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    • 专利摘要:
    The present invention relates to new carboxamido-derivatives of 5H-1,3,4-thiadiazolo[3,2-a]pyrimidines, to a process for their preparation and to pharmaceutical (i.e. anti-inflammatory and analgesic) compositions containing them. The invention provides compounds having the following general formula (I) <IMAGE> (1) wherein R1 represents: (a) a hydrogen or halogen atom or a C1-C6 alkyl group unsubstituted or substituted by C1-C6 alkoxy; (b) a <IMAGE> group, wherein n is zero, 1, 2 or 3 and each of R4 and R5 is, independently, hydrogen or C1-C6 alkyl, or R4 and R5, taken together with the nitrogen atom to which they are linked, form an unsubstituted N-pyrrolidinyl ring or a piperidino, morpholino, N-piperazinyl or <IMAGE> ring, wherein m is zero, 1 or 2, the piperidino and morpholino rings are unsubstituted or substituted by one or two C1-C6 alkyl groups and the N-piperazinyl ring is unsubstituted or substituted by a substituent chosen from C1-C6 alkyl, phenyl and pyridyl; (c) trihalomethyl or a R6-S(O)p- group, wherein p is zero, 1 or 2 and R6 is C1-C6 alkyl or benzyl, wherein the phenyl ring is unsubstituted or substituted by a substituent chosen from halogen, C1-C6 alkyl and C1-C6 alkoxy; or (d) an unsubstituted pyridyl, pyridyl-N-oxide or thienyl ring or a phenyl ring unsubstituted or substituted by one, two or three substituents independently chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, formyloxy, C2-C8 alkanoyloxy, nitro, amino, formylamino, C2-C8 alkanoylamino and di-(C1-C6) alkyl-amino; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents: (a') a phenyl ring, unsubstituted or substituted by one or two substituents independently chosen from C1-C6 alkyl, C1-C6 alkoxy and halogen; (b') an unsaturated heteromonocyclic or heterobicyclic ring, containing one or more heteroatoms chosen from nitrogen and sulphur, unsubstituted or substituted by one or two substituents independently chosen from halogen, C1-C6 alkyl and C1-C6 alkoxy; and the pharmaceutically acceptable salts thereof.
    公开号:SU1297731A3
    申请号:SU833682101
    申请日:1983-12-22
    公开日:1987-03-15
    发明作者:Дориа Джанфедерико；Пассаротти Карло；Буттинони Ада
    申请人:Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing carboxamide derivatives of thiadiazolor, 2 and pyrimidine or their pharmaceutically acceptable salts - new biologically active, 1x compounds that can find npi-change in medicine.
    The purpose of the invention is a method of producing new pyrimidine thiadiazolo derivatives of 3.2 a, which have a higher anti-inflammatory activity and low toxicity. Example. At a boiling point under reflux for 23 hours, the reaction is carried out with 2-amine no-) 3A-thiadiazole A (5 g) with diethyl ethoxymethylenemalonate (26.5 g) in ethanol (20 ml). After cooling, the precipitate was filtered off and purified with hexane to give diethyl N- (l, 3.4 thiadiazol-2-yl) aminomethylenemalonate, m.p. 107-111 C (10 g), which is treated with polyphosphoric acid (57.6 g, 30.8 g, 99% and 26.6 g) and POC1 (25 g) with stirring at 120 ° C for 30 minutes.
    After cooling the reaction mixture, it is diluted with ice-water and then the solution is neutralized with 35% sodium hydroxide, the precipitate is filtered and washed with water, and 5-oCO75H-1,3,4-thiadiazole is obtained, 2-a pyri-M1 - 6-carboxylic acid ethyl ester with m.p., 228-230 C (5.75 g) and the compound is reacted with 2-amino-pyridine (4.9 g) in polyphosphoric acid (57.5 g, 31 g 99% K PO and 26.5 g P, j, 0j.) with stirring and 120 ° C for 12 hours. After cooling, diluting with ice water and neutralizing with 35% sodium hydroxide and residue; filtered and washed crystallized from chloroform-methanol to give 3.3 g (24.5%) of 5-oxo-5H-1,3,4 tiadiazolo, 2-a pyrimidine-6-K- (2-pi - Ridyl) -carboxamide with so pl. 240 - 245 s (with decomposition).
    G1P (dimethyl sulfoxide d6 / (h / ml 7.15 multiplet, 1H, C-5 pyridyl proton); 7.84 (doublet, 1H, C-4, pyrvdyl proton); 8.15-8.40 (multiplet , 2H, C-3 and C-6 pyridyl protons); 8.92 (singlet, 1H, C-7 prton); 9.57 (singlet, 1H, C-2 proton In a similar way and with similar yields were obtained the following compounds :.

    l:
    2977312
    2-methyl-5-oxo-5H-1,3,4-thiadiazolo 3,2-a pyrimidine-6-N- (2-pyri-, dil) -carboxamide, m.p. 23-233 ° C;
    2-ETHYL-5-OXO-5H-1,3,4-thiadiazo-5, 2-a pyrimidine-6-N- (2-pyridyl) -carboxamide, m.p. 247-248 ° C;
    2-methoxymethyl-5-oxo-5H-1,3,4-β-thiadiazo 3,2-a pyrimidine-6-K- - (2-pyridyl) -carboxamide, m.p. 21810
    f5
    20
    25
    thirty
    35
    40
    45
    50
    55
    (27.8 g) in dc at 120 ° C at a temperature of 22 ° C.
    Example 2: 2-amino-5- (3-pyridyl) -1,3,4-thiadiazole (10 g) is reacted with diethyl ethoxymethylene malonate (18 g) under stirring conditions. after 9 hours. After cooling, the reaction mixture is crystallized from a mixture of methylene chloride and isopropyl ether to obtain diethyl-H- (5- (3-pyridyl) -1,. 3,4-thiadiazol-2-yl) -amino-methylene- malonate, mp, 144-145 0 (15.8 g), which is treated with polyphosphoric acid (6.6 g: 3.5 g, 99% and 3.1 g) and POC. catch shuffle 40 min.
    After cooling, the reaction mixture is diluted with ice water and then the solution is neutralized with 35% sodium hydroxide. The precipitate is filtered off and washed with water: crystallization from a mixture of methylene chloride - isopropyl alcohol results in 2- (3-pyridyl) 5-oxo-5H-1,3,4-thiadiazolo (3,2-a) pyrimidine 6-carboxylic acid, ethyl ester, m.p. 200-202 C (6.6 g). This ester is then reacted with 2-amino-pyridine (10.02 g) in polyphosphoric acid (330 g: 176 g 99% and 154 g P, jOj) with stirring and 120 ° C for 7 hours. After cooling, dilution with ice water and neutralization with 35% sodium hydroxide, the precipitate is filtered and washed with water: crystallization from a mixture of methylene-methanol chlorides gives 5.3 g (27%) of 2- (3-pyridyl) -5-OXO- 5H-1,3,4-thiadiazo olo, 2-aj pyrimidine-6-N- (2-pyridsh1) -carboxamide, m.p. 274-277 ° C,
    NMR (CDCl + CF COOD / ppm: 7.75 (multiplet, 2H, C-5 pyridyl C-5 pyridyl-amide protons); 8.45 (multiplet, 3N, C-4 pyridyl and C- 3 and C-4 pyridyl-amide protons); 9.20 (multiplet, 2H, C-6 pyridyl and C-6 pyridyl amide protons); 9.29 (singlet, W,
    C-7 proton); 9 | 67 (broad singlet, 1H, C-2 pyridyl protons).
    :,
    In a similar way and with similar yields, the following compounds were obtained:
    2-Morpholino-5-oxo-5H-1,3,4-thiadiazo 3,2-a pyrimidine-6-N- (2-pyridyl) -carboxamide, mp, 274-275 C, NMR (CDC1, + CF, COOD) 8 ppm: 3.4- 4.0 (multiplet, 8H, morpholinyl protons); 7.6 (multiplet, 2H, C-4 and C-5 pyridyl protons); 8.3-8.6 (multiplet, 2H, C-3 and C-6 pyridyl protons); 8.9 (singlet, 1H, C-7 proton);
    2- (4-pyridyl) -5-o.xo-5H-1,3,4-thia diaeolo 3,2-a pyrimidine-6-N- (2-pyridyl) -carboxamide, so pl. 279-280 ° C;
    2- (3-pyridyl) -5-oxo-5H-1,3,4-β-thiadiazolo (3, 2-a pyrimidine-6-N- (6- -methyl-2-pyridyl) -carboxamide, mp 305-307 ° C;
    2-MORFOLINO-5-OXO-5H-1,3,4-thiadiazolo, 2-a pyrimidine-6-N- (4,6-dimethyl -2-pyridsh1) -carboxamide, so pl.
    310-313 ° C;
    2-MORFOLINO-5-OXO-5H-1,3,4-thiadiazo 3,2-a pyrimidine-6-N- (b-methyl-2-pyridyl) -carboxamide, m.p. 274275 V,}
    2-MORFOLINO-5-OXO-5H-1,3,4-thiadiazo 3,2-a-pyrimidine-6-N- (5-methyl-2-pyridine-carboxamide, mp 301-303 ° WITH;
    2- (pyrrolidin-1-Sh1) -5-oxo-5H- -1,3,4-thiadiaeolo b, 2-a-pyrimidine-6-N-pyridyl) -carboxamide, m.p. 302-304 ° C}
     2-piperidino-5-oxo-5H -}, 3,4-thiadiazolo, 2-ci pyrimidine-6-N- (2-pyridyl) -carboxamide, m.p. 242-244 ° C;
    2- (4-methyl-piperazin-1-yl) -5-ok, —CO-5H-1,3,4-thiadiazole, 2-a-pyrimi din-6-N- (2-pyridyl) -carboxamide m.p. 220-221 ° C;
    5-OXO-5H-1,3,4-thiadiazolo 3,2-aJ pyrimndin-N- (6-methyl-2-pyridyl) -carboxamide, m.p. 258-268 C (decomposition). I.
    Example 3: Conducted Reaction
    2-amino-5-morpholino-1,3,4-thiadiazole (6.25 g) with diethyloxymethylenemalonate (9 g) under stirring conditions at 120 ° C for 4 hours. After cooling, the crude product diestil-K - (5-morpholino-1,3,4-thiadiazol-2-yl) amino methylenemalonate is treated with polyphosphoric acid (5 g: 2.6 g 99% H, P04 and 2.4 g) and POClj (20 , 5 g)
    d
    five
    0
    five
    -
    ,
    with stirring and 120 ° C for 30 minutes.
    After cooling, the reaction mixture is diluted with ice-water and then the solution is neutralized with 35% sodium hydroxide. The precipitate is filtered off and washed with water: crystallization of 1THIUM from a mixture of methylene chloride - iso-propyl ether results in 2-MORFOLIN-5-OXO-5H-, 3,4-thiadiazole, 2-a3 pyrimidine-6-carboxylic acid, ethyl ester with so pl. 2 7-219 ° C (8 g). Then, this compound is reacted with 2-aminothiol (5.2 g) in polyphosphoric acid (120 g: 64 g 99% H, P04 and 56 g) with stirring and 110 ° C for 30 h. After cooling dilution water with ice and neutralization with 35% sodium hydroxide, the precipitate is filtered and washed with water: crystallization from a mixture of methylene chloride - ethanol results in 5 g (41%) of 2-morpholino-5-ok CO-5H-1,3,4- thiadiazolo b, 2-a} pyrimidine-6-N- (2-thiazolchI) -carbox with a m.p. 274-276 ° C.
    HItP (CDC1, + CF, COOD) 6 ppm: 3.58 (multiplet, 4H, C-3 and C-5 morpholinyl protons); 3.85 (multiplet, 4H, C-2, and C-5 morfolInil protons); 6.69 (doublet, 1H, C-5 thiazolyl proton); 7.75 (doublet, 1H, C-4 thiazole proton); 8.94 (singlet, 1H, C-7 proton). . In a similar way and with similar yields, the following compounds were obtained:
    5-OXO-5H-1,3,4-thiadiazolo 3,2-a pyrimidine-6-N- (4-methyl-2- -thiazolyl) -5kboxamide, m.p. 230-240 s (decomposition);
    5-OXO-5H-1,3,4-thiadiazolo Gz, pyrimidine-6-N- (2-thiazolyl) -carboxamide, m.p. 230-240 ° C (decomposition);
    5-OXO-5H-1,3,4-thiadiazolo of 3,2-a3-pyrimidine-6-K- (2-benzothiazolyl) -carboxes III, melting point 162-164 ° C;
    2-methyl-5-oxo-5H-1,3,4-thiadiazole, 2-a pyrimidine-6-N- (2-thiazolyl) -carboxyamide, m.p. 246-249 ° C;
    2- (3-pyridyl) -5-oxo-5H-1,3,4-β-thiadiazolo, 2-a pyrimidine-6-N- (2- -thiazolyl) carboxamide, m.p. 322- 326 ° C;
    2- (4-pyridium Yp) -5-OXO-5H-1,3,4-thiadiazolo Cz, 2-a pyrimidine-6-N- (2-thia t zolyl) -carboxamide, so pl. 310-316 C;
    2-ETHYL-5-OXO-5H-1,3,4-thiadiazolo 3 |, 2-aZpyrimidine 6-K- (2-thiazolyl) -carboxamide, so pl. 239-241 ° C;
    2- (D-pyridyl) -5-OXO-5P 1,3,4-β-thiadiaelo 3,2-aJ pyrimidine-6-N- (4- -methyl-2-thiazolyl) -carboxamide, mp. 276-279 C;
    2- (4-pyridine) -5-OXO-5H-1,3,4--thiadiazolo, 2-pyrimidine-6-N- (4,5-dimethyl-2-thiazolyl) -carboxamide, T.Sh1 . 330-332 ° C;
    2- (4-pyridyl) -5-OXO-5H-1,3,4-thiadiazolo 3,2-a pyrimidine-6-N- (2- -benzothiazolyl) -carboxamide, mp 333–337 ° WITH;
    2-MORFOLINO-5-OXO-5H-1,3,4-thiadiazolo, 2-aj pyrimidine-6-N (4-me-t {4l-2-thiazolyl) -carboxamide, tpl 259 -261 ° C;
    2-morpholino 5-oxo-5H-1,3,4-thiadiazolo, 2-a pyrimidine-6 H- (2-benzothiazolyl) -carbokeamide, m.p. 380-385 ° C (decomposition);
    2 morpholino-5-oxo-5H-1,3,4-thiadiazolo, 2-a pyrimidine-6-M- (4,5-di-
    methyl 2 thiazolyl) -carboxamide, so pl. 325-328 ° C;
    2-piperidino-5-oxo-5H-1,3,4-thiadiazolo, 2-a pyrimidine-5-N- (2-thiazolyl) -carboxamide, m.p. 249-250 ° C;
    2- (4-methyl-piperazin-1-yl) -5-ok-, 3,4-thiadiazolo, 2-a pyrimidine-6-L- (2-thiazolyl) -carboxamide, m.p. 264-266 ° C.
    Example 4: 2-Amino-5-morpholino-1,3,4-thiadiazole (5 g) was reacted with dizethyl (1-ethoxy-ethylidene) -malonate (6.2 g) in diglyme (40 ml) at 150 ° C for 20 hours. After cooling, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. After evaporation in vacuo to dryness, the residue is purified on a silica column using
    as an eluent, chloroform-45 is sodium oxide; the precipitate is filtered off
    methanol 98: 2. Crystallization from isopropyl ester gives 7-methyl-2-morpholino-5-oxo-5H--1,3,4-thiadiazolo 3,2-a pyrimidine-6-carboxylic acid, ethyl ester with mp. 196-198 C (2.6 g). Then, this compound is reacted with 2-amino-pyridine (2.25 g) in polyphosphoric acid (130 g) with stirring and 120 G for 4 hours. After cooling, diluting with water and ice and neutralizing with 35% sodium hydroxide, the precipitate is filtered and washed
    and washed with water until neutral.
    Crystallization from a mixture of methylene chloride - isopropyl ether gives 2- (2-methyl-morpholi- Q but) -5-oxo-5H-1,3,4-thiadiazolo 3, pyrimidine-6-carboxylic acid, ethyl ester, m.p. 189191 ° С (12.5 g). This compound is then reacted with 2-amino-55-pyridine (11.2 g) in polyphosphoric acid (625 g: 320 g of 99% and 305 g of PjOg) with stirring and for 120 s for 8 h. After cooling, diluting ice water and
    fO
    -
    -
    25
    297731. 6
    with water to obtain 1.9 g (19%) of 7-methyl-2-morpholino-5-oxo-5H 1,3,4-thiadiazolo, 2-a pyrmidine-6-N- (2-pyri -, Dil) -carboxamide with m.p. 285-287 s. 5 In the same way and with similar yields, the following compounds were obtained:
    7-methyl-2- (3-pyridyl) -5-oxo-5H- -1,3,4-thiadiazolo 3, 2-a J pyrimidine- (2-pyridyl) -carboxamide, m.p. 253-255 ° C;
    7-methyl-2- (4-pyridyl) -5-oxo-5H- -1,3,4-thiadiazolo 3,2-aJ pyrimidine-6-N- (2-pyridyl) -carboxamide, m.p. 255-256 ° C;
    7-methyl-2- (3-pyridyl) -5-oxo-5H- -1,3,4-thiadia. Solo 3,2-a pyrimidine- (2-thiazolyl) -carboxamide, m.p. 322-326 ° C;
    7-methyl-2- (4-pyridyl) -5-ОКСО-5Нf5
    20

    - thirty
    -1,3,4-thiadiazolo 3,2-a pyrimidine-6-N- (2-thiazolyl) -carboxamide, m.p. 275-277 ° C;
    7-met1-t-2-morpholino-5-oxo-5H- -1,3,4-thiadiazo 3,2-aj pyrimidine-6- -N- (2-thiazolyl) -carboxamide, m.p. 251-254 ° C.
    EXAMPLE 5 2-Amino-5- (2-methyl-morpholino) -1,3,4-β-thiadiazole (10 g) is reacted with diethyl-toxymethylene-malonate (11.3 g) at 120 s for 30 min. After cooling, the reaction mixture is crystallized from isopropyl ether to give di-JC ethyl-N-5- (2-methyl-morpholino) -1,3,4-β-thiadiazole-2-sh1-amino-methylene-maloonate with m. square 89-91 ° C (16.4 g), which is treated with polyphosphoric acid (6.9 g) and OClj (27.15 g) with stirring and 120 ° C for 30 minutes.
    After cooling, the reaction mixture is diluted with ice water and then the solution is neutralized with 35% hydro.
    sodium oxide; the precipitate is filtered off
    and washed with water until neutral.
    Crystallization from a mixture of methylene chloride - isopropyl ether gives 2- (2-methyl-morpholino) -5-oxo-5H-1,3,4-thiadiazolo 3, pyrimidine-6-carboxylic acid, ethyl ester, t .pl. 189191 ° С (12.5 g). This compound is then reacted with 2-amino-pyridine (11.2 g) in a polyphosphoric acid (625 g: 320 g of 99% and 305 g of PjOg) with stirring for 120 h for 8 hours. After cooling, diluting with water with ice and
    7
    neutralization with sodium hydroxide, the resulting solution is extracted with ethyl acetate.
    The organic phase is washed with water and then evaporated to dryness in vacuo: crystallization from a mixture of methylene chloride and methanol gives 7.6 (41%) g of 2- (2-methyl-morpholino) -5-oxo-5H-1.3, 4-thiadiazolo 3,2-a pyrimidine-6-N- (2-pyri-dyl) -carboxamide, m.p. 263-265 s, NMR (CDCi3 + CF, GOOD) S ppm: 1.33 (doublet, 3N, CH); 3.00-4.4 (multi plet, 7H, morpholine protons); 7.6 (multiplet, 2H, C-3 and C-5 pyridyl protons); 6.4 (multiplet, 2H, C-2 and C-6 pyridyl protons), 9.0 (singlet, 1H, C-7 protons).
    In a similar way and with the same yield, the compound was obtained:
    2- (cis-2,6-dimethyl-morpholino) -5-OXO-5H-1,3,4-thiadiazole, 2-aJ pyrimidine-6-N- (2-pyridyl) -carboxamide, t .pl. 272-273 ° C.
    NMR SOSTS + СЬ COOD) 8 ppm: 1.26 (doublet, 611, two CH); 2.95 (multiplet, 2H, C-3 and C-5 morpholinyl axial protons); 3.70 (multiplet, 4H, C-3 and C-5 morpholinyl equatorial protons, C-2 and C-6 morpholinyl equatorial protons); 7.46 (double doublet, IH, C-5 pyridyl proton); 8.0-8.4 (multiplet, 2H, C-3 and C-4 pyridyl protons); 8.60 (wide doublet, 1H, C-6 pyridyl proton); 8.82 (singlet, W, C-7 pro. Tone); 12.45 (broad singlet, 1H, -CONH-).
    Example 6. 5-OXO-5H-1,3,4-β-thiadiazole, 2-a pyrimidine-6-N- (2-pyridyl) -carboxamide (2 g) prepared in Example I suspended in a hot dioxane (500 ml), with stirring, is treated with a slight excess of gaseous hydrogen chloride dissolved in dioxane for 1 hour. After cooling, the precipitate is filtered and washed with dioxane to obtain 2.1 g (93%) of 5-OXO-5H-1.3, 4-thiadiazolo, 2-a pyrimidine-6-N- (2-pyridine) -carboxamide, hydrochloride, mp, 300 ° C (decomposition), 93% yield.
    EXAMPLE 7 Ethyl ester of 5-OXO-5H-1,3,4-thiadiazole, 2 pyrimidine-6-carboxylic acid (2.4 g) reacts in xylene (250 ml at reflux with 2- aminopyridine (2.82 g), introduced
    977318
    NfbiM in portions over
    ) 8 hours, so that the solvent is slowly distilled off.) After cooling, the precipitate is filtered 5. and rinsed with isopropyl ether, crystallized from chloroform-ethanol and as a result, 1.7 (63%) g of 5-oxo-5H-, 3,4-β-thiadiazole 3, -2-a-pyrimidine-6- N- (2-O-pyridyl) -carboxamide with so pl. 240-.
    Carrying out the process in the same way, the following compounds are obtained with the same yields: 2- (3-pyridyl) -5-oxo-5H-, 3,4-β-thiadiazole, 2-a pyrimidine-6-N-2-pyridyl - carboxam 1ad, so pl. 274-277 ° C;
    2-MORFOLINO-5-OXO-5H-1,3,4-thia-20 diazole, 2-a pyrimidine-6-N- (2-pyridyl) -carboxamide, m.p. 274-275 C;
    . 2-MORFOLINO-5-OXO-5H-1,3,4-thia diazole, 2-a pyrimidine-6-N- (2-thiazolyl) -carboxamide, m.p. 274-276 C; 2-morpholinr-5-oxo-5H-1,3,4-thia25
    diazole 3) 2-a pyrimidine-6-N- (6-methyl-2-pyridyl) -carboxamide, m.p. 274-275 ° C;
    5-OXO-5H-1,3,4-thiadiazole h, -aJ-30 pyrimidine-6-N- (2-thiazole1) -carboxamide, m.p. 230-240 ° С (with decomposition).
    Similar to cnoco6oNf and c. the following compounds were obtained in similar yields:
    2- (3-pnridsh1) -5 oxo-5H-1,3,4-β-thiadiazolo, 2-a pyrimidine-6-N- - (2-pyridyl) -carboxamide, hydrochloride, m.p. 270 ° C (decomposition); 40 2-MORFOLINO-5-OXO-5N-1,3,4-thiadiazole h, 2-aj | pyrimidine-6-N- (2-pyridyl) -carboxamide, hydrochloride, so pl. 300 ° C.
    Biological tests of the carboxamido derivatives of thiadiazolo s, 2-a | pyrimidine, obtained by the proposed method, were carried out.
    The proposed compounds have anti-inflammatory activity 50, in particular, are active after oral administration, in inhibiting after: A) the formation of edema on the hindpaw, in response to a subplantar injection of carrageenan, according to method 55 of Winter, B) the reversible passive Arthus / RPAR reaction / in the rat paw caused by the interaction of the antigen and the antibody produced during the formation of the precipitated immunocom13
    ash 3,2-a pyrimidine-6- -N (2-pyridyl) -carboxamide; CE 23454: 2-ethyl-5-oxo-5K-1,3,4 thiadiazole, .- a | pyrmium-5. din-6-N- (2-pyridyl) -carboxamide;
    CE 23369: 2- (4-pyridsh1) -5-ocean-5H- -1,3,4-thiazolol 3, pyrimidine-6-N- (2 pyridyl) -fO -carboxamide;
    CE 23606: 2- (3-methylmorpholino) -5- -ОКСО-5H-1,3,4-thiadiazo Gz, 2-a pyrimidine-6-N- - (2-pyridyl) -carbox scramide {f5 CE 23607 : 2- (3,5-Dimethylmorpholino) -5-OXO-5H-1,3,4-thiadiazolo 3, 2-aZpyrimidine-6-N- (2-pyridyl) -carboxam.amide; .20
    CE 23804: 7-methyl-2- (3-pyridyl) 5- -okco-5H-1, 3,4-thiadiazo Gz, 2-aCIIyrimidin-6-N- - (2-pyridyl) -carboxamide; CE 22978: 5- oxo-5H-1,3,4-thiadia-25 sol Gz, 2-a pyrimidine-6- -15- (2-thiazolyl) - carboxamide; CE 23144: 2-piperidino-5-oxo-5H-:
    -1,3,4-thiadiazolo 3, zo-pyrimidine-6-1T- (2-thiazolyl) -carboxamide;
    FCE 23153: 2-morpholino-5-oxo-5H-1, 3,4-thiadiazolo 3, pyrimidine-6-H- (2-thiazo-, lsh1) -carboksa1 id}
    FCE 23433: 2-methyl-5-oxo-51Y "3,4-β-thiazole 3,2-α-pyrimidine-6-H- (2-thiazolyl) -carboxamide; 40
    FCE 23459: 2- (4-pyridyl) -5-oxo-5H-1, 3,4-thiadiazole 3, 2-a} pyrimidine-6-N- (2-tiisolyl) -carboxamide;
    FCE 23641: 2- (4-metsh1piperazin-1-45-ip) -5-OXO-5H-I, 3,4-thiadiazolo G, 2-a pyrimidine-6-N- (2-thiazolyl) -carboxamide;
    FCK 23803: 7-methyl-2-morpholino-5-about-50 CO-5H-1,3,4-thiadiazole 3,2-aZ pyrimidine-6-N- (2- -thiazolyl) -carboxamide;
    FCE 23225: 5-oxo-5H-thiadiazolo
    Gz, 2-a pyrimidine-6 HH- (2-55 -benzothiazolyl) -carboxamide;
    FCE 23446: 5-oxo-5H-thiadiazolo
    3,2-a pyrimidine-6-N- (65 fO
    f5 20
    25
    zo
     ,
    40

    -methyl-2-pyridyl) -carboxamide;
    FCE 23456: 2- (3-pyridyl) -5-oxo-5H-thiadiazolo 3,2-a pyrimidine-6-N- (6-methyl-2-pyridyl) carboxamide; FCE 23566: 2-msrfolino-5-oxo-5H-thiadiazo 3,2-a pyrimidine-6-N- (4-methyl-2-thiazolyl) -carboxamide; FCE 23614: 2-morpholino-5-oxo-5H-thiadiazolo 3,2-a pyrimidine-6-N- (4,6-dimesh1-2-pyridyl) -carboxamide; FCE 23642: 2-morpholino-5-oxo-5H-thiadiazole, 2 and pyrimidine-6-N- (6-methyl-2-pyridyl) carboxamide;
    Co-2- (3-pyridyl) -5-oxo-5H-, D.J-thiadiazole | 3,2-a pyrimidine-6-carboxylic acid, ethyl ester,
    The tests performed show that the compounds of the general formula obtained under the conditions of the proposed method have a higher anti-inflammatory activity than the known compounds - analogues in structure and action. In addition, from the point of view of their therapeutic index and toxicity, they can be safely used in medicine,
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing carboxamido derivatives of thiadiazolo jjj, 2-a pyrimidine of the general formula
    ABOUT
    .
    where R, is hydrogen or C, -C4-alkyl, unsubstituted or substituted by C, -04 is an alkoxy group, N-pyrrolidinyl, piperidium-morpholino, unsubstituted or substituted by one or two C -C-alkyl groups, or K-pi - perazinip, substituted C, -Od-alkyl, pyridyl, Ry - hydrogen or C -C4-al-
    kil
    - R thiazolyl, unsubstituted or substituted with C, -C4-alkyl, pyridyl unsubstituted or substituted with C, kilo, or benzothiazolyl, or their pharmaceutically acceptable salts, distinguished by that.
    15129773116
    that the chemical interlock is at a temperature of 110 to 120 ° C
    the action of a compound of the formula or in xylene at its temperature ki
    Penny the target product is in the
    . m p. in free form or in the form of its pharmaceutical t lf 5 of all acceptable salts.
    oh x
    1 about ISi XPriority based on:
    where RI and Rj have the indicated values, 23.12,82 with R, are all indicated in the forR — C —C-alkoxycarbonyl, the mule values of R, besides the morpholino
    with an amine of the formula .tO groups substituted by one or two
     With alkyl groups C, -C; d. 11, .83 with R, is a morpholino group,
    where R, has the indicated value, substituted by one or two alkyls when heated in full-phosphorus kin-C, -C groups.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1297731A3|1987-03-15|Method for producing carboxamido-derivatives of thiadiazolo /3,2-a/ pyrimidine or pharmaceutically acceptable salts thereof
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    AU651353B2|1994-07-21|Pyrazolopyridine compound and processes for preparation thereof
    RU2100357C1|1997-12-27|Heteroarylamines or their pharmaceutically acceptable salts and pharmaceutical composition based on thereof
    EP0154190A1|1985-09-11|Pyridones
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    GB2132200A|1984-07-04|Carboxamido-derivatives of 5H-1,3,4-thiadiazolo[3,2-a]-pyrimidines and process for their preparation
    同族专利:
    公开号 | 公开日
    GR79479B|1984-10-30|
    CH657136A5|1986-08-15|
    IT1194521B|1988-09-22|
    SE8307133L|1984-06-24|
    AU558600B2|1987-02-05|
    DK593983D0|1983-12-22|
    AT385036B|1988-02-10|
    FR2538392A1|1984-06-29|
    AU2252583A|1984-06-28|
    FR2538392B1|1987-01-16|
    FI834698A|1984-06-24|
    DE3346223A1|1984-06-28|
    ATA438383A|1987-07-15|
    SE8307133D0|1983-12-22|
    DK593983A|1984-06-24|
    SE454698B|1988-05-24|
    IL70522A|1986-02-28|
    FI834698A0|1983-12-20|
    IT8324207D0|1983-12-16|
    NL8304340A|1984-07-16|
    US4522944A|1985-06-11|
    CA1211440A|1986-09-16|
    IL70522D0|1984-03-30|
    引用文献:
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    JPS5129981B2|1973-07-17|1976-08-28|
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    WO2017172811A1|2016-03-28|2017-10-05|Intra-Cellular Therapies, Inc.|Novel co-crystals|
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    US10961245B2|2016-12-29|2021-03-30|Intra-Cellular Therapies, Inc.|Substituted heterocycle fused gamma-carbolines for treatment of central nervous system disorders|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8236642|1982-12-23|
    GB838329746A|GB8329746D0|1983-11-08|1983-11-08|Carboxamido-derivatives|
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