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    • 专利摘要:
    Compounds of the formula:- (wherein R3 represents -CONRR9, -COOR or -COC(R'°) (R")R; R4 represents -NR12R13 or -OR'2; R5, R6, R 7 and R8 each independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, (optionally substituted aryl)alkyl, fluoroalkyl, haloalkenyl, alkoxyalkyl, hydroxyalkyl, halogen, alkoxy, alkenyloxy, hydroxy, nitro, cyano or optionally substituted amino; R and R9 each independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, (optionally substituted aryl) alkyl, 4,5-dihydro-2-thiazolyl, alkoxyalkyl, hydroxyalkyl, fluoroalkyl or haloalkenyl, or R and R9 together form an alkylene group optionally interrupted by an oxygen atom or an alkenylene group; R10 and R" each independently represent hydrogen or alkyl; R12 and R13 each independently represent hydrogen, alkyl, acyl or cycloalkylalkyl) and the pharmaceutically acceptable salts and 1- or 2- position N-oxides thereof possess anxiolytic activity.
    公开号:SU1500158A3
    申请号:SU864027693
    申请日:1986-05-29
    公开日:1989-08-07
    发明作者:Франклин Джеймс
    申请人:Ай Си Ай Америказ, Инк.(Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new zolinin derivatives which can be used as depressants of the central nervous system.
    The purpose of the invention is the synthesis of new derivatives of zolinol, possessing biological activity that is not typical for this range of compounds.
    Example 1
    a) 4-Amino-8-pentyl-K- (2-propenyl) -3-zinolin-carboxamide (of formula I, R-i CONReRr, Ra Rt. R4
    sn
    3,150 Rfc-H, RS pentyl, R-f - 2-propyl).
    To a suspension of 4-amino-8 pentyl-3-cinnolinecarboxylic acid (2.46 g) in dry DMF (100 ml) was added 1.1-β-carbonyldiimidazole (1.69 g). The resulting mixture was stirred under nitrogen at room temperature for one hour. Then 2-propenylamine (0.61 g) was added and: (the mixture was stirred for another 2 hours. The resulting solution was poured into water (200 ml) and the product was extracted with two portions of ethyl acetate (each 100 ml). The combined organic extracts were washed with water and then with brine and finally dried (MgSOii). Evaporation yielded 2.42 g (yield 85%) of the title product as a white solid, substance. By recrystallization from a toluene / hexane mixture, an analytical sample was obtained as white crystals. Mp 122.5-124 ° C. H NMR spectrum (CHClg-d) 0.89 (triplet-, 3N), 1.32-1.4 8 (multiplet, 4H), 1.83 (triplet of the quartet, 2H), 3.41 (triplet, 2H), 4.16 (broad, triplet, 2H), 5.20 (doublet, 1H), 5, 30 (doublet, 1H), 5.98 (multiplet, 1H), 7.55-7.73 (multiplet, 3N), 8.68 (broad triplet, with exchange, 1H) ppm.
    Calculated: C 68.43; H 7.43 N 18.70 .-
    C H aN / iO
    Found: C 68.73; H 7.41; N 18.74.
    b). 2-Cyano-2- (2-pentsh1phenyl) hydronazone-acetamide (formula X, R (R4-H, RS -pentyl).
    Water (5 ml) and concentrated hydrochloric acid (5 ml) were added to a solution of 2-pantylaniline (2.56 g) in HOAc (10 ml). The solution was cooled to stirring, resulting in a suspension of white crystals. To the resulting mixture was added dropwise a solution of sodium nitrite (1.1 to 7. g) in water (6 ml), while maintaining the temperature inside the reactor below 5 ° C. The resulting solution was stirred for ten minutes at -5 ° C and then added to a solution of 2-cyano acetamide (4.1 g), in water (165 ml) containing sodium acetate (22 g), with cooling to 0 ° C. This mixture
    were mechanically stirred for 1 h at and then diluted with water (150 ml). After 10 minutes, the precipitated solid was collected by filtration and the filtrate was separated. . The solid was washed with water and then with hexane and dried in vacuo. The additional product which had precipitated upon standing of the filtrate at room temperature was similarly collected, washed and dried. Thus, 2.76 g (yield 66%) of the desired product was obtained as a mixture of (E) - and (Z) -isomers. As a result of recrystallization of a small sample from a mixture of ethyl acetate / hexane, an analytical sample of (E) -isomer was obtained as yellow crystals. Mp. 141-143,5 S.
    Calculated: C 65.09 H 7.02; N 21.68.
    C 4H4aN40
    Found: C, 65.27; H 6.92-; N 21.72. :
    B) 4-Amino-8-pentyl-3-zinolincarboxamide (Formula IX, R (, R 5 -pentyl).
    Aluminum chloride (3.54 g) was added to a suspension of the product from Example 1. (D (2.76 g) in dry toluene (50 ml). The resulting mixture was stirred under nitrogen for 1 hour under an atmosphere. Then the reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 ml) and stirred, carefully adding water until the precipitate had stopped, then the mixture was stirred with an aqueous solution of sodium hydroxide (200 ml 10% w / v solution) for 30 minutes, the aqueous layer was separated and discarded, leaving a suspension of the product in the organ The resulting suspension was subsequently shaken with an aqueous solution of sodium hydroxide (100 ml of 10 May./vol.% solution) and water (100 ml) and the resulting aqueous layers were discarded. The organic phase was diluted with hexane (200 ml) and cooled to. A precipitated white solid was collected by filtration to obtain 2.02 g (yield 73%) of the desired product. An analytical sample was obtained in the form of white crystals by recrystallization from ethanol. M.p. 229-.
    Calculated: C 65.09; H 7.02) N 21.68.
    See H, g
    Found: C, 64.87; H 7.06; N 21.63.
    d) A-Amino-B-pentyl-3-cynoclicarboxylic acid (VI, R / I-H, Cp-pentyl,).
    To a suspension of 2.0 g of the product from Example 1.0 in ethanol (100 ml) was added an aqueous solution of sodium hydroxide (20 ml of a 10 May / vol.% Solution). The mixture was heated until reflux was started while stirring for 16 hours. The resulting solution was cooled to room temperature and treated with NOLS until reaching. The resulting slurry was cooled to and then filtered, resulting in a white solid, which was washed with water and then dried under vacuum. 1.5 g (75% yield) of the desired product was obtained. By recrystallization from ethanol, an analytical sample was obtained in the form of white crystals. M.p. 208-210 ° C.
     Calculated: C, 64.85; H 6.61; N 16.20.
    .rNjOQ
    Found: C, 64.59; H 6.63; N 16.01
    Examples 2-13. Following the procedures described in examples 1, a-1., But replacing with 2-propenyl, using 10
    15
    1500158 -6
    After warming to room temperature overnight, the mixture was diluted with water (100 ml) and the reaction product was extracted with ethyl acetate (100 ml). The organic phase was washed with water (100 ml) and then brine (100 ml) and finally dried (MgSO4. After evaporation, a solid remained, which was purified by flash chromatography on silica gel, elution was carried out with a mixture of hexane / ethyl acetate. As a result of recrystallization of the mixture Toluene / hexane obtained the whole compound in the form of white crystals and in the amount of 0.43 g (yield 35%). mp. 124-125 ° C.
    Calculated: C, 68.48; H 7.43; 18.70.
    ,
    Found: C 68.60; H 7.40; 18.84.
    Example 15. 4-Am1P1o-8-ne 25 -N- (2-propynyl) -3-zinolin-carbox (forgul I, RI - CONRfiR, R6-H, R5-pentil, R - 2-propynyl
    An alternative method for preparing the compound of Example 13 is the following. The procedure of Example 14 was used, but replacing 2-propenylamine with 2-propynylamine. The target compound was obtained in the form of white crystals in 38% yield. M.p. 129-130 C, and NMR (CHClg-d
    20
    N
    N
    thirty
    in stage (a) in order to provide 35 only characteristic peaks):
    wei
    corresponding substituents for the radicals R and R7 to the corresponding amine, a number of compounds of the formula I were obtained (R 2 CONR 6 Rr, R5 pentil, and the values of RS and R 7 are listed in Table 1). The data obtained in examples 2-13, are presented in table. one... :
    Example 14. 4-Amino-8-pen-tsh1-K- (2-propenyl) -3-zolinolin-carboxamide (formula I, R - CONReR, Rb-pentyl, R-f - 2- -propenyl).
    An alternative method for preparing the compound of Example 1.a. To a suspension of 4-amino-8-pentyl-3-zolinolinecarboxylic acid (1.08 g) in dry (25 ml) were added 2-propenylamine (0.24 g) and diphenylphosphoryl azide (1.15 g). After cooling, triztilamine (0.42 g) was added and the mixture was stirred under a nitrogen atmosphere for two hours.
    2.28 (triplet, 1H), 4.31 (doublet of doublet, 2H), 8.73 (wide triple with 1H exchange) ppm.
    40
    45
    Calculated: C 68.90, H 6.80, N 18.90.
    C, .HzdN / 0
    Found: C 68.66; H 6.68; N 18.73.
    Example 16. 4-Amino-Y-meth-8-pentyl-K-propyl-3-nucleolcarboamide (formula I, Ri - CONRoRf, Ri2 Ro ,, R-neHTitn, K-propyl, RY-methyl).
    An alternative method for the compound of Example 4 is the following. Method 14 was used, but replacing 2-propenylamine with N-MCTHJi-N-npoinu 55 amine. The target compound was obtained in the form of a white solid powder with a yield of 39% and this is true of all aspects of the bicho-i.i; g; 1entich
    50
    ten
    15
    500158 -6
    After warming to room temperature overnight, the mixture was diluted with water (100 ml) and the reaction product was extracted with ethyl acetate (100 ml). The organic phase was washed with water (100 ml) and then brine (100 ml) and finally dried (MgSO4). As a result of evaporation, a solid remained, which was purified by flash chromatography on silica gel, elution was carried out with a mixture of hexane / ethyl acetate in a ratio of 2: 1. As a result of recrystallization from a mixture of toluene / hexane, the target compound was obtained in the form of white crystals and in the amount of 0.43 g (yield 35%). M.p. 124-125 ° C.
    Calculated: C, 68.48; H 7.43; 18.70.
    ,
    Found: C 68.60; H 7.40; 18.84.
    Example 15. 4-Am1P1o-8-pentyl-25 -N- (2-propynyl) -3-zinolin-carboxamide (forgul I, RI - CONRfiR, R6-H, R5-pentil, R - 2-propynyl).
    An alternative method for preparing the compound of Example 13 is the following. The procedure of Example 14 was used, but the 2-propenylamine was replaced with 2-propynylamine. The target compound was obtained in the form of white crystals with a yield of 38%. M.p. 129-130 C, and NMR (CHClg-d,
    20
    N
    N
    thirty
    35 characteristic peaks only):
    2.28 (triplet, 1H), 4.31 (doublet of the doublet, 2H), 8.73 (broad triplet, with an exchange of 1H) ppm.
    Calculated: C 68.90, H 6.80, N 18.90.
    C, .HzdN / 0
    Found: C 68.66; H 6.68; N 18.73.
    Example 16. 4-Amino-Y-methyl-8-pentyl-K-propyl-3-cycloalkylcarboxamide (formula I, Ri is CONRoRf, Ri2 Ro ,, R-neHTitn, K-propyl, RY-methyl).
    Alternatively, the method of preparing the compound of Example 4 is the following operation. Method 14 was used, but the 2-propenylamine was replaced with the N-MCTHJi-N-npoinuT-amine. The target compound was obtained as a white solid with a yield of 39%, and this was true of all aspects of the bicho-i.i; g; 1entich
    but the compound obtained in example 4.
    Example 17, a) 4-Amino-8- -butyl-H- (2-propenyl) -3-zinolincarb-oxamide (formula I, R (- CONRuRTi, Rg-butkp, Rj - 2-propyl).
    The procedure of Example 1.a was used to substitute D-amino-B-pentip-3-tsyn-lincarboxylic acid for 4-amino-8-β-butyl-3-1D1-lino-carboxylic acid. The crude product was purified by flash chromatography on silica gel, eluting with hexane / ethyl acetate (1: 1). By recrystallization from toluene / hexane, the title compound was obtained as white crystals with a yield of 69%. M.p. 126-127 "S.N. NMR (CHClj-d, only characteristic peaks): 4.15 (wide triplet 2H), 5.20 (doublet, 1H), 5.33 (doublet 1H), 5.96 ( multiplet, 1H), 8.68 (wide triplet with exchange, 1H).
    Calculated: C, 67.58; H 7.08; N 19.70.
    C bHcoN / iO
    Found: C, 67.39; H 7.23-, N 19.60.
    5) 2-L (2-Butylphenyl) hydrazonol-2-cyanoacetate (formula X, Rq -H, Rg-butyl).
    Following the procedure of Example 1. But replacing 2-pentylaniline with 2-butyl-aniline and maintaining the internal temperature below -10 ° C during the addition of sodium nitrite solution, in 75% yield, the desired product was obtained as a mixture (E) - and (Z) -isomers. Recrystallization from ethyl acetate / hexane gave an analytical sample. M.p. TZO-PZ S.
    Calculated: C, 63.92; H 6.60 N 22.93.
    C ,,, 0
    Found: C, 63.77; H 6.73; N 22.84.
    B) 4-Amino-8-butyl-3-zinolincarb oxamide (Formula IX, R6 is butyl).
    Following the procedure of Example 1.b, but replacing 2-cyano-2-C (2-pentylphenyl) - hydrazonoZ-acetamide by 2-G (2-butt-phenyl) hydrazono-1-2-cyanoacetamide. The desired compound was obtained in 86% yield. By recrystallization from ethanol, an analytical sample was obtained. Mp. 215-217.5 ° C.
    Calculated: C 63.92, H 6.60; N 22.93.
    Found: C, 63.61; H, 6.48, - N 22.45.
    2) 4-Л№1но-8-butyl-3-zolinolcarboxylic acid (formula VI, R (R (-H, R5- (5ytil,)).
    Following the procedure of Example 1.2, but replacing 4-amino-8-pentyl-3-zinolin-carboxyamide with 4-amino-8-butyl-3-quinoline-carboxamide, the target compound was obtained in 61% yield. By recrystallization from ethanol, an e-analytical sample was obtained. M.p. 218-220 ° C.
    Calculated: C 63.65, H 6.16, N 17.13.
    CwHisNjOu Q Found: C 63.23; H 6.14; N 16.70.
    Example 18-22. Following the method described in Examples 17.-17.3, but replacing 2-propenylamine used in step (a) to provide the appropriate substituents for Rt and t for the corresponding amine, a number of compounds of formula I were obtained. (R CONR6R - (,, R 4-H, K5-butyl, and the values of R and R are listed in Table 2)., Obtained in Examples 18-22, are presented in Table 2.
    0
    Example 23
    a) 4-Amino-N- (2-propenyl) -8-propyl-3-zolinolin-carboxamide (Formula I, R -CONR6R7,, R6-propyl, R-f - 2-propenyl).
    The procedure of Example 1 was used, a, replacing 4-amino-8-pentyl-3-zolinolin-carboxylic acid with 4-amino-8-propyl-3-zinolincarboxylic acid. The crude product was purified by flash chromatography on silica gel, eluting with hexane / ethyl acetate.
    (1: 1).
    0
    By recrystallization from a mixture of toluene / hexane, the target compound was obtained in 74% yield as white crystals. M.p. 115-117 ° C. Spectrum H NMR (, only characteristic peaks): 4.16 (broad triplet, 2H), 5.21 (doublet, 1H), 5.34 (doublet, 1H), 5.96 (multiplet, 1H), 8.68 (wide triplet with exchange, 1H).
    Calculated: C, 66.65; H 6.71; N 20.73.
    91
    Found: C 66.73 N 6.71 N 20.6
    5) 2-Cyano-2- (2-propylphenyl) Sodium acetamide (formula X, Cs-H, K5-progls).
    Following the procedure of Example 1., but replacing 2-pentylaniline with 2-propyl-aniline and maintaining the internal temperature below -12 ° C during the addition of sodium nitrite solution, the target product was obtained in 89% yield as a mixture (E) - and (d) isomers. Recrystallization from ethyl acetate / hexane gave an anilithic sample of the {E) -isomer, m.p.
    128-130 C.
    Calculated: C 62,59; H 6.13, N 24.33.
    C aHwN40
    Found: C, 62.56; H, 6.16; N 24.37
    B) 4-Amino-8-propyl-3-zolinolincarboxamide (formula IX, R ,, EE-PROPIL),
    Following the procedure of Example 1.b, but replacing 2-cyano-2-G (2-pentiphenyl) -hydrazono-acetamide with 2-cyano-2- (2- -propylphenyl) hydraz-tamide, the desired product was obtained in 81% yield. By recrystallization from ethanol, an analytical sample was obtained in
    as white crystals. M.p. 249-250 C.
    Calculated: C 62,59; H 6.13; N 24.33.
    , 0
    Found: C, 62.31; H, 6.30; N 23.47.
    2) 4-Amino-8-propyl-3-zolinolcarboxylic acid (formula VI, R4-H, Rg-nponmi,).
    Following the procedure of Example 1.2, but replacing 4-amino-8-pentyl-Z-zolinolin-carboxamide with 4-amino-8-propyl-3-quinoline-carboxamide, the target compound was obtained in 62% yield. Crystallization from ethanol gave an analytical sample in the form of white crystals. M.p. 216-218 C.
    Calculated: From 59.99; H 5.87; N 17.49.
    CipHijNjOQ- 1/2 HgO
    Found: C, 59.35; H 5.54; N 17.16.
    Examples 24-28. Following the procedures described in examples 23.a.23.3, but replacing 2-propenylamine (used in part (a) to provide the corresponding 1111 substituents for R6 and RT) with the corresponding
    58
    ten
    vuyupaj amine, received a number of compounds of the formula I (R, CONR6R7,, N, propyl, and R6 and RT are listed in table 3). The data of examples 24-28 are presented in table. 3
    Example 29. a) 4-Lm1io-8- -pentyl-H- (2-propenyl) -3-zinoline-carboxamide (formula I, R -CONRcRf,, R5-pentil, R-2-pr-phenyl),
    The third way to prepare the compound of Example 1.a is the following. To a solution of (g) -2-cyano--2- (2-pentylphenyl) hydrazono-C- (2-propane l) -acetamide (1.2 g) in nitrobenzene (20 ml) was added aluminum chloride (1, 6 g) and the stirred mixture was heated to 40-50 ° C in an atmosphere and the mixture was diluted with ethyl acetate (1.00 ml) and then cooled to O c. An aqueous solution of sodium hydroxide (100 ml of 10 May, / v / v% solution) was added and stirring was continued for an hour. The organic phase was separated, successively washed with an aqueous solution of sodium hydroxide ((50 ml of a 10 May / vol.% Solution), water (5 ml) and brine (50 mp) and finally dried (MgSOfl). As a result, the reddish a liquid that was concentrated to distillate 1. The oily residue was purified by flash chromatography on silica gel, elution was carried out first with dichloromethane in order to remove the residual nitrobenzene. substances in the amount of 0.70 g (yield 58%). A sample was obtained by recrystallization from a toluene / hexane mixture analytically, in all respects identical to the substance obtained in Example 1a.
    5) (E) -2-Cyano-2-C2-pentylphenyl hydrazonot-M- (2-propeyl) acetamide (formula VIII, RT-2-propenyl).
    A solution of 2-pentylaniline (1.63 g) in HOAc (7 ml) containing water (3.5 ml) was cooled before and concentrated hydrochloric acid (3.5 ml) was added, resulting in a suspension of neine. rx crystals. To the resulting mixture, pacTB jp of sodium nitrite (0.94 g) in water (4 ml) was added dropwise, ensuring that the rate was cooled to keep the internal temperature at a lower level. After the addition was complete, the clear yellow solution was stirred for ten minutes and then carefully added to the stirred mixture of 2-cyano-2-2 propenylacetamide (1.36 g), sodium acetate (7.0 g), ethanol (35 ml) and an aqueous solution of sodium carbonate (70 ml of a 1M solution) of KOTopbDi was pre-cooled to. There was a release of gas. The resulting slurry was stirred for 2 hours at 0 ° C, then diluted with water (100 ml) and extracted with ethyl acetate (200 ml). Prepared by the reaction of ethyl cyanoacetate with 2-propenylamine according to a known procedure. M.p. 60-62 ° C.
    The organic phase was separated, washed with water (100 ml) and then brine (100 ml), and finally dried (MgSOif). As a result of plugging in, a solid was obtained, which was purified by flash chromatography on silica gel, elution was carried out first with hexane in order to remove non-polar impurities. As a result of elution with an ether / hexane mixture (1: 1), a product was obtained, which was recrystallized from hexane with the addition of 1.24 g (yield 42%) of the product as yellow needles. M.p. 81.5.
    Calculated: C 68.43; H 7.43J N 18.78. ,
    CnH iNflO
    Found: C 68.48; H 7.12; N 18.88.
    Example 30. 4- Amino-N-8-dipropyl-3-zolinolin-carboxamide hydrochloride (formula I, R -CONRuR, ,, R5-propyl, Rr-propyl, hydrochloride).
    To a solution of a portion of the product from example 24 (0.55 g) in ethyl ether (50 ml) was added an ether solution of hydrogen chloride to stop the precipitation. The resulting mixture was cooled to and filtered, and then the collected solid was washed with ethyl ether. Thus, 0.59 g (yield 95%) of the title compound was obtained as a white solid, m.p. 215-233 ° C (decomposition).
    Calculated: C 58.34J H 6.85; N 18.14.
    C, 5 HnpNjO HC1
    Bulk: C 57.95) H 6.92- N 17.93.
    PRI me R 31.
    a) 4-A yno-8-butyl-N-cyclopropyl-methyl-3-zolinolin-carboxamide (Formula I, R-t-CONRuR, Rr2., R i-butyl, R7-ICCHKlpropylmethyl).
    The preparation of the product of example 20 was carried out on a larger scale as follows. A suspension of 4-am1-1-no-8-butyl-3-zincolinecarboxylic acid (25.0 g) in dry DMF (625 ml) was prepared by gradually adding a solid to the rapidly stirred solvent at room temperature under a nitrogen atmosphere. 1,1-Carbonyldimidazole (19.96 g) was added to this suspension and the creeping mixture was stirred at room temperature for 60 minutes. The resulting clear, light brown solution was cooled before and with vigorous stirring (aminomethyl) cyclopropane (8.71 g) was added with a syringe. After 2 hours, the mixture was allowed to warm to room temperature. The resulting mixture was diluted with ethyl acetate (500 ml) and water (500 ml) was added. The phases were separated and the organic layer was washed three times with water (each portion 500 ml) and once with brine (500 ml). After drying (MgSO4), the resulting solution was filtered through a layer of silica gel above the diatomaceous earth, and the filter was washed with ethyl acetate. The combined filtrate and ethyl acetate wash were evaporated to give 25.83 g (yield 85%) of the title compound as a light brown solid.
    Analytical pure material was obtained according to the following procedure. 25.83 g of the obtained material were combined with 23.11 g of the product obtained as follows. After dissolving in ethyl acetate (300 ml), a solid was applied by scrubbing the solution onto silica gel (100 g). This material was placed at the top of the column with an additional amount of silica gel (250 g), eluted with hexane / ethyl acetate (3: 1). As a result of elution
    The solvent mixture gave a purified product (45.93 g) after evaporation of the corresponding fractions. This material was recrystallized from toluene / hexane to form 38.53 g of analytically pure white crystals. M.p. 125-127 C.
    H NMR spectrum (CHCl j, -d characteristic peaks only): O, 30 (multiplet, 2H), 0.56 (multiplet, 2H), 0.96 (triplet, 3N), 3.34-3.45 ( multiplet, 4H), 8.68 (broad singlet with an overtone, 1H) ppm
    Calculated: C 68.43; H 7.43; N 18.78.
    CirH sN / iO
    Found: C 68.41, H 7.30; N 18.76.
    5) 2-Methyl-3-propylindole.
    Phenylhydrazine (162.2 g) was placed in a reaction flask equipped with a mechanical stirrer, a reflux condenser with a drying tube attached to it, an internal thermometer and a dropping funnel. Acetic acid (900 ml) was added, resulting in an orange solution. Then to the mixture
    0
    which was combined with the obtained, distilled 1 to form a total of 159.1 g (yield 61%) of the target compound, which was used immediately in step (&).
    fe) N-2-1-Oxobutyl / phenyl acetamide.
    To a stirred solution of 2-methyl-3-propylindole (159 g) in methanol (1370 ml) under nitrogen atmosphere, a solution of sodium periodate (430.4 g) in water (2450 ml) was added over an hour. If necessary, external cooling was used to maintain the reaction temperature at or below 25 s. After stirring overnight at room temperature, the resulting mixture was diluted with water (7 L) and extracted with dghloromethane (2 L). The phases were separated and the aqueous layer was extracted twice with dichloromethane (o 1 liter each), the combined 5 organic phases were washed twice with water (1.5 liter portions), dried (MgSOi) and evaporated to give 246 5 g raw product. This substance was purified by two followers5
    0
    2-hexanone (170 g) was added over the course of Q chromatography operations.
    5 minutes and the resulting mixture was heated under reflux and with stirring for three hours. After cooling, the acetic acid was removed on a rotary evaporator and the residue was poured into water (4.5 L). This mixture was extracted three times with ethyl ether (each portion of 1 l) and the combined organic extracts were washed twice with IN solution of HCl (each time with 1 l), once with water (1.5 l), once with saturated sodium bicarbonate solution (1 l) and then once with brine (1 l). Then the organic layer was dried (MgSO4) and sharpened to form an oil, which was purified by two successive vacuum distillations. The target compound (72.1 g) was obtained as an oil distilled in the range of 91.5-95 ° C at a pressure of 0.0067 Pa.
    An additional portion of the target compound was obtained by chromatographing the residue on silica gel (500 g), eluting with dichloromethane. Evaporation of the appropriate fractions provided an additional amount of the substance.
    35
    40
    on silica gel, wire. elution of the desired product with dichloromethane. After evaporation of the corresponding fractions, 160.6 g (yield 85%) of the desired product is obtained in the form of white solid crystals. M.p. 46,
    2) N- 2- (1-Hydroxybutyl) phenyl / - acetamide.
    A solution of sodium borohydride (30.54 g) in absolute ethanol (2400 ml) was prepared and it was stirred in a nitrogen atmosphere while cooling the reaction mixture until. A solution of (1-oxobutyl / phenyl-tacetamide (156 g) in dry THF (1200 ml) was added over 25 minutes, using, if necessary, external cooling, in order to maintain the internal temperature of the systems) 1 in the interval 5-7 ° C. After the addition was complete, the mixture was allowed to warm to room temperature overnight with stirring under a nitrogen atmosphere. The solvents were removed on a rotary evaporator, and the residue was treated with water (1575 ml). The resulting mixture was cooled with ice, while adding in a small portion of 50
    55
    five
    0
    on silica gel, wire. elution of the desired product with dichloromethane. After evaporation of the corresponding fractions, 160.6 g (yield 85%) of the desired product is obtained in the form of white solid crystals. M.p. 46,
    2) N- 2- (1-Hydroxybutyl) phenyl / - acetamide.
    A solution of sodium borohydride (30.54 g) in absolute ethanol (2400 ml) was prepared and it was stirred under a nitrogen atmosphere while cooling the reaction mixture until. A solution of (1-oxobutyl / phenyl-tacetamide (156 g) in dry THF (1200 ml) was added over 25 minutes, using, if necessary, external cooling, in order to maintain the internal temperature of the systems) 1 in the interval 5-7 ° C. After the addition was complete, the mixture was allowed to warm to room temperature overnight with stirring under a nitrogen atmosphere. The solvents were removed on a rotary evaporator, and the residue was treated with water (1575 ml). The resulting mixture was cooled with ice, while adding in small portions 0
    five
    MI IN solution of HCl (945 ml) until gas is stopped. Then, solid potassium carbonate (150 g) was carefully added and the resulting solution was extracted with ethyl acetate (1575 ml). The organic phase was washed with brine (1 L), dried (MgSOfl) and added to give 156.1 g (99% cake) of the desired product as a yellow oil. This substance was used in step (f) without further purification.
    Q) H- (2-Buthphenyl) acetamide. A suspension of 10% by weight of palladium on carbon (7.8 g, moistened with an additional 50% by weight of water) in absolute alcohol (625 ml) containing 156 g of N-2- (1-hydroxybutyl) -phenyl-acetic amide, and add 3.2 ml of concentrated hydrochloric acid. The mixture is shaken with an excess pressure of about 345 Pa (50 pounds per square inch) of hydrogen gas. When the uptake of hydrogen ceased (after about 24 hours), the mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give 135.3 g (yield 94%) of the title compound as a white solid with mp. 96.5-99.5 C. This material is used in step () without further purification.
    e) 2-Butane-1-hl hydrochloride (Formula XI, R / i-H, Rs-butyl, hydrochloride salt).
    A mixture of L- (2-butylphenyl) acetamide (135.3 g), concentrated hydrochloric acid (300 mp) and 30Q ml of 95% ethanol is heated to reflux with refluxing and stirred for 4 hours. After cooling to room temperature, the mixture is diluted with water (800 mp) and cooled with ice while solid potassium carbonate (approximately 275 g) is carefully added to a pH value of 10. This solution is extracted twice with cyethyl 1 M ether (750 ml each time) , the combined ether extracts are washed with 1 liter of brine and dried with magnesium sulfate. When the solvent is removed, an oil is obtained which is distilled at a pressure of from 0.008 to 0.013 Pa (from 0.06 to 0.1 µm Hg), obtaining 100.1 g of a liquid that is distilled between
    do 55 and. This distillate is dissolved in 800 MP of diethyl ether, and with vigorous stirring under a nitrogen atmosphere, a saturated solution of hLorous hydrogen (400 mp) is added. The precipitate formed is collected by filtration, washed with diethyl ether and dried in a vacuum desiccator over phosphorus pentoxide, to obtain 122.8 g (out, 94% progress) of the title compound as white crystals with mp. 144.5.
    G) 2- (2-Butylphenyl) hydrazone-2-cyanoacetamide (formula X, R5-butyl).
    A suspension of hydrochloric 2- -butylaniline (61.89 g) is prepared in a pre-cooled mixture of solvents — acetic acid (200 ml), water (128 ml) and concentrated hydrochloric acid (72 ml) and held with efficient stirring. With strong external cooling, which is necessary to maintain the temperature inside the mixture between -13 and a solution of 25.68 g of sodium nitrate in 117 ml of water is added dropwise in about 20 minutes. The resulting clear solution is dissolved for 15 minutes at and then filtered into a previously prepared pre-cooled (to) solution of 2-cyano-acetamide (84.08 g) in water (3.33 L) containing 444.5 g of sodium acetate. There is an instant color change to an intense yellow, and then a yellow precipitate forms. The reaction mixture is stirred in a bath at -12 ° C for 3 days. After lowering the temperature, the precipitated product is precipitated by
    filtration and washed with hexane (300 ml), then with cold water with ice (300 ml) and again with hexane (300 ml). After drying in vacuo
    50
    55
    at 40 ° C over phosphorus pentoxide, the indicated compound is obtained as a mixture of (E) - and (2) -isomers in an approximate 2: 1 ratio. The product yield is 95%, 77.39 g, yellow powder with so pl. 160-162 ° C.
    In another preparative synthesis, part of this compound is subjected to recrystallization from a mixture of ethyl acetate and hexane and get
    analytical sample, which is dominated by (E) -isomer and which has so pl. 130-138 C.
    Calculated: C, 63.92; H 6.60; N 22.93.
    C, iH,
    Found: C 63.77, H 6.73, N 22.84.
     j) 4-Amino-8-butyl-3-zinc. lin-carboxamide (formula XI, (H C-butyl).
    Three identical reaction mixtures were prepared as follows. A suspension of 2- (2-butylphene1) hydrazo-2-cyanoacetamide (25.59 g) in dry toluene (600 ml) was stirred under nitrogen atmosphere, while 35 g of anhydrous aluminum chloride. The mixture is heated to 90. with stirring under nitrogen for 3.5 hours. After cooling to room temperature, each mixture is diluted with ethyl acetate (800 ml). With external cooling and effective stirring, a solution of sodium hydroxide (20 g in 100 ml of solution) is added dropwise until the intense yellow color of each mixture disappears. An additional hour (500 ml) of sodium hydroxide solution (100 g) is then added to each mixture and the resulting suspensions are stirred for 2 hours while cooling with ice. The phases are then separated, and the aqueous phase is poured. The organic layers containing the suspended product are then washed with an aqueous solution of sodium hydroxide (50 g) in 250 ml of the solution (for the dead layer), and the aqueous phases are also poured. Finally, the organic phases are washed with water (250 ml for each phase). The suspended product is then isolated by filtration of the combined organic phases. This solid is washed with water (300 ml), twice with ethyl acetate (300 ml) and twice with diethyl ether (300 ml). After drying in vacuo over phosphorus pentricide, 73.5 g (yield 96%) of the title compound are obtained as a white solid.
    Using material from another analogous preparative synthesis, a part of this substance is subjected to recrystallization from ethanol to obtain an analytically pure sample with mp. 215-217.5 ° C.
    Calculated: C, 63.92; H 6.60, N 22.93.
    C,
    Found: C, 63.61; H 6.48, N 22.45.
    U) 4-Amino-8-butyl-3-tsylnolpk-Q boic acid (formula VI, CL-H, Cs-butyl,).
    Two identical reaction mixtures were prepared as follows. A mixture of 4-amino-8-butyl-3-cinnoline-5 boxed (36.71 g), absolutized ethanol (1400 ml) and 300 ml of an aqueous solution of sodium hydroxide (60 g of alkali) is heated under reflux with stirring. 6 hours. 0 After cooling to room temperature, the solvent (ethyl alcohol) is removed on a rotary evaporator. The solids are combined and treated with water (2.5 L). Using effective stirring and external cooling, concentrated hydrochloric acid is added to achieve a final pH of 5.1. After cooling Q, no precipitated solid is collected by filtration and washed twice with diethyl ether (250 ml each time). After drying in vacuo with phosphorus pentoxide, 62.77 g (yield 85%) of the title compound are obtained as slightly yellowish white powder.
    Using material from another analogous preparative synthesis, part of the title compound is recrystallized from ethyl alcohol to obtain an analytically pure sample with mp. 218-220 C.
    Vyisleno: C 63.65; H 6.16; N 17.13.
    С, г, Н, 5Нз05
    Found: C, 63.23; H 6.14, N 16.70.
    Example 32, 4-Amino-8-butyl-N-cyclopropylmethyl-3-cinnolinecarb-oxamide hydrochloride monohydrate (Formula I, R -CONReR7,, KB of butyl, R7-CIPLopropylmethyl, hydrochloride salt monohydrate). To a vigorously stirred solution of a portion of the product from example 64 (6.0 g) in diztypom ether
    0
    five
    0
    nineteen
    1500158
    (650 mp) an ethereal solution of hydrogen chloride is added until the precipitation stops. The mixture is cooled before and then filtered. After washing the collected solids with two portions of ethyl ether (but 50 ml in each portion), the product is dried at 35 ° C under vacuum. In this way, 6.73 g (yield 95.6%) of the title compound are obtained in the form of a slightly yellowish white solid, Art. Ш1. 174-181.5 C (with decomposition).
    Calculated: C 57.86; H 7.14, N 15.88.C R NifO HC1- Found: C 57.60; H 6.93; N 15.48.,
    Example 33
    a) 4-Amino-H-cyclopropylmethyl-8-β-propyl-3-cinnoline-carboxamide (Formula I. R-CONR R7, R5, propyl, R7-cyclopropylmethyl),.
    The product of example 26 is prepared in a preparative synthesis of a larger scale as follows. A suspension of 4-amino-8-propyl-3-cinnoline-carboxylic acid (39.8 g) is obtained in dried dimethylformamide (1 l) by slowly adding a solid to a thoroughly mixed solvent under a nitrogen atmosphere. To this suspension, 40 g of 1,1-carbonidiimide dazole are added in small portions over 1 hour with vigorous stirring. After another hour, 29 g of triethylamine (dried by distillation over potassium hydroxide) and then 23 g of hydrochloride (a (nomethyl) cyclopropane) are added. The resulting mixture is stirred for 1.5 hours at room temperature under a nitrogen atmosphere. 1300 MP of water are drunk and the product is extracted with 5 portions of ethyl acetate (500 MP each each). The combined organic layers are washed with 1 l of brine, dried with magnesium sulfate and evaporated to obtain a light brown solid. This material is purified by chromatography on a silica gel on the next m todike. After dissolving in ethyl acetate (1 liter) non oMischenny product was evaporated onto the surface of the annealed silica gel (250 g). This was loaded onto a silica gel column with additional top annealed silica
    20
    0
    (1 kg) in a mixture of hexane / ethyl acetate (3: 1 by volume). The desired product is eluted from the column with a mixture of hexane / ethyl acetate (2: 1 by volume). The compacted fractions are combined and isolated, giving 39.01 g (yield 80%) of the title compound as a white solid. Upon recrystallization from a mixture of toluene and hexane, 31.5 g of analytically pure material are obtained in the form of white crystals with m.p. 128-129 0.
    PMR spectrum (in deuterium chloroform, only characteristic peaks):
    0.30 (multiplet, 2H), 0.57 (m, 2H), 1.05 (triplet, 3N), 3.35-3.42 (m, 4H), 8.69 (broad singlet, capable of to exchange, 1H) h / million
    Calculated: C, 67.58; H 7.09 $ 19.70.
    C feH-zoNflO
    Found: C, 67.52; H 7.09 19.68.
    o) 2-Cyano-2- (2-prrpylphenyl) hydrazono-acetamide (formula X, Rj (-H, RQ-npomvi),
    The 2-propyl-aniline hydrochloride salt is obtained by dissolving an industrial sample of 2-propyl aniline in diethyl ether with the addition of an ethereal solution of chloro-hydrogen to hydrogen until a precipitate forms. This precipitate is collected by filtration, washed with ether and dried (quickly under vacuum) to give 2-propylaniline hydrochloride, which is immediately, but used in accordance with the following procedure. A suspension of this material (34.33 g) is prepared in a pre-cooled mixed solvent consisting of 120 ml of acetic acid, 77 ml of water and 43.4 ml of concentrated chloride.
    N
    five
    0
    0,
    five
    prenatal acid, and hold it with and efficient mixing. Using the strong external cooling that is needed for
    mixture temperature between
    flow
    a period of about 20 minutes, a solution of sodium nitrite (14.21 g) in 67 ml of water. The mixture is then stirred for 15 minutes at and then filtered into a solution prepared in advance and cooled to 50.44 g of 2-cyanoacetamide in 2 l of water containing 266.7 g of sodium acetate
    -15 and add to
    five
    -
    ri. An immediate color change to an intense yellow is observed, followed by the formation of a yellow precipitate. The reaction mixture is stirred in a cooling bath for 2 days. After heating to a precipitate, it is collected by filtration and alternately held with hexane and cold ice water. After drying at 45 s under vacuum over phosphorus pentoxide, 42.12 g (yield 91%) of the title compound are obtained as a mixture of (E) - and (d) isomers.
    Using the material obtained by repeating this procedure, a part of the indicated substance is subjected to recrystallization from a mixture of ethyl acetate / hexane, to obtain analytically
    pure sample (E) -isomer with t.pl, 128-130 ° C.
    Calculated: C 62,59; H 6.13, N 24.33.
    C iH NflO
    Found: C 62.56, H 6.16, N 24.37.
    &) 4-Amino-8-pro-1-3-cinnoline-carboxamide (Formula IX, R (K5 propyl).
    Prepare two identical reaction mixture as follows. A suspension of 2- (2-butshphenyl) hydrazo-2-cyano-acetamide (21.05 g) in dry toluene (502 ml) is stirred under a nitrogen atmosphere, while anhydrous aluminum chloride (30.5 g) is added . These mixtures are heated to with stirring for two hours. After cooling to room temperature, each mixture was diluted with ethyl acetate (800 ml each). Using external cooling and effective mixing, a 20% (mass-volume) aqueous solution of sodium hydroxide is added dropwise until the orange color of each reaction mixture completely disappears. When the addition of alkali is completed, an additional portion of a 20% w / v solution (500 ml) of sodium hydroxide is added to each mixture, and the resulting suspensions are stirred under external cooling with ice for 2 hours. The phases are then separated and the aqueous layers are poured .
    The organic phases containing the suspended product are carefully
    01
    d 5
    20
    25

    thirty
    40
    0
    5822
    Shake with 250 ml of an aqueous solution of sodium hydroxide (50 g of alkali), and these aqueous layers are also drunk. Finally, each organic phase is washed with water (250 ml). At this point, the suspended solid is poured by filtration of the combined organic layers. After washing with water (250 ml), double washing with ethyl acetate (200 ml each time) and triple washing with diethyl ether (200 ml each), the resulting solid was dried under vacuum with phosphorus pentoxide. Thus, 40.17 g (yield 95%) of the indicated substance are obtained in the form of a white solid.
    Using the material from re-synthesis, a part of this substance is subjected to recrystallization from ethyl alcohol, to obtain a sample with so pl. 249-250 C.
    Calculated: C 62,59; H 6.13, N 24.33.
    C 2HnN /, 0
    Found: C, 62.31; H 6.30; N 23.47.
    2) 4-Amino-8-propyl-3-cinnolin-carboxylic acid (formula VI, .Rb-prosh,).
    A suspension of 4-amino-8-propyl-3-cinnolinecarboxamide (40.1 g) in ethanol (1650 ml) is treated with 348 ml of aqueous 20% (w / v) sodium hydroxide solution, and the mixture is heated for 8 hours under nitrogen at reflux temperature. After cooling to room temperature, the solvent (ethanol) is removed on a rotary evaporator, and the residue is suspended in water (1500 ml). Using external cooling, which is necessary in order to maintain the temperature of the mixture below 40 ° C, concentrated hydrochloric acid is added with effective stirring until the final pH value of 5.0 is established. After cooling, the precipitated product is taken up by filtration and rinsed twice with cold water and ice (200 ml each) and four times with diethyl ether (200 ml portions). After drying in vacuo over phosphorus pentoxide, the title compound is obtained as a white solid. Yield 39.50 g (98%).
    Using the re-synthesis material according to the etSam method, a part of this compound is recrystallized from ethyl alcohol to obtain an analytically pure sample with mp. 224 C (with decomposition).
    Calculated: C, 62.33; H 5.67; N 18.17.
    C, 2H bN50Q
    Found: C, 61.99; H 5.85, N 17.89.
    Example 34. 4-Amino-N-cyclo-propylmethyl-8-propyl-3-cinnolinecarboxamide, hydrochloride, monohydrate (Formula 1, RH COKbct, Kb-H, R5-propyl, R7-cyclo propylmethyl, hydrochloride monohydrate salt).
    To a vigorously stirred solution of a portion of the product from Example 33 (6.5 g) in DIETSH1 ETHER (750 ml) was added a solution of hydrogen chloride in diethyl ether until further precipitate formation ceased. This mixture was stirred at room temperature for 15 minutes and then filtered. The collected solid is washed with diethyl ether (approximately 150 ml) and then with hexane (approximately 150 ml) and finally dried at room temperature in vacuo. Thus, 7.2 g (yield 98%) of the title compound are obtained in the form of a slightly yellowish white solid with mp. 212- 218 C (with decomposition).
    Calculated: C 56.73; H 6.84; N 1-6,54.
    C46HuoN-iO НС1- Н О
    Found: C, 56.96; H 6.69; N 16.32.
    Example 35 4-Amino-8-butyl 10
    15
    20
    25
    thirty
    35
    40
    The spectrum of SHGR (in deuterium chloroform, only characteristic peaks): h / mn: 0.96 (triplet, ZN), 3.41 (t, 2H), 3.54 (t, ZN), 8.55 (wide singlet exchangeable, 1H).
    Calculated: C, 69.20; H 7.74; N 17.93.
    C gH-JL4N40
    Found: C, 69.27; H 7.74; N 17.84.
    (Aminomethyl) cyclobutane is crawled by reduction of cyclobutane oxamide with lithium aluminum hydride according to a well-known Procedure. Cyclobutancarboxamide is prepared as follows: The solution of available available cyclobutanecarboxylic acid chloride (10-g) in 500 ml of diethyl ether is stirred at 0 ° C and ammonia gas is simultaneously introduced, which causes the white residue to dissolve. This material is collected by filtration. and redissolved in 50 ml of aqueous ethanol (80% v / v alcohol). This solution is fed to a column containing 75 g of ion-exchange resin AG 1-X8 (in the form of a hydroxy ion, obtained from Bio-Rad), and the elution with ethanol (1 l) is continued. Upon evaporation of the eluate, a quantitative yield (8.36 g) of cyclobutane carboxes is obtained.
    Yes. - - g
    Example 36. 1- (4-Amino-8-butyl-3-cinnolinyl) carbonyl -2,5- -dihydro-1H-pyrrole (formula I, R, -CONR6R7, -H, Rg-butyl, Rj, and Rf taken together form the -CH group CHCHCH2 .-).
    Following the methods of examples 17.ano replace the 2-propenylamine used in example 17.a with an industrial sample of pyrroline (purity 75%
    -N-cyclobutylmethyl-3-cinnolinecarboxy- obtained from the company Aldrich), polusamide (formula I, Rj-CONReRi, 4, R5-butyl, R7-cyclobylmethyl).
    Following the procedure of examples 17.a-2, but the deputy of n-2-propyleneil shn, used in example 17.a, on (aminomethyl / cyclobutyl, the indicated compound is obtained with a yield of 62% in the form of a beige solid. When recrystallized from a mixture toluene / hexane obtained an analytically pure sample of white crystals from T.Sh1. 118.5-119.
    five
    0
    five
    0
    five
    0
    The spectrum of SGR (in deuterium chloroform, only characteristic peaks): h / mn: 0.96 (triplet, ZN), 3.41 (t, 2H), 3.54 (t, ZN), 8.55 (broad singlet exchangeable, 1H).
    Calculated: C, 69.20; H 7.74; N 17.93.
    C gH-JL4N40
    Found: C, 69.27; H 7.74; N 17.84.
    (Aminomethyl) cyclobutane is crawled by reducing cyclobutanecarboxamide with lithium aluminum hydride according to a known Procedure. Cyclobutancarboxamide is prepared as follows: a solution of commercially available cyclobutanecarboxylic acid chloride (10-g) in 500 ml of diethyl ether is stirred at 0 ° C and at the same time gaseous ammonia is introduced, which results in the precipitation of a white precipitate. dissolved in 50 ml of aqueous ethanol (80% v / v alcohol). This solution is fed to a column containing 75 g of an ion-exchange resin AG 1-X8 (in the form of a hydroxy ion, obtained from Bio-Rad), and the elution with ethanol (1 l) is continued. Upon evaporation of the eluate, a quantitative yield (8.36 g) of cyclobutane carboxes of DA is obtained. - - g
    Example 36. 1- (4-Amino-8-butyl-3-cinnolinyl) carbonyl -2,5- -dihydro-1H-pyrrole (formula I, R, -CONR6R7, -H, Rg-butyl, Rj, and Rf taken together form the -CH group CHCHCH2 .-).
    Following the methods of examples 17.a2, but replacing the 2-propenylamine used in example 17.a, with an industrial sample of pyrroline (75% purity,
    50
    said compound as a light tan yellow-pink powder with a yield of 20% after recrystallization from ethyl acetate. M.p. 164-165 C (with decomposition). Attempts
    to purify this material by means of additional recrystallization led to intensive decomposition of the substance. PMR spectrum (in chloroform, only characteristic peaks): ppm: 0.96 (triplet, 3N), 4.58 (multiplet, 2H), 5.00 (m, 2H), 5.90 (wide singlet, 2H).
    251
    Calculated: C 68.90; H 6.80; N 18.90.

    Found: C, 67.96; H 6.67; N 18,58.
    Example 37. 4-A ai-8-butyl-N-cyclopropyl-3-cinnoline-carboxamide 1/4-hydrate hydrochloride salt (formula I, R | -CONR R7,
    , K5-butyl, K-cycloproshsh, quarter-hydrate hydrochloride salt).
    Following the procedures of examples 17, a-2 but replacing 2-propenylamine, used in example 17.a with cyclopropylamine, the title compound (the free base form as a white solid (substance, 86% yield This material is dissolved in diethyl ether, filtered, and a solution of hydrogen chloride in diethyl ether is added to the filter until further precipitation stops. The precipitated material is collected by filtration and dried in vacuo to obtain the indicated substance with a yield of 55%, mp. 198-210 C (with pa false).
    Spectrum of PNR (in deuterodimethylsulfoxide, only characteristic peaks), ppm: 0.69-0.79 (multiplet, 4H), 0.91 (triplet, 3N), 2.95 (multistet, 1H) , 3.20 (t. ZN).
    Calculated: C 59.07; H 6.66; N 17.22.
       HCl- 1 / 4HQO.
    Found: C 58.93; H 6.8 D; N 17.18.
    Example 38, -4-Amino-H-methyl-8-propyl-M- (2-propynyl) -3-cinnoline-carboxamide (Formula I, Ri-CONRfcRj, Rj R3 Rfl-H, Rj-propyl, R - 2-propynyl, Ry-methyl).
    Following the procedures described in Examples 23.a-2, but replacing the examples used in Example 23.a 2-propenylamine with N-methyl-H- (2-propynyl) amine, the indicated compound is obtained as
    light brown solid with a yield of 38% after recrystallization from toluene, so pl. 133-135 C (with decomposition). When trying to purify the substance by additional recrystallization, intense decomposition was observed. The SHER spectrum (in deuterochloroform, only characteristic peaks) ppm: 1.04 (triplet, 3N)

    Q
    5 0 5 0
    five
    0
    five
    0
    five
    5826
    2.28 (broad singlet, EUT, 4.46 and 4.83 (two broad singlets, 2H).
    Listed: C 68.09; H 6.43; N 19.84.
    Cffch gn o
    Found: C 68.43; H 6.48; N 19.03.
    Example 39. 4-AmiHo-N- (2- -methylpropyl) -8-pro-1-3-cinnoline-carboxamide (Formula 1, K4 CONTx Rr R2 R5-Ri R6-H, Rs-nponnn, R7-methylpropyl) .
    Following the procedures described in examples 23.a-2, but replacing that used in example 23.a 2-propenylamine with 2-methylpropylamine, the indicated compound is obtained as off-white crystals, 46% yield after recrystallization from a mixture of toluene and hexane, t .pl. 104-1.
    PMR spectrum (in deuterium chloroform, only characteristic peaks ;: ppm: 1.02 (doublet, 6H), 1.05 (triplet, 3N), 3.30-3.42 (multiplet, 2H), 8.50 (wide triplet, capable of exchange, 1H).
    Calculated: C 67.11; H 7.74; N 19.56.
    CfgHceNijO
    Found: C, 66.91; H 7.63; N 19.63.
    Example 40. 1- (4-Amin0-8-β-propyl-3-cinnolinyl) carbonyl pyrrolidine (Formula I, R -CONRfiR, .Rfj, R5-propyl, Re, and R7, taken together, represent - CH CHcCHjCHQ-).
    Following the procedures described in examples 23.a-2, but replacing 2-propenylamine, used in example 23.a, with pyrrolidine, the indicated compound is obtained as white crystals with a yield of 67% after recrystallization from a mixture of toluene and hexane, m.p. . 154-156 C. PMR spectrum (in deuterium chloroform, only characteristic peaks), ppm: 1.04 (triplet, 3N), 3.42 (t. 3N), 3.77 (t. 2H), 4 , 11 (t. 2H),
    Calculated: C, 67.58; H 7.09, N 19.70.
    C 6HeoN40
    Found: C, 67.38; H 7.11; N 19.56.
    Example 41. 1- (4-Amino-8- -propyl-3-cinnolin) carbonyl piperidine, 1/4-hydrochloride hydrate ((bopNryla I, R, -CONRsR7, R2 R3 Rfl-4. R.
    .271
    -propyl, Ky and RT, taken together, represents the group -CH, 2CH | 2CH, quarter-hydrate hydrochloride salt).
    Following the procedures described in Examples 23.a-d, but replacing 2-propylamine, as used in Example 23, a, with piperidine, the indicated compound is obtained in the form of the free base as a clear oil. This oil is dissolved in diethyl ether and a solution of hydrogen chloride in diethyl ether is added until precipitation stops. This precipitate is collected and dried in vacuo to give the title compound as a white powder. Yield 78%, mp. 142-150 C. Spectrum 1SHR (in deuterodimethylsulfide side, only characteristic peaks), ppm: 0.99 (triplet, 3N), 1.4-1.8 (multiplet, 6H), 3.13 (t 2H), 3.42 (broad singlet, 2H), 3.71 (broad singlet, 2H).
    Calculated: C 60.17; H 6-, 98; N 16.51.
    C rHceN O-HC1 1/4 NbO Found: C 59.88; H 6.89, N 16.44.
    Pr and 1 ep 42 .. 4-G (4-Amino-8- -propyl-3-cinnolinyl) carbonyl S-morpholine, 1/6-hydrate hydrochloride (formula I, R-CONR 6ll 7, R4-propyl, R and Ry, taken together, represents a group -CHraCHg-O-CHriCHg-, hydrochloride salt, 1/6 - hydrate.
    Following the procedures described in Examples 23.a-2, but replacing 2-propenylamine, as used in Example 23.a with morpholine, the indicated compound is obtained in the form of a free base in the form of a clear oil. This oil is dissolved in diethyl ether and an ether solution of hydrogen chloride is added until the precipitate is stopped. The precipitated material was collected by filtration and dried in vacuo to give the title compound in 55% yield as a white powder with mp. 210-213 C. PMR spectrum (in deuterodime tilsulfoxide, only characteristic peaks), ppm: 0.99 (triplicate EF), 3.13 (t, 2H), 3.55 (multiplet 4H), 3 , 75 (broad singlet, 4H).
    Calculated: C 56.65; H 6.98; N 16.49.
    0
    five
    0
    five
    158
    28
    , 2 () N40.HCl 1/6 NeO
    Found: C, 56.54; H 6.23; N 16.07.
    Examples 43-45. Compounds of formula I (R / -CONR6Rr, Rfa-H, R-nopyl, and R (2, RS R / i and R5 such as indicated in Table 4) are listed in Table 4.
    Example 46
    a) 4-Amino-8-butyl-7-chloro-K-prr-pil-3-dinolyn-carboxamide (formula I, R -CONR6R7, chlorine, R5-butyl, R7-propyl).
    To a suspension of 4-amino-8-butyl-7-chloro-3-cinnolinecarboxylic acid (1.2 g) in dried dimethylformamide (30 ml) was added 1.1-carbonyldiimidazole (0.84 g) and the mixture was stirred at at room temperature under a nitrogen atmosphere for 2 hours. Then, 0.425 ml of propylamine is added and the mixture is stirred at room temperature for an additional 30 minutes. 75 ml of etipacetate and the mixture were washed three times with water (100 ml each) and once with brine (100 ml). After drying with magnesium sulfate and evaporation of the solvent, the resulting crude product is purified by flash chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate (2: 1 by volume). The corresponding fractions were combined and evaporated to give a light beige solid, which after recrystallization from a mixture of ethyl acetate and hexane gave the title compound (0.50 g, 36% yield) as white crystals with mp. 156-158 C. PMR spectrum (in deutero-chloroform, only characteristic peaks), ppm: 0.97 (triplet, 3N), 1.03 (triplet, 3N), 7.63 (AB-quartet, 2H).
    Calculated: C 59.90) H 6.60; N 17.46.
    With NShDOS
    Found: C 59.90, H 6.62; N 17.36.
    5) 3-Hlop-N- (2,2-dimethyl-propion-1) -2-methyl 1-aniline.
    Industrial sample Z-chloro-2- -methylaniline is purified before use by repeated distillation. To a solution of this distilled material (16.5 ml) in 200 ml of dichloromethane was added 200 ml of an effective aqueous solution of sodium carbonate 30
    40
    45
    50
    55
    The ri and the resulting two-phase system are thoroughly mixed. Using external cooling, which is necessary in order to maintain the temperature of the mixture below, 18.71 ml of trimethylacetyl chloride was added dropwise. The mixture is stirred at room temperature overnight and then the phases are separated. The aqueous phase is extracted with additional dichloromethane (100 ml). The combined dichloromethane extracts were washed with 100 ml of brine, dried with magnesium sulfate and evaporated to give a white solid, which was subjected to recrystallization from hexane. Thus, 28.79 g (yield 92%) of the indicated substance are obtained in the form of white needles with m, pl. 113-113.3 pp.
    Calculated: C, 63.86; H 7.14; N 6.20.
      NOC1
    Found: C 64.02J H 7.08; N 6.36.
    ) 2-Butsh I-3-chlorop-N- (2,2-dimethyl-propionyl) aniline.
    A solution of 3-chloro-H- (2,2-dimethylpropionyl) -2-methylaniline (9.79 g) in dried tetrahydrofuran (150 ml) is stirred under a nitrogen atmosphere while a solution of n is added dropwise - butyl lithium in hexane, until a weak orange color is obtained on the mixture. The volume of the n-butyl lithium solution added is noted, and then an equal volume of this n-butyl lithium solution is added to the mixture to complete the formation of the raw material dianion. Then the final solution with a deep orange color is stirred for 15 min and then 7.92 g are added After 15 minutes, the reaction mixture was diluted with water (250 ml) and extracted with diethyl ether (300 ml).
    The organic layer was washed with brine, dried with magnesium sulfate and evaporated to obtain the title compound as a white solid (yield 97%, 11.38 g), upon recrystallization from hexane, an analytically pure sample was obtained with mp. 88-89 C.
    Calculated: C, 67.28; H 8.28; N 5.23.
    ten
    five
    0
    c, 5H, 2eNoci
    Found: C 67.43, H 8.42, N 4.98. .) 2-Butyl-3-chloroaniline hydrochloride (formula XI, R (2.Rs, -H, K-chloro, teel).
    2-Butyl-3-chloro-L- (2,2-dnmethylpropionyl) ash1 1 (12.89 g) is combined with 6 N. hydrochloric acid (145 ml) and acetic acid (145 ml) and heated with stirring in over night The reaction mixture is then cooled to room temperature, which results in a white precipitate of this compound, which is filtered and washed with diethyl ether. The filtrate is alkalinized by adding a 20% w / v solution of sodium hydroxide and then extracted with diethyl ether. This organic extract is rinsed with water and successively brine, then dried with magnesium sulfate. After cooling 5, an ethereal solution of hydrogen chloride is added, which results in the precipitation of an additional amount of the indicated compound. This precipitate is collected by filtration and combined with the previously separated solid. A total of 8.47 g (75% yield) of the title compound is obtained, with a mp. 1b9-179 C.
    Calculated: C 54.56, H 6.87, N 6.36.
     Im NC1 HC1
    Found: C 54.48, H 6.90; N 6.17. ) 2-f (2-Butyl-3-chlorophenyl) hydrazone-J-2-cyanoacetamide (formula X, Rc-chloro, Rg-butyl).
    A suspension of 2-butyl-3-chloroaniline-β-hydrochloride (10.37 g) in a mixture of acetic acid (29 Mji), concentrated hydrochloric acid (15 ml) and 45 ml of water is cooled to -15 ° C with stirring. Sodium nitrite solution is added dropwise to this mixture (3.41 g in 15 ml of water, keeping the temperature of the mixture below. The resulting yellow color is stirred for 15 minutes and then the entire solution is poured into the prepared solution 11 at a time, 9 g of 2-cyanoacetamide in 500 ml of water containing 59 g of sodium acetate and pre-cooled to. This mixture is stirred at 0 ° C for four hours and then allowed to warm.
    0
    five
    0
    five
    0
    to room temperature overnight. The mixture is then diluted with water and the product is extracted with ethyl acetate. The ethylatetate solution is washed with brine and condensed to a small volume in order to obtain crystals of the compound in the form of a mixture of (E) - and (d) -isomers. Yield 83%. (10.9 g), m.p. 166.5 C.
    Calculated: C 56.02; H 5.42; N 20.10.
    .
    NaDdeno: C 55.38-, H 5.35; N 19.94 e) 4-Amino-8-butyl-8-chloro-3-cinnolin-carboxamide (Formula IX, Rg Rb-H, Cd-chloro, Rg-butyl) .:
    Anhydrous aluminum chloride (13.0 g) is added to a suspension of 2- {(2-butyl-3-chlorophenyl) hydrazonoT-2-cyano-adamide (10.9 g) in dried toluene (250 ml) and the mixture is heated to nitrogen with stirring for 3 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate (500 ml) and cooled to. A 20% w / v solution of sodium hydroxide in water (200 ml) is then added and the mixture is stirred for about 1 hour at room temperature or below. The phases are separated and the organic layer is washed with a 20 ppm / v% solution of sodium hydroxide, water, and brine in the sequence indicated. Upon evaporation, a yellow solid is obtained which is triturated with hexane and filtered. By recrystallizing this solid from ethyl acetate, 5.3 g (yield 49%) of the title compound are obtained as a white solid. Analytically pure sample is obtained by additional recrystallization from ethyl alcohol, so pl. 234-235 C
    Calculated: C 56.02; H 5.42; N 20.10.
    , 5N40C1
    Found: C, 56.15; H 5.48; N 20.07.
    ICC) 4-Amino-8-butyl-7-chloro-3-cinnolin-carboxylic acid (Formula VI,. -H, R4-hlop, R5-butyl,).
    A mixture of 4-amino-8-butyl-7-chloro-3-cinnolinecarboxamide (5.3 g), 180 ml of ethyl alcohol and 40 ml of aqueous 20 May / vol,% sodium hydroxide solution is refluxed. in nitrogen atmosphere in
    for 5 hours. The mixture is cooled to room temperature, with most of the ethanol being removed on a rotary evaporator. The remaining precipitate is treated with water (200 ml) and cooled in ice with vigorous stirring, while concentrated hydrochloric acid is added to bring the pH of the mixture to 5.0. The resulting solid is taken up by filtration, washed with water and dried under vacuum with phosphorus pentoxide to give 2.9 g (yield 55%) of the title compound as a yellowish white solid with mp. 200-204 ° C.
    Example 47. 4-Amino-8-butyl-7-chloro-H-cyclopropylmeth-1-3-cyn-lincarboxide (Formula I, R-CGNR R,, R4-xlop, Rg-bytih, R-j-cyclopropylmethyl).
    Following the procedure of example 46.a, but replacing propyl amide with (aminomethyl) cyclopropane, the indicated compound is obtained in a yield of 42% after recrystallization from a mixture of diethyl ether and hexane: mp. 160.5-162 ,.
    Spectrum of the NDP (in deuterium chloroform, only xaractistically kie peaks), ppm: 0.30 (multiplet, 2H), 0.59 (m, 2H), 0.98 (triplet, 3N), 7.63 (broad singlet , 2H).
    Calculated: C, 61.35; H, 6.36; N, 16.83.
    C 7He N / jC01
    Found: C, 61.50; H 6.41; N 16.87.
    Example 48
    but). 4-amino-7-chloro-H-8-dipropsh-1 -3-cinnolinecarboxamide (formula I, Ri-CGNRuRr,, R4-xlop, R5 R7 Propyl.
    Following the procedure of Example 46a, but replacing 4-amino-8-butyl-7-chloro-3-cinnolinecarboxylic acid with 4-amino-7-chloro-8-propyl-3-cinnoline carboxylic acid, this compound is obtained in as an off-white solid, 75% yield. Upon recrystallization from toluene i, analytically pure white crystals are obtained with mp. 167.5-168.5 C.
     Spectrum of Poland (in deuterium chloroform, only characteristic peaks), ppm: 1.03 (triplet, 3N), 1.10 (triplet, 3N), 7.63 (broad singlet).
    33
    Calculated: C 58.73; H 6.24; 18.26. C jHigNflOCl fiauaeHo: C 58.88; H 6.26;
    N 18.31.
    S) 3-Chloro-K- (2,2-dimethylpropionyl) -2-propyl da1ilin.
    Following the winner of 46.4, but replacing with iodoethane, get a pointer compound with a yield of 73%. This material is suitable for the subsequent step without further purification.
    s) Z-Chloro-2-propylaniline hydrochloride (formula XI, K-chlorine U-propyl).
    Following the procedure of Example 46.2. But replacing 2-butyl-3-chloro-M- (2,2-dimethylpropionylaniline) with 3-chloro-N- - (2,2-dimethylpropion1) -2-propaniline, this compound is obtained with a yield of 73%, so pl. 185-190 C.
    Calculated: C 52.45; H 6.36; N 6.80.
    C 9 NC1 HC1
    Found: C, 52.80; H, 6.10; N 6,81
    2- (3-Chloro-2-propnylphenyl) hydrazono -2-cyanoacetamide (formula X,
    Cg | -CHLOR, KZ-PROPIL).
    Following the procedure of example bl, but replacing 2-butyl-3-chloroaniline hydrochloride with 3-chloro-2-propylaniline hydrochloride, the indicated compound is obtained as a mixture of (E) - and (g) isomers in 97% yield, t. square 175-182 With i. .
    Calculated: C 54.44; H 4.95; N 21.17.
    Found: C 54.35; H 5.03 ,. N 21.60.
    2) 4-Amino-7-chloro-8-propyl-3-zinc. Olyn carboxamide (formula IX, RC R5-H, K4-chloro, Rs-propyl).
    Following the procedure of Example 46.e, but replacing 2-G (2-butyl-3-chlorophenyl) hydrazone-3-2-cyanoacetamide by 2-G (3-chloro-2-propyl-phenyl) hydrazono-2-cyano-ietamide, this compound is obtained with a yield of 89%, so pl. 252-254 С,
    Calculated: C 54.44; H 4.95; N 21.17.
    Found: C 54.65, H 5.20; N.
    Q) 4-Amino-7-chloro-8-propyl-3-cinnolinecarboxylic acid (form 150015834
    la vi ,, ,, - H, K; chlorine, poison-propyl,),.
    Following the procedure of Example 46.7 (but replacing 4-am {o-8-butyl-7-chloro-3-cinnolinecarboxamide with 4-amino-7-chloro-8-propyl-3-nnnolinecarboxam 1dz), this compound is obtained from the output
    five
    five
    N
    N
    house 86%, so pl. 209-2.
    Example 49. 4-Amino-7-chloro-N-cyclopropylmethyl-8-g1ropyl-3-cinnolin-carboxamide (formula I, R CONRfiRj, Re R5 R6 is H, R-chloro, Rg- -propyl, K7- cyclopropylmethyl).
    Following the procedure of Example 4B.a, but replacing propylamine with (aminomethyl) cyclopropane, p-receive said compound in 65% yield. Recrystallization from toluene yields an ana-lytic sample with mp. 176-178 ° C.
    Calculated: C, 60.28; H 6.01; 17.57.
    , gN40Cl
    Found: C, 60.49; I - 6.02; 17.64.
    Examples 50-80. Using the method of example 1.a-2 or 14, the compounds of formula I were obtained, where R} (CONR6R7, (the original 2-propenyl amine of the above examples was replaced with amine formulas), where R, and RT are defined in Table 5.
    M.p. product of example 75 is given as the strength of its hydrochloride salt 3/4 hydrate, example 77 is given as tnA hydrochloride salt of monohydrate.
    The solvents used in the recrystallization of the compounds are as follows: in examples 50 and 70 - ethyl acetate / hexane (1: 1); in examples 51, 65-67, 69, 74, 75 - toluene / hexane; in examples 52, 53 , 56, 63, 64 - ethyl acetate, in examples 55, 71 and 72 - methanol / water, in examples 58-62, 68, 73 and 79 - toluene, in example 80 - diethyl sufir / hexane.
    Example 81 4-AMINO-8-TSI1SPO-propyl-Y-propyl-3-cinnolinecarboxamide (Formula I, R CONRjR7, Rcr
    0
    five
    five
    0
    five
    R5-cyclopropyl, R7-propyl).
    Following the procedure of Example 90, but replacing 1-bromo-3-pentine cyclopropyl bromide, the indicated compound is obtained in a yield of 88%. An analytically pure sample is obtained by recrystallization from toluene, mp. 153-155 ° C.
    HCH
    The spectrum of roiP (in deuterium chloroform only characteristic peaks), h.7mpn: 0.90 (multiplet, 2H),. 1.03 (triplet), 1.23 (m. 2H), 3.37 (m, 1H), 3.49 (doublet triplet.,
    comrade, 2H), 8.60 (broad for exchange, 1H).
    Calculated: C, 66.65; H N 20.72.
    capable
    6.71;
    C.sH.
    N
    Found: C, 66.80; H 6.69; 20.73.
    Example 82 4-Amino-8-phenyl-N-propyl-3-cinnoline-carboxamide (formula I, R / (SOYKbKt, R (j., Rg-phenyl, R7-propyl).
    Following the procedure of Example 90, but replacing the solution of 3-penteninyl magnesium bromide in tetrahydrofuran with an industrially available solution of phenyl magnesium chloride in tetrahydrofuran, the compound indicated in the preparation is obtained in a yield of 69% as a solid. An analytically pure sample is prepared by recrystallization from a mixture of toluene and hexane: the resulting white crystals have so pl. 115-117 ° C and contain 1/10 equivalent of residual toluene even after drying in vacuum. Sector PNR (in deuterium chloroform, only characteristic peaks) ppm: 1.00 (triplet, ЗН), 3.46 (doublet of triplets, .2Н), 7.40-7.54 (multiplet, ЗН), 7 , 68-7.88 (m. 5H), 8.60 (broad t., Capable of exchange, 1H).
    Calculated: C, 71.17; H 6.00, N 17.75. .
    C.
    1/10 toluene C 71.30; H 6.04;
    . Found: N 17.65.
    Example 83. 4-Amino-8-phenyl methyl-N-propyl-3-dinnolinecarboxamide (Formula I, R-CONR 6 R 7 R 6 -H, R s-Phenylmethyl, R f-shp). Following the procedure of Example 80, but replacing the solution of 3-Pentinyl Magnesium Bromide in tetrahydrofuran with a commercially available solution of benzyl Magnesium Chloride in tetrahydrofuran, this compound is obtained in 47% yield. An analytically pure sample is prepared by recrystallization from a mixture of toluene and hexane. Get white crystals with so pl. 176-177 ° C, which contain 1/10 equivalent of toluene even after drying in vacuum. Spectrum NDP (in deuterochloro
    form, only characteristic peaks), ppm: 1.03 (triplet, EF), 3.48 (doublet triplet, 2H), 4.83 (singlet, 2H), 8.58 (broad triplet, capable of exchange, 1H).
    Calculated: C, 71.79; H 6.36; N 16.99.
      1/10 toluene.
    Found: C, 71.93; H 6.39 N 16.99.
    Example 84. 4-AMINO-8-CIKPO-pentylmethyl-N-propyl-3-cinnolinecarb-oxamide hydrochloride monohydrate (formula 5, I, R, -CONRfeR,
    Cd-cyclopentylmeaste, R-f-propyl, hydrochloride salt monohydrate).
    Following the procedure of Example 80, but replacing 1-bromo-3-pentyl with (bromomethyl) 0 cyclopentane, the title compound is obtained in 16% yield in the form of a free base as a white solid. A portion of this material was dissolved in diethyl ether, and 5 the solution was treated with ethereal hydrogen chloride solution until the formation of a precipitate was stopped. This precipitate is collected and. dried under vacuum to obtain an analytically pure sample of the substance as a white powder with m.p. 210-214 C. The spectrum of the PNR (in deiodimethylsulfoxide, only characteristic peaks), ppm: 0.92 (triplet, 3N), 3.22 (doublet, 2H), 3.33 (doublet of triplets, 2H ), 8.98 (wide triplet, capable of exchange, 1H).
    Calculated: C 58.93; H 7.42; N 15.77.
    CijH24NflO HC1
    Found: C 59.94, H 7.25, N 15.24.
    (Bromomethyl) cyclopentane is prepared according to the following procedure. A solution of commercially available cyclopentanmethanol (20 g) in dried pyridine (220 ml) is stirred at, while 42 g of 4-toluene sulfonyl chloride are added. This mixture was stirred for 2 hours and then held overnight with no stirring. The mixture is then poured into water and the product is extracted with dichloromethane. The dichloromethane extract is washed with hydrochloric acid solution.
    (10 wt.% Vol. - HC1), with water, brine in the specified sequence and then dried with magnesium sulfate
    0
    0
    and evaporated. Thus, the desired intermediate compound, cycllopentyl methyl ether (A-methylphenip) sulfonic acid (44.42 g, yield 87%) is obtained in the form of a clear oil. This material was dissolved in dried dimethylformamide (175 ml) without further purification. Then, 45.5 g of lithium bromide is added with stirring. The mixture is heated to within three hours and then cooled to room temperature. The mixture is then diluted with pentane (800 ml) and washed with water (800 ml).
    The aqueous layer is extracted with additional pentane (200 W and poured. The combined pentane phases are washed with water (fOO ml) and brine (200 ml) in that order and then dried with magnesium sulfate. The solvent is distilled off at atmospheric pressure and the residue is then distilled in vacuo. The target (bromomethyl) cyclopentane is obtained in a yield of 83% (23.64 g) as a colorless mobile oil, distilled at 54–55 ° C and a pressure of 2 kPa (15 mm Hg).
    The results of biological tests (S.S.D tests for shock induction, suppression of drinking needs in rats, as well as F.N.B tests for flunitrazepam binding) are given in Table. 6
    Since there are no structural analogs with anxiolytic activity, known preparations based on compounds of the formulas are used as a comparison.
    NH2
    . t С02СН2СНз
    N 1
    -CsHu
    (SSD is inactive at doses of 50 mg / kg parenterally and 50 mg / kg intraperitoneally, FNB is inactive at doses up to
    500 mM, SSD 50 mg / kg, FNB (130 nM), which were tested on SSD and FNB using the above method.
    According to the reported data, the compounds exhibit excellent activity in SSD tests at a dose of 50 mg / kg, and in FNB tests, i.e. the ICcjc inhibitory concentration at which the compound exhibits 50% or more of the substitution of flingoanean specific (GH) flunitrazepam at test concentrations in the order of 50 nM and below.
    With regard to toxicity, the proposed compounds, at the tested doses, did not manifest as such and can be categorized as little toxic.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining the quinoline derivative of the general formula
    25
    R, NH2
    thirty
    where is r,
    About II
    -C-NRgR;
    five
    0
    five
    0
    five
    Rg-Rg
     identical or different, each hydrogen, C-C5 alkyl butenyl, pentynyl, cyclopentyl, cyclopropyl, cyclopentylmethyl, benzyl, phenyl, halogen, methoxy, hydroxybutyl, Rk and RI are the same or different, each hydrogen, provided that KB and RJ both cannot be hydrogen at the same time, C (-C4 alkyl, propyl, C-C-alkyn, phenyl, benzyl, cyclo-butylmethyl, cyclopropylmethyl, thienyl, 4,5-dihydrothiazol-2-yl ,: hydroxypropyl, fluoro-ethyl, having at least one fluorine atom, provided that there is no fluorine or carbon atom bound to the nitrogen, or K b and RT
    39
    together form a pyrrole, pyrrolidine, piperidine, morpholine group, or its acid addition salts, characterized in that the compound of the general formula
    15
    Note. By passing gaseous ash through the reaction mixture, the reaction temperature dropped to.
    1500158
    40
    where A is the carboxylic acid residue, is reacted with an amine of the general formula
    NH
    / Re rv
    where Rf and R-f have the indicated meanings, with isolation of the desired product as a base or interaction of the base obtained with an acid and isolation of the target product as a pharmaceutically acceptable acid addition salt.
    t a 6 l and c a 1
     Spreadsheets
    Note. By passing a gaseous amine through the reaction mixture, the reaction temperature dropped to 0 ° C.
    Table A
     Example 43 - the reaction temperature is up to the temperature of solvent P1, P1,
    reaction time increased to 8 h.
    Example 44 — The reaction temperature is raised to the boiling point of the solvent, the reaction time is increased to 28.5 hours.
    Table 3
    Table 5
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    同族专利:
    公开号 | 公开日
    IL78992D0|1986-09-30|
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    PL149227B1|1990-01-31|
    IE861267L|1986-11-30|
    IE58782B1|1993-11-17|
    US4886800A|1989-12-12|
    DK256386D0|1986-05-30|
    ES8802611A1|1988-10-01|
    AR242026A1|1993-02-26|
    EP0205272A3|1987-11-19|
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    CN86104358A|1987-04-01|
    FI85584B|1992-01-31|
    FI85584C|1992-05-11|
    PH23518A|1989-08-16|
    NO862141L|1986-12-01|
    CA1309406C|1992-10-27|
    DK162221C|1992-03-02|
    ZA863664B|1987-03-25|
    FI862315A|1986-12-01|
    GB8611419D0|1986-06-18|
    GB8513639D0|1985-07-03|
    EP0205272B1|1991-08-14|
    AU592086B2|1990-01-04|
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    DE3680828D1|1991-09-19|
    FI862315A0|1986-05-30|
    KR900004402B1|1990-06-25|
    ES557790A0|1988-10-01|
    AT66215T|1991-08-15|
    KR860008986A|1986-12-19|
    HUT41012A|1987-03-30|
    ES8801903A1|1988-03-01|
    NO171592C|1993-04-07|
    GR861411B|1986-08-28|
    MW4386A1|1987-06-19|
    DK162221B|1991-09-30|
    ES8801803A1|1988-02-16|
    ES555546A0|1988-02-16|
    CN1014060B|1991-09-25|
    DK256386A|1986-12-01|
    HU199433B|1990-02-28|
    EP0205272A2|1986-12-17|
    JPS61280483A|1986-12-11|
    ES557522A0|1988-03-01|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB858513639A|GB8513639D0|1985-05-30|1985-05-30|Cinnoline compounds|
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