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    • 专利摘要:
    Compounds of general formula (I) <IMAGE> (I) wherein R1 is a 2-pyridyl, 3-pyridyl or 4-pyridyl group; (b) a phenyl ring, unsubstituted or substituted by one or two groups chosen from halogen, trihalo-C1-C4 alkyl, C1-C6 alkyl, nitro, amino and C2-C6 alkanoylamino; (c) benzyl; or (d) C1-C6 alkyl; each of R2 and R3 independently is a hydrogen or a halogen atom or C1-C6 alkyl; R4 is hydrogen, C1-C6 alkyl or phenyl; R5 is (a') <IMAGE> wherein each of R6 and R7 independently is hydrogen or C1-C6 alkyl, or R6 and R7, taken together with the nitrogen atom to which they are linked, form a morpholino, piperidino, N-pyrrolidinyl or N-piperazinyl ring, wherein the N-piperazinyl ring is unsubstituted or substituted by C1-C6 alkyl; (b') a <IMAGE> wherein R8 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy or halogen; (c') -NHR9, wherein R9 is a 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyrazolyl, 2-thiazolyl or 2-benzothiazolyl group, each of these groups being unsubstituted or substituted by one or two groups chosen from halogen, C1-C6 alkyl, phenyl, hydroxy and C1-C6 alkoxy; (d') <IMAGE> wherein m is 1, 2 or 3 and R6 and R7 are as defined above; or the pharmaceutically acceptable salts thereof; are disclosed as anti-inflammatory agents.
    公开号:SU1366060A3
    申请号:SU833565748
    申请日:1983-03-15
    公开日:1988-01-07
    发明作者:Dzhanfederiko Doria；Karlo Passarotti；Ada Buttinoni
    申请人:Erba Farmitalia；
    IPC主号:
    专利说明:

    The invention relates to substituted heterocyclic systems, in particular the production of substituted 1H-pyrazolo
    G1,5-a] pyrimidines (ZP) of the general formula (I)
    - ^ - С (0) -С-СЮ) -Б (5
    where K ] is phenyl (non- or substituted by halogen or ΝΗ 2 ), C, -C is alkyl or pyridyl; E 2 is H or halo; K 3 -K 4 N, C g -C 4 -alkyl; K 5 - OH; ΝΗ - C, -C 4 alkyl or ΝΗ- (MF 2 ) - piperidino; t = 1-3 or K 5 -MHK ς at K 6 thiazolyl, benzothiazolyl, pyridyl (not - or substituted by halogen or C, -C 4 -alkyl), moreover, when K 4 C 4 -C 4 -alkyl, K 5 It should not be HE, or their salts, which as anti-inflammatory drugs can be used in medicine. The goal is to create more active substances of the specified class. Their synthesis is carried out by cyclization of compounds of general Formula (II)
    Νι _Ν-ΝΗ К 5 С-С-С (О) К 7
    E5gS = CB g -C = C — C – B 4
    where.K 7 -K 5 indicated above; K 7 - hydroxyl, C 7 -C ^ alkoxy group, using polyphosphoric acid in the presence of phosphorus oxychloride at a temperature of from 120 ° C to boiling point
    the following selection of the target product in free form or in salt form.
    In the case when K 5 - OH, the isolated product is treated with the amine HH ^ K ^, where it is indicated above, to release the compound, where Ku- ΝΗΚ 6 , or transfer the product (where K 5 - OH) to the acid halide, followed by treatment with the compound of the formula ( III) H 2 And-C 7 -C 4 -alkyl or ΝΗ (CH 2 ) ^ - piperidino, where m is indicated above, with the release of the corresponding product. Tests of new substances show their better anti-inflammatory activity than the known 1-methyl-7-oxo-1H, 711-pyrazolo [1,5-aZpyrimidine-6-carboxylic acid. 2 tab.
    5i „„ 1366060 a z
    one
    1366060
    2
    The invention relates to a method for producing new chemical compounds, namely, substituted 1H-pyrazolo E1,5-a] pyrimidines of the general formula
    where K 1 is pyridyl, (C 1 -C + ) -alkyl or phenyl, unsubstituted or substituted by halogen or amino group;
    H 2 - hydrogen or halogen;
    - hydrogen or (C p -C 4 ) -alkyl ;.
    H 4 - hydrogen or (C., - C 4 ) -alkyl;
    K $ is a hydroxy group, -ΝΗ- (C l -C 4 ) -alkyl, -ΝΗ- (CH 2 ) t is piperidino, where t = I, 2 or 3, or B 5 - -ΝΗΚ έ , where is thiazolyl, benzothiazolyl, pyridyl, unsubstituted or substituted by halogen or (C, -C ^ -alkyl, provided that B 5 is not hydroxy, if K, - (C-C 4 ) -alkyl,
    or their salts, which can be used in medicine as anti-inflammatory drugs.
    The aim of the invention is to develop a method of obtaining new substituted 1H-pyrazolo [1,5-a] pyrimidines, which have a higher anti-inflammatory activity compared with a structural analogue, which has the same type of activity.
    Example 1. 1-Phenyl-7-oxo-1H, 7H-pyrazolo E1,5-a 1 pyrimidine-6-carboxylic acid (BCE 21783).
    Stage 1. Preparation of starting diethyl-No - ({- phenylpyrazol-3-yl) -amine-methylmalonate.
    To 18 g of 1-phenyl-3-aminopyrazole (bp 90-91 ° C), 29.3 g of diethylethoxymethylenemalonate in 180 ml of anhydrous ethanol are added and refluxed for 15 hours. After cooling, the solution is evaporated under vacuum to dryness, The residue is dissolved in 200 ml of isopropyl ether and decolorized with activated charcoal. After precipitation with hexane, 31 g of diethyl-Ν- (1-phenylpyrazol-3-yl) aminomethyl enmalonate are obtained, m.p. 81-82 ° C.
    Stage 2, Obtaining the target product.
    31 g of the compound obtained in step 1 are reacted with 13 g
    polyphosphoric acid (6,1 G Py about 2 and
    6.9 g H 3 P0 4 ) and 57 g ROSP-s under stirring and boiling with a return chiller for 30 minutes. After cooling, the reaction mixture is diluted with ice water, and then the solution is decolorized with activated carbon, neutralized with 35% NaOH, the resulting precipitate is filtered off and washed with water. After washing with hexane, 24.2 g of ethyl 1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid are obtained,
    -μ m.p. 187-190 ° C, which is hydrolyzed by heating in a mixture of 37% HC1 and acetic acid (1.2 l) 1: 1 at reflux temperature for 4 hours. After cooling, the reaction mixture is neutralized to pH 6 35% - NaOH, the precipitate is filtered off and washed with water. Crystallization from isopropyl alcohol gives 9.7 g of 1-phenyl-7-oxo-1H,
    25 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid, m.p. 185-190 ° C (decomp.).
    NMR spectrum (DMSO-SC), £, ppm:
    6.94 (d.) (1H, C-3 proton).
    thirty
    Working by a similar technique, get ethyl esters, and after hydrolysis - acid:
    2-chloro-1-phenyl-7-1H, 7H-pyrazolo [1,5-a] pyrimidine-635 -carboxylic acid ethyl ester, m.p. 196 ° C;
    1- (4-nitrophenyl) -7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl ester, m.p. 240250 ° C;
    40 ethyl ester of 1- (4-fluorophenyl) -7-oxo-, 7H-pyrazolO [1,5-a] pyrimidine-6-carboxylic acid, m.p. 215220 ° C (decomp.);
    1 - (3-chlorophenyl) -745 -oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl ester, m.p. 200205 ° C;
    1- (4-chlorophenyl) -7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimyl 50 din-6-carboxylic acid ethyl ester, m.p. 181—183 ° C;
    1- (3-trifluoromethylphenyl) -7-cc-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl ester, m.p. 181 —
    55 '183 ° C;
    3-methyl-1-phenyl-7- ^ oxo-1H, 7H-pyrazolo [1,5-a]) pyrimidine-6-carboxylic acid ethyl ester, m.p. 182—
    185 ° C;
    1366060
    four
    2-methyl-1-phenyl-7'-oxo-1H, 7H-pyrazolo G1,5-a] pyrimidine-6-carboxylic acid ethyl ester, mp. 160163 ° C;
    3-bromo-1-phenyl-7-oxo-ΙΗ, 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl ester, m.p. 185187 ° С;
    1- (4-methylphenyl) -7-oxo-1H, 7H-pyrazolo C1,5-a] pyrimidine-6-carboxylic acid, mp. 185–188 ° 0.
    PRI mme R 2. Using the method of example 1, receive the following compounds with the same output:
    1-phenyl-7-oxo-1H, 7H-pyrazolo C, 5-a] pyrimidine-b-N-methyl-carboxamide (UCE 21859), m.p. 244-246 ° C, data analysis of the NMR spectrum (SBS1 3 ),
    And ppm: 2,92 (d.) (ZN, -CH 3 ); 6.73
    (e.) (1H, C-3 proton); 7.37-7.75 (m) (5H, phenyl protons); 7.91 (d.) 1H, C-2 proton) ·, 8.70 (sh. S.)
    (1H, -YNCH 3 ); 9.10 (s) (1H, C-5 proton);
    1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-P-ethylcarboxamide, m.p. 225-230 ° C (decomp.);
    1-phenyl-7-oxo-1H, 7H-pyrazolo -
    S1,5-a] pyrimidine-6-P-isopropylcarboxamide, m.p. 220-225 ° C (decomp.);
    1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (3-pyridyl) -carboxamide, m.p. 207-21 ° C;
    1-phenyl-7-pkso-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (2-piperidino-ethyl) -carboxamide (ECE 22689), mp. 136-138 ° C;
    1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-P- (2-thiazolyl) -carboxamide (ECE 22367), mp. 245247 ° C (decomp.), NMR spectrum data (ATP1 5 ), cG, ppm: 6.72 (d) (1H,
    C-3 proton); 6.84 (d) (1H, C-5 thiazolyl proton); 7.4-7.7 (m.)
    (6H, phenyl protons and C-4 thiazolyl proton); 7.98 (d) (1H, C-2 proton); 9.45 (s) (1H, C-5 proton) 11.0 / w. s.) (1H, -SOY-);
    5-methyl-1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-N- (2-pyridyl) -carboxamide (ECE 22383), t; pl. 186-187 ° С, NMR spectrum analysis data (СРС1 d ), ppm: 2.88 (s) (ЗН,
    -CH e ); 6.62 (d) (1H, C-3 proton); 6.99 (m) (1H, C-5 pyridine proton); 7.38-7.50 (m) (5H, phenyl protons); 7.70 (dv. D.) (1H, C-4 pyridine proton); 7.82 (d) (1H,
    C-2 proton); 8.26 (dv. D.) (1H, C-3 pyridine proton); 8.34 (d.) (1H, C-6 pyridine proton); more than 10.5
    5 (w. S.) (1H, -0ΟΝΗ-);
    1-phenyl-7-oxo-1H, 7H-'pyrazolo ί1,5-a] pyrimidine-6-Ν- (5-chloro-2-pyridyl) -carboxamide, (ECE 22614), mp. 260 ° C (decomp.);
    10 1-phenyl-7-oxo-1H, 7H-pyrazolo [1, 5-a] pyrimidine-6-11- (5-methyl-2-pyridyl) -carboxamide, m.p. 268-270 ° C;
    1-phenyl-7-oxo-1H, 7H-pyrazolo I1,5-a] pyrimidine-6--(4-methyl-2-py15 Rydyl) -carboxamide, m.p. 210-215 C (decomp.);
    1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (6-methyl-2-piperidyl) -carboxamide, m.p. 235-240 ° С
    20 (decomp.); . .
    1-phenyl-7-oxo-1H, 7H-pyrazolo0.5-a] pyrimidine-6-Ν- (3-methyl-2-pyridyl) -carboxamide, m.p. 252-254 ° C;
    1-phenyl-7-oxo-1H, 7H-pyrazolo -
    25 0.5-a] pyrimidine-6-Η- (2-benzothiazolyl) -carboxamide (ECE 22386), mp. 245-250 ° C;
    1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (4-pyridyl) 30 -carboxamide, m.p. 270-275 ° C
    (different);
    1- (4-aminophenyl) -7-oxo-1H, 7H-pyrazolo 1,5-a pyrimidine-6-I- (2-pyridyl) -carboxamide (ECE 22791), mp.
    35,235-245 ° С (decomp.);
    1-methyl-7-oxo-1H, 7H-pyrazolo E1,5-a] pyrimidine-6-H- (5-bromo-2-pyridyl) -carboxamide, m.p. 255-260 ° C (decomp.).
    Example Obtaining the proposed compounds with Ν-substituted 6-carboxamide group.
    3 g of 1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid are reacted with 2.8 g of thionyl chloride in 70 ml of dioxane under reflux for 1 hour. Then the reaction mixture is evaporated to dryness in vacuo. The crude 6-chlorocarbonyl-1-phenyl-7-oxo-1H, 7H-pyrazolo (1,5-a] pyrimidine) is suspended in 60 ml of dioxane and reacted with 3.75 g of methylamine with stirring at room temperature for 30 minutes. The precipitate is filtered off and washed with water until neutral, crystallized from isopropyl alcohol to obtain 1.7 g of 1-phenyl-7-oxo-1H, 7H-pyrazolo G1.5-a] 1366060
    1H, C-3 proton); 7.37-7.75 (5H, phenyl protons); 7.91 (1H, C-2 proton); 8.70 (bhp) IHH 3 ); 9.10 (s) <1H, C-5 propyrimidine-6-P-methyl-carboxamide, so pl. 244-246 ° C, NMR spectrum (C0C1 3 ),
    8 1 ppm: 2.92 (d) (3N, -CH 3 ); 6.73
    (d.)
    (m.)
    (d.)
    (1H,
    tone), yield 54%.
    Using the same procedure, using the appropriate amines, the following compounds are obtained in the same way:
    1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6th-isopropyl-carboxamide, m.p. 220-225 ° C (decomp.);
    1-phenyl-7-oxo-1H, 7H-pyrazolo E1,5-a] pyrimidine-6-Ν- (3-pyridyl) -carboxamide, m.p. 207-210 ° 0.
    PRI me R 4. 1-Phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a '] pyrimidine-6-y- (2-piperidinoethyl) -carboxamide (ECE 22686).
    2.7 g of 6-chlorocarbonyl-1-phenyl-7-oxo-1H, 7H-pyrazole of 1,5-a] pyrimidine are reacted with 2.5 g of Ν- (2-aminoethyl) -piperidine in 55 ml of dioxane at room temperature. temperature for 30 min. After evaporation to dryness in vacuo, the reaction product is dissolved in chloroform and then purified on a column of silica, using
    as eluent CHC1
    and SZON 85:
    15.
    Crystallization from CH-isopropyl ether gives 2.1 g of 1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (2-piperidinoethyl ^ carboxamide (ECE 22686), t. Square 13b-138 ° С, yield 1.58%.
    Example 5. 1-Phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-y- (2-thiazolyl) -carboxamide (ECE 22367).
    5.1 g of 1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid are reacted with 4 g of 2-aminothiazole in 90 g of polyphosphoric acid (47.7 g H 3 PO 4 and 42.3 g P ^ 0 5 ) with stirring and 120 ° C for 20 h.
    After cooling, diluting with ice water and neutralizing with 35% PaOH, the precipitate is filtered off and washed with water. Crystallization from CHCl of methanol gives 4.5 g of 1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (2-thiazolyl) -carboxamide, mp. 245-247 ° C (decomp.), NMR spectrum (ATP1 3 ), ppm; 6.72 (d.)
    (1H, C-3 proton); 6.84 (d.) (1H, C-5 thiazolyl proton); 7.4-7.7 (m.)
    ten
    15
    20
    25
    thirty
    40
    55
    (6H, phenyl protons and C-4 thiazolyl proton); 7.98 (d) (CH, C-2 proton); 9.45 (s) (1H, C-5 proton); > 11 (bs) (1H, -SOYN-).
    By the same method, the following compounds are obtained:
    1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a) pyrimidine-6-L- (2-pyridyl) -carboxamide (ECE 21863), m.p. 207-210 ° C | (decomp.);
    5-methyl-1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (2-pyridyl) -carboxamide (ECE 22383), mp. 184-187 ° C;
    1-phenyl-7-oxo-1H, 7H-pyrazoloE1,5-a] pyrimidine-6--(5-chloro-2-pyridyl) -carboxamide (ECE 22614), mp. 260 ° C (decomp.);
    1-phenyl-7-oxo-1H, 7H-pyrazolo, 5-a] pyrimidine-6-y- (3-methyl-2-pyridyl) -carboxamide, m.p. 268-270 ° C;
    1-phenyl-7-oxo-1H, 7H-pyrazolo E1,5-a] pyrimidine-6-Ν- (4-methyl-2-pyridyl) -carboxamide, m.p. 210-215 ° C (decomp.);
    1-phenyl-7-oxo-1H, 7N.-pyrazolo [1,5-a] pyrimidine-6-Η- (6-methyl-2-pyridyl) -carboxamide, m.p. 235-240 ° C (decomp.);
    1-phenyl-7-oxo-1H, 7H-pyrazoloE1,5-a) pyrimidine-6-Ν- (3-methyl-2-pyridyl) -carboxamide, m.p. 252-254 ° C;
    1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6--(2-benzothiazo 35 lil) -carboxamide (ECE 22386), mp. 245-250 ° C;
    1-phenyl-7-oxo-1H, 7H-pyrazolo C1,5-a] pyrimidine-6-Ν- (4-pyridyl) -carboxamide, m.p. 270-275 ° C;
    1- (4-chlorophenyl) -7-oxo-1H, 7H-pyrazolo E1,5-a] pyrimidine-6-Ν- (2-pyridyl) -carboxamide (ECE 22662), mp. 254257 ° C;
    1- (4-fluorophenyl) -7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (2-pyridyl) -carboxamide, m.p. 202-210 ° C (decomp.);
    1- (3-chlorophenyl) -7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (2-pyridyl) -carboxamide, m.p. 284-286 ° C;
    3-methyl-1-phenyl-7-oxo-1H, 7H-pyrazolo {1,5-a] pyrimidine-6-Η- (2-pyridyl) -carboxamide (ECE 22666), mp.
    274-277 ° C;
    2-chloro-1-phenyl-7-oxo-1H, 7H-pirao olo [1,5-a] pyrimidine-6-Ν-ί · (2-pyridyl) -carboxamide (ECE 22672), so pl.
    275-278 ° C;
    45
    50
    , 1366060
    eight
    5-ethyl-1-phenyl-7-oxo-1H, 711-pyrazolo C 1,5-a] pyrimidine-6-N- (2-pyridyl) -carboxamide (ECE 23151), mp. 160-170 ° C (decomp.);
    1-methyl-7-oxo-1H, 711-pyrazolo-G1,5-a) pyrimidine-6--(2-pyridyl) -carboxamide (ECE 23081), m.p. 222226 ° C NMR Spectrum (SOS1 3 -CP 3 000ϋ), h / million: 4.71 (s.) (SH, CH 3); 6.97 (d) (1H, C-3 proton); 7.80 (m.)
    (2H, C-4 and C-5 pyridyl protons); 8.50 (m) (3N, C-2 proton, C-3 and C-6 pyridyl protons); 9.11 (s) (1H,
    C-5 proton);
    1.5-dimethyl-7-oxo-1H, 7H-pyrazolo ~
    S1,5-a] pyrimidine-6-Ν- (2-pyridyl) -carboxamide, m.p. 212-214 ° C;
    1-methyl-7-oxo-1H, 7H-pyrazolo—
    £ 1,5-a] pyrimidine-6-Ν- (5-chloro-2-pyridyl) -carboxamide, m.p. 270-293 ° C (decomp.);
    1-methyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-H- (6-methyl-2-pi '· ridyl) -carboxamide (ECE 23227), mp. 225-227 ° C;
    1.5-dimethyl-7-oxo-1H, 7H-pyrazolo 11,5-a] pyrimidine-6--(5-chloro-2-pyridyl) -carboxamide, m.p. 256-259 ° C;
    1.5-dimethyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-M- (b-methyl ~ 2-pyridyl) -carboxamide, m.p. 220-221 ° C;
    1-methyl-7-oxo-1H, 7H-pyrazolo, C1,5-a] pyrimidine-6-Η- (2-thiazolyl) -carboxamide, m.p. 265-268 ° C (decomp.)
    1-methyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-L- (2-benzothiazolyl) -carboxamide, m.p. 293-298 ° C (decomp.);
    1,5-dimethyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-L- (2-thiazolyl) -carboxamide, m.p. 243-245 ° C;
    1- (2-pyridyl) -7-oxo-1H, 7H-pyrazolo £ 1,5-a] lirimidine-6-P- (2-pyridyl) -carboxamide, m.p. 202-204 ° C;
    1- (2-pyridyl) -7-oxo-1H, 7H-pyrazo-45o [1,5-a] pyrimidine-6-P- (2-thiazolyl). Carboxamide, m.p. 218-220 ° C;
    1- (2-pyridyl) -7-oxo-1H, 7H-pyrazolo G1,5-a) pyrimidine-6-Ν- (6-methyl-2-pyridyl) -carboxamide, m.p. 212214 ° C;
    1- (3-pyridyl) -7-oxo-1H, 7H-pyrazolo [1,5-a) pyrimidine-6-Ν- (2-pyridyl) -carboxamide (ECE 22260), mp. 29110
    15
    20
    25
    thirty
    35
    40
    293 ° C (decomp.);
    5-methyl-1- (2-pyridyl) -7-oxo-1H,
    7H-pyrazolo £ 1,5-a] pyrimidine-6-And- (2-pyridyl) -carboxamide, m.p. 183— 187 ° C (decomp.);
    5-methyl-1 - (2-pyridyl) -7-oxo-1H,
    "7H-pyrazolo C1,5-a) pyrimidine-6-Ν- (2-thiazolyl) -carboxamide, mp 235240 ° C;
    1- (2-pyridyl) -7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (5-chloro-2-pyridyl) -carboxamide, mp 292294 P C ( different);
    1-methyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-L- (5-bromo-2-pyridyl) -carboxamide, m.p. 255-260 ° C (decomp.).
    Иrimer 6. 1-Phenyl-7-oxo-1H, 7H-pyrazolo C1,5-a] pyrimidine-6-L- (2-pyridyl) -carboxamide (ECE 21863).
    4.86 g of 2-aminopyridine dissolved in 10 ml of anhydrous pyridine are reacted with 1.24 g of PC1 ^ at 55 ° C for 30 minutes. After cooling the mixture to 20 ° C, 4 g of 1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid is added, and then heated under reflux for 30 minutes. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate is filtered off, washed with water and purified on a column of silica with ethyl acetate and methanol 98: 2 as eluent. Crystallized from methanol and get 2 g of 1-phenyl-7-ox with-1H, 7H-pyrazolo (I, 5-a] pyrimidine-6- (2-pyridyl) -carboxamide, so pl. 207 210 ° C (dec .).
    NMR spectrum (SPS1 3 ), s / 1 , ppm:
    6.74 (d) (1H, C-3 proton); 7.04 (m) (1H, C-5 pyridyl proton);
    7.3-7.9 (m) (6H, C-4 pyridyl proton and phenyl protons); 7.94 (d) (1H, C-2 proton); 7.94 (d.)
    (1H, C-2 proton); 8.2-9.45 (m) (2H, C-3 and C-6 pyridyl protons); 9.25 (s) (1H, C-5 proton); 11.2 (bs)
    (1Η, ΟΟΝΗ-).
    By the same method, the following compounds are obtained:
    3-methyl-1-phenyl-7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (2-pyri50 dil) -carboxamide (ECE 22666), mp. 274-. 277 "C '
    5-metip-1-phenyl-7-oxo-1H, 711-pyrazolo [1, 5-a] pyrimidine-6-P- (2-pyridyl) carboxamide (ECE 22383), so pl. 184187 ° C.
    , Example 7. 1- (4-Aminophenyl) -7-oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-N- (2-pyridyl) -carboxamide
    hydrochloride (ECE 22791).
    .551366060
    ten
    4 g of 1- (4-aminophenyl) -7 ~ oxo-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-I- (2-pyridyl) -carboxamide dissolved in a solvent chloroform / dioxane (3: 7 ), is subjected to reaction with a stoichiometric amount of HC1 at room temperature. The precipitate is filtered off and washed with dioxane. Get 1- (4-aminophenyl) -7-oxo-1H, 7H-pyrazolo G1,5-a] pyrimidine-6-Ν- (2-pyridyl) carboxamide hydrochloride, so pl. 7 350 ° C, yield 98%.
    Offering aemye compound Ί obtained by the method described, have anti-inflammatory activity which is compared with the anti-inflammatory activity of a known compound - 1-methyl-7-oxo-1H, 711-pyrazolo [1, 5-a] pyrimidine-6-carboxylic acid (8E 5444 /50).
    Anti-inflammatory activity in oral administration was studied in an inhibition test: an odeoma formed on a rat hind paw in response to a subcutaneous injection of carragenin according to the method of CA Winter et al. and antibodies as a result of the formation of a precipitated immune complex, followed by fixation of the complement and accumulation of polymorphonuclear leukocytes in the focal point.
    In tab. 1 shows the values of ЕЕ ^ $ anti-inflammatory activity in the test for carrageenin caused in rats after oral administration of some of the proposed compounds. .
    Table 1
    Connection | EEι, mg / kg* 3 5 1-Phenyl-7-ca co-1H, 7H-pyrazolo [1,5-a} pyrimidine-6-Ν- (2-pyridyl) carboxamide (ECE 21863) sixteen 5-Methyl-1-phenyl-7-ocso-1H, 7H-pyrazolo [1,5-a] pyrimidine-6-Ν- (pyridyl) carboxamide (ECE 22383) 9.8
    Pharmacological comparison showed that the proposed compounds are more active as pro-
    ECE 223383 N, 1 ECE 232227 7.1 ECE 21863 6.2 ECE 22662 3.6
    tivovospalitelnyh agents than previously known compounds.
    For example, 1-methyl-7-oxo-1H, 7H-pyrazolo G1,5-a] pyrimidine-6--. (2-pyridyl) -carboxamide (ECE 23081) was tested in comparison with the known compound - 1-methyl-7-oxo-1H, 7H-pyrazolo [1,5-a] -pyrimidine-6-carboxylic 10 slots (ЗЕ 5444 / 50) in accordance with the described tests for carrageenin and PPAP. The following results were obtained: in the test with carrageenin odeoma, in rats after oral administration of a dose of 100 mg / kg body weight was
    It was found that the anti-inflammatory activity of ECE 23081 is three times higher than that of WE 5444/50; in the test РРАР on rats after
    0 2 oral doses of 100 mg / kg body weight has been found that the compound WE 5444/50 is completely inactive on the contrary, the compound 23081 ECE largely in25 PPAP inhibits reaction.
    Sixteen of the proposed compounds with different radicals are compared with compound WE 5444/50 when studying edema in rats caused by
    20 Irish (pearl) moss.
    In tab. 2 shows an approximate
    the ratio of the strength of anti-inflammatory activity between the proposed / compounds and the compound WE 5444/50.
    The effectiveness of all proposed
    35 above compounds and, in some cases, compounds such as ECE ECE 22383 and 23081 were of significant activity above 1 Tel'nykh than compound WE 5444/50. Because of the high therapeutic in-, dex, the proposed compounds can be successfully used in medicine. All proposed compounds included in the table. 2, have S) 5o higher than 800 mg / kg regov in mice.
    Table 2 Compound Activity Ratio * ^ (ZE 5444 / 50-1) 7 2
    1366060
    ί 2
    Continued table. 2
    -g 2 EVERYTHING 21783 3.1 EVERYTHING 23081 30.0 EVERYTHING 22614 2.7 EVERYTHING 21859 2.5 EVERYTHING 22666 . 2 · 5EVERYTHING 23151 2.0 EVERYTHING 22791 1.9 EVERYTHING 22672 1.8 EVERYTHING 22689 1.8 EVERYTHING 22367 1.7 EVERYTHING 23260 1.7 EVERYTHING 22386 1.6 EVERYTHING 22791 HC1 1.9
    · *.
    When testing for edema caused by carrageenin, in rats after oral administration.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining substituted 1H-pyrazolo [1, 5-a] pyrimidines of the general formula
    where K is phenyl, unsubstituted or -substituted with halogen or amino group, C 1 -C ^ -alkyl, pyridyl;
    K2 is hydrogen or halo;
    Vd - hydrogen or C, -C 4 -alkyl;
    B 4 - hydrogen or C 1 -C 4 - al kil;
    In - hydroxy, -ΝΗ-C 4 -C + -alkyl,
    -ΝΗ- (CH 2 ) ^, - piperidium, where r is 1, 2 or 3, or B 5 -HH-B ^, 1 Where B & is thiazolyl, benzothiazolyl, pyridyl, unsubstituted or substituted by halogen or C 4 -C 4 - alkyp
    with the proviso that B5 is not a hydroxy group if B, C 1 -C 4 -alkyl,
    or salts thereof, characterized in that the compound of formula
    Where B, -B 5 have the indicated meanings
    B is a hydroxy group or a C 4 -C ^ alkoxy group,
    cyclized in the presence of an acidic condensing agent, such as polyphosphoric acid, in the presence of phosphorus oxychloride at a temperature from 120 ° C to the boiling point of the reaction mixture and the desired product is isolated in free form or salt, where is the hydroxy group, or is further reacted with compound of formula
    Η, Ν-Κ ^,
    where Ε έ have the specified values, and emit the target product, where B 5 -ΝΗ-Β έ , or transfer the target product where B. g is an hydroxy group, into anhydride and react with a compound of the formula
    Η 2 Ν-0, -C 4 -alkyl or H, Ν- (CH2) ^ - piperidino,
    where w has the indicated values, and the desired product is isolated, where B 5 - -MH-C 1 -C 4 -alkyl or B 5 - -PH- (CH 2 ) t is piperidino.
    Priority featured:
    I6.03.82 - at K, is phenyl, unsubstituted or substituted by halogen of ili-amino group, C 1 -C 4 ~ alkyl, pyridyl,
    B 2 is hydrogen or halo; In - hydrogen or C, -C 4 ~ alkyl, B 4 - hydrogen or C, -C 4 -alkyl, B ί - hydroxy group, -ΝΗC 4 -C 4 -alkyl, -ΝΗ-Κ ( , where Β ς is thiazolyl, benzothiazolyl, pyridyl, unsubstituted or substituted by halogen or C 1 -C-alkyl; provided that B ^ is not a hydroxy group, if B 4 C, is C 4 -alkyl, if B 4 is C 1 -CL-alkyl, then It will also help to be -IN- (CH g ) m piperidino, where go = 1, 2 or 3;
    04.02.83 - at В l - phenyl, unsubstituted or substituted by halogen or
    amino group, pyridyl, B $ - -ΝΗ- (0Η 2 ) μ
    piperidino, where w = 1, 2 or 3.
    类似技术:
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    同族专利:
    公开号 | 公开日
    SE8301412L|1983-09-17|
    FR2523582A1|1983-09-23|
    IT1194555B|1988-09-22|
    CH654306A5|1986-02-14|
    SE450573B|1987-07-06|
    IL68133D0|1983-06-15|
    SE8301412D0|1983-03-15|
    DE3309432A1|1983-09-22|
    AU1230483A|1983-09-22|
    US4482555A|1984-11-13|
    AU557300B2|1986-12-18|
    DK120783D0|1983-03-15|
    DK120783A|1983-09-17|
    FI830864A0|1983-03-15|
    FI74469B|1987-10-30|
    IL68133A|1985-12-31|
    IT8320024D0|1983-03-11|
    CA1192546A|1985-08-27|
    NL8300934A|1983-10-17|
    FI830864L|1983-09-17|
    FI74469C|1988-02-08|
    FR2523582B1|1985-12-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3907799A|1971-08-16|1975-09-23|Icn Pharmaceuticals|Xanthine oxidase inhibitors|
    BE786611A|1971-08-16|1973-01-22|Int Chem & Nuclear Corp|NEW XANTHINE OXIDASE INHIBITORS AND THEIR PREPARATION PROCESS|
    BE792533A|1971-12-09|1973-06-08|Int Chem & Nuclear Corp|NEW PYRAZOLO PYRIMIDINES AND THEIR PREPARATION PROCESS|
    US3925385A|1972-04-20|1975-12-09|Icn Pharmaceuticals|6-Carbethoxy-3,7-disubstitutedpyrazolo{8 1,5a{9 pyrimidines|
    US4093617A|1974-11-12|1978-06-06|Icn Pharmaceuticals, Inc.|3,5,7-Trisubstituted pyrazolo[1,5-a]pyrimidines|
    US4048184A|1976-11-15|1977-09-13|E. R. Squibb & Sons, Inc.|6-Phenyl-2H-pyrazolo[3,4-b]pyridines|
    US4281000A|1979-07-09|1981-07-28|American Cyanamid Company|Substituted pyrazolo pyrimidines and their use as anxiolytic agents|US6245759B1|1999-03-11|2001-06-12|Merck & Co., Inc.|Tyrosine kinase inhibitors|
    MY125533A|1999-12-06|2006-08-30|Squibb Bristol Myers Co|Heterocyclic dihydropyrimidine compounds|
    EP1615697A2|2003-04-11|2006-01-18|Novo Nordisk A/S|New pyrazolo[1,5-a] pyrimidine derivatives and pharmaceutical use thereof|
    EP1782859A3|2003-04-11|2009-09-30|High Point Pharmaceuticals, LLC|Pharmaceutical use of substituted pyrazolo [1,5- a]pyrimidines|
    US7772232B2|2004-04-15|2010-08-10|Bristol-Myers Squibb Company|Quinazolinyl compounds as inhibitors of potassium channel function|
    US8138342B2|2004-10-12|2012-03-20|High Point Pharmacueticals, LLC|11β-hydroxysteroid dehydrogenase type 1 active spiro compounds|
    JP2009514818A|2005-11-01|2009-04-09|ハイポイントファーマシューティカルズ，リミティドライアビリティカンパニー|Pharmaceutical use of substituted amides|
    KR20080069189A|2005-11-01|2008-07-25|트랜스테크 파르마, 인크.|Pharmaceutical use of substituted amides|
    CA2646588A1|2006-03-21|2007-09-27|High Point Pharmaceuticals, Llc|Adamantane derivatives for the treatment of the metabolic syndrome|
    WO2007115935A1|2006-04-07|2007-10-18|High Point Pharmaceuticals, Llc|11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVE COMPOUNDS|
    US20090306048A1|2006-06-16|2009-12-10|John Paul Kilburn|Pharmaceutical use of substituted piperidine carboxamides|
    US8048908B2|2006-07-13|2011-11-01|High Point Pharmaceuticals, Llc|11β-hydroxysteroid dehydrogenase type 1 active compounds|
    EP1878721A1|2006-07-13|2008-01-16|Novo Nordisk A/S|4-Piperidylbenzamides as 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors|
    CN101679217A|2007-02-23|2010-03-24|高点制药有限责任公司|N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase|
    JP2010519240A|2007-02-23|2010-06-03|ハイポイントファーマシューティカルズ，リミティドライアビリティカンパニー|N-adamantylbenzamide as an inhibitor of 11-beta-hydroxysteroid dehydrogenase|
    WO2008101907A2|2007-02-23|2008-08-28|High Point Pharmaceuticals, Llc|N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase|
    EP2146952A1|2007-02-23|2010-01-27|High Point Pharmaceuticals, LLC|N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase|
    US8153798B2|2007-03-09|2012-04-10|High Point Pharmaceuticals, Llc|Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors|
    CA2681934A1|2007-03-28|2008-10-02|High Point Pharmaceuticals, Llc|11beta-hsd1 active compounds|
    CN101677562A|2007-04-11|2010-03-24|高点制药有限责任公司|Novel compounds|
    WO2008134221A1|2007-04-24|2008-11-06|High Point Pharmaceuticals, Llc|Pharmaceutical use of substituted amides|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8207637|1982-03-16|
    GB838303089A|GB8303089D0|1983-02-04|1983-02-04|Substituted 1h-pyrazolo 1,5-a pyrimidines|
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