimidin-5-one, mp 322-325 with;
    2- (4-acetylaminophenyl) -7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadia-3 olo (3,2-a) pyrimidin-5-one;
    2-methyl-7-trans-2- (3-pyridyl) ethylene) -5H-1,3,4-thiadiazolo (3,2-a) pyri-MIDIN-5-OH, mp 261- 265 ° C;
    EXAMPLE 7, 2-Amino-5-FANIL-1 3,4-thiadiazole (10 g) is reacted with 18.6 g of 2-chloroacetoacetate and 100 g of polyphosphoric acid with stirring at 100 ° C. 2 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate is filtered and washed with water until neutral; after crystallization from isopropyl alcohol, 16.9 g of 6-chloro-7-methyl-7-phenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one are obtained, which are reacted with N-bromo succinimide (10.9 g, added in portions) in 200 ml of benzene at reflux temperature for 32 hours. After cooling, the reaction mixture is diluted with ethyl acetate, treated with aqueous NaHCO and then with water; the separated organic solution is evaporated to dryness in vacuo and the residue is crystallized from methanol to give 7-bromomethyl-6-chloro-2-fench1-5H-1,3,4-thiadiazolo (3,2-a) pyrimidin-5-one (12 , 3 g), which is reacted with triphenylphosphine (8.6 g) in 700 ml of acetonitrile at reflux temperature for 4 h. After cooling and evaporating the solvent in vacuo, the residue is purified with ethyl acetate to 17.6 g of b-chloro-5-oxo-2-phenyl-5H-1,3,4-thiadiazolo (3,2-a) pyrimidin-7-yl-methyltriphenylphosphonium bromide, which is treated in nym NaHCO) with stirring at room temperature until a precipitate b-chloro-5-oxo-2-phenyl-5H-1,3 4-thiadiazole (3,2-a) pyrimidin-7-ilJ- -metilentrifenilfosforana.
    This compound is filtered, washed with water, dried under vacuum at room temperature, and then suspended (15.1 g) in 600 ml of dichloroethane and reacted with 3-pyridine carboxaldehyde (2.6 g) at reflux temperature. 3 hours. After cooling, the organic solution is evaporated in vacuo to dryness; the residue is purified on a column of SiO using 98: 2 chloroform-methanol as eluent. After crystallization of the resulting product from the mixture, j-ethyl acetate gives 5.4 g of 6-chloro-2-phenyl-7-trans-2- (3-pyridyl) ethenyl-5H-1,3,4-thiadiazolo ( 3, 2-a) pyrimidin-5-one, Topl „297-2E9 ° С,
    NMR spectrum (CDC1, -CF, GOOD), B MD: 7.4-8.2 (m, 3H, od-ir-ethenyl protons, phenyl protons, C-5-pyridyl proton) , 8.80 (d, 2H, C-4- and C-5-pyridyl protons), 9.1 (bs, 1H, C-2-pyridyl proton) „
    EXAMPLE 8 2- 4-Nitrophenyl-7-trans-2- (3-pyridyl) ethenyl 5H-1,3, 4-thiadiazolo (3,2-a) pyrimidin-5-one j (5 , 7 g) is reacted with SnCl, -2HjO (33.7 g) in 37% HC1 (25 ml) and acetic acid (80 ml) with stirring at 60 ° C for
    five
    Q Q g
    P
    g
    five
    4 hours. After cooling, the residue is filtered and washed with water, and then suspended with stirring in 2N. NaOH. The resulting product is filtered, washed with water until neutralized, and then after crystallization from chloroform-ethanol mixture, 2.8 g of 2- (4-aminophenyl) -7-trans-2- (3-pyridyl) -ethenyl-5H- 1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one; m.p. 322 -. NMR spectrum (VMSOdb), J ppm: 6.16 (bs, 2H, NH.p, 6.42 (s, 1H, C-6 - proton), 6.65 (bs, 2H , C-3- and C-5-phenyl protons), 7.32 (d, 1H, oi -ethyl proton), 7.43 (dd, 1H, C-5-pyridyl proton), 7, 60 (bs, 2H, C-2 and C-5-Fensh protons), 7.72 (d, 1H, p-ethenyl proton), 8.11 (dd, 1H, C-4-pyridyl proton), 8 , 50 (dd, 1H, C-6-pyridyl proton), 8.83 (d, 1H, C-2-pyridyl proton),
    EXAMPLE 9 2-G4-AminophenylZ-7-trans-2 (3-pyridyl) -ethenyl-5H-1,3, 4-thiadiazolo (3,2-a) pyrimidin-5-one ( 1.9 g) are reacted with acetic anhydride (4 ml) and 4 ml of pyridine in dimethylformamide (25 ml) at 140 ° C for 13 hours. After dilution with ice water, a precipitate is obtained which is filtered and washed with water. As a result of crystallization from a mixture of dimethylformamide - ethanol, 0.85 g of 2- (4-azithylaminophenyl-7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3.2 -a) pyrimi-DIN-5-OH, Top 380-383 ° C.
    I'll try it on. 7-trans- 2- (4-hydroxy-phenyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one (1 g) is reacted with acetic anhydride (2 ml) in pyridine (4 ml) at room temperature for 20 hours. After dilution with ice water, a precipitate is obtained, which is filtered and washed with water; after crystallization from methanol, 0.78 g of 7-trans-2- (4-acetoxyphenyl-ethenyl-5H-1,3,4-β-thiadiazolo (3,2-a) pyrimidin-5-one) is obtained, m.p. 249-251 ° C.
    I ..
    Similarly, 2- 3-acetoxyphenyl-7-trans-f2- (3-pyridyl) -ethenyl-511-1, 3,4-thiadiazolo (3, 2-a) pyrimidin-5-one and (- (- acetoxyphenyl-7-trans-2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3,2-a) pyrimi-DIN-5-OH.
    91
    Example 11. 2-Phenyl-7-trans- - 2- (3-pyridyl) -ethenyl 5H-1,3, D-tia-diazolo (3,2-a) pyrimidine-5-one (2 g) is dissolved in dioxane (200 ml) and about- / worked out with a stoichiometric amount of gaseous HC1 at room temperature. The precipitate is filtered off and washed with dioxane, resulting in 1.9 g of 2-phenyl-7-trans-2- (3-pyridyl) -ethenyl-5H-1.3 4-thiadiazolo (3,2-a) pyrimidine 5-on-hydrochloride, mp 260 ° C (with decomposition).
    In a similar way, hydrochlorides of the compounds obtained in examples 1-10 are obtained.

    Biological tests of thiazolo- (3,2-a) pyrimidic derivatives
    on.
    The anti-ulcer activity of the compounds obtained by the described method is confirmed by the fact that they are active in the test of inhibition of moderate ulcers in rats according to the Bonfils method.
    Male Sprague-Dawley rats (100-120 g) were not fed for 24 hours and then a flexible wire mesh with small square cells was used to immobilize them. 4 hours after immobilization, the rats were killed, their stomachs were removed and the affected areas were examined using a dissecting microscope. Test compounds were administered per os (oral) one hour after immobilization. Near

    the actual value of U. for antiulcer activity after oral administration of 2-phenyl-7-trans 2- (3-pyridyl) -ethenyl-5H-1,3,4-thiadiazolo (3, 2-a) -pyrimidin-5-it is 3 mg / kg
    The activity of the compounds in the treatment of ulcer disease, expressed as a ratio to the activity of the known compound 2, 3-dihydro-7- (3-pyridyl) -ti azolo (3,2-a) -pyrimidnn-5-one, taken as 1, is:
    2-Phenyl-7-trans 2- (3-pyridyl) zhenyl 3 5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one 13 2- (4-Methylphenyl) -7-trans-2 - - (3-pyridyl) -ethenyl-5H-1,3, 4-tnadiazolo (3,2-a) pyrimi-DIN-5-OH5
    2-Benzylthio-7-trans-2- (3-pyridyl) -ethenylZ-5H-1,3,410
    0
    d pH metres
    -thiadiazolo (3,2-a) pyrimi-DIN-5-OH, 7
    2- (4-Aminophenyl -) - 7-trans- (3-pyridyl) -ethenyl-5H- -1,3,4-thiadiazolo- (3,2-a) pyrimidin-5-one-5
    Thus, the compounds obtained by the proposed method show the best activity in the treatment of ulcer disease. These compounds also have antispecific activity in the treatment of diseases of the stomach - after administration to the duodenal ulcer they slow down gastric secretion 5 / in rats according to Shayet et al. Antisecretory activity in the treatment of gastric diseases is determined by the method of pyloric ligature in rats. Each group had 6 male Sprague-Dawley rats (110-130 g). 24 hours before the test, the rats stopped feeding, but left them with water to drink. On the day of surgery, the pylorus was transferred under light ether 5 anesthesia. Each compound was administered as an injection into the duodenum (i ,, d) during the ligature. Four hours after the ligature, the rats were killed, the gastric juice was collected, centrifuged at 3500 rpm for 10 minutes and the volume of sediment was determined. The amount of free hydrochloric acid in the gastric juice was determined by titration of 0.01 n, caustic soda to pH 7.0
     d pH metres
    One of the preferred compounds with antisecretory activity in the treatment of diseases of the same 40 of the vessels is 2- (4-methylphenyl) -7- -trans-2- (3-pyridyl) -ethenylZ-5H-1,3 4-thiadiazolo (3, 2-a) pyrimidine-5-one, EDdd 50 mg / kg.
    Compounds obtained by the proposed method also have an anti-inflammatory effect, which is confirmed after oral administration by slowing the formation of edema on the hind paw of rats in response to
    Q sub-plantar injection of carrageenin by the method of Winter et al., As well as the reverse passive Arthus phenomenon (RPAR) in the rat paw induced by the interaction of the antigen with the antibody, resulting in a precipitated immune complex followed by fixation of the complement and accumulation of the polymorph nuclear leukocytes at the focal point.
    The activity of the compounds in the treatment of edema caused by the administration of carrageenan is shown as related to the activity of the known compound 2,3-dihydro-7- (3-pyridyl) -thiazolo (3,2-a) pyrimidine-5-one , taken as 1, and is:
    7-Trans- (2-phenylethyl) -5H- -1,3,4-thiadiazolo (3,2-a) - -pyrimidin-5-on3,5
    7-trans-2- (4-fluorophenyl) -ethyl-5H-1,3,4-thia-diazolo (3,2-a) pyrimidin-5-on 6.5
    The data show that the compounds obtained by the proposed method have the best anti-inflammatory activity.
    These compounds also have analgesic activity, which was evaluated, for example, using the phenylquinone test in mice by the Sigmund method. The compounds can be used to treat inflammatory processes, such as rheumatoid arthritis and osteoarthritis, as analgesics.
    Due to their high therapeutic index, the compounds obtained by the proposed method can be safely used in medicine. For example, the acute toxicity () of the compound 7-trans- (2-phenylethenyl) -5P-1,3,4-ty-adiazolo is approximate. (3,2-a) pyrimidin-5-one, 2-methyl-7-trans- (2-phenylethenyl) -5H-1,3,4-β-thiadiazolo (3,2-a) pyrimidine-5- she, 7-trans-2- (2,6-dichlorophenyl) ethylene 1 -5H-1,3,4-thiadiazolo (3,2-a) pyrimidine-5-one, 7-trans-2- (3 -pyridyl) - -ethenyl) | -5H-1,3,4-thiadiazolo- (3,2-a) pyrimidin-5-one, 7-trans-2- (4-fluorophenyl) -ethenyl-5H- 1,3,4-thiadiazolo (3 2-a) pyrimidin-5-one, 2-phenyl-7-tra ns- 2- (3-pyridyl) -ethenylZ-5H-1,3,4-thiadiazolo (3, 2-a) pyrimidin-5-one and 2- (4-methylphenyl) -7-trans-2- ( 3-pyridyl) -ethenylP-5H-1,3,4-thiadiazolo (3,2-a) pyrimidin-5-one in mice, determined by simple administration of higher doses and measured on the seventh day after treatment, above 800 mg / kg (oral administration)
    Thus, the compounds obtained by the proposed method are low-toxic and have a higher antiulcer activity than 2, 3-dihydro-7- (3-pyridyl) -thiazolo (3, 2-a) -pyrimidin-5-one ,
    权利要求:
    Claims (2)
    [1]
    1. A method for producing 1,3,4-thiadiazolo derivatives (3,2-a) pyrimidine-5-α of the general formula
    ABOUT
    1 S T4 CH CH-R2
    where R, is hydrogen. C, -C-alkyl
    a group unsubstituted or substituted by a C, -C4 alkoxy group, phenyl, unsubstituted or substituted by a C, -C4 alkyl or amino group, or a benzylthio group; R is pyridyl
    or their pharmaceutically acceptable salts, characterized in that the compounds of the general formula II
    where R has the indicated meanings; Q is aryl;
    acid anion,
    is introduced into the reaction with pyridinecarboxaldehyde in an inert organic solvent in the presence of an alkaline condensing agent and, if necessary, converts the resulting compound of formula I into its pharmaceutically acceptable salt.
    [2]
    2. A process for the preparation of 1,3,4-thiadiazole (3,2-a) -pyrimidin-5-β-derivatives of general formula I
    0 BKL
    “All,
    1 S N CH CH-Eg
    R, is hydrogen. C, -C4-alkyl, unsubstituted or substituted by C, -C-alkoxy, phenyl, unsubstituted or substituted by C, -C-alkyl or amino group, or a benzylthio group; Rj-pyridyl
    their pharmaceutically acceptable, characterized in that the compounds of general formula III
    NM
    rally
    1 S XI
    S N CHO
    131321377 14
    where R) has the indicated meanings, where R, Q and are defined above are brought into interaction with the compound in an inert organic solvent of the formula IV in the presence of an alkaline cheschogenic, agent and, if necessary,
    R —CHij —P (Q) Y, 5 converts a compound of formula I into its
    pharmaceutically acceptable salt.
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    同族专利:
    公开号 | 公开日
    DK44383A|1983-08-05|
    NL8300304A|1983-09-01|
    DK44383D0|1983-02-03|
    FI830276A0|1983-01-26|
    US4537962A|1985-08-27|
    IT8319192D0|1983-01-20|
    BE895784A|1983-08-02|
    FR2520742B1|1985-12-13|
    IL67720A|1985-12-31|
    AU553266B2|1986-07-10|
    GB2114129B|1985-05-15|
    FR2520742A1|1983-08-05|
    FI830276L|1983-08-05|
    FI74472B|1987-10-30|
    SE8300580D0|1983-02-03|
    CH654581A5|1986-02-28|
    IT1193604B|1988-07-21|
    GB2114129A|1983-08-17|
    DE3303663A1|1983-08-11|
    FI74472C|1988-02-08|
    SE8300580L|1983-08-05|
    CA1211439A|1986-09-16|
    AU1058083A|1983-08-11|
    GB8302660D0|1983-03-02|
    IL67720D0|1983-05-15|
    JPS58134098A|1983-08-10|
    ZA83451B|1983-10-26|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPS5129981B2|1973-07-17|1976-08-28|
    JPS6233239B2|1979-02-28|1987-07-20|Teijin Ltd|
    US4310526A|1979-05-08|1982-01-12|Farmitalia Carlo Erba S.P.A.|Substituted 6,7-methylene pyrido[1,2-a]pyrimidines useful as anti-allergic and anti-ulcer agents|
    JPS5642989A|1979-09-18|1981-04-21|Mitsubishi Electric Corp|Centralized lillumination control system illumination|
    AT377586B|1981-06-30|1985-04-10|Erba Farmitalia|METHOD FOR PRODUCING SUBSTITUTED PYRROLO- -QUINAZOLINES AND PYRIDO -QUINAZOLINES|
    NL8202706A|1981-07-15|1983-02-01|Erba Farmitalia|SUBSTITUTED THIAZOLO3,2-APYRIMIDINES AND METHODS FOR PREPARING THE SAME|US4548938A|1981-07-15|1985-10-22|Janssen Pharmaceutica N.V.|5-H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one compounds|
    GB8300728D0|1983-01-12|1983-02-16|Erba Farmitalia|Substituted carboxy-thiazolo / 3 2 - a / pyrimidine derivatives|
    EP0238059B1|1986-03-19|1993-06-16|Kumiai Chemical Industry Co., Ltd.|5H-1,3,4-Thiazole[3,2-a]pyrimidin-5-one derivatives and fungicidal compositions containing the same|
    CA2706566A1|2007-12-18|2009-07-09|Glenmark Pharmaceuticals, S.A.|Chromane derivatives as trpv3 modulators|
    WO2009109987A2|2008-01-11|2009-09-11|Glenmark Pharmaceuticals, S.A.|Fused pyrimidine derivatives as trpv3 modulators|
    US8492568B2|2008-06-17|2013-07-23|Glenmark Pharamceuticals S.A.|Chromane derivatives as TRPV3 modulators|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8203238|1982-02-04|
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