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    • 专利摘要:
    1. A method for producing N-substituted 1-oxy-nicotinamide of the general formula -CO-NH-CH2-CHj-C Hg- where X is a nitrogen atom or a group; CH. Am - lower dialkylamine, lower dialkylamine ,. substituted by phenyl, pyrrolidine, morpholine, hexamethylene-imine, piperidine, piperidine, substituted once or twice with methyl kp hydroxyl or oxymethyl, piperazine, substituted in position 4 by lower alkyl or their pharmaceutically acceptable salts, o l and h and y and with the fact that they treat the amine of the general formula CMgAwi - CMP-CM2-CIR-0, where X and Am have the indicated values, a functional derivative of carbonic acid of the general formula O, in an organic solvent at 0-50 ° C, obtained the compound is isolated in free form and, if necessary, awns transfer tv odnuiz pharmaceutically priemlemk salts. 2. Method as described in Claim 1, characterized in that acid chloride is used as a functional derivative in the form of hydrochloride. 3. Method POP.1, different from the fact that the functional derivative has the general formula O N a. where k is nitrophenyl. Priority on the grounds of 13.08.82npuAff, -dialkylamine, piperidine, pyrrolidine, morpholine; 04/22/83 when A is lower dialkylamine, substituted by phenyl, hexamethylenimine, piperidine, substituted by methyl, hydroxyl, or hydroxymethyl.
    公开号:SU1212323A3
    申请号:SU833634875
    申请日:1983-08-12
    公开日:1986-02-15
    发明作者:Низато Дино；Бовери Сержио
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of N-substituted nicotinamide 1-oxides of the general formula
    CMjAm
    but
    co-NHl-CHj-CH-CHj-O where X is a nitrogen atom or a CH group;
    Atn - lower diapkylamine, lower dialkipamine, substituted by phenyl, pyrrolidine, morpholine, hexamethylenymia, piperidine, piperidine, substituted one or two times with methyl or hydroxyl or oxymethyl, piperazine, substitute at a position 4 with lower alkyl, or a pharmaceutical agent, or a pharmaceutical agent, or a pharmaceutical agent, or a pharmaceutical agent, or a substitute, or a pharmaceutical agent, or a pharmaceutical agent, or a substitute, or a pharmaceutical agent, or a pharmaceutical company, would replace a pharmaceutical agent with a mixture of 2 or more.
    The aim of the invention is the development, on the basis of known methods, of a method for the preparation of N-substituted 1-xynicotinamide or their salts, which can be used as selective and highly efficient receptor blockers for K. Receptors.
    Example I. To a mixture of 0.03 mol of 3- (3-pyrrolidin-methylphenoxy) -propylamine and 0.095 mol of pyridine in 10 ml of methylene chloride, while stirring with OS, portions of 0.047 mol of 1-hydroxychloride hydrochloride, mixture of sewed for 1 h at ambient temperature, after which the solvent is evaporated under reduced pressure. Using IN hydrochloric acid, the residue is removed, the resulting salts are removed {by diluting the formed salts and then extracted three times with 100 MP of ethyl acetate, sodium hydroxide is added to obtain basic pH. In 100 ml of ethyl acetate, the mixture is extracted four times, the organic phase is dried on anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The silica obtained is chromatographed on silica using methanol as eluant, the fractions of the obtained purified product are combined, the solution thus obtained is treated with a solution of oxalic acid in ethanol and the resulting precipitate is crystallized from ethanol.
    Obtain 3.5 g of one-and-a-half oxalt of N-3- (3-pyrrolidine-methylphenol
    S
    CI-propyl-3-pyrpdincarb6ximcd-1-oxyl, CM 57891A; m.p. 1.115-116 ° C Yield 30% of theoretical. I
    Calculated,%: C 56.32; H 5.75; N 8.57 SgoNg5 "uh .5 Found,%: C 55.98; H 5.58; N 8.38.
    A suspension of 1 g is obtained in this way; 1 o of the product is obtained in concentrated sodium hydroxide, then extracted in ethyl acetate, and the organic solution of tfi is evaporated under reduced pressure to dryness. After 24-48 hours, the residue crystallizes to form N-3- (3-pyrrolidinemethylphenoxy) -propyl-3-pyridine-carboxamide-1-oxide, CM 57891 i t.1.10G-103 C. Yield 90% of terre
    C, 67.58; H 7.09;
    Tic.
    Calculated,%: N G1,82.
    zoHjs d
    Found,%: C 67.01; H 7.02;
    . And, 68.
     examples 2-6. Similarly, for example I, and by the reaction of 0.03 mol of 3- (3-piperidinemethylphenoxy) propyl-amine, 3- (3-morpholinomethylphenoxy) -shch opila bina, 3- (3-dimetsch1aminmethyl-phenoxy) propylamine, 3- (3-di-n-g propylamine, methylphenoxy) -propylamine and 3- (3-d-d-and-butylaminomethylphenoxy) -propylamine with 0.047 mol of 1-hydroxycitric acid chloride, carried out in methylene chloride. Before each, the following compounds are obtained respectively.
    Sesquamate oxalat 3H-P3-piperidinemethylphenoxy) -propyl-3-pyridinecarbdxamide-1-oxide, SR58017A; T.SH1. 115-118 with example 2; yield 30% of theory.
    Calculated,%: C 57.13; H 5.99; N 8.33.
    C2,, 0, .1,5 С, Н, 0
    Found,%: C 57.00; H 5.93; N 8.27
    One-and-a-half oxapate (3-morpholinomethylphenoxy) -propyl-3-pyridinecarboxamide-1-oxide, SR580I6A; m.p. 152-155 With example-3; yield 32% From teopii.
    Calculated,%: C 54.54; H 5.57; H 8.30.
    С, „Н„ Ы, 0, 1.5 СН, 04
    Found,%: C 54.26; H 5.66; N 8.18
    N (3-dimethylamine-methylphenoxy) -propyl-3-pyridine-carboxamide-1-oxide oxalate, SR 58059A; m.p. 148-151 C (example 4) yield 35% of theory.
    Calculated: C 57.27; H 6.00; N 10.02.
    C, eH ,, N, 0 ,.
    WITH.
    Found,%: C 56.83; H 6.04; N9.97
    Oxalate (3-di-n-propionamine-methyl-phenoxy-propyl-3-pyridine carboxamide-1-oxide, SR 58030 A; mp. 168-170 with example j; yield 30% of theory.
    Calculated,%: C 60.62; H 6.92; K 8.84
    С „Н„ К, 0, С, Н, 04
    Found,%: C 60.83; H 7.13; N 8.91.
    N- 3- {3-di-n-butylamine methylpheno si) -propyl-3-pyridinecarboxamide-1-oxide, SR 58062, oil (Example 6), yield 33% of theory.
    Calculated,%: C, 69.70; And 8.53; 10.16.
    P4 "95", 0h
    Found,%: C 69.20; H 8.10; N 9.9
    PRI me R 7 ,. To a mixture of 0.023 mol of 3- 3- (4-methylpiperidinemethyl) -phenoxy-propylamine and 30 ml of pyridine, first mixed with OS, portions of 0.047 mol of 1-oxydnicotinic acid hydrochloride hydrochloride are added, then the mixture is stirred for 1 hour at ambient temperature medium and the solvent is evaporated under reduced pressure. The residue is extracted with hydrochloric acid, the resulting salts are then removed by filtration, then the extracts are extracted with 100 ml of ethyl acetate, sodium hydroxide is added until the pH has reached a pH value. Extraction with ethyl acetate, containing 10% ethanol, is carried out; the organic phase is dried on anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. An oil is obtained which slowly crystallizes. The resulting material is triturated in diethyl ether and fed. 4.5 g of crude compound is obtained, which is chromatographed on silica in a mixture of methanol: chloroform 15:35 and crystallized with ethyl acetate.
    2.7 g of N - {; 3- 3- (4-methylpiperidinomethyl-phenoxy-propyl-3) are obtained.
    pyridine carboxamide -1-oxide,
    SR 58037, t.SH1, Sh9-1P ° S, yykhod 35%
    from theory.
    Calculated,%: C 68.90; H 7.62j N 10.96
    C, N „S, 0,
    Found,%: C 68.69; H 7.85;
    11.11
    Examples 8 and 9. Analogously to Example 7, by reacting 0.03 mol of (3-methylpiperidinemethyl) phenoxyT-propylamine and 3-H- (4-hydroxypiperidinemethyl) -pheyoxyT-propylamica with 0.047 mol of 1-oxoic acid hydrochloride of Kotilic acid, the following compounds, respectively, are obtained.
    N - {3- {3- 3-Methylsperidiimetkl) - phenoxy-propyl-3-pyridinecarboxamide-1-oxide, SR 58042, mp. 108 software ° C example 8); yield 35% of theory.
    Calculated,%: C 68.90; And 7.62; N 10.96
    C2, H ,, N, 03
    Naidio,%: C 65.14; H 7.11; N 10.77
    N-3- 3- (4-hydroxypiperidinomethyl) phenoxy-propyl-3-pyridinecarboxamide-1-oxide, 5R 58067, mp PL-116 ° C (Example 9), yield 30% of theory.
    Calculated,%: C 65.44; H 7.06; N 10.90
    .2lH
     "four
    Found -,%: C 65,14; H 7.11;
    10.77.
    EXAMPLE 10 To a mixture of 0.03 mol of 3- (3-hexamethyleneimmethylphenoxy) -propylamine and 0.095 mol of pyridine in 100 ml of methylene chloride, stirred at, was added in portions of 0.047 mol of 1-hydroxydinic acid hydrochloride, then the reactive the mixture is stirred for 90 minutes at ambient temperature and the solvent is evaporated under reduced pressure. By proceeding further as in Example 7, K-3- / 3-hexamethyleneimmethylphenoxy) -propsch) -3-pyridnicarboxy- amide-oxide, 5R 58052, etc., is obtained. 91-93 C, the output of 33% of theory.
    Calculated,%: C 68.90; H, 62; N 10.96
    CjjHz, N, 0,
    Found,%: C 69.00; H 7.89; 11.06
    Examples are 11-13. Analogously to Example 7, by reacting 0.03 mol of 3- (3-benes-methyl-3-methyl-phenyl) -propylamino, (3-oxymethyl) -shperidine-methylphenoxy-propylamine and (4-methyl-piperazine-3-phenoxy-propene; 3-phenoxy-propylamine-3-phenoxy-phenoxy-propylamine and 4-methyl-piperazine-3-phenoxy-propylamine-3-phenoxy-phenoxy-propylamine and (4-methyl-piperazine-3-phenoxy-propylamine-3); - Sidnicotinic acid, carried out in methylene chloride, is obtained according to the following compound.
    (3 -benzylmethyl-aminomethylphenoxy) -thopyl-3-pyridinecarboxamnd-1-oxide, SR 58083; mp. EA-EB S at measure 11, yield 30% of theory.
    Calculated,%: C 71.09; H 6.71; N 10.36
    С „H2, Ы, 0,
    Found,%: C, 70.87; H 6.75; N 10.1
    N-f3-t3- {3-hydroxymethyl-piperidine methylphenoxy) -propyl-3-pyridine carboxamide-1-oxide, SR 58087, having the appearance of a vitreous solid
    example 12; yield 20% of theory.
    Calculated,%; From 68.94 | H 6.71; Ы 9,65
    Found,%: C 68.56; H 6.81; 9.47
     NMNR (DMSO-d6): 3.2 rrgp {m, OljOH); 4.0 ppmft, Ar OCKj); 8.55 ppm (, 2CH pyrndine).
    L-C-Cs- (4-metsh1piperazinmetil - phenoxy-propyl-3-pyridinecarbok- | samide-1-oxide in the form of trichlorohydrate, BYa 58084A, so pl. 200-205 "C (example 13), yield 45% from theories.
    Calculated,%: C 51.07; Kb, 33; N 8.51.
    Found,%: C 50.85; H, 6.35; N, 8.44. Example 14. To a solution of 0.04 mol. {3-methylpiperidine-methyl) -phenoxy-propylamine in 40 ml of acetonitrile was added 0.04 mol of 1-oxidic acid anhydride, then the reaction mixture Mix the mixture for 2 hours at 50 ° C, then dry it under reduced pressure. Remove the residue using 20 ml of hydro-. the sodium oxide is concentrated, and the compound is extracted four times using 30 ml of ethyl acetate. The organic phase is dried on anhydrous sodium sulfate, the solvent is evaporated under reduced pressure and the thus obtained is purified.
    5 10
    15
    20
    five
    0
    five

    five
    substance by chromatography on silica as i g /
    N-p- |, 3- 3-methylpiperidinemethyl -phenoxy-propyl-3-pyridinecarboxamide-1-oxide is obtained, identical to the compound obtained in Example 8; m.p. 108 ° C.
    PRI me R 15. To a solution of 0.03 mol of 1-oxide-nicotinic acid in 40 MP of methyl chloride containing 10 MP of triethylamine, approximately 0.03 mol of isobutyl chloroformate dissolved at 0–5 ° C are added over 10 min. in 15 MP of methylene chloride, then the mixture is stirred for 30 minutes at the same temperature, 0.03 mol of 3-C3 (3-methylpiperidinemethyl) phenoxy - propylamine, dissolved in 15 mp (datylenchloride, stirred 2 h at ambient temperature, then the reaction mixture is washed with 10 ml of water. The organic phase filtered, dried it over anhydrous sodium sulphate and evaporated to dry under reduced pressure, after which the residue was purified by chromatography on silica, similarly to example 7.
    N - {3 - 3- (3-methylpiperidinemethyl) -phenoxy-3-propyl-3-pyridine carboxamide-1-oxide, identical to that obtained in Example b, is obtained.
    Example 16. To a solution of 11.6 g of 1-oxidicotinic acid, 11.2 g of 4-nitrophenol and 8.2 g of triethylamine in 160 ml of methylene chloride were added 17.6 g of hexafluorophosphate benzotriazolyloxy-tris-dimethylamine phosphonium. Increase the temperature of the mixture to obtain a solution in which the active ester is separated. Stirring is continued for another 30 minutes, after which the precipitate is filtered and washed first, in methylene chloride, and then in diethyl ether.
    4 g of 3-nitrophenyl-1-oxide 3-pyrvdincarboxylate, m.p. 234-236 ° C.
    The resulting active ester is added to a solution of 3.8 g. (3-methylpipervdinmethyl) -phenoxy-propylamine in 70 ml of methanol and the mixture is stirred for 3 hours at. Rastvo-
    The solvent is evaporated, the residue is extracted using 30 ml of IN hydrochloric acid, and an acidic solution of the tride is washed in 20 ml of ethyl acetate. The pH of the solution was adjusted to a value of 7.8, refilled using sodium chloride and extracted six times using 30 ml of ethyl acetate. The combined organic extracts are dried on anhydrous sodium sulphate and the solvent is evaporated dry. The compound is purified by chromatography on silica, similarly to Example 7.
    N (3-methylpiperidinomethyl-phenoxy} -propyl-3-pyridine-carboxamide-1-oxide, identical to that obtained in Example 8, is obtained.
    Example 17. To a solution of 5 g of 4-dimethylaminpyridine ml of acetonitrile was added 5.6 g of 1-oxide-tioic acid. The mixture was stirred for 10 minutes at ambient temperature, then 9.2 g of dicyclohexylcarbodiimide was added to it. After 5 minutes, 10 g (methylpiperidinemethyl-phenoxy-propylamine, dissolved in 20 ml of acetonitrile) was added at ambient temperature. It was noted that the reaction proceeded in a slightly exothermic mode (20-25 s) and dissolved in 5 minutes is almost complete. The mixture is then stirred for 4 hours at 40 ° C, the dicyclohexane urea that has formed is filtered off and washed with acetonitrile. The mixture is evaporated under reduced pressure and the residue is chromatographed under silica gel in the same manner as in Example 7.
    N (3-methylpiperidinmethyl) -phenoxy-propyl-3-pyridine-carboxamide-i-oxide, identical to that obtained in example 8, is obtained, mp 108-110 C.
    Example 1B. To a suspension of 2.8 g of 1-oxycotinic acid, 2.5 g of dimethylamine pyridine, 8.8 g of benzotriazolyloxy-tris-, di-hexafluoro phosphate
    Methylamine phosphonium in 40 ml of acetonitrile is added at 20 ° C and at reorption 20 and 21. Analogously to Example 7 and by reacting 0.03 mol of 3- (4-piperidinemethyl-pyrid-2-yloxy) -Propylamine and 3- (4-dimethylaminomethylpyrid-2-yloxy) -50 propylamine with 0.047 mol of 1-oxydnicotinic acid chloride-hydrochloride, the following compound is added to MHT.
    N - 3- (4-piperidinemethylpyrid-2 shift 5 g of 3- З- (З-methylpiperidinmetnl) -phenoxy-propylamine, dissolved in 10 ml of acetonitrile. Elimination-55 CI) -propyl-3-pyridinecarboxylate increase in temperature up to 30 C samid-I-oxide, SR 58065, so pl. 87- and the formation of a solution, which is then (Example 20), the yield of 35% of the oT Theo is stirred for 2 hours at an ambient temperature.
    environment. The mixture is concentrated under reduced pressure, the residue is treated with 20 ml of concentrated sodium hydroxide and extracted four times with 40 ml of ethyl acetate. After evaporation of the organic extracts, the residue was purified by chromatography using silica as in Example 7.
    N (3-methylpiperidinomethyl-phenoxy-propyl-3-pyridine-carboxamide-1-oxide) is obtained, identical to that obtained in Example 8.
    Example 19 "To a mixture of 0.03 mol of 3- (4-dimethylaminomethylpyrid-2-Sh1OK-si) -propylamine and 0.095 mol of pyridine in 100 ml of methylene chloride, stirred at 0 ° C, is added in portions of 0.047 mol of 1-hydroxychloride chloride 1 acid, then the mixture is stirred for 90 minutes at ambient temperature and the solvent is evaporated under reduced pressure. Next, as in Example 1, N-3- (4-dimethylaminomethylpyrid-2-yloxy) propyl-3-pyridinecarboxamide-1-oxide half-oxalate is obtained. By neutralizing the compound thus obtained with sodium hydroxide, N-3- (4-dimethylaminomethylpyrid-2-yloxy) -propyl-3-pyridinecarboxamide-1-oxide, SR 58098, m.p. 106-10 ° C, is obtained.
    Calculated,%: C, 61.80; H 6.71; N 17.04.
    C ,,
    Found,%: C 61.21; H 6.78; N 16.97 ..
    Examples 20 and 21. Analogously to Example 7 and by reacting 0.03 mol of 3- (4-piperidinemethyl-pyrid-2-yloxy) -propylamine and 3- 4-dimethylamine-methyl pyrid-2-yloxy) -propylamine with 0.047 mol of 1-oxide-nicotinic acid chloride-hydrochloride is prepared by the following compound covalent with TB.
    N - 3- (4-piperidinemethyl pyrid-2-loxCi) -propyl-3-pyridinecarboxamiside-I-oxide, SR 58065, mp. 87- (example 20), yield 35% oT theory.
    Calculated,%: C 64.84; H 7.07; N 15.22
    SgoNgb "40,
    in examples 1-12 and 18-22, have the following composition, mg:
    Primary active
    150
    75 15
    thirty
    Found,%: C 64.98; H 7.16; N 15.14
    N- 3- (4-dimethylaminmethylpyrvd-2-yloxy) -propyl-3-1 Shridinarboksamid-1-oxide, 5R 58098, mp 103- (example 21), 35% yield of theory, the compound is identical to the substance obtained in example 19,
    PRI me R 22. According to the method of example 16, BUT on the basis of 0.03 mol of 3- (3,5-dimesh1piperidinomethylphenoxy) - propylamine and 0.03 mol of 3-pyridinecarmine lubricant) for
    to
    component Microcrystalline cellulose Talc
    Polyvinylpyrrolidone
    Precipitated Silica
    Magnesium stearate
    Initially all ingredients are mixed in the mix (except for
    25 5
    4-nitrofenkp-1-oxide boxylate, N, nCs- (3,5-dimethylpiperidine-methylphenone: i) -propylT-3-pyridinecarboxamide-1-oxide, m.p. 102-105 С, yield 30% ...
    Calculated,%: C 69.49; H 7.86; N 10.57.
    15 minutes, then mix the composition by gradually adding water. Pass the mass through the net 1.25 Granules Dried in a drying oven with
    20 forced ventilation until the residual humidity reaches relatively low (approximately 2%). Granules are given the property of uniformity, a lubricant is introduced.
    C2, H, .N, 0,
    C 69.24; H 7.95;
    Found,%: 10.66,
    Example 23. To a hot solution of 0.003 mol N - {3- {3-methylpiperid dinomethyl) phenoxy-propyl U-3-pyridinecarboxamide-1-oxide in 30 ml of ethanol was added to a hot solution of 0.003 mol of fumaric acid in 20 ml of ethanol. The resulting solution is evaporated to dryness and the residue is dissolved in acetone. The crystallized product is filtered, dried, triturated and the cHOBd suspended in hot acetone for 5 minutes. After cooling, filtering and drying, N monofumarate is obtained (3-methylpipervdi20 by forced ventilation until the residual moisture is relatively low (approximately 2%). The granules are given a uniformity property and a lubricant is introduced.
    25 and form tablets by pressing vani. The weight of one tablet is 300 mg. In the same way he receives tablets containing 250 mg of the main active ingredient.
    30 The selectivity of the activity of the proposed compounds to the Hj receptor is confirmed by the absence of type H activity in the test for contraction caused by histamine in
    35 ileum colonized in mumps.
    Counteractive activity of the proposed compounds in relation to gastric receptors H hista
    methyl) -phenoxy3-prosh-3-pyr1adincar-40 mine was confirmed in the test for boxamide-1-oxide. So pl.138-140 With, the yield of 90%.
    Calculated,%: C 62.51; H 6.66; N8.41
    antisecretory activity based on antagonism to hypersection caused by histamine in rats exposed to atropine
    C ,, H ,, N, 0,
    .ABOUT
    Found,%: C 62.14; H 6.44; N 8.19.
    In the same way, with the action of maleinic acid, N - ((3-methylpiperidinomethyl) -phenoxy-propyl-3-pyridinecarboxamide-1-oxide monomelate is obtained, mp 120-122 C, yield 92%.
    Calculated,%: C 62.51; H 6.66; N 8.41
    C ,, N N, 0
    Found,%: C 62.29; H 6.47; N8,28.
    PRI me R 24. Tablets on the basis of one of the compounds described
    1232310
    in examples 1-12 and 18-22, have the following composition, mg:
    Primary active
    150
    75 15
    thirty
     eat lubricant) for
    to
    component Microcrystalline cellulose Talc
    Polyvinylpyrrolidone
    Precipitated Silica
    Magnesium stearate
    Initially all ingredients are mixed in the mixer (except for 25 5
    eat lubricant) for
    15 minutes, then mix the composition by gradually adding water. Pass the mass through the net 1.25mm. The granules are dried in a drying oven with
    forced ventilation to achieve a residual moisture content of relatively low (about 2%). Granules are given the property of uniformity, a lubricant is introduced.
    and form tablets by compression. The weight of one tablet is 300 mg. In the same way he receives tablets containing 250 mg of the main active ingredient.
    The selectivity of the activity of the predicted compounds to the Hj receptor is confirmed by the absence of activity of the type H in the test for the reduction caused by histamine in
    ileum of the guinea pig.
    The counteracting activity of the proposed compounds on the gastric receptor H histamine was confirmed in a test for
    antisecretory activity based on antagonism to hypersection caused by histamine in a rat exposed to atropine.
    In accordance with this test, hypersecretion of gastric acid is caused by intravenous infusion of a submaximal dose of histamine, to an equivalent of 15 µmol / kg / h,
    and measuring gastric secretions by perfusion of saline at a constant rate into the stomach of the animal. . Simetidine and ranitidine, which are standard antihistamine compounds, were used as a comparison compound.
    As characteristic compounds of the invention, compounds from examples 1, 2, 640 and 20 were shown under their codes, respectively: CM 57891A, 58 58017A, 5B 58062, SR 58037, 5R 5VOAA, 51 58067, 6Y 58052 and SR 58P65.
    Table 1 shows the dose in µmol / kg for each compound, administered intravenously in a single dose that inhibits by 50% the gastric hypersecretion caused by histamine (Tfljj), as well as the relative activity with respect to symmetry, and for the two compounds this activity twice the activity of ranitidol. Compared with the known compounds IV and Y, the compounds of the invention have a 20-fold antisecretory activity.
    The toxicity of the proposed compounds is compatible with their therapeutic use,
    DL,, 0 for infants with intravenous administration of the compounds according to the invention: are given in table 2.
    1C .. T a b l and c a 2
    权利要求:
    Claims (3)
    [1]
    1. A method for producing N-substituted 1-hydroxycotinamide of the general formula άΟΗ, Απϊ co-nh-cu 2 -si 2 -sn 2 -o where X is a nitrogen atom or a group. CH.
    Am - lower dialkylamine, lower dialkylamine, substituted by phenyl, pyrrolidine, morpholine, hexamethylene imine, piperidine, piperidine, substituted once or twice with methyl or hydroxyl or hydroxymethyl, piperazine,. substituted at position 4 with lower alkyl, or their pharmaceutically acceptable salts, characterized in that the amine is treated with the general formula
    Mid 2 aia
    H 2 L - SC 2 - si, where X and At have the indicated meanings, a functional derivative of a carboxylic acid of the general formula coon · in an organic solvent at 0-50 ° C, the resulting compound is isolated in free form and, if necessary, is converted into one of its pharmaceutically acceptable salts .
    [2]
    2. The method of pop. 1, characterized in that the acid chloride in the form of hydrochloride is used as a functional derivative.
    [3]
    3. The method of pop. 1, characterized in that the functional derivative has the General formula where
    ABOUT
    Cool
    R is nitrophenyl.
    Featured Priority
    08/13/82 at At - dyalkylamine, piperidine, pyrrolidine, morpholine; 04/22/83 at At lower dialkylamine substituted with phenyl, hexame * tylenimine, piperidine substituted with methyl, hydroxyl or oxime.
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    FI57590C|1980-09-10|SAOSOM MELLANPRODUKT VID FRAMSTAELLNING AV BLODTRYCKSNEDSAETTANDE 2-SUBSTITUERADE-4-AMINO-6,7,8-TRIALKOXIKINAZOLINER ANVAENDBARA 2-HALOGEN-4-AMINO-6,7,8-TRIALKOXIKINAZOLINER
    同族专利:
    公开号 | 公开日
    PH19511A|1986-05-14|
    CS241064B2|1986-03-13|
    FI832919A|1984-02-14|
    IL69392D0|1983-11-30|
    US4514408A|1985-04-30|
    NO832894L|1984-02-14|
    NZ205239A|1985-09-13|
    EP0101380A3|1985-10-16|
    DK367683D0|1983-08-12|
    EP0101380A2|1984-02-22|
    GR78927B|1984-10-02|
    PT77192A|1983-09-01|
    AU1780783A|1984-02-16|
    DD213921A5|1984-09-26|
    CS587683A2|1985-07-16|
    AU556247B2|1986-10-30|
    MA19871A1|1984-04-01|
    DK367683A|1984-02-14|
    PT77192B|1986-02-03|
    PL141540B1|1987-08-31|
    FI832919A0|1983-08-12|
    OA07521A|1985-03-31|
    IL69392A|1987-01-30|
    PL243410A1|1985-05-07|
    CA1209995A|1986-08-19|
    HU191869B|1987-04-28|
    YU169083A|1986-12-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    NL131190C|1961-12-06|
    US4293557A|1979-07-03|1981-10-06|Teikoku Hormone Mfg. Co., Ltd.|Antiulcer phenoxypropylamine derivatives|
    JPS6242895B2|1979-07-03|1987-09-10|Shionogi & Co|US4764598A|1985-08-22|1988-08-16|The United States Of America As Represented By The Department Of Energy|Precursors to radiopharmaceutical agents for tissue imaging|
    MA20552A1|1985-10-11|1986-07-01|Pan Medica Sa|PYRIDYLALKYLAMINE ALKYLACARBOXAMIDES, THEIR PREPARATIONS AND THEIR USES|
    US4994456A|1989-03-01|1991-02-19|Nisshin Flour Milling Co., Ltd.|Pyridinecarboxylic acid amide derivatives and pharmaceutical compositions comprising same|
    WO1992013854A1|1991-01-30|1992-08-20|Central Glass Company, Limited|Phthalimide compound and production thereof|
    DE69209576T4|1991-05-10|1997-01-30|Takeda Chemical Industries Ltd|Pyridine derivatives, their production and use|
    EP1891065A4|2005-05-31|2010-07-28|Astrazeneca Ab|Novel mchr1 antagonists and their use for the treatment of mchr1 mediated conditions and disorders|
    WO2022034121A1|2020-08-11|2022-02-17|Université De Strasbourg|H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8214128A|FR2531704B1|1982-08-13|1982-08-13|N-SUBSTITUTED AROMATIC ACIDAMIDES, THEIR SALTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|
    FR8306681A|FR2544717B1|1983-04-22|1983-04-22|NICOTINAMIDE L-OXIDE N-SUBSTITUTED, ITS SALTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|
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