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    • 专利摘要:
    Novel aniline derivatives represented by the general formula (1): …<CHEM>… [wherein, subject to certain provisos R<0>, R<1> and R<2> are hydrogen, halogen, nitro, amino, carboxy, cyano, hydroxy, sulphonamido, lower alkyl, lower alkoxycarbonyl, lower alkoxy, lower alkanoyl, lower alkylamino, lower alkylthio, lower alkanoylamino or a group …<CHEM>… (wherein R<5> and R<6> are hydrogen, lower alkyl or cycloalkyl or form a heterocyclic group with the adjacent nitrogen atom); R<3> is cyano, nitro, halogen, lower alkyl or a lower alkoxy; m is an integer of 1 to 3; R<4> is hydrogen or lower alkyl; and A is lower alkylene] and their salts act directly on the heart, and have myocardial contraction activity (positive inotropic activity) and coronary blood flow increasing activity, and are thus useful as cardiotonics.
    公开号:SU1316560A3
    申请号:SU823511152
    申请日:1982-10-19
    公开日:1987-06-07
    发明作者:Томинага Митиаки；Юн-Сюн-Ян；Огава Хиденора；Накагава Казуюки
    申请人:Оцука Фармасьютикал Ко.,Лтд (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new aniline derivatives of the general formula
    o / - ii / -and
    (; N- with n

    LKG
    de R - nitro, amino, carboxy, cyano, hydroxy, sulfonamido, lower C, - Cd-alkoxycarbo-f5 NILE, lower c, - C-alkoxy, lower C, - C4 talkanoyl, lower C, -C-alkylamino, lower C, - C-alkylthio, lower C, - C4-alkanoylamino radical or a group of the general formula
    O d
    „K.
    6
    -C-n
    20
    25
    e R and R
    or
    - identical or different, hydrogen, lower C, -C-alkyl - or CYCLO-JQ hexyl group, Rg form a 6-membered saturated heterocyclic group containing, in addition to the nitrogen atom, also oxygen;
    Rg is hydrogen, nitro or lower C-alkoxy;
    R, is hydrogen, lower C, alkoxy;
    R, is cyano, nitro, halogen.
    35
    40
    lower c, -C-alkyl or lower C-alkoxy radical; m is an integer from 1 to 3,
    moreover, m is 2 or 3 in the case when Rj is a lower C, - C-alkoxy radical; R is hydrogen or lower Cj
    C-alkyl radical; A - lower C4-alkylene 5 or their pharmaceutically acceptable salts.
    The purpose of the invention is new aniline derivatives and their salts of general formula (I), having a different spectrum
    ten
    f5
    20
    25
    -Jq
    35
    40

    s
    45
    50
    biological properties than structural analogues, in particular, positive inotropic activity and activity to increase coronary blood flow 5, and, thus, may be useful as cardiotonic agents.
    Example. 10.06 g of o- (bb-chloro-acetylamino) -benzoic acid methyl ester, 15.2 g of K- (3,4-dimethoxy-benzoyl) piperazine monohydrochloride and 16 g of triethylamine are suspended in 55 ml of acetonitrile and the mixture is reacted at 49- 50 ° C for 4 hours. After completion of the reaction, the reaction mixture is cooled with ice and the resulting crystals are collected by filtration. Recrystallization from acetone gives 14.68 g of o-methoxycarbonyl-about-C4- (3.47 dimethoxybenzoyl) -1-piperazinyl acetanilide as colorless needle-like crystals. T. pl. 167.5-169.0 ° C.
    Calculated,%: C, 62.57; H 6.16; N 9.52.
    with „n ,, oh, k.
    Found,%: C 62.48; H 6.16; N 9.43.
    Example2. 5 g of m- (o-chloro-acetylamino) -benzoic acid methyl ester, 7.56 g of H- (3,4-dimethoxybenzoyl) piperazine monohydrochloride, 7.76 g of triethylamine and 30 ml of acetonitrile are mixed together and reacted at a temperature of from 45 to 50 ° C for 5 h. After completion of the reaction, the uniform mixture was cooled with ice and the resulting crystals were removed by filtration. The mother liquor is concentrated to dryness and extracted by adding a 1N aqueous solution of sodium hydroxide and chloroform. The chloroform layer was washed with water, dried and the solvent was removed by distillation. The resulting oily substance is purified by silica gel column chromatography to obtain 10.08 g of metamethoxycarbonyl- (3,4-dimethoxybenzoyl) -1 - piperazinyl acetanilide as a colorless oily substance.
    Calculated,%: C, 62.57; H 6.16; N 9.52.
    C.Ha.OeN,
    Found,%: C 62.42; H 6.23; N 9.61.
    5IMP (CDC1}); Sr / min 2.63 (t, 4H); 3.17 (s, 2H); 3.70 (m, 4H); 3.86 (s, 6H); 3.88 (s, 3H); 6.73-7.03 (m, 3H); 7.337, 46 (m, lH); 7.66-7.82 (m, lH); 7.90- 8.03 (s, 2H), 9.05 (s, lH) ..
    By adding hydrochloric acid-ethanol, metametoxycarbonyl- - 4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monohydrochloride is obtained.
     Colorless needles (from methanol -. Isopropanol) ..
    M.p. 234.0-235.0 C (decomposition). PRI me R 3. In a manner similar to that described in Example 1, p-methoxycarbonyl-ot-C4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide was prepared. Colorless oily substance.
    NMR (CDCl1), S h / min 2.63 (t, 4H); 3.17 (, 2H); 3.70 (t, 4H); 3.85 (, 9H); 6.74-7.03 (t, 3N); 7.58 (d ,, 5Hz, 2H); 7.97 (d 8.5 Hz, 2H); 9., 14 (wide (s, 1H).
    Monohydrochloride hemihydrate of the indicated compound. Colorless prismatic crystals (from methanol). M.p. 222.5-227.5 ° C (decomposition).
    Example 4. 5.00 g of o-carbamoyl-c-chloroacetanilide, 8.09 g of 3,4-dimethoxybenzoyl piperazine monohydrochloride, 8.31 g of triethylamine and 30 g of acetonitrile are mixed together and the mixture is mixed at 50 C for 5 hours. Then the reaction mixture is cooled with ice and the resulting crystals are removed by filtration. The filtrate is concentrated to dryness. The resulting residue was extracted with chloroform-1N aqueous sodium hydroxide solution and the chloroform layer was washed with water, dried, and then the chloroform was removed by distillation. The residue obtained is purified by chromatography on a silica gel column, and the target product is converted to hydrochloride using a mixture of hydrochloric acid-ethanol, then the product is recrystallized from a mixture of water — acetone, yielding 7.43 g of o-carbamo1 - (/ - 4- ( 3,4-dimethoxane ibenzoyl) -1-pyrazinyl acetanilide monohydrochloride monohydrate in the form of colorless needle crystals. Mp. 122.0-125.0 ° С (decomposed).
    Examples 5-35. Using this procedure, the following compounds are obtained.
    Example 5. Methoxycarbonyl-Sb- 4- (3 4-dimethoxybenzoyl) -1-piperazinyl acetaiylide monohydrochloride hemihydrate. Colorless amorphous crystals (from ethanol - ether). M.p. 99-101 C (decomposition).
    five
    0
    five
    0
    five
    0
    five
    0
    five
    Example 6: m-Methoxycarbonyl-et-4- (3,4-dimethoxybenzoyl) -1-piperazinyl-acetanilide monohydrochloride. Colorless needles (from methanol - isopropanol). M.p. 234.0-235.0 (decomposition).
    Example 7. p-Methoxycarbonyl- - 4- (3,4-dimethoxybenzoyl) -1-piperazine acetanilide monohydrochloride. Colorless prismatic crystals (from methanol). M.p. 225.5-227.5 s (decomposition).
    EXAMPLE 8 o-Carboxy-oO-4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetade or monohydrochloride. Colorless cotton-like crystals (from 80% aqueous methanol). M.p. 250.0-251, (decomposition).
    PRI me R 9. o-Morpholinocarbonyl-ei- 4- (3,4-fimethoxybenzosh1) -1-piperazinsht acetanilide monohydrochloride. Colorless cotton-like crystals (made from ethanol). M.p. 201.5-203, (decomposition).
    P.P. and meper 10. o-Nitro-oi- 4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monohydrochloride. Light yellow powdery crystals (from, ethanol). M.p. 187, 5-188, (decomposition).
    Example 11. o-Amio-oi- 4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide dihydrochloride hemihydrate. Colorless powdery crystals (from methanol). M.p. 204.0-205.0 s (decomposition).
    EXAMPLE 12 O-Acetamido-ob-4- (3,4-Dimethoxybenzoyl) -1-piperazinyl acetanilide monooxalate. Colorless powdery crystals (from ethanol). M.p. 174.5-176.0 ° C (decomposition).
    Example 13. o-Acetyl-oi, - 4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide. Colorless prismatic crystals (from ethanol). M.p. 153.5-155.5 C.
    EXAMPLE 14. O-Cyano-eb-L4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monooxalate. Colorless powdery crystals (from metaiol). M.p. 198.0-199.5 C (decomposition).
    Example 15. p-Dimethylamino-ci-4- (3,4-dimethoxybenzoyl) -1-pyrazinyl acetanilide dihydrochloride dihydrate. Colorless needles (ethanol). M.p. 159.0-162, O c (decomposition),
    Example 16. m-Methylthio-oi. - 4- 3,4-dimethoxybenzoyl -1-piperazi-acetanilide monohydrochloride. Colorless needles from eta, nola. T.pl. 188.5-190 ,.
    Example 17. p-Sulfonamido-od-4- (3,4-dimethoxybenzoyl) -1-piperazine-acetanilide monohydrochloride. Colorless needles e crystals (from methanol). M.p. 189.0-192.0 ° С (decomposition).
    EXAMPLE 18 O-hydroxy-; - 4- (3,4-dimethoxybenzoyl) -l-piperidinyl acet-tanilide monohydrochloride. Colorless prismatic crystals (from ethanol). M.p. 209.0-210, (decomposition).
    Example 19. m-Carbamoyl-ot, (3,4-dimethoxybenzoyl) -1-piperazinyl-acetanilide monooxalate. Colorless powdery crystals (from water - acetone). Mp 206.5-207 ° C (decomposition).
    EXAMPLE 20 p-Carbamoyl-oi- 4- (3,4-dimethoxybenzoyl) -1-piperazinyl-acetanilide monohydrochloride monohydrate. Colorless needles (from water - acetone). M.p. 237.5-239.0 ° С (decomposition).
    EXAMPLE 21 o-Oxy-meta-nitro (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monohydrochloride 3/4 hydrate. Yellow powder crystals (from methanol - ether). M.p. 185.8-188.0 ° С (decomposition).
    EXAMPLE 22 O-Carbamoyl-ob-4- (3,4-dimethoxybenzoyl) -1-piperazinyl-butyroanilide monooxalate. Colorless powder crystals (from methanol - ether). M.p. 169-170,5 ° C (decomposition).
    EXAMPLE 23 O-Carbamoyl-U-4 (3,4-dimethoxybenzoyl) -1-piperazinyl-butyroanilide monooxalate. Colorless powder crystals (from water - acetone). M.p.106-206, (decomposition).
    EXAMPLE 24 O-Carbamoyl- - 4- (3,4-dimethoxybenzoyl), - 1-piperazinyl caproanilide monooxalate. Colorless flaky crystals (from ethanol). M.p. 130-132 ° C (decomposition).
    EXAMPLE 25. O-Carbamoyl-4- (3,4,5-trimethoxybenzosch1) -I-piperazineJ acetanilide. Colorless prismatic crystals (from ethanol). M.p. 198.0-199.5 ° C.
    Example 26. O-Carbamoyl-about-4- (3-chlorobenzoyl) -1-piperazinyl acetanilide monohydrochloride sesquihydrate. Colorless powder crystals (out of water). M.p. 158-160 S.
    Note 27. O-Carbamoyl- «- 4- (4-nitrobenzosch1) -1 -piperazinyl acetanilide. Yellow needles (from ethanol - water). Mp. 222.0-24.0 ° C (decomposition).
    EXAMPLE 28 o-Methoxycarbonyl-N-methyl-4- (3,4-dimethoxybenzoyl) piperazinyl acetanilide dioxalate. Colorless powder crystals (from methanol - ether). Mp.181.0-182.0 С (decomposition).
    EXAMPLE 29 3,4,5-Trimethoxy-4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monohydrochloride. Colorless needles (from methanol). M.p.234.0-235, (decomposition).
    EXAMPLE 30 O-Cyclohexylaminocarbonyl-c - 4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide. Colorless prismatic crystals (from ethanol). M.p.194,5-196,
    Example o-n-Butylaminocarbonone-C-4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monooxalate. Colorless powder crystals (from ethanol - ether). M.p. 167-168 ° C
    (decomposition).
    PRI me R 32. o-Diethylaminocarbonyl-od-4- (3,4-dimethoxybenzoyl) -1 - piperazinyl acetanilide. Colorless granule-shaped crystals (from acetone). M.p. D06-109 ° C.
    PRI me R 33. o-Kap6aMomi-oi- 4- (4-metsh1benzosh1) -1-peep razinshL acetanilide. Colorless prismatic crystals (from ethanol). M.p. 182.5-185.5 ° C.
    PRI me R 34. o-Carbamoyl-o-C4- (4-cyanobenzosch1) - Npiperazinsh acetanilide. Colorless flaky crystals (from methanol). M.p. 213-215.5 ° C.
    PRI me R 35. p-Carboxy-ci- 4- (3,4-dimethoxybenzocle) -1-piperazinyl acetanilide monohydrochloride sesquihydrate. Colorless needles (from methanol). Mp.170-174 ° C.
    and the output of the final 5-35 are given
    The reaction conditions of the products of examples are easy.
    Obtaining a pharmaceutical composition 1.
    Using known methods, tablets are obtained having the following composition, mg:
    wasps - 4- (3,4-Dimethoxy-benzoyl) -1-piperazininyl acetanilide monohydrochloride Starch magnesium stearate Lactose
    five
    132 18 45
    200 total
    Obtaining pharmaceutical composition 2, g:
    o-Methoxycarbonyl-e.4 (3,4-dimethoxybenzoyl) - 1-piperazine acetanilide Polyethylene glycol (mol
    weight: 4000) Sodium chloride Polyoxyethylensor-bit monooleate Sodium metabisulfate
    P-Hydroxybenzoic acid methyl ester Para-hydroxybenzoic acid propyl ester
    Distilled water for injection
    The prescribed substances, para-hydroxybenzoic acid methyl ester, para-hydroxybenzoic acid propyl ester, sodium metabisulfate and sodium chloride are dissolved in distilled water at 80 ° C with heating. The resulting solution is cooled to 40, then the compound is dissolved in the specified solution in this order according to the invention, polyethylene glycol and polyoxyethylene sorbitan monoole. Then enough distilled water for injection is added to this solution in order to bring the final volume to the desired value the barrel is sterilized by sterile filtration using appropriate filter paper. Portions of the resulting solution, each in one milliliter, are individually poured into ampoules to form preparations for injection.
    500 mg
    0.3 0.9
    0.4 0.1 0.18
    0.02
    100 ml
    O
    five
    0
    five
    0
    five
    0
    five
    132
    18
    45
    200
    Obtaining pharmaceutical composition 3.
    Using known methods, tablets are obtained having the following composition, mg:
    o-Carbamoyl-C - 4 (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monohydrochloride monohydrate
    Starch
    Magnesium stearate
    Lactose
    Total
    The pharmacological activities of the compounds of general formula (I) according to the invention were determined using test methods, which are described below along with the results.
    The following compounds are used in the tests:
    o-methoxycarbonyl-1x- 4- (3,4-dimethoxybenzoyl) - Npiperazinyl acetanilide (1);
    m-methoxycarbonyl-ci. 4- (3,4-dimethoxybenzoyl) -1-piperazine acetanilide monohydrochloride (2);
    p-methoxycarbonyl-o6-C4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monohydrochloride (3);
    o-carboxy-o - 4- (3,4-dimethoxyben-soim) -1 -piperazine acetanilide mono-hydrochloride (4);
    o-carbamoyl-OL-4- (33,4-dimethoxy-benzoyl) -1-piperazinyl acetanilide monohydrochloride monohydrate (5);
    o-labels of sicarbonyl-11-methyl-s-4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide dioxalate (6);
    o-morpholinocarbonyl-cl-4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monohydrochloride (7);
    o-nitro-ui- 4- (3,4-dimethoxyben-5-soyl) -1-piperazinyl acetanilide monohydrochloride (8);
    o-amino-oC-C4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide di- Q hydrochloride hemihydrate (9);
    3,4,5-trimethoxy-1 1-4- (3,4-dimethoxybenzoyl) -1 piperazinyl | acetanilide monohydrochloride (10);
    o-acetamido-oi- 4- (3,4-dimethoxy-5 benzoyl) -1-piperazinyl acetanilide monooxalate (11);
    o-acetyl-about-4- (3,4-dimethoxybenzoyl) - -piperazinyl acetanilide (12);
    o-cyano-ob-4- (3,4-dimethoxy-6-enzoyl) -1-piperazinyl acetanilide mono-oxalate (13);
    p-dimethylamino-o - 4- (3,4-dimethoxesibenzoyl) -1-piperazinyl acetanilide dihydrochloride dihydrate (14);
    m-methylthio-o-4- (3,4-dimethoxy-benzoyl) -1-piperazinyl acetanilide monohydrochloride (15);
    p-sulphonamido-c6-4- (3,4-dimethoksibenzoyl) -1-piperazinyl acetanilide monohydrochloride (16);
    o-hydroxy-o (.- C4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide moio hydrochloride (17);
    o-cyclohexylaminocarbonyl-oi- 4- (3,4-dimethoxybenzoyl) -1-piperazyl-acetanilide (18);
    m-carbamoyl-o-4- (3,4-dimethoxy-benzoyl) -1-piperazinyl acetanilide myo-oxalate (19);
    o-carbamoyl-2-ei- 4- (4-nitrobeisoyl) -1 -piperazinyl acetanilide (20)
    p-carbamal-6- 4- (3,4-dimethoxy-benzoyl) -1-piperazinyl acetanilide monohydrochloride monohydrate (21);
    o-hydroxy-m-nitro: -4- (3,4-dimethoksibenzoyl) -1-piperazionyl acetanilide monohydrochloride 3/4-hydrate (22);
     o-carbamoyl - ,, (3,4-dimethoxy-benzoyl) - -piperazinyl outyronylide monooxalate (23);
    o-carbamoyl-ot-4- (3,4-dimethoxy benzoyl) -1-piperazinyl butyroanilide monooxalate (24);
    o-carbamoyl-cii-4- (3,4-dimethoxy-benzoyl) -1-piperazinyl caproanilide monooxalate (25);
    o-n-butylaminocarbonyl- |) -C4- (3,4-dimethoxybenzoyl) -1-piperazinyl acetanilide monooxalate (26);
    o-carbamoyl-o6- 4- (3,4-trimethoxybenzoyl) - -piperazinyl acetanilide (27
    o-carbamoyl- "6- 4- (4-methylbenzoyl) 1-piperazinyl acetanilide (28);
    o-carbamoyl-si- 4- (4-cyanobeisoyl) 1-piperazinyl acetanilide (29);
    o-carbamoyl-ob-C4- (3-chlorobenzoyl) -1-piperazinyl acetanilide monohydrochloride one and a half hydrate (30);
    Amrinone: (3-amino-5- (5-pyridinyl) 2 (H) -pyridinone) (comparative, 31).
    Pharmacological Test 1. An adult mongrel dog of both sexes weighing 8-13 kg was anesthetized with sodium pentobarbital by intravenous administration at a dose rate of mg / kg. After another intravenous administration.
    heparin sodium at a dosage of 1000 units / kg, experimental dogs were killed by bleeding. The dog's heart was cut out and immediately placed in Lock's solution (Lock), then the right coronary artery was connected to the artery with the cannula and the right atrium was carefully isolated.
    Then donor adult mongrel dogs of both sexes weighing 18-27 kg were anesthetized with sodium pentobarbital at a dosage of 30 mg / kg by intravenous administration of sodium heparin at a dosage of 1000 units / kg.
    The specified right atrium was filled with blood supplied from the carotid artery of the donor dog using a peristaltic pump. The transfusion pressure was maintained constant. at 100 mm Hg The movement of the right atrium was measured using a displacement force sensor with a static voltage of 2 g. The amount of blood flowing in the coronary arteries was measured using an electromagnetic flow meter. All data was recorded on a recorder with an ink recording.
    The solution containing the test compound in the artery through a rubber tube attached near the cannula 10-30 μl.
    The positive inotropic effect of the test compound was expressed in c. as a percentage of the pressure developed before and after the injection of the compound. The effect of the compound on the blood flow in the coronary artery was expressed as an absolute value (ml / min) increase immediately after administration of the compound.
    The test results of the effect of the compound on blood flow in the coronary artery are shown in Table 1.
    Pharmacological test. 2. Adult mongrel dogs of both sexes weighing 8-13 kg were anesthetized with sodium pentobarbital at a dosage of 30 mg / kg by intravenous administration. After the next intravenous administration of heparin sodium at a dose of 1000 units / kg, the experimental dog was killed by bleeding. The dog's heart was excised and received a preparation consisting mainly of the anterior papillary muscle and the atrial ventricular septum. The drug was filled by a tube inserted into the anterior artery.
    septum, blood from a donor dog at a constant pressure of 100 mm Hg. Art. The batches used as donors weighed 18-27 kg and they were anesthetized by intravenous administration of sodium pentobarbital at a dosage of 30 mg / kg and then treated by intravenous administration of heparin sodium at a dose of 1000 cd / kg. The papillary muscle is driven by a rectangular pulse exceeding the threshold voltage by about 1.5 times (0.5-3 V) and a duration of 5 s, at a stable speed of 120 beats / min, which was applied to bipolar control electrodes. The force exerted by the papillary muscle was measured with a voltage sensor. Mishida was loaded with a load of approximately 1.5 g. Blood flow through the anterior artery of the septum was measured using an electromagnetic flow meter. The magnitudes of the voltage and blood flow developed were recorded on a tape recorder with an ink recording.
    The test compound was injected into the artery in the amount of 10-30 μl for 4 s.
    The inotropic effects of the compound were expressed as the percentage of voltage developed relative to the value prior to the injection of the compound.
    The effect of the compound on the blood flow was expressed as the difference (ml / min) of the values before and after administration of the compound. The results are presented in table 2.
    Pharmacological test 3. Outbred dogs of both sexes weighing 9–15 kg were anesthetized with sodium pentobarbital, which was first administered intravenously at a dosage of 30 mg / kg and then at a dosage of 4 mg / kg, h, which was administered intravenously with an infusion pump. Breathing of animals was maintained in room air using an artificial respirator with a volume of air exchanged per breath of about 20 ml at a speed of 18 inlets / min. The rib cage was cut through a midline incision and the heart was suspended in the pericardial bag.
    Contractile myocardial force was measured using a Walton-Brodie arc voltage transducer sewn to the left ventricle.
    five
    0
    five
    Systematic blood pressure was measured from the left femoral artery using a pressure transducer. All data was recorded on a chart using a linear recorder.
    The test compound was injected into the left femoral vein.
    The effects of the compounds were expressed as the percentage of the voltage developed relative to the value prior to compound administration.
    The effect of the compound on blood pressure (mm Hg) was expressed as the difference between the values before and after compound administration. The results are shown in table 3.
    Each of the following compounds of general formula (I) of the invention was administered orally to a short-horned male to determine acute toxicity (LDjg mg / kg).
     All tested compounds are more than 300.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining aniline derivative of the general formula
    SO
    R / t-i-c-A-QN-J- / DNZ
    m
    where RI is nitro, amino, carboxy, cyano, hydroxy, sulfonamido, lower Cj-C-alkoxycarbonyl, lower C, -C-alkoxy, lower C (-C-alkanoyl, lower C -C-alkylamino, lower With, -C-altilthio, lower C, -C-alkanoyl amino radical or group of the general formula
    -C - N
    /
    50
    ,
    five
    where is r,
    or R and Rg
    and R, is the same or different hydrogen, lower C, -C-alkyl or cyclo. hexyl group} - form a 6-membered heterogenic heterocyclic group containing, in addition to the atom, nitrogen
    1313
    additionally still oxygen;
    - hydrogen, nitro or lower C, -C-alkoxy;
    , - hydrogen, lower C, alkoxy;
    - cyano, nitro, halogen, lower C, -C-alkyl or lower C, -C-alkoxyradical;
    is an integer from 1 to 3, with m being 2 or 3 only in the case when
    RJ is a lower C.-Cd-alkoxy radical;
    R. A
    hydrogen or lower C-C4-alkyl radical; lower C-C4 alkylene, or a pharmaceutically acceptable salt thereof, characterized in that the piperazine derivative of the general formula
    About HNQN-C
    16560 .14
    Where. RJ and m have the indicated meanings, are reacted with an aniline derivative of the total
    R - I-C-A-X
    0
    where R, R ,, R2,
    R.
    R
    and a
    have the indicated meanings
    X is halogen
    at a temperature of from room temperature to 100 ° C in the presence of the basic compound in an inert organic solvent medium, followed by isolation of the desired product in the free state or in the form of a pharmaceutically acceptable salt.
    Priority featured:
    08.05.81 - with RP Rj, R is hydrogen, R, is lower C –C4-Alkoxycarbonyl, hydrogen, RJ is lower with C, –C4-alkoxy radical, A is lower C –C-alkylene, t -1 or 2;
    11/06/81 - for all other values of the radicals.
    Table 1
    17
    1 5 8 13
    Dobutamine (comparative compound)
    Compiled by G. Konnov Editor A. Shandor Tehred V. Kadar Proofreader S. Cherni
    I -.-- - -.- - - "". "..
    Order 2375/58 Circulation 371 Subscription
    VNISHI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, Projecto st., 4
    1316560
    18 Table 3
    -28
    -eight
    -32
    -32
    -36
    -ten
    -eight
    -34
    -28
    28
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    同族专利:
    公开号 | 公开日
    EP0064878A1|1982-11-17|
    DE3264889D1|1985-08-29|
    ES8403469A1|1984-03-16|
    WO1982003861A1|1982-11-11|
    KR860000062B1|1986-02-06|
    US4585774A|1986-04-29|
    EP0064878B1|1985-07-24|
    ES512024A0|1983-06-01|
    PH18071A|1985-03-18|
    CA1201121A|1986-02-25|
    PT74858B|1983-12-07|
    PT74858A|1982-06-01|
    DK465282A|1982-11-09|
    AU8400082A|1982-12-07|
    FI823575L|1982-11-09|
    FI74704C|1988-03-10|
    DK159971C|1991-05-27|
    DK159971B|1991-01-07|
    FI823575A0|1982-10-19|
    ES8306733A1|1983-06-01|
    FI74704B|1987-11-30|
    AU535498B2|1984-03-22|
    KR830010090A|1983-12-26|
    ES519853A0|1984-03-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE4410822A1|1994-03-24|1995-09-28|Schering Ag|New piperidine derivatives|GB1143882A|1966-06-21|
    FR2209560A1|1972-12-07|1974-07-05|Degussa|N--ethylenediamine derivs - useful as cardioactive medicaments, exhibit anti-ischaemic activity comparable to nitroglycerin|
    DE2304155A1|1973-01-29|1974-08-01|Ichthyol Ges Cordes Hermanni &|N-ACYLATED SUBSTITUTED PIPERAZINE AND HOMOPIPERAZINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION|
    GB1561023A|1977-04-22|1980-02-13|Beecham Group Ltd|2-methoxy - 5 - chloro aniline derivatives|DE3315424A1|1983-04-28|1984-12-20|Cassella Ag, 6000 Frankfurt|SUBSTITUTED PIPERAZIN-1-YL-ACETIC ACID AMIDES, METHOD FOR THEIR PRODUCTION AND THEIR USE|
    IL92011D0|1988-10-19|1990-07-12|Abbott Lab|Heterocyclic peptide renin inhibitors|
    US5164388A|1988-10-19|1992-11-17|Abbott Laboratories|Heterocyclic peptide renin inhibitors|
    US5719151A|1990-05-04|1998-02-17|Shall; Sydney|Substituted benzene compounds|
    GB2244704B|1990-05-04|1995-05-17|Consultants Suppliers Limited|Substituted benzene compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP56069690A|JPS643195B2|1981-05-08|1981-05-08|
    JP56178722A|JPH0129790B2|1981-11-06|1981-11-06|
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