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    • 专利摘要:
    The invention relates to amidine derivatives, in particular, benzamidine (PB) of the general formula HN C (ha) - CfeH, - X - A - OH, where A is n - or isoalkyl-Cz-C; X is oxygen or a direct bond, provided that X is a direct bond, then the amidine group is in the para position with respect to the alkanol group. PBs have pharmacological activity and can be used as antiseptics and disinfectants in medicine. To reveal the actiosity among the indicated class of compounds, new PB were obtained. Their synthesis is carried out by hydrogenation of nitro-substituted phenyl-alkanol, followed by sequential treatment of the resulting aniline derivative with sodium nitrite in an acidic medium, copper cyanide, ethanol with HCI and ammonia. PB tests show that they exhibit high antimicrobial activity and have low toxicity, well soluble in water, that. allows their use in the form of aqueous preparations in contrast to the well-known phenethyl alcohol. 3 tab. i WITH with co 00 4; cm
    公开号:SU1319784A3
    申请号:SU843781801
    申请日:1984-08-03
    公开日:1987-06-23
    发明作者:Мосс Мадлен；Демарн Анри；Филол Робер
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    1 131 The invention relates to the field of biologically active compounds, in particular to a method for producing new benzamidine derivatives corresponding to the general formula
    -X - A-OH
    (I)
    NHN
    where A is straight or branched
    alkyl chain containing 3-8 carbon atoms; X is an oxygen atom or a direct bond, and when X is a direct bond, the amidine group is in a para - ° position with respect to the alkanol group,
    which exhibit antimicrobial activity, therefore, can be used as antiseptics in the treatment of humans and animals, as disinfectants on inert outer surfaces, or as preservatives for products with external use.
    The aim of the invention is to develop a method for producing new compounds exhibiting high antimicrobial activity, low toxicity, well soluble in water.
    Example 1. 4- (3-α-oxypropyl) benzamidine hydrochloride: SR41326 A
    but). 3- (4-Nitrophenyl) -1-propanol.
    To 171.5 g of 3-phenyl-1-propanol, 95 ml of acetyl chloride are added over one hour with stirring. The reflux is heated for 2 hours with hydrochloric acid, which is liberated, and the excess adylethyl chloride is removed. When the reaction mixture returns to room temperature, it is poured drop by drop while stirring in 800 ml of concentrated nitric acid (oi 1.49 ), cooled to -25 ° C, the addition continues for 1 hour, during which the temperature is maintained between -15 and -20 ° C. ”Then poured into 1.5 l of water, to which crushed ice is added, then extracted 3 times with ether, washed 3 times with water, 3 times with a 10% solution of sodium carbonate solution, then 3 times with water. The ether phases are dried over magnesium sulfate, then the {1 is evaporated to dryness under reduced pressure. 0c4 -2
    The cake is taken up in 800 ml of methanol, then gaseous hydrochloric acid is bubbled with barb. 1 hour at 0 ° C, then heated for 14 hours under reflux.
    After evaporation of the solvent, it is taken up in a water-ether mixture, the aqueous phase is decanted, washed 2 times with water, 3 times with saturated sodium bicarbonate solution, then 3 times with water; then dry the ether phase on
    magnesium sulfate, then evaporated to dry under reduced pressure.
    259 g of an orange oil are obtained, which is purified by chromatography on
    3 kg silica gel in chloroform; recover 218 g of orange oil; yield 95%.
    c)., 4- (3-Hydroxypropyl) -aniline.
    218 g of 3- (4-nitrophenyl) -1-propanol is dissolved in 500 ml of methanol, 10 g of 1P% palladium on carbon, pre-moistened with 10 ml of water, are added.
    The hydrogenation is carried out at a pressure of 40 bar and with stirring, it lasts 1 hour and 30 minutes. It is then filtered on zeolite, washed with methanome, and evaporated to dryness under reduced pressure to obtain 168 g of chestnut-colored oil. The latter is purified by three consecutive chromatographs per 6 kg (total) of alumina using dichloromethane as eluent.
    49.2 g of a light brown powder are obtained; m.p. (Fc) 43-45 С, - yield 27% ...
    with). 4- (3-hydroxypropyl) -benzonitrile.
    49.07 g of the product obtained above is poured into 87 ml of concentrated hydrochloric acid, to which 400 g of crushed ice are attached. . Maintaining the temperature between O and 5C,
    a solution of 25.15 g of sodium nitrite in 80 ml of water is added drop by drop, then after 10 minutes of stirring it is neutralized with 300 ml of 10% sodium carbonate solution.
    A solution of copper cyanide is obtained: 40.35 g of copper chloride is suspended in 150 ml of water, and a solution of 54 g of nitri cyanide in 80 ml of water is added. See heat generation, copper chloride
    dissolves, the solution becomes colorless. To this solution, cooled to 0 ° C and combined with 200 ml of benzene, is added drop by drop over 40 minutes with vigorous stirring, the diazonium solution cooled to 0 ° C. After AO min, additional stirring is brought to room temperature, while stirring, to 50 ° C without stirring and brought to room temperature. Extracted 3 times with ether, washed 2 times with water, then with a saturated solution of sodium chloride. The ether phases are dried over magnesium sulphate and evaporated to dryness under reduced pressure. 51 g of dark brown oil are obtained. The latter is purified by chromatography on 1500 g of silica gel. The column is made in toluene, the elution solvent is a toluene-ether mixture (9/1 by volume). 41.6 g of pure product are obtained in the form of a red oil; yield 79%
    NMR spectrum, ppm: 2H between 1.7 and 2.2 (m, -CHj-CHj-CHj-OH); 1H at 2.4 (s, -OH); 2H at 2.8 (t; j 7 Hz, j N-C H -CHj-CH); 2 H at .3.6 (t; j 6 Hz, -CHN-CH--OH); 2H at 7.3 (d; j 9 Hz, H ortho CH); 2H at 7.6 (d; j 9 Hz, H ortho CN).
    d) 4- (3-hydroxypropyl) -phenylethylformedate hydrochloride.
    30.6 g of the product obtained above is dissolved in -300 ml of absolute alcohol, hydrochloric acid gas is bubbled in for 5 hours, then left for 24 hours at room temperature, the solvents are evaporated to dryness under reduced pressure, and the residue is precipitated in 1 l of ether . It is left under stirring for 1 hour under OC, then filtered, washed with ether and dried under vacuum in a desiccator on phosphoric anhydride. Get 40 g of pink powder; so pl., 1 04-105 ° C with decomposition, yield 86%.
    e). SR 41326 A.
    40 g of the product obtained above is dissolved in 400 ml of absolute alcohol. Ammonia gas was bubbled at 0 ° C for 5 hours, then left at room temperature with stirring and left to rest for 48 hours. The solvents are then evaporated to dryness under reduced pressure, and the residue is taken up in
    5 Elution of amidine from the resin was carried out in portions of 500 ml of 5% hydrochloric acid in water. Then the solvent is discharged under reduced pressure, yellow crystals are obtained, W is taken up in alcohol, then the alcohol is evaporated (3 times). The residue is taken up in 1 liter of ether and triturated cold, a yellow powder is obtained, which is filtered, washed 5 times with ether and dried in a vacuum in a desiccator on phosphoric anhydride. 20.1 g of the expected product are obtained in the form of a light yellow powder; Fc 195-205 С, yield 57% 20 Calculated,%: C 55.94; H 6.99; N 13.05; CI 16.55.
    Found,%: C 55.55; H 6.96; N13.20; C1 16.36.
    Example 2. 4- (2- -oxobutyl) -benzamidine hydrochloride: CM41092A. a), 1-Phenyl-2-butanol. Under a nitrogen atmosphere, drop by drop, at a rate sufficient to maintain a slight reflux, of a solution of 7.5 ml of ethyl bromide in 50 ml of anhydrous ether is added to 2.92 g of magnesium in the turning sawdust. All the time under nitrogen atmosphere, it is stirred for 2 hours at room temperature 35, then 9.4 ml of phenylacetaldehyde is added drop by drop and it is left for 2 hours at room temperature with stirring.
    40 Then, the decomposition is carried out in 200 ml of 20% ammonium chloride, cooled to, and extracted 3 times with ether. After three washes with water, the ethereal phases are dried on magnesium sulfate and extracted under reduced pressure. 12.2 g of a slightly yellow oil are obtained.
    c) .4- (2-Oxybutyl) -benzonitrile. Working as in Example 1a, 1- (4-nitrophenyl) -2-butanol is obtained.
    NMR spectrum, ppm: ZN at 0.9 (t, asymmetric, J 7 Hz, -CH; ZN between 1.2 and 1.8 (block, -CH (OH) - 500 ml of distilled water. Pere - -QH-i-CH,); 2H between 4.6 and 2.9 (m, stirred for 1 hour with 450 ml of amberly-Cy-C NF-CH resin); 1H between 3.4 and 3.9 and IRA -400 in the form of acetate, then (m, (OH) -CH); 2H at 7.3 is filtered and washed 3 times with (d, J 9 Hz, H ortho CH); 2H with power 300 ml of water. Then stirring - 8.1 (d, J 9 Hz, D orto CN).

    ,
    3197844
    The filtrate is treated with 400 ml of Bis-Rex-70 resin in acid form, then filtered and washed 3 times with 500 ml of water.
    5 Elution of amidine from the resin was carried out in portions of 500 ml of 5% hydrochloric acid in water. Then the solvent is discharged under reduced pressure, yellow crystals are obtained, W is taken up in alcohol, then the alcohol is evaporated (3 times). The residue is taken up in 1 liter of ether and triturated in a cold state, a yellow powder is obtained, which is filtered, washed 5 times with ether and dried in a vacuum in a desiccator on phosphoric anhydride. 20.1 g of the expected product are obtained in the form of a light yellow powder; Fc 195-205 С, yield 57%. 20 Calculated,%: C 55.94; H 6.99; N 13.05; CI 16.55.
    Found,%: C 55.55; H 6.96; N13.20; C1 16.36.
    Example 2. 4- (2- -oxobutyl) -benzamidine hydrochloride: CM41092A. a), 1-Phenyl-2-butanol. Under a nitrogen atmosphere, drop by drop, at a rate sufficient to maintain a slight reflux, of a solution of 7.5 ml of ethyl bromide in 50 ml of anhydrous ether is added to 2.92 g of magnesium in the turning sawdust. All the time under nitrogen atmosphere, it is stirred for 2 hours at room temperature 35, then 9.4 ml of phenylacetaldehyde is added drop by drop and it is left for 2 hours at room temperature with stirring.
    Then, decomposition is carried out in 200 ml of 20% ammonium chloride cooled to and extracted 3 times with ether. After three washes with water, the ether phases are dried over magnesium sulphate and evaporated under reduced pressure. 12.2 g of a slightly yellow oil are obtained.
    c) .4- (2-Oxybutyl) -benzonitrile. Working as in Example 1a, 1- (4-nitrophenyl) -2-butanol is obtained.
    Then, as in Example 1c and 1c, 4- (2-hydroxybutyl) -benzonitr1 is prepared.
    NMR spectrum, ppm: ZN at 0.8 (t, asymmetric, J 6 Hz, -CM-CH,); 2H at 1.25 (q, J 6 Hz, -CH (OH) -CHN-CH3); 2H between 2.5 and 2.8 (t, CK-SbH4-CH); 1H between: i, 2 and 3.8 (t, CH-CH (OH) -CH2); 1H at 4.5 (d, J 6 Hz, -OH); 2H at 7.4 (d, J 9 Hz, H ortho CH); 2H at 7.7 (d, J 9 Hz, H ortho CN).
    with). Hydrochloride 4- (2-oxybutsh1) - -ethyl formimidate,
     Obtained according to the principle of operation described in Example Id, this product is recrystallized from ethanol-ether; RS 118-122 ° C with decomposition.
    d). SM 41092 A.
    The product is prepared as in example 1e; FC 159-161 ° C, recrystallization solvent: ethanol-ether
    Calculated,%: C 57.77; H 7.44; N 12.25; C1 15.54.
    Found,%: C 57.22; H 7.59; N 11.91; C1 15.38.
    PRI me R 3. Chlorohydrate of 4- (2-hydroxy-1,1-di-n-propylethyl) benzamidine: SR 41946 A.
    but). 1,1-Di-p-propylphenylacetonitrile.
    A suspension of 52.4 g of sodium hydride in 250 ml of dimethylformamide is obtained. Under nitrogen atmosphere, maintaining mechanical agitation, 47 ml of benzyl cyanide are added, after 35 minutes, cooled in an ice bath, then 145 ml of p-propyl bromide are added very slowly. Maintain agitation for 3 hours at room temperature.
    It is boiled into 2 l of water, mixed with ice, then extracted 2 times with 1 × ether, washed 3 times with water and 45–7.3 (s, H aromatic). ) the ether phases are dried on magnesium sulphite d). 1,1-di-p-propylphenyl ethanol
    30 ether, extracted 3 times with ether, passed 2 times with saturated bicarbonate solution, once with water, 2 times with normal hydrochloric acid, then 3 times with
    35 Then the ether phases are dried on magnesium sulfate and evaporated to dryness under continuous pressure.
    9.82 g of orange ma are obtained, yield 99%.
    NMR spectrum, ppm: 1ZN between and 1.4 (block, -COj-CHj-CHj, (-CH)); 4H between and 2.2 (block, (CH,)); 2H at (q, J 7 Hz,,); 5H
    40
    after evaporation of the ether. The residue is distilled in vacuo; bp 72-80 with at 0.01 mm Hg 50.4 g of a yellow oil are obtained; yield 63%
    at). 1,1-Di-p-propylphenylacetic acid.
    25.1 g of the product obtained are dissolved in 65 ml of glycol and 15.5 g of potassium in tablets are added. Heat with stirring, first distil 2 ml of water, then keep heating under reflux with stirring for 40 hours and pour out
    197846
    in 1.5 liters of water combined with ice. Extractgartilt 2 times with hexane, filter the aqueous phase on zeolite and acidify to pH 1 with concentrated hydrochloric acid. The pellet is left to stand in the refrigerator for 48 hours, filtered, washed with water and recrystallized from methanol-water (50/50 by volume).
     О The crystals formed are filtered, washed with water and dried under vacuum.
    7.3 (s, H aromatic). d). 1,1-di-p-propylphenyl ethanol
    18.75 g of greyish white crystals are obtained; m.p. 97-100 ° C; yield 68%.
    c) 1,1-di-p-propylphenylethyl acetate.
    The following reaction is carried out under a nitrogen atmosphere. To 8.8 g of the precursor product is added drop by drop and under stirring 10 ml.
    loristy thionyl. Maintain peemeshivanie 2 h at room temperature, then cooled and extracted with excess thionyl chloride under reduced pressure. Then 50 ml of absolute alcohol and 3.5 ml of anhydrous pyridine are added at 0 ° C. After 1 hour of stirring, they are heated for 15 hours under reflux, then cooled, alcohol is added and placed in a mixture of water-ether, extracted 3 times with ether, and sieved. 2 times with a saturated sodium bicarbonate solution, 1 time with water, 2 times with normal hydrochloric acid, then 3 times with water.
    The ether phases on magnesium sulfate are then dried and evaporated to dryness under reduced pressure.
    9.82 g of an orange oil are obtained; yield 99%.
    NMR spectrum, ppm: 1ZN between 0.6 and 1.4 (block, -COj-CHj-CHj, ()); 4H between and 2.2 (block, (CH,)); 2H at 4.1 (q, J 7 Hz,,); 5H at
    3.2 g of aluminum lithium hydride are suspended in 50 ml of benzohydrous tetrahydrofuran under nitrogen. Up to 50 bavlut drops drop by drop, maintaining a weak reflux solution of 9.8 g of the product obtained in part c) in 50 ml of tetrahydrofuran, then heated for 4 hours under reflux all the time in the atmosphere
    55 nitrogen. After cooling, decomposition is carried out with the help of 10 ml of water and 100 M.P of 15% sulfuric acid. Extracted 3 times with ether, washed 3 times with water, dried ether
    the phases are on magnesium sulfate and the residue is dried under reduced pressure.
    8.30 g of a yellow oil are obtained,. which is purified by chromatography on 25.0 g of silica gel, using chloroform-hexane (50-50 by volume) as eluent for elution. In this case, 7.91 g of a slightly yellow oil is selected; yield 97%.
    NMR spectrum, ppm: 15H between 0.5 and 1.8 (block, 14H aliphatic chains + OH); 2H at 3.7 (s; -gi., - OH); 5H at 7.25 (s, H aromatic).
    e) SR 41946 A.
    The synthesis steps described in Example 1 are carried out to obtain SR 41946 A; m.p. 110-115 s, the recrystallization solvent is a mixture of ethanol - ether.
    Calculated,%: C 63.27; H 8.79; N 9.84; C1 12.48.
    Found,%: C 63.47; H 8.70; N 9.42; C1 12.75.
    Example4; Chlorigdrate 4- (4- -oxybutyloxy) -benzamidine: CM 40847 A.
    but). 1- (4-Nitrophenoxy) -4-bromobutane.
    83 ml of 1,4-dibromobutane is added to a solution of 4-nitrophenol in 275 ml: water, then 49.5 ml of 10 N sodium is added drop by drop with stirring. The mixture is heated under reflux with stirring for 24 hours. After cooling, it is extracted 3 times with ether.
    evaporated to dryness, the residue was obtained in vacuo. 70 g of orange oil are obtained; yield 100%.
    c) f 1- (4-Nitrsphenoxy) -4-butanol 70 g of the product obtained above is dissolved in 300 ml of methanol, 30 ml of 10N sodium is added, and then heated under reflux for 4 hours with stirring. After drying to methanol, the residue is taken up in a water-ether mixture, extracted three times with ether, and washed three times with a saturated solution of sodium chloride. The ether phases 15 on magnesium sulfate are then dried and evaporated to dryness. The crystals formed are triturated in hexane, filtered, washed with hexane and dried under vacuum in a desiccator. 48.8 g of slightly yellow crystals are obtained; m.p. 53-55 C. d). CM 40847.
    Work as in Example 1, the following compounds were obtained:
    4- (4-hydroxybutyloxy) -aniline 5 25 mp, 56-58 ° C;
    4- (4-hydroxybuty 1) -benzonitrile,
    m.p. 54-58 C;
    CM 40847 A, m.p. 210-213 ° C. Calculated,%: C 53.98; H 6.95; 30 N 11.45, Cl 14.52.
    Found,%: C 53.80; H 7.02; N11.3 C1 14.40.
    Using similar methods
    - preparations get offered
    wash b times with normal sodium,% h35 compounds,
    J times water. The ether phases are dried
    the characteristic of which is given in tabLo1 (melting point is measured after recrystallization from ethanol-ether mixture).
    on sodium sulphate and insulate, filter out the insoluble portion. The filtrate is evaporated to dryness and the residue is obtained in vacuo (0.05 mm Hg). After trituration in hexane, crystals are obtained, which are filtered, washed with hexane and dried in a vacuum in a desiccator, 1) 75 g of a cream-colored pasty product are obtained; yield 55%.
    at). 1- (4-Nitrophenoxy) -4-acetyloxibutane.
    75 g of the previous product is dissolved in 80 ml of glacial acetic acid, 45 g of anhydrous acetate are added to the surface of sodium agart, then heated under reflux for 15 hours with stirring. The reaction mixture was poured into 1 L of ice water, to which 500 ml of ether was added, and neutralized to pH 7.5 with solid sodium carbonate. After three extractions with ether, ether and three washes with water, the ether phases are dried on magnesium sulfate and
    agar nutrient medium containing a neutralizing agent for the antibacterial activity of the product.
    The retained bactericidal concentration is the minimum concentration at which bacteria no longer spread. This concentration is expressed in mg / ml and is shown in Table 3.
    evaporated to dryness, the residue was obtained in vacuo. 70 g of orange oil are obtained; yield 100%.
    c) f 1- (4-Nitrsphenoxy) -4-butanol. 70 g of the product obtained above are dissolved in 300 ml of methanol, 30 ml of 10N sodium are added, then heated under reflux for 4 hours with stirring. After extraction of methanol, the residue is taken up in a water-ether mixture, extracted three times with ether, washed three times with a saturated solution of sodium chloride. The ether phases on magnesium sulfate are then dried and evaporated to dryness. The crystals formed are triturated in hexane, filtered, washed with hexane and dried under vacuum in a desiccator. 48.8 g of slightly yellow crystals are obtained; m.p. 53-55 C. d). CM 40847.
    Work as in Example 1, the following compounds were obtained:
    4- (4-hydroxybutyloxy) -aniline 5 m.p. 56-58 ° C;
    4- (4-hydroxybuty 1) -benzonitrile,
    m.p. 54-58 C;
    CM 40847 A, m.p. 210-213 ° C. Calculated,%: C 53.98; H 6.95; N 11.45, C1 14.52.
    Found,%: C 53.80; H 7.02; N11.30; C1 14.40.
    Using similar methods
    35 compounds
    40
    the characteristic of which is given in tabLo1 (melting point is measured after recrystallization from ethanol-ether mixture).
    Elemental analysis data lagged compounds are listed in Table 2,
    The study of bactericidal activity.
    4S Bacteria grafting is carried out by contacting various solutions of the test product over a fixed time. At the end of the contact is a multiple of a mixture of bacterial suspension / food carbon medium containing a neutralizing agent for the anti-bacterial activity of the product.
    The bactericidal concentration retained is the minimum concentration of the product at which the bacteria no longer spread. This concentration is expressed in mg / ml and is shown in Table 3.
    Bacterial sources choose the following:
    1- Escherichia
    2CNCM 54125;
    Clebsiella pneumonial capsulee030;
    3- Pseudomonas
    aeryginosa GNCM A22;
    four-; Streptococcus
    faecolus CNCM 5855;
    5- Starhylococcus
    aureus CNCM 53154.
    The second is cultivated in the Worgel Tergusson environment, the others are cultivated on Trypfic Soy Agar - Difco (ISA).
    After 24 hours of cultivation at 37 ° C., germinated microbes are collected using glass beads and 10 ml of diluent containing 1 g of trypto. The results are shown in Table 3. The results show that the compounds of formula 1 have an activity level that can be compared with everything tested. bacterial sources.
    Compared with phenylethyl alcohol, a bactericidal product used both as an antiseptic, fO and as a preservative.
    C1) the food products offered have the highest average level of activity and 5 moreover, they dissolve in water, which
    greatly facilitates their use, J5 especially in herbal preparations.
    The tolerance of the compounds of the formula I is examined in guinea pigs. In animals, the hair is cut off from both Styron midline backs, sheared and 8.5 g of sodium chloride in 1000 ml20 ku, if necessary, through distilled water. The resulting suspension is stirred and the percentage of light transfer at 620 nm is measured on a spectrophotometer: source days. Groups of 6 animals are applied to the sheared place with 0.2 ml of an aqueous or alcoholic solution of the compound of formula I. In the case of 1 - 70%; 2 - 80%; 3 - 70%; 4-60%; 25 no alcohol solution control
    5 - 60%.
    Bacteria vaccination corresponds to the suspension at 1 / 20e of this bacterial suspension.
    Plates, including ampoules, receive various dilutions of the test product. These dilutions of the test product are brought into contact with various bacterial suspensions using a reusable local inoculant of the Steers type. After a 20-minute contact, aliquot parts are transferred using this inoculum to the surface of an agar-agar medium (TSA) placed in Petri dishes containing a neutralizing agent, namely 20 g Zubrol W, 2.5 g Tween-80 and 2.5 f- thio-sodium sulphate in 1000 ml TSA (Dif-: s) in the Control sample of the effectiveness of the neutralizing agent were used for each test product by placing an aliquot of the diluent of the test product on the surface of the nutrient medium. After drying, the appropriate graft is placed in the same place. A control sample of the grafting material is obtained on agar-agar medium with and without neutralizing agent. The reading was made after 48 hours of incubation at 37 C.
    31978410
    The results are shown in Table 3. The results show that the compounds of formula 1 have a level of activity that can be compared with all test bacterial sources.
    Compared with phenylethyl alcohol, a bactericidal product used both as an antiseptic, fO and as a preservative.
    C1) the food products offered have the highest average activity level and 5 moreover, they dissolve in water, which
    greatly facilitates their use, J5 especially in herbal preparations.
    The tolerance of the compounds of the formula I is examined in guinea pigs. In animals, the hair is cut from both Styron midline backs, the haircut is repeated, if necessary, through
    every 2 days Groups of 6 animals are applied to the sheared place with 0.2 ml of an aqueous or alcoholic solution of the compound of formula I. In the case of application
    na group of animals gets alcohol in the side.
    For the study of preliminary skin tolerance, treatment is applied once a day, for 6 days from I-7. The duration of the experiment is 3 weeks. Skin observations relate to the presence of erythema, skin rash or hyperkeratosis, the intensity of which is graduated on a specific scale.
    A skin sensitization test was performed on the same animals after a two-week break. Processing continues for one week, it is identical to the previous one. The evaluation is carried out according to the same criteria and the same scale that is used for national tolerance.
    In the same way, it is investigated by known methods whether the compounds of the formula I have a phototoxic or photoallergic effect in the guinea pig.
    None of the products studied showed poor tolerance, poor sensitizing effects and poor phototoxic or photoallergic effects in the guinea pig.
    Compounds of formula 1 that have good antimicrobial activity and tolerance may be
    111
    used as antiseptics, preserving or disinfecting agents for the treatment of people, animals, cosmetics and agriculture.
    In particular, they can be used as antiseptics in preparations for therapeutic purposes, for example, in the treatment of impetigo, acne, infectious dermatoses, infectious open wounds, closed infections, such as boils, felon, impetiginous scabies, etc. . It may also be envisaged to be used with a precautionary purpose, for example for treating a surgical floor, for treating the hands of a surgeon or maintenance staff.
    In veterinary medicine, the products offered can be used either as antiseptics (for example, in preventing mastitis), or as disinfectants (material disinfection, sheds, etc.).
    The good tolerance and weak toxicity of these products make it possible to use them as preservatives, not only in pharmaceuticals and cosmetology, but also in the preservation of agricultural products.
    The galenic preparations of the compounds of formula 1 are prepared depending on the method of application.
    EXAMPLE 5 Foaming, washing liquid antiseptic preparation, g:


    SR 41613 P3
    Alkyldimethylcarboxymethyl-amine (30% solution) 15
    Secondary acid sodium tetrazemate 0.1 Propylene glycol 10 Sodium hydroxide or lactic acid - amount to reach pH 5.8 Purified water Up to 100
    EXAMPLE 6 Foaming detergent and antiseptic preparation, g: SR 41946 A2
    Paraffinsulfonate sodium 15
    Sodium hydroxide or lactic acid is sufficient to achieve a pH of 5.2 Purified water up to 100
    12
    Example. Disinfectant for inert surfaces, SR 41579 A5
    Dodecyl dimethylcarboxydimethylamine 20 Secondary acidic tetraceman sodium 2 Lactic acid - an amount sufficient to achieve a pH of 3.5 Purified water Up to 100
    5 o 5
    35
    20
    25
    thirty
    40
    45
    0
    five
    PRI me R 8. Alcohol antiseptic solution, g:
    SK 41946 A2
    Alkyldimethylcarboxymethylamine (30%
    solution) 0.5
    Oxide condensate
    ethylene and propylene glycol L 62 1
    Purified water Up to 100
    Example 9. The proposed product can be used as a preservative in a shampoo, g:
    Potassium Palmitate and Amino Acids 20 Sodium Acid Sulfates 2
    Diethanolamide
    copra5
    Linoyl acetate 0,200 SR 41946 A0,150
    Sodium hydroxide to pH7. Purified water Up to 100 Example 10. The proposed product can be used as a preservative in cream emulsion, g:
    Thick petrolatum oil6 A mixture of cetostearyl alcohol and hydroxymethylated ceto-stearyl
    alcohol9
    Anhydrous monosodium phosphate 0,300 Acidic sodium tetraacetate 0.010 Vaseline 15
    SR 41946 A0,150
    Phosphonic acid - until reaching pH 4.5 Purified water Up to 100
    Example 11. The proposed product can be used as a preservative in a cream for use in cosmetics, g:
    Collagen 0.500
    Carboxypolymethylene 9340,400
    Hydrogenated
    lanolin4
    Perhydrosqualene 20
    Monopalmitate
    polyoxymethylated sorbitol 2
    SR 41946 A 0.150
    Lactic acid
    or hydroxide
    sodium until pH is reached. 6.5
    Purified water Up to 100
    Thus, the proposed method allows to obtain new compounds, possessing high antimicrobial activity, low toxicity, which are readily soluble in water, which makes it possible to include them in aqueous or partially aqueous preparations without any problems. Phenethyl alcohol, used according to a known method, requires the search for an soluble solvent in it and the study of its properties.
    Form l. a and 3 o brete n i. The method of obtaining pharmaceutically acceptable salts of derivatives of benzene cin General formula
    XA-OH
    A is a straight or branched apical chain containing 3-8 carbon atoms, X is oxygen or a direct bond, provided that when X is a direct bond, the amidine group is in the para-position with respect to the group alkanol,
    liable for
    ineni general formula
    O) - X - A - OH
    Ogn
    where A, X have the indicated meanings, hydrogenate to obtain the corresponding aniline derivatives, which are treated with sodium nitrite in an acidic medium to obtain the corresponding diazonium, which is confirmed to react with copper cyanide, to obtain benzonitrile, which is converted into an imidoester hydrochloride by the action of ethanol and hydrochloric acid and then the resulting imidoester is treated with ammonia to obtain the desired product as a salt.
    Table 1
    TYAN
    XA-OH
    (I)
    1613 A 41947 A 41149 A 40721 A 40940 41579 A
    steam vapor steam vapor meta
    ABOUT
    ABOUT
    about
    SzN7
    eleven
    2 4
    4 4
    178-180 210-215 85-90 161-163 180-185 141-143
    Compiled by N.Kulikov. Editor by N.Egorov. Tehred Lo-Oliynyk Proofreader A Zakimokos
    2537/59
    Circulation 371 Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., d.A / 5
    Production and printing company, Uzhgorod, Projecto st., 4
    权利要求:
    Claims (1)
    [1]
    Claim . The method of obtaining pharmaceutically acceptable salts of benzamycin derivatives of the general formula in the medium to obtain the corresponding diazonium, which is subjected to interaction with copper cyanide, to obtain benzonitrile, which is converted 30 to imidoether hydrochloride by the action of ethanol and hydrochloric acid, and then the resulting imido ether is treated with ammonia to obtain the target product in the form of salt.
    Table 1 N 7®U X - A - ° N h "n g
    Product Position X AND HE Received by example Mp FROM 1g . 3 4 5 6 Sr 41613 A couple - (mon 2 ) 4 he 1 178-180 Sr 41947 A couple - '(d. 2 ) 5 he 1 210-215 Sr 41149 A couple - sn 2 - sn (he) p s e n 72 85-90 CM 40721 A couple 0 ~ (sn 2 ) uh he 4 161-163 cm 40940couple 0 - (CH g ) 5 0H 4 180-185 Sr 41579 A meta 0 - (CH 2 ) 4 OH 4 141-143
    16 ·
    Continuation of the table. 1.
    1 3 4 5
    SR 41616 Ortho. O - (CH 2 ) 4 0H 4 152-154
    SR 42748 A. steam - -С (SND СН 2 0Н 3 181
    table 2
    CompoundCalculated Found,% FROM I and1 N C1 57.77 7.4412.25 15,54SR 41613 A 57.48 7.4512.18 15.43SR 41947 A 59 d 38 7.847.6411 d 55 14 D 64 Ϊ 4.87 58.941Ϊ, 47SR 41149 A 59 d 38 77 d 8411 d 55 14 D 64 59, Ϊ3 7.79ϊϊ, 56 14.62SR 40721 A 52 d 06 6 D 5112 D 14 15 d 40 5Ϊ.82 6.471Ϊ, 86 Ϊ5.20SR 40940 A 55 d 71 7 D 3510 d 83 13 d 73 55.81 7.3010.84 14.08SR 4157953.98 6.9511.45 14.52A 53.75 7.07.11.21 14.43SR 41616 A 53 d 98 6 D 9511 d 45 ΪΪ, 4Ϊ 14 d 52 53.75 6.9314.76SR 42748 A 57 d 75 7 D 4912 d 25 15 d 52 57.89 7.4411.97 Ϊ5.42 Table and 3 - ------------- - - -, ---------- ---- --- g ------- --L ..------ L ___ Product Bacterial sourcesmg / kg1 J 2 i 3 1 4 Sr 14613 A10,000 10,000 15,000 10,000 5000 250 Sr 41946 A4000 5000 4000 2000 2000 500-1000 Sr 41149. A5000 6000 6000 20000 20000 500-1000 CM 40721 A8000 8000 8000 8000 8000 250 CM 40847 A5000 5000 5000 5000 5000 250
    17 1319784 18
    Continuation of table.Z
    Product GBacterial sources .g ------------ 1 1 11 1 1 1 1 I I 1 1'1 1 1 W 1 1 1’1 1 1 1. .-------------- mg / kg ’I 2 Ί P SR 41616 A 7500 5000 5000 15,000 15,000 250 SM 40940 A 16000 15,000 15,000 20000 15,000 250 SR 41579 A 8000 8000 8000 10,000 15,000 250 SR 42748 A 10,000 10,000 * 5000 20000 10,000 .250 Phenylethyl alcohol 15,000 15,000 15,000 15,000 20000
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    同族专利:
    公开号 | 公开日
    ES8504112A1|1985-04-16|
    ZA845682B|1985-02-27|
    CS584184A2|1985-12-16|
    DE3464362D1|1987-07-30|
    FI843061A|1985-02-04|
    JPS6054351A|1985-03-28|
    US4720581A|1988-01-19|
    PT79003A|1984-08-01|
    HU192567B|1987-06-29|
    DK362384A|1985-02-04|
    KR850001730A|1985-04-01|
    AR242556A1|1993-04-30|
    NO843114L|1985-02-04|
    DD220025A5|1985-03-20|
    FR2550192B1|1986-04-04|
    AU3079084A|1985-02-07|
    NO157618C|1988-04-20|
    MA20180A1|1985-04-01|
    ES534828A0|1985-04-16|
    EP0136195A1|1985-04-03|
    PT79003B|1986-06-18|
    DK362384D0|1984-07-24|
    DK158662B|1990-07-02|
    GR82449B|1984-12-13|
    DK158662C|1990-12-10|
    EP0136195B1|1987-06-24|
    NO157618B|1988-01-11|
    HUT34724A|1985-04-28|
    YU127684A|1986-12-31|
    CS246088B2|1986-10-16|
    CA1238922A|1988-07-05|
    IL72480D0|1984-11-30|
    AU563648B2|1987-07-16|
    IL72480A|1987-10-30|
    KR920000373B1|1992-01-13|
    FR2550192A1|1985-02-08|
    AT27952T|1987-07-15|
    FI843061A0|1984-08-02|
    FI77020B|1988-09-30|
    FI77020C|1989-01-10|
    NZ209092A|1987-03-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2934438A|1958-03-20|1960-04-26|Michener Harold David|Preservation process with alkyl guanidines|
    US3769427A|1970-10-01|1973-10-30|Armour Pharma|Pharmaceutical compositions and methods of using same|
    IT1153988B|1981-10-05|1987-01-21|Medea Res Srl|COMPOSITIONS WITH ANTI-MICROBIAL ACTIVITY|JP2504361Y2|1990-12-14|1996-07-10|大和ハウス工業株式会社|Building piping fixed structure|
    DE4447361A1|1994-12-21|1996-06-27|Schuelke & Mayr Gmbh|Biocidal alcohols, their production and their use|
    AU2004218187C1|2003-02-19|2011-04-07|Eisai R&D Management Co., Ltd.|Methods for producing cyclic benzamidine derivatives|
    US7585979B2|2004-07-05|2009-09-08|Dong Wha Pharmaceutical Ind. Co., Ltd.|Process for preparing N-hydroxy-4-{5-[4--phenoxy]-pentoxy}-benzamidine|
    CN111362834B|2020-02-26|2021-04-02|湖南大学|Antibacterial amidine oligomer with drug resistance and preparation method and application thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8312824A|FR2550192B1|1983-08-03|1983-08-03|NOVEL BENZAMIDINE DERIVATIVES WITH ANTIMICROBIAL ACTIVITY, PROCESS FOR THEIR PREPARATION, AND THEIR USE AS DISINFECTANT OR PRESERVATIVE MEDICINES|
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