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    • 专利摘要:
    Novel (4-piperidinylmethyl and hetero)purines of formula …<CHEM>… wherein -A<1>=A<2>-A<3>=A<4>- is -N=CH-N=CH- or -CH=N-CH=N- and L is a radical L<1>-CrH2r-T-CsH2s- or …<CHEM>… the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are anti-allergic agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
    公开号:SU1581221A3
    申请号:SU864027617
    申请日:1986-06-10
    公开日:1990-07-23
    发明作者:Эдуард Жансенс Франс；Станислав Марселла Диелс Гастон
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    varies from 1 to 4, and these heteroatoms are selected from the group containing oxygen, sulfur and nitrogen, provided that no more than two oxygen atoms or sulfur are present in the cycle, and these five or six-digit cycles are possibly condensed with five or six membered carbocyclic or heterocyclic rings, also containing several heteroatoms, the number of which varies from 1 to 4 and which are selected from the group containing oxygen, sulfur and nitrogen, provided that no more than two atoms of oxygen or sulfur, and if Het means a bicyclic ring system, then such a system can be substituted with up to four substituents, if Het means a monocyclic ring system, then such a system can be replaced with up to two substituents, and these substituents in Het are selected from the group containing the bivalent radical X, where X independently takes the value 9 previously indicated for X, halogen, C (-C-alkyl,, -alkyloxy, hydroxyl, mercapto, C f-alkylthio, nitro, amino, mono- or di-SC-C the alkylamino group is a member of the group in which Phenyl, phenyl substituted with one to two substituents each independently selected from the group consisting of halogen, hydroxyl, С С4
    C 7 -C 4-alkyloxy-alkyl,
    group, amino group, with
    provided that
    five
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    I) if I., is hydrogen or T Z -C X t-Y, where Y is different from a simple bond, Z 0 and X 0, then g 0; II) if Lf is a halo, hydroxyl, C-C-alkyloxy group, mercapto group, C-Cd-alkylthio group, isocyanato group, iothiocyanato group or Het is attached to CGN at the nitrogen atom and where g is 0, then T means a simple bond or a radical of the formula -C (X) -Yj. Ill) if T is Y, where Y is different from a simple bond, or T is a radical of the formula -Z-C (X) -Y-, where Y is different from a single bond of the simple bond, then
    Iv) if C is hydrogen, then g / Ј 0 or, or T is different from a simple bond, or their pharmaceutically acceptable salts with acids, or stereoisomers, characterized in that N-alkylate piperidine of the common mule II
    R,
    TO
    one
     i
    -BUT. l
    0
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    0
    R.
    B and A, A „-A A j have
    Where R 1, K. f OIL, -P Ј-L j.
    the indicated values with a reagent of the formula L, —СН4г- Т - –CSX3 - W,
    where g, S, T and L, have the indicated meanings and mean a reactive leaving group such as a halide or a sulfonyloxy group,
    inert in the reaction conditions of the solvent and, if desired, transform the compounds of formula I into a pharmaceutically acceptable salt with an acid by reacting with the corresponding acid, or vice versa, the salt with the acid is converted into alkaline by reaction with an alkali.
    The invention relates to a method for producing new chemical compounds and relates to the preparation of new (4-piperidinylmethyl or hetero) purines, their
    pharmaceutically acceptable salts with acids or stereoisomers with antihistamine properties.
    The purpose of the invention is the synthesis of new piperidinylpurins in their properties superior to a structural analogue possessing similar properties. (
    Obtaining intermediate compounds.
    Example 1. A mixture of 3.7 parts of 2-pyridinemethanamine, 4.1 parts of 4,6-di "- chloropyrimidine-5-amine, 3.03 parts of N, N-diethylethanamine and 150h. water is stirred for 8 h at room temperature. After cooling, the mixture is stirred for 24 hours. The resulting product is filtered, washed with water and dried for 24 hours in vacuo at 80 ° C to obtain 5.35 parts (90.8%) of b-chloro-N - (4-fluorophenyl) methyl-4,5-pyrimidinediamine, m.p. 244, (intermediate compound 2); B-chloro-N - - (2-furanylmethyl) -4,5-pyrimidinedimine, m.p. 138.7 ° C (intermediate 3); 6-chloro-N4- (2-thienylmethyl) -4,5-pyrimidinediamine, m.p.
    ten
    15
    20
    9.86 parts lithium tetrahydroaluminate in portions under nitrogen atmosphere. The mixture was stirred for 6 hours, after which an additional 10 hours was added in portions. aluminum tetrahydroaluminate and stirring are continued for 2 hours at room temperature. The reaction mixture is then decomposed with water, the layers are separated, the aqueous phase is extracted with tetrahydrofuran, the combined organic layers are dried, filtered and evaporated. The residue is recrystallized from acetonitrile. The resulting product is filtered and dried to give 18 parts (63.5%) of Ng-H (4-fluorophenyl) methyl J-4, 5-pyrimidinediamine (intermediate 12).
    Using the above procedure and using equivalent amounts of the starting compounds, the following compounds are also obtained: K- (4-amino-6-β-hydroxy-5-pyrimidinyl) -4-fluorobenzamide (intermediate 13)
    165.5 ° C (intermediate 4); 25 and 6-amino-5 - {(4-fluorophenyl) -methyl} b-chloro-N -C (5-methyl-2-furanyl) methyl-J-amino-4-pyrimidinol (intermediate
    -4,5-pyrimidinediamine (intermediate compound 5); b-chloro-N - (2-pyrazinylmethyl) -4,5-pyrimidinediamine (intermediate 6); 6-chloro-K - - (4 - thia z ol or e thyl) -4,5-pyrimidinediamine, m.p. 145.5 ° C (intermediate compound 7); b-chloro-N - (4-methoxyphenyl) methylJ-4,5-pyrimidinediamine, m.p. 183.5 ° C (intermediate compound 8) and (X4-fluorophenyl) methyl-6-methyl-4,5-pyrimidinediamine (intermediate 9).
    In a similar way, b-chloro-N4-C (2,4-dimethylphenyl) methyl-4,5-pyrimidinediamine (intermediate compound 10) was also obtained.
    Example 2. To a stirred mixture of 20.2 hours, 4,5-pyrimidinediam, 40 parts of pyridine, and 144 parts of NjN-dimethylformamide, a solution of 24.2 parts was added dropwise at 10 ° C. 4-fluorobenzoyl - chloride in 36 h. K, K-dimethylformamide. After completion of the addition, the compound 14).
    Example 3. A mixture of 62.2 parts of 6-chloro-N- (2-pyridinylmethyl) -4,5-pyri30 midindiamine, 3 parts of a 4% solution
    thiophene in methanol, 20 parts of calcium oxide and 400 parts of water are hydrogenated at normal pressure and 50 ° C in the presence of 5 hours as a catalyst. 10% fell, get on coal. After absorbing the paci amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated, yielding 63.5 parts (100%) of the residue N - (2-pyridinylmethyl) -4.5 dd-pyrimidinediamine (intermediate 15).
    Intermediates are also prepared in a similar way: (4- -fluorophenyl) -methyl J-U, 5-pyrimidine-45 amine as residue (16); (2-furanylmethyl) -4,5-pyrimidinediamine, m.p. 116.4 ° C (17); K4 - (2-thienylmethyl) -4,5-pyrimidinediamine (18); N4- (5-methyl--2-furanyl) methyl} -4,5-pyrimidinediami ;;
    sewing is continued for 30 minutes at rooms 50 (19); N - (2-pyrazinylmethyl) -4,5-pyrene temperature, after which midindiamine is added as residue (20); (4-methoxyphenyl) methyl-pyrimidinediamine (21) nN - (4-thiazolylmethyl) 600 parts of water. The resulting product was filtered and dried to give 30 parts (70%) of K- (4-amino-5-pyrimidinyl) -4-fluorobenzamide (intermediate 11).
    To the stirred mixture, 30 parts of N- (4-amino-5-pyrimidinyl) -4-fluorobenzamide and 360 parts of tetrahydrofuran are added
    -4,5-pyrimidinediamine (22); N4- (2,4-, -dimethylphenyl) -methyl} -4,5-pyrimidinediamine (intermediate 23). Example 4. A mixture of 8.72 parts of N - - (4-fluorophenyl) methyl} -4, 5-pyrimidinediamine, 63 parts of carbon disulfide and 45 hours
    0
    five
    0
    9.86 parts lithium tetrahydroaluminate in portions under nitrogen atmosphere. The mixture was stirred for 6 hours, after which an additional 10 hours was added in portions. aluminum tetrahydroaluminate and stirring are continued for 2 hours at room temperature. The reaction mixture is then decomposed with water, the layers are separated, the aqueous phase is extracted with tetrahydrofuran, the combined organic layers are dried, filtered and evaporated. The residue is recrystallized from acetonitrile. The resulting product is filtered and dried to give 18 parts (63.5%) of Ng-H (4-fluorophenyl) methyl J-4, 5-pyrimidinediamine (intermediate 12).
    Using the above procedure and using equivalent amounts of the starting compounds, the following compounds are also obtained: K- (4-amino-6-β-hydroxy-5-pyrimidinyl) -4-fluorobenzamide (intermediate 13)
    5 and 6-amino-5 - {(4-fluorophenyl) -methyl} aminoj-4-pyrimidinol (intermediate
    compound 14).
    Example 3. A mixture of 62.2 parts of 6-chloro-N- (2-pyridinylmethyl) -4,5-pyrimidinediamine, 3 parts of a 4% solution
    thiophene in methanol, 20 parts of calcium oxide and 400 parts of water are hydrogenated at normal pressure and 50 ° C in the presence of 5 hours as a catalyst. 10% palladium on coal. After absorbing the paci amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated to give 63.5 parts (100%) of the residue N - (2-pyridinylmethyl) -4,5-pyrimidinediamine (intermediate 15).
    Intermediates are also prepared in a similar way: (4- -fluorophenyl) -methyl J-U, 5-pyrimidine-amine as residue (16); (2-furanylmethyl) -4,5-pyrimidinediamine, m.p. 116.4 ° C (17); K4 - (2-thienylmethyl) -4,5-pyrimidinediamine (18); N4- (5-methyl--2-furanyl) methyl} -4,5-pyrimidinediami ;;
    - (4-methoxyphenyl) methyl-pyrimidinediamine (21) nN - (4-thiazolylmethyl) -4, 5-pyrimidinediamine (22); N4- (2,4-dimethylphenyl) -methyl} -4,5-pyrimidinediamine (intermediate 23). Example 4. A mixture of 8.72 parts of N - - (4-fluorophenyl) methyl} -4, 5-pyrimidinediamine, 63 parts of carbon disulfide and 45 hours
    M, 1L-dimethylformamide is stirred i at boiling point for 3 hours. After cooling, the reaction mixture is transferred to water. The precipitated product was filtered and dried to give 10.1 parts (78.9%) of 9-C (4-fluorophenyl) methyl 3 9H-purine-8-thiol (intermediate compound 24).
    To a stirred mixture of 4.6 parts of potassium hydroxide and 200 parts of water are added in portions of 1.7 parts of iodomethane, after which they are added dropwise 3.8 parts of 9- (4-fluorophenyl) methyl 9i-purin-8-thiol.
    i
    After the completion of the dropping, the mixture was stirred for 2 hours at room temperature. The precipitate formed is filtered off and dried to obtain parts (73.9%) of 9-C (4-fluorophenyl) methyl-8-methylthio-9H-purine, m.p. 167.1 ° C (intermediate 25).
    Example 5. A mixture of 26 parts of 3-methyl-4-oxo-1-piperidinecarboxylic acid methyl ester, 16.5 parts of ben- methanamine, 2 parts of a 4% solution of thiophene in ethanol and 200 parts of methanol is hydrogenated at normal pressure and room temperature in the presence of as a catalyst Zch. 10% palladium on coal. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dryness to give 40.2 parts of 3-methyl-4- (phenylmethyl) amino J-1-piperidinecarboxylic acid methyl ester as a residue (intermediate compound 26).
    A mixture of methyl 3-methyl-4- - (phenylmethyl) amino -1-piperidinecarboxylic acid (40 h) and 160 parts of methanol is hydrogenated at normal pressure and room temperature in the presence of 10% palladium on carbon as a catalyst ( 2 hours). After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is distilled (bp. 80 ° C at 0.1 mm Hg). The distillate is subjected to further purification using gas chromatography (215 ° C 10 pounds / inch 2,7 ati with getting 8.6 hours of methyl 4-amino-3-methyl-1-piperidinecarboxylic acid (intermediate compound 27)
    To a stirred and cooled (-10 ° C) mixture of 138.6 parts of carbon disulfide, 113.8 parts of N, N-methane-tetrailbis (cyclohexanamine) and 450 parts of tetrahydrofuran are added at the same temperature.

    -
    $
    five
    drops of 106 parts of 4-amino-3-methyl-1-piperidinecarboxylic acid methyl ester. The reaction mixture is then brought to room temperature, at which it is stirred for 1 hour. The mixture is evaporated and the residue is stirred in 2,2-oxybis bis-propane. The precipitate formed is filtered off and the filtrate is evaporated, yielding 141.1 parts (100%) of cis-4-isothiocyanato-3-methyl-1-piperidinecarboxylic acid methyl ester (intermediate 28).
    Using the same procedure and using equivalent amounts of the corresponding starting materials, the following intermediate compounds are also obtained: (cis- + trans-) -4-amino-3-methyl-1-piperidinecarboxylic acid methyl ester, b.p. 136 - 140 ° C (water jet pump) (29) and methyl ester (cis- + trans -) - 4-isothiocyanato-3-methyl-1-piperidinecarboxylic acid (30) as a residue.
    4 EXAMPLE 6 A mixture of 42.5 parts of N - (2-furanylmethyl) -4,5-pyrimidinediamine, 50.5 parts of 4-isothiocyanato-1-piperidinecarboxylic acid ethyl ester and 630 including tetrahydrofuran stirred for 48 h at the boiling point of the mixture. After cooling, the product obtained is filtered off, washed with tetrahydrofuran and 1,1-oxybisethane and dried to obtain 86.4 parts (96.2%) of 4-Ј ((2-α-furanylmethyl) aminoJ-5-pyrimidinyl amino) ethyl ester) thiooxomethyl amino V-1-piperidinecarboxylic acid (intermediate 31).
    In a similar way, the following compounds are obtained (Table 1).
    In a similar manner, the following intermediates are also prepared; N- (4-amino-6-hydroxy-5-pyrimidinyl) -N- (4-fluorophenyl) methyl} -K - (phenylmethyl) -4-piperidinyl and urea, m.p. 192.9 ° C (A2); 4- (((4-amino-6-hydroxy-5-pyrimidinyl) ethyl ester (4-fluorophenyl) methyl amino hyo oxo-methyl-amino) -1-piperidinylcarboxylic acid (43); 4- (4 - - {(2,4-dimethylphenyl) methyl amino} -5-pyrimidinyl) aminothioxymethyl} amino J-1-piperidinecarboxylic acid (44).
    Example 7. A mixture of 52.4 parts of 1- (phenylmethyl) -4-piperidine acetic acid hydrochloride, 38.7 parts of (4- -fluorophenyl) methyl -4.5-pyrimidinediamine and 765 parts of phosphoryl ne
    stir for 30 minutes at the boiling point of the mixture. The reaction mixture is then evaporated and the residue is decomposed with ice water. The product obtained after treatment with sodium hydroxide is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The resulting product is filtered and dried to give 37 parts (61%) of N- (4-J (4-fluorophenyl) methylJaMH-but} -5-pyrimidinyl) -1- (phenylmethyl) -4-β-piperidine acetamide, mp. 157.3 ° C (intermediate 45).
    Example 8. To a stirred mixture of 14.2 parts of isocyanate ethane, 29.2 hours of sodium azide and 135 parts of dry tetragon.
    dofuran solution was added 39 parts of aluminum chloride in 225 parts of dry tetrahydrofuran. The resulting mixture is stirred for one day at reflux. The reaction mixture is then cooled and acidified with 6N hydrochloric acid. The resulting mixture was evaporated to dryness and the resulting product was extracted four times with 2-propanone. The combined extracts are dried overnight to give 18 parts (65%) of 1-ethyl-1,4-dihydro-5H-tetrazole-5-one (intermediate 46)
    To a stirred solution of 109 parts of 1,2-dibromoethane and 21.2 parts of sodium carbonate in 5 parts of water and 18 parts of N, M-dimethylformamide, a solution of 22.5 is added dropwise at about 40 ° C. including 1-ethyl-1,4-dihydro-5H-tetrazol-5-one in 5 parts of water and 27 parts of NjN-dimethylformamide. After the completion of the dropping, the mixture is stirred for a day at 40 ° C. The organic phase is then separated, dried and distilled to give 9.8 parts (22%) of 1- (2-bromoethyl) -4-ETHYL-1,4-dihydro-5H-tetrazole-5-α, t .kip. 110 C at 0.1 mm Hg (intermediate 47).
    Example 9. A mixture of 50 parts of 2 azolamines, 76 parts of 3-acetyl-4,5-dihydro-2 (3N) -furanone, 1.2 hours. concentrated hydrochloric acid and 270 parts of methylbenzene are stirred at reflux for 2 hours using a water trap. The reaction mixture is cooled and at that
    ,
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    Perform between 20 and 340 parts of phosphoryl chloride. The resulting mixture is slowly heated to 100- 11 0 ° C, then stirred for 2 hours at the same temperature. The reaction mixture was evaporated and the residue was taken up in a mixture of crushed ice and ammonium hydroxide. The resulting product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) for leaching. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanol and. 1,1-oxybisethane to obtain 36 parts of 6- (2-chloroethyl) -7-methyl-5H-thiazolo (3,2-a) -pyrimidin-5-one (intermediate compound 48).
    Example 10. A mixture of 20.65 parts of 1- (phenylmethyl) -4-piperidineacetic acid in the form of hydrochloride, 19.5 parts of b-chloro-N4-C (4-fluorophenyl) -methyl J-4,5-pyrimidinediamine and 510 parts of phosphoryl chloride are stirred at boiling for 13 hours. The reaction mixture is then evaporated, the residue is taken up in ice-cold water and treated with sodium hydroxide.
    The product obtained is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) for leaching with saturated ammonia. The first fraction was collected and the eluent was evaporated to give 23.6 parts (75%) of 6-chloro-9- (4-fluorophenyl) methyl J-8-1- (phenylmethyl) -4-piperid and nyl methyl-9CH-purine in the form of an oily residue (intermediate 49).
    In a similar way, the following intermediates are also prepared: 6-chloro-7- (4-fluorophenyl) methyl J-8-0 (phenylmethyl) -4-piperidinyl methyl | -7H-purine (50); 9- (4-fluorophenyl) methyl-6-methyl-8- 1- (phenylmethyl) -4- -piperidinyl methyl-9H-purine as an oily residue (51).
    Example 11. A mixture of 36 parts of K- - (4- {(4-fluorophenyl) methyl amino} -5-pyrimidinyl) -1- (phenylmethyl) -4-piperidine-acetamide and 935 parts of phosphoryl chloride is mixed with bale After cooling, the reaction mixture is evaporated. The residue is decomposed with ice water and treated with a solution of hydro
    sodium oxide. The resulting product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) for leaching with saturated ammonia. Pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2-oxibispropane. The resulting product is filtered and crystallized from acetonitrile. After filtration and drying, 10.6 h are obtained. (30.4%) 9- (4-fluorophenyl) methyl J-8 - {1 - (phenylmethyl) -4-piperyl dienyl methyl} -9H-purine, m.p. 136.4 ° C (intermediate 52).
    Example 12. A mixture of 12.6 parts of 1- (phenylmethyl) -4-piperidinol, 3.2 parts of 50% sodium hydride dispersion and. 200 h. K, M-dimethylacetamide is stirred for 1 h at room temperature. Then, 18 parts of 9-C (4-fluorophenyl) methyl} -8- (methylthio) -9H-purine are added in portions and stirring is continued for 4 hours at room temperature. The reaction mixture is taken up in water, the product is filtered and taken up in trichloromethane. The organic layer is washed with water and filtered through diatomaceous earth. The filtrate is dried, filtered and evaporated. After crystallization from acetonitrile, the product is filtered and dried to give 16.75 parts (61.1%) of 9-C (4-fluorophenyl) methyl -8-0- (phenylmethyl) -4-piperidinyl JOKCH 9H-purine, m.p. 117 ° C (intermediate 53).
    Example 13. To a stirred mixture of 13 parts of 9-C (4-fluorophenyl) methylJ-9H-purin-8-thiol and 300 parts of water was added 2 parts of sodium hydroxide. The resulting reaction mixture is filtered through diatomaceous earth. After evaporation, the residue is taken up in methylbenol and the solvent is evaporated again (this operation is repeated twice). The residue is taken up in 27C parts of M-dimethyl acetamide, and then 19.3 parts of 1- (4-methylphenylsulfonyl J-4-piperidinol in the form of methanesulfonate (ester) is added. The mixture is stirred for 2 days- at 60 The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone, the extract was washed with water, dried, filtered and evaporated to give 27 parts (100%) 4- (9-1 (4- fluorophenyl) IU
    five
    Jq 5 -q.
    Tyl-9H-purin-8-yl thio) -1- -methyl-phenyl) sulfonyl hyperidine (intermediate 54), I
    Example 14. A mixture of 4 h, 4 - ({4- (2-feranylmethyl) amino-5-pygmidinyl} amino) thioxomethyl amino} -1-piperidinecarboxylic acid ethyl ester, 6 parts of mercury oxide ( Ii) and 80 parts of ethanol is stirred for 2 hours at boiling point. The resulting mixture was filtered hot through NaЈ1o® and the filtrate was evaporated. The residue is crystallized from a mixture of acetonitrile and ethanol. The product is filtered and dried to give 0.8 parts (21.5%) of 4- {C9- (2-furanylmethyl) -9H-purin-8-yl amino -1 -piperidinecarboxylic acid ethyl ester, m.p. 171.9 ° C (intermediate compound 55).
    Using the same procedure and using equivalent amounts of the corresponding starting compounds, 4- (9-Ј (4-fluorophenyl) methyl} -9H-purin-8-yl-amino) -} - -piperidinecarboxylic acid ethyl ester is also obtained, t .pl. 174.5 ° C (intermediate compound 5b5.
    Example 15. A mixture of 24 parts of 4- - (4- (phenylmethyl) amino-5-pyrimidinyl-amino) thio-oxymethyl-Damino} -1-piperidinecarboxylic acid in the form of ethyl ester, 24 parts of mercury (II) oxide and 240 hours of methanol, saturated with ammonia, stirred for a day at boiling point. The reaction mixture is then filtered hot and evaporated. The residue is taken up in a mixture of trichloromethane and ethanol. After-; After washing with water, the organic layer is evaporated and the residue is crystallized from acetonitrile. The product is filtered and dried to give 20.3 parts (92.1%) of (phenylmethyl) -9H-nypHH-8-nriJaMHHo j-1-piperidinecarboxylic acid ethyl ester, mp, 156.9 ° C (intermediate 57).
    In a similar manner, the following intermediates are prepared: (2-Thienylmethyl) -9H-purin-8-yl-3-amino J-1-piperidinecarboxylic acid ethyl ester (58) as a residue; 4-y9- (2-pyridinylmethyl) -9H-purin-8-yl anino -1-piperidinecarboxylic acid ethyl ester (59); 4- (Ј9- (5-methyl-2-furanyl) methyl-9H-purin-8-yl} amino) -1-piperidinecarboxylic acid ethyl ester in the form of (6C) j ethyl ester (2-pyranemyl-. i ethyl ) -9H-purin-8-yl} -amino} -1-piperidinecarboxylic acid as residue (61); 4-Ј (9-methyl-9H- -purin-8-yl) amino | -1-piperidinecarboxylic acid ethyl ester, m.p. 169.6 ° C (62); 4- (9-C (4-methoxyphenyl) methyl} -9H-purin-8-yl} amino) - piperidinecarboxylic acid ethyl ester, m.p. 168.1 ° C (63); N-C1- (phenylmethyl) -4-piperidinyl-9H-purin-8-amine, m.p. 276.1 ° C (64).
    Example 16. A mixture of 15.7 parts of 4- ({C4- (cyclopropyl-amino) -5-pyrimidine amino- thiooxomethyl) amino-1-piperidinecarboxylic acid ethyl ester, 20. parts of mercury (II) oxide, 40 including ethanol and 135 parts of M, M-dimethylacetamide are stirred at 80 ° C for 24 hours. The resulting reaction mixture is filtered while hot through diatomaceous earth. The filtrate is taken up in water and the product is extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is crystallized from acetonitrile. The product is filtered and dried to give 2.2 parts (14.1%) of ethyl 4- (9-cyclopropyl-9H-purin-8-yl) amino -1-piperidinecarboxylic acid, m.p. 177 ° C (intermediate compound 65).
    In a similar way, 4-fЈ9- (4-thiazolylmethyl) -9H-purin-8-yl} amino J-1-piperidinecarboxylic acid ethyl ester is also prepared (intermediate 66).
    Example 17. A mixture of 13 parts of cis-4- (Ј (4- (4-fluorophenyl) methylZamino) -5-pyrimidinyl) amino-3 thiooxomethyl amino) -3-methyl-1-piperidinecarboxylic acid methyl ester, 13h. mercury (II) oxides, 0.1 parts of sulfur and 160 parts of methanol, saturated with ammonia, stirred for 0.5 h at boiling point. The resulting reaction mixture is filtered hot through diatomaceous earth and the filtrate is evaporated. The residue is taken up in water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is precipitated with 1,1-oxybis ethane. The product is filtered and dried to give 7 parts (58.5%) of cis-4- (9-C (4-fluorophenyl) methyl-9H-purin-8-yl y-amino) methyl-3-methyl- methyl ester -1-piperidinecarboxylic acid, so pl. 152, (intermediate compound 67).
    In a similar way, the following intermediates are also prepared: 7- (4-fluorophenyl) methyl J-N-1- (phenylmethyl) -4-piperidinyl-7H-purin-8-amine, mp. 251, 1 ° C (68); (cis- + trans -) - 4- (Ј-9- (4-fluorophenyl) methyl} -9H-purin-8-yl amino) methyl ester) -3-methyl-1-piperidinecarboxylic acid (69); 4- (f9-C (2,4-dimethylphenyl) methyl} -9H-purin-8-yl} -amino) -piperidinecarboxylic acid ethyl ester (70); 4 - ({9-C (4-ft6 p-phenyl) methyl} -9H purin-8-yl} methylamino) -1-piperidinecarboxylic acid ethyl ester (71).
    Example 18. A mixture of 88.8 parts of 4 - ((4-amino-6-hydroxy-5-pyrimidinyl) (4-fluorophenyl) methyl ethyl ester) thiooxomethyl-amino) -piperidinecarboxylic acid, 88 parts of mercury oxide (II ), 0.1 parts of sulfur and 1200 parts of ethanol are stirred for a day at boiling point. The resulting reaction mixture was filtered hot through diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) to displace saturated ammonia. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethyl acetate. The resulting product is filtered and dried to give 50.7 parts (66.1%) of ethyl 4- (7-amino--1- (4-fluorophenyl) methyl J-oxazolo} 5,4 - pyrimidin-2 (1H ) -ylidene JaMHHo) -1-piperidinecarboxylic acid, so pl. 174.6 ° C (intermediate 72).
    A mixture of 50.7 parts of 4- - (7-amino-1- (4-fluorophenyl) methyl-JOK-Cazolo 5,4-d pyrimidine-2- (1H) ethyl ester of pyrimidine-2- (1H) ethyl ester J-1-piperidinecarboxylic acid and 3050 h The phosphorus chloride is stirred at reflux temperature for 90 minutes. The resulting reaction mixture is evaporated, the residue is taken up in ice-cold water. The resulting mixture is treated with ammonium hydroxide. The product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated The residue was purified by column chromatography on silica gel using three times for washing with a saturated ammonia mixture. lormethane with methanol (95: 5 by volume). The pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The products are filtered and dried to give 21.6 h.
    (41.5%) ethyl 4 - ({b-chloro-7-C (4-fluorophen l) methyl -7H-purin-8-yl) amino) -1-piperidinecarboxylic acid
    lots, so pl. 126.6 ° C (intermediate 73).
    Using the same procedure and using equivalent amounts of the corresponding starting materials, the following intermediates are also prepared: 1- (4-fluorophenyl) methyl J-2, hydro-2 C 1- (phenylmethyl) 4-piperidine imino} oxazolo 5.4 -c1} pyrmidine-4-amine, m.p. 178, (74); 6-chloro-7- - C (4 fluoro-phenyl) methylJ-N-fl- (phenylmethyl) -4-piperidinyl} -7H-purin-8-amine, m.p., 248.6 ° C (75 ).
    Example 19. A mixture of 16h. 6- -chloro-7- (4-fluorophenyl) methyl-8- - (phenylmethyl) -4-piperidinyl methyl} -7H-purine, 4.65 parts of ethyl chloroformate and 180 parts of methylbeneol are stirred for 2 hours at reflux temperature. After cooling, the reaction mixture is treated with ammonium hydroxide and the product is extracted with ethyl benzene. The extract is washed with water, dried, filtered and evaporated to give 18.7 parts (100%) of 4-f6-chloro-7-α-fluorophenyl) methyl} -7H-purin-8-yl} -1 pip ethyl ester epidincarboxylic acid as a residue (intermediate 76).
    In a similar way, they also get
    the following intermediates: 4 - ({9-4-fluorophenyl) methyl} -b-methyl-EN-purin-3-yl methyl) -1-piperidinecarboxylic acid ethyl ester (intermediate 77); 4- (f6-chloro-9-C (4-fluorophenyl) methyl-9H-purin-8-yl y-methyl) -1-piperidine hydroxy acid ethyl ester as a residue (intermediate 78).
    Example 20. A mixture of 24.8 hours
    40
    45
    4- (9- (4-fluorophenyl) methyl J-9H-nypHH-8-yl 1 thio) -1 - Ј (4-methylphenyl) sulfonyl piperidine and 300 parts of acetic acid saturated with hydrogen bromide are stirred for 24 hours at room temperature temperature After evaporation, the residue is taken up in water. The mixture was treated with sodium hydroxide solution and extracted with dichloromethane. The extract is acidified with hydrochloric acid and extracted with water. The aqueous layer is treated with sodium hydroxide solution and the product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography on 55 silica gel using first a mixture of trichloromethane and methanol (95: 5 by volume) for washing out, then
    five
    -
    . five
    No
    iv 35 „
    0
    40
    45
    55 mixtures of trichloromethane with methanol, saturated with ammonia (90: 1 0 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered and dried to give 3 parts (17.4%) of 9- - (4-fluorophenyl) methyl J-8- (4-piperidinylthio) -9H-purine, m.p. 113.5 eC (intermediate 79).
    In a similar manner, 9- (X4-fluorophenyl) methyl T-8- (4-piperidine sulfonyl) -9H-purine (intermediate compound 80) is also prepared.
    Example 21. A mixture of 60.5 parts of (2-furanylmethyl) 9H-purin-8-yl amino} -1-piperidinecarboxylic acid ethyl ester, 90 parts of potassium hydroxide, 800 parts of 2-propanol and 20 hours Water is stirred for 48 hours at boiling point. The reaction mixture is then evaporated, the residue is taken up in water with stirring. The product is filtered off and dried to give the first fraction 36.2 hours of 9- (2-furanylmethyl) -M- (4-piperidinyl) -9H-purine-8- -amine as a hemihydrate. The aqueous phase is extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The oily residue is stirred in acetonitrile-e and 2,2-oxy-bispropane. The product is filtered and dried to give a second fraction of 5.6 parts of 9- (2-furanylmethyl) -I- (4-pyrididinyl) -9H-purine-8-amine. The total yield of 41.8 parts (86%) of the hemihydrate of 9- (2- -furanylmethyl) -K- (4-piperidinyl) -9H- -purine-8-amine, so pl. 164.1 ° C (intermediate 81).
    Using the same procedure and using equivalent amounts of the corresponding starting materials, the following intermediates are also obtained: 9-Ј (4-fluorophenyl) methyl} -K- (4-piperidinyl) -9H-purine-8-α-amine d-hydrochloride, m.p. 275 ° C (82); K- (4-piperidinyl) -9- (2-thienylmethyl) -9H-purin-8-amine, m.p. 189.6 ° C (83); N- (4-rm-peridinyl) -9- (2 pyridinylmethyl) -9H-- -purine-8-amine, m.p. 194.8 ° C (84); 9- C (5-methyl-2-furanyl) methyl) -H- (4-perperdinyl) -9H-purin-8-amine, m.p., 165, G (85); K- (4-piperidinyl) -9- (2- -pyrazinylmethyl) -9H-purin-8-amine as residue (86); and 9- (4-methoxyphenyl) methyl-N- (4-piperidinyl) -9H-purin-8-amine, m.p. 144.1 ° C (87); 9- (2,4-dimethylphenyl) methyl -M- (4-piperidinyl) -9H-purin-8-amine (88).
    rin-8-amine, 1 part of sodium carbonate and 45 hours M, K-dimethylacetamide were stirred for 24 hours with heating at 90 ° C. The reaction mixture is then transferred to water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) for leaching with ammonia-saturated. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered and dried to give 0.9 h (31.6%) of 2- -methyl-3- 2 - ((2-pyrazinylmethyl) - -9H-pyrin-8-yl Jamino} -1 -piperidinyl) ethyl} -4H -pyrido 1, 2-a} -pyramidin-4- -one, so pl. 180.1 ° C (compound 27). Data on other compounds are presented in Table. four.
    The following compounds are also prepared in a similar manner (Table 5).
    In a similar manner, the following compounds are also prepared: 3-f2- 4- (9- - (4-fluorophenyl) methyl} -6hydroxy-9H- -purin-8-yl-methyl) -1-piperidinyl ethyl) -6,7,8 , 9-tetrahydro-2-methyl-4H-pyrido (1,2-aJ pyrimidin-4-one, mp. 171.1 ° C (compound 48); (f9- - (4-fluorophenyl) methyl} -6-methoxy-9H- -purin-8-yl} -methyl) -1-piperidinyl propyl U-1,3-dihydro-2H-benzimidazol-2-one (E) -2-butandioate (2: 3) , mp. 179.9 ° C (compound 49); 9- (4-fluorophenyl) methyl JN-.fi-2- (4-morpholinyl) ethyl-4-piperidinyl-9H-purin-8-amine , mp 176, (compound 50); 7-methyl-6-2 - ((2-thienylmethyl) -9H-purin-8-yl amino} -1-piperidinyl) ethyl} -5H-thiaz hemihydrate olo 3,2-a pyramidine-5-one, mp 104.5 ° C (compound 5); 1-ethyl-4 - ((G9- (4-fluorogphenyl) methyl-9H -purin-8-yl} amino) -1-piperidinyl ethyl} -1,4-dihydro-5H-tetraeol-5-one, mp 160.3 C (compound 52); 3- ( ({9- (4-fluorophenyl) methyl.-9H-purin-8-yl1-amino) -1-piperidinyl ethyl) -2.4- (HI, 3N) -quinazoline-, dione, mp. 241 ° C (compound 53). Example 32. A mixture of 1.8 parts of 1- - (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 2.7 parts of 9- (4- Fluorophenyl) methyl J-8- (4-piperidinylmethyl) -9H-purine, 1 part of sodium carbonate and 45 hours N, N-dimethylformamide are stirred for a day at 70 ° C. After cooling, the reaction mixture is transferred to
    0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    water and the product is extracted three times with chloromethane. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) for leaching with ammonia-saturated. Pure fractions are collected and the eluent is evaporated. The residue is converted in ethanol to the salt (E) -2-butendeonic acid. The salt is filtered and dried to give 2.85 parts (45.9%) of (E) -2-butenioate (9- (4-fluorophenyl) methylJ-9H-purine-8-yl methyl) -1-piperidinylJnpo - drank-1,3-dihydro 2H-benzimidazol-2-one (1: 2), so pl. 186.2 ° C (compound 54).
    In a similar way, the following compounds are also prepared: 1-f /: - f4 - ({9 - - (4-fluorophenyl) methyl 7-9H-purin-8-yl} - amino) -1-piperidinyl ethyl 1-1.3 -dihydro-2H-benzimidol-2-one, so pl. 242.4 ° C (compound 55); (9- - (4-fluorophenyl) methyl 6-hydroxy-9H- -purin-8-yl-methyl) -1-piperidinyl propyl} -1,3-dihydro-2H-benzimidazol-2--one, m.p. 245.8 ° C (compound 56).
    Example 33. A mixture of 1.2 parts of bromo-1-propane, 3.26 parts of 9- (4-fluorophenyl) methyl -N- (4-piperidinylmethyl) -9H- -purin-8-amine, 1.5 hours Sodium bicarbonate and 40 parts of ethanol are stirred at reflux temperature for 1 hour. Then the reaction mixture is filtered while hot through diatomaceous earth and the filtrate is evaporated. The residue is taken up in water and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and m-methanol (95: 5 by volume) for leaching with saturated ammonia. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered and dried to give 0.8 parts (22%) of 9 (4-fluorophenyl) methyl J-N-1- (2-propenyl) -4-pyridine-9H-purine-8-amine, mp. 144.8 ° C (compound 57).
    In a similar way, (E) -2-butenioate-4 - ({9- (4-fluorophenyl) methyl} -9H-purin-8-Cl | amino) -N- (1-methyl-ethyl) -1- piperidinepropanamide (1: 2), so pl. 202.5 ° C (compound 58).
    Example 34. A mixture of 3.46 parts of N- (dihydro-3, 3-diphenyl-2 (3N) -furanilidene) -M-methylmethanammonium bromide,
    -j15812
    3.1 parts of M- (4-cis Ridinyl) -9- (2-riridinylmethyl) -9I-purin-8-amine, 1.5 parts of sodium carbonate and 45 parts of M, H-dimethyl-acetamide stirred at 8 ° C for 1 day. After cooling, the reaction mixture was taken up in water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of ammonia for washing out with saturated ammonia trichloromethane with methanol. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered and dried to obtain 4.1 ppm (71%) M, K-dimethyl-o /, / -diphenyl-4-c 9- (2-pyridinylmethyl) -9H-purin-8-yl but) -1-piperidinbutanamide, t .pl.
    ten
    15
    191.6 ° C. (compound 59). Data on
    20
    other compounds table. 6
    shown in
    In a similar way, the following compounds are also prepared: NN-r-trimethyl-V, / - diphenyl-4- 9- (2-pyridinylmethyl) -9H-purin-8-ylZamino J-1-piperi- Dinbutanamide, so pl. 143 ° C (compound 68). i
    Using the procedure of any of examples 27-33 using the appropriate starting materials, the following compounds are also obtained: 9- (4- -fluorophenyl) methyl-N-1- (1-methyl-ethyl) -4-piperidinyl-9H-puryl-8-amine ,
    thirty
    35
    (compound 88); (9- (4-fluorophenyl) methyl | -9H-purin-8-yl1 amino) -1 -1-pip yrididinyl ethyl} - / .- thifencarboxamide (E) -2-butenioate (1: 2) monohydrate, t .pl. 135.2 ° C (compound 89); ({9- (4-fluorophenyl) methyl 3-9K- -purin-8-yl amino) -1-piperidinyl J ethyl J-2-thiazolecarboxamide (E) -2-bundioate (1: 2), m.p. 184.8 ° C (compound 90); 2-amino-M- 2- 4 - ({9-C (4- -fluorophenyl) methyl-9H-puryl-8-yl} -amino) -1 -piperidini) ethyl J benamide (E) -2- butandioate (2: 5), so pl. 16 ° C (compound 91); N - ((Ј9- (5-fluorophenyl) methyl-9H-puryl-8-yl} amino -1 - piperidinyl ethyl) -N-methylthiourea 184, (compound 69); 7- (4- on, t. mp 204.8 ° C (compound 92);
    - GLG-U G “l - /, .. h
    m.p.
    -fluorophenyl) methyl J-8- (1-methyl-4-piperidinyl) amino 3-7H-purin-6-ol, m.p. 255 ° C (compound 70); 9- (4-fluorophenyl) -methyl} -8- (1-methyl-4-piperidinyl) methyl 3 9H7Purin-6-ol, so pl. 218.5 ° C (compound 71); 9- (4-fluorophenylmethyl J-N- {1 -2- (2-pyridinyl))
    40
    N-2- 4- (9- (4-fluorophenyl) methyl J-9H- -purin-8-yl1methyl) -1 -, - 9- (4-fluorophenyl) methyl JN- (1-2 2- C (1 H-imidazo D, 5-c (pyridin-2-yl) amino-4-pyrididinyl} 9H-purin-8) -amine (E) -2-bundioate (1: 3) monohydrate, mp (compound 93); 9- (4-fluoro-ethyl-4-piperidinyl} 9H-purin-8-amine; nyl) methyl J-1,9-dihydro-8-1- (phenyl-4-l (- „„ „„ Oi ,, 0-p. 45 methyl) -4-piperidinyl methyl} -bN-puryl. Pl. 173, (compound 72); 9- (2-furanylmethyl) 2- (2-pyridinyl) - -ethyl J4-piperidinyl y-9H-8-purine-8-α-amnn, mp 145.3 ° C (compound 73);
    N- {1- 2- (2-pyridinyl) ethyl 1-4-piperisl. . ff. . r ...
    i п / ч "..„ 50 (compound 95): 4-GG4- (G7-G (4- (typpdinyl) 9- (2-thienylmethyl) -9H-puryl-8-- - VL v
    -amin, m.p. (compound 74); N-f1 (2-pyridinyl) ethyl J-4-piperidinyl J-9- (2-pyridinylmethyl) -9H-purine-8-amine, m.p. 164 ° C (compound 75); 9- (5-methyl-2-furanyl) methyl {1 - 2- - (2-pyridinyl) ethylJ-4-piperidinyl A,
    m.p. 196, (compound 94); , 9-K4-fluorophenyl) methyl J-8- (1 -12- (4-hydroxyphenyl) ethyl-4-piperidinyl j methyl) 9H-purine 6-ol, mp. 214.8 ° C
    . - - --.- phenyl) methyl 7H-purin-8-yl amimo) -1t. pl. 228 ° С
    -9H-puryl-8-amine, m.p. 163.2 ° C (compound 76) -; 4 - ({9-U4-fluorophenyl)
    piperidinyl} methyl yaphenol, (compound 96).
    Pharmacological examples.
    Useful antihistamine properties of compounds of formula (I), which can be used as an active ingredient in pharmaceutical preparations,
    24
    0
    five
    0
    methyl} -9H-purin-8-yl} amino) -1-piperidine ethanol, m.p. 158, (compound 77); 9- (4-fluorophenyl) -methylJ-N- (2-pilyridinyl-amino) -pipshdinyl-9H-puryl-8-amine, mp. 164.1 ° C (compound 78). Data on other compounds are given in Table. 7
    Similarly, compounds are obtained: 9- (4-fluorophenyl) methyl JN- (1-f2- (2-thiazolylamino) ethyl} -4-piperidyl-9H-8--amine, mp. 165 ° C (compound 86 ); 9- (2-furanylmethyl) -K- ((2-thiazolyl) amino} pentyl j-4-piperidine 1 - -9H-purin-8-amine, mp 188.5 ° С (compound 87 ); ((4-fluorophenyl) methyl-9H-purine-8-amino-1-piperidinyl) ethyl} -3-furancarboxamide (E) -2-butandioate (1: 2), mp 133 ° C
    e
    0
    35
    (compound 88); (9- (4-fluorophenyl) methyl | -9H-purin-8-yl1 amino) -1 -1-pip yrididinyl ethyl} - / .- thifencarboxamide (E) -2-butenioate (1: 2) monohydrate, t .pl. 135.2 ° C (compound 89); ({9- (4-fluorophenyl) methyl 3-9K- -purin-8-yl amino) -1-piperidinyl J ethyl J-2-thiazolecarboxamide (E) -2-bundioate (1: 2), m.p. 184.8 ° C (compound 90); 2-amino-M- 2- 4 - ({9-C (4- -fluorophenyl) methyl-9H-puryl-8-yl} -amino) -1 -piperidini) ethyl J benamide (E) -2- butandioate (2: 5), so pl. 16 ° C (compound 91); N - ((Ј9- (5-fluorophenyl) methyl-9H-puryl-8-yl} amino -1 - piperidinyl ethyl) -N-methylthiourea, mp 204.8 ° C (compound 92);
    on, so pl. 204.8 ° C (compound 92);
    - GLG-U G “l - /, .. h
    0
    N-2- 4- (9- (4-fluorophenyl) methyl J-9H- -purin-8-yl1methyl) -1 -, - 9- (4-fluorophenyl) methyl JN- (1-2 2- C (1 H-imidazo D, 5-c (pyridin-2-yl) amino-4-pyrididinyl} 9H-purin-8) -amine (E) -2-bundioate (1: 3) monohydrate, m.p. (compound 93); 9- (4-fluorof / Von.n.. ff.. r ...
    m.p. 196, (compound 94); , 9-K4-fluorophenyl) methyl J-8- (1 -12- (4-hydroxyphenyl) ethyl-4-piperidinyl j methyl) 9H-purine 6-ol, mp. 214.8 ° C
     (compound 95): 4-GG4- (G7-G (4- (Lpps- - VL v
    . - - --.- phenyl) methyl 7H-purin-8-yl amimo) -1t. pl. 228 ° С
    piperidinyl} methyl yaphenol, (compound 96).
    Pharmacological examples.
    Useful antihistamine properties of compounds of formula (I), which can be used as an active ingredient in pharmaceutical preparations,
    as demonstrated by the following tests.
    Example 35. Protection of rats against mortality caused by the compound 48/80.
    Compound 48/80, which is a mixture of oligomers formed by the condensation of 4-methoxy-N-methylbenzool ethane with formaldehyde, is a potent agent that removes histamine (Int.Areh, Allergy Protection against collapse, leading to fatal caused by compound 48/80 is a simple way to quantify the anti-histamine activity of test compounds. In the experiments, inbred males of Wistar rats weighing 240-260 g were used. Rats were not allowed to eat overnight, after which they were tolerated in the laboratory room where the temperature was maintained at 21 ± 1 C and relative humidity of 65 + 5%. The test compound or solvent (0.9% Nad solution) was injected subcutaneously or orally to the rats. An hour later, they were injected intravenously immediately before
    C NuOCOCHjOCOCHjOCOS with osoCaH /) SON 2-Pirazinyl-CK 4-FC H4-CH2 --N CN C3-CH j-4-FC H + -CH g - N ON CH 4-CH30-CtH 4-CH2-- N CN CH 4-Thiazolyl-CM g - N C-No Compound 48/80, srennoe in water in an amount of 0.5 mg / kg (0.2 ml / 100 g mass). In control experiments in which 250 solvent-treated animals were injected with a standard dose of 48/80, no more than 2.8% of the rats survived after 4 hours. Therefore, the criterion of the protective effect of the drug took the survival of animals after 4 hours.
    The values for the compound of formula (I) are given in table. 8. These values are those amounts of test compounds (in mg / kg mass) that protect 50% of experimental animals from death caused by 48/80.
    Example 36. Comparative data (table. 9).
    a) proposed compounds.
    b) known compounds (Table 10). Toxicity data Test subjects
    the compounds were administered to rats in various doses, the D ° 3U value was determined in mg / kg of mass at which 50% of the experimental animals died (Table 11).
    Table 1
    R
    one
    Cis-cis + trance
    27
    1581221
    Ri

    At
     fc
    cHj-O-tf-iUH
     x- / HiHVk.
    A:
    28 Table 2
    At
    k.
    A:
    CH9- CH9R
    R
    Table.4
    Table
    .31
    1581221
    About CH.
    32 table
    33 Table
    Compound by.
    L
    (CH2) 2 4-FC HfCHj
    IN
    QpCH2-CH2 f Vwi-CH9-CH9 Ay-gn
    UJj- 2 2 n iT CH.c

    Jnt
    A-CKjO-C H -CH rCH4 r N-CH,
    J
    1581221
    34 Continuation of table 8
    T a l and ca 9
    R
    LD 48/80 test
    0.04
    0.01
    0.02 0.01
    - 35
    I
    f N-CH2-CH2 4-F-ctH4-c
    Cg
    CH
    fr
     4-F-ceH4-i
    L
    tf-CH2-CH2 G lTCH2o, i6
    4-CH 30-C4 H 4-CH 2
    Table 11
    Compound Size LDj ,,, ResultsExcellent
    mg / kg 48/80 test, safe
    ED value mg / kg
    75400,
    172400,
    141400,
    115400,
    7440 0,
    Compiled by G. Zhukova Editor N, Yatsola Tehred M. Morgental Proofreader A. Promoted)
    Order 2026 Circulation 323 Subscription
    VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, F - 35, 4/5 Raushsk nab.
    Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
    LD50 48/80 test
    c
    Ch.
    0.08
    i
    CH0, 16
    Cho
    .
    0.16
    权利要求:
    Claims (1)
    [1]
    IV) if is hydrogen, then g / 0 or S / 0, or T is different from a simple bond, or their pharmaceutically acceptable salts with acids, or stereoisomers, characterized in that N is acylated with piperidine of the general formula II where R p R 2 , B and A, = A 2 -A 3 -A 4 have the indicated meanings with a reagent of the formula L, - СУН 4r - Т -C S X 3 - W, where r, S, Т and L- have the indicated meanings and mean a reactive cleaved group such as a halogen or sulfonyloxy group,.
    in a solvent inert under the reaction conditions and, if desired, the compounds of the formula I are converted into a pharmaceutically acceptable salt with an acid by reaction with the corresponding acid, or vice versa, the salt with an acid by reaction with alkali is converted to the free base.
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    同族专利:
    公开号 | 公开日
    FI862655A0|1986-06-23|
    KR930009356B1|1993-09-28|
    EP0206415B1|1993-01-27|
    CA1267889A|1990-04-17|
    FI85704C|1992-05-25|
    NO862504D0|1986-06-23|
    IE861674L|1986-12-24|
    US5041448A|1991-08-20|
    DK295286A|1986-12-25|
    ES8800682A1|1987-11-16|
    PT82824A|1986-07-01|
    GB8515934D0|1985-07-24|
    IL79193D0|1986-09-30|
    AU588890B2|1989-09-28|
    AT85055T|1993-02-15|
    GR861580B|1986-10-21|
    EP0206415A2|1986-12-30|
    DK169073B1|1994-08-08|
    ES556381A0|1987-11-16|
    DE3687601D1|1993-03-11|
    JPS62487A|1987-01-06|
    EP0206415A3|1988-03-16|
    NO163956C|1990-08-15|
    ZA864677B|1988-02-24|
    FI85704B|1992-02-14|
    HUT42095A|1987-06-29|
    NZ216536A|1988-10-28|
    DE3687601T2|1993-06-03|
    NO862504L|1986-12-29|
    HU199143B|1990-01-29|
    NO163956B|1990-05-07|
    KR870000335A|1987-02-17|
    DK295286D0|1986-06-23|
    PT82824B|1988-07-29|
    IE59658B1|1994-03-09|
    FI862655A|1986-12-25|
    AU5919186A|1987-01-08|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB858515934A|GB8515934D0|1985-06-24|1985-06-24|purines|
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