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    • 专利摘要:
    (Diphenylmethyl) -1-piperazinyl3-acetic acids or their amides of the general formula X- / O, If CVH jMCHjCHjplniCHrCC I where y is the group —OH or W; m 1 or 2; X is a hydrogen, chlorine, fluorine, methoxy or trifluoromethyl radical; X is hydrogen or fluorine, and x is always hydrogen, except when x and x are fluorine simultaneously; X is methoxy or trifluoromethyl when y is only the group M L 1 or 2 when X is hydrogen or chlorine, m 1 when X is fluorine or methoxy ,. ha 2 with X-trifluoromethyl or X and x simultaneously fluorine, or their non-toxic, pharmaceutically acceptable salts exhibiting antispasmodic and antihistamine activity. I (L with with with Nj
    公开号:SU1310397A1
    申请号:SU823478400
    申请日:1982-08-18
    公开日:1987-05-15
    发明作者:Бальтес Эжен；Де Ланнои Жан；Родригез Людовик
    申请人:Эжен Бальтес, Жан де Ланнои и Людовик Родригез (BE)；
    IPC主号:
    专利说明:

    g
    This invention relates to new piperazine derivatives - (diphenylmethyl) -1-piperazinyl acetic acids of the general formula
    131
    tu- jQbbtcH cHiavcH ,:
    ,
    de y is the group —OH or —MH, m. 1 or 2j
    X is a hydrogen, chlorine, fluorine, methoxy or trifluoromethyl radical; x is hydrogen or fluorine, and
    X is always hydrogen, except when x and x are simultaneously fluorine5 X is methoxy or trifluoromethyl at
    u only group, m 1 or 2 when X is hydrogen or
    chlorine;
    m 1 at X is fluorine or methoxy; m 2 at X, is trifluoromethyl or X and x is simultaneously fluorine.
    2- 2- (diphenylmethyl) -1-piperazinyl ethoxy ethoxy-acetamide. 25 The resulting crude product is used in this form, without further purification, to obtain the corresponding acid (Example 2.2).
    2- 12- 2- 4- (4-chlorophenyl) phenylmethyl, their non-toxic, pharmaceutically acceptable salts. These compounds exhibit antispasmodic and antihistamine activity.
    . The purpose of the invention is a new 1-piperazinyl-ethoxy ethoxy piperazine that has the best acetamide. properties than the known structural, (4-fluorophenyl) phenylmethyl 1 m t / t m 7 t
    analogs.-1-piperazinyl ethoxy-acetamide.
    1. Getting amides
    35
    45
    Formula example. I (in w).
    1.1. (Diphenylmethyl) -1-piperazinyl ethoxy-acetamide dihydrochloride.
    A mixture of 37.8 g (0.15 mol) of 1- (diphenylmethyl) -piperazine, 27.5 g (0.2 mol) of 2- (2-chloroethoxy) - is heated at 90-120 ° C for 4 hours at 90-120 ° C. acetamide, and 26.5 g of anhydrous sodium carbonate in 120 MP of xylene, then 120 ml of benzene was added to the mixture, the resulting residue was filtered, and the organic layer was extracted with a dilute hydrochloric acid solution (30 ml of concentrated hydrochloric acid and 100 ml of water). After adding 40 mp of concentrated sodium hydroxide solution and extraction with benzene, the benzene solution is washed with water, dried over anhydrous sodium carbonate and benzene is evaporated to dryness. The residue after evaporation is triturated with ethyl ether and left to crystallize. Get 2 Exit 54,7%. Melting point 105-107 ° C (acetonitrile).
    .Analysis C-i., H26FN ,, Oj.
    Calculated,%: C 67.90; H 7.09; N 11.31.
    Found,%: C 68.3; H, 7.40; N, 11.21. 2-2-C4- (4-methoxy-phenyl) phenylmethyl -1-piperazinyl ethoc-CHj-acetamide dichlorohydrate.
    Yield 20%. Melting point 175-176 ° C (acetonitrile).
    50
    Analysis of C22HigN 3 Oz 2HC1
    Calculated,%: C 57.8; H 6.8; N 9.2; C1 15.5.
    Found,%: C 57.8; H 7.2; N 9.5 C1 15.9.
    2- 4 4- (trifluoromethyl) phenyl phenylmethyl -1-piperazinyl-J-toxy ethoxy-acetamide. The yield is 78%. The dihydrohydrate melts at 178-181 ° C (acetonitrile).
    Analysis C, NzoReN, O, 2HC1.,
    Calculated,%: C 53.53; H 5.99; N 7.80 C1 13.17.
    Found,%: C 51.47; H 5.60; N 7.89; C1 13.10.

    310397 2
    (diphenylmethyl) -1-piperazinyl ethoxy-acetamide in 73% yield. Melting point 119-120 C.
    The dihydrochloride obtained in ethano-5 le melts at 230 ° C with decomposition. Analysis of Cj, Hj7N, Oj-2HCl. Calculated,%: C 59.15; H 6.85; N 9.85; C1 16.63.
    Found,%: C 58.99; H, 6.80; N 9.79; JO C1 16.46.
    According to the described method, the following compounds are obtained.
    (4-chlorophenyl) phenylmethyl - -1-piperazinyl ethoxy-acetamide. Output 47%. Melting point 111-112 ° C (ethanol).
    Analysis of Cj, H2gClN, 02. Calculated,%: C 65.02; H 6.71, N 10.83J C1 9.14.
    Found,%: C 64.59 H, 7.00; ; N 10.82; C1 9.54.
    2- 2- (diphenylmethyl) -1-piperazinyl ethoxy ethoxy-acetamide. 25 The resulting crude product is used in this form without additional purification.
    to obtain the corresponding acid (Example 2.2).
    2- 12- 2- 4- (4-chlorophenyl) phenylmethyl -1-piperazinyl-ethoxy ethoxy-acetamide. (4-fluorophenyl) phenylmethyl1
    Yield 54.7%. Melting point 105-107 ° C (acetonitrile).
    .Analysis C-i., H26FN ,, Oj.
    Calculated,%: C 67.90; H 7.09; N 11.31.
    Found,%: C 68.3; H, 7.40; N, 11.21. 2- 2-C4- (4-methoxy-phenyl) phenylmethyl -1-piperazinyl ethoch-CHj-acetamide dihydrochloride.
    Yield 20%. Melting point 175-176 ° C (acetonitrile).
    45

    50
    Analysis of C22HigN 3 Oz 2HC1
    Calculated,%: C 57.8; H 6.8; N 9.2; C1 15.5.
    Found,%: C 57.8; H 7.2; N 9.5 C1 15.9.
    2- 4 4- (trifluoromethyl) phenyl phenylmethyl -1-piperazinyl-J-toxy ethoxy-acetamide. The yield is 78%. The dihydrohydrate melts at 178-181 ° C (acetonitrile).
    Analysis C, NzoReN, O, 2HC1.,
    Calculated,%: C 53.53; H 5.99; N 7.80 C1 13.17.
    Found,%: C 51.47; H 5.60; N 7.89; C1 13.10.
    313103974
    2- 2-C2-4-bis (4-fluorophenyl me- (Analysis of C,, CjH OH-ZHCl.
    Calculated,%: C 55.27; H 7.16; N 7.43; C1 12.55, 22.
    Found,%: C 53.10, H 6.93, 5 N 7.18; C1 12.56; С1оец18,79.
    1.3. 2- 2-f4-t (4-chlorophenyl) phenylmethyl -1-piperazinyl ethoxy-acetated -1-piperazinyl ethoxy 3-ethoxy 3 - acetamide. Yield 90%. The dihydrochloride melts at 188-190 ° C (acetonitrile).
    Analysis of C23 Ng) FZ e HCl.
    Calculated,%: C 54.54; H 6.17) N 8.29; C1 14.0.
    Found,%: C 54.01, H 6.38; N 8.07; C1 13.75.
    1.2. (Diphenylmethyl) -1-piperazinyl-toxoxy-ethoxy-acetamide dihydrochloride.
    24.2 g (0.53 mol) of sodium hydride are added to a solution of 172.9 g (0.508 mol) of 2-L2-4- (diphenylmethyl) -1 -1-piperazinyl 3 -toxy ethanol in 180 ml of dimethylformamide. After completing the addition, the mixture is heated to 40 ° C for 30 minutes. After cooling, 60 g (0.624 mol) of 2-chloroacetamide are added to the mixture in 10 minutes. The temperature of the reaction mixture rises to 40 ° C and this temperature is held for an additional 30 minutes. Cool, add 30 ml of water and evaporate to jcyxoro residue. The residue is shaken in 1 liter of water and the creeping suspension is extracted in benzene. Organic surname.
    2.3 g (0.0057 mol) of methyl-10-methyl (4-chlorophenyl) fensch1metx13-1-piperidinylJethoxy Sodium acetate is dissolved in 100 ml of anhydrous methanol. This solution is cooled to 5–10 ° C and ammonia is introduced into it for 20 hours. 15 solvent is vacuumized, the residue is triturated in ether and left to crystallize. 1.2 g of 2- (4-chlorophenyl) phenylmethyl -1-Sh1perazinyl7ethoxyacetamide are obtained.
    Yield 54%. Melting point 109-110 ° C.
    Analysis of Cj HjgClN, 0.
    Calculated,%: C 65.02; H 6.7G, N 10.83; C1 9.14.
    Found,%: with b5,13; H 6.59; N 10.95; C1 9.54.
    Methyl (4-chlorophenyl) phenylmethyl -1-piperazinyl ethoxy 20 is used as the starting material.
    The charger is dried over potassium carbonate and 30 acetate is prepared as follows, then sharpen. The residue is purified. It is heated under reflux by chromatography on a column for two hours over 40 hours with good silica-silica mixture (eluant: chloroformming a mixture of 87 g (0.30 mol)) 1- (4-ethanol, 95: 5). The resulting product is chlorophenyl) phenylmethyl-piperazine,
    35
    dissolved in 45 MP of ethanol, to which was added 24 ml of ethanol solution of hydrochloric acid 5.1 N.
    19 g of hydrochloride 2- 4- (diphenylmethyl) -1 -piperazinshtG toxy-ethoxyacetamide are obtained with a yield of 8%.
    58 g (0.38 mol) of methyl (2-chloro ethoxy) acetate and 40.3 g (0.38 mol) of sodium carbonate in 500 ml of anhydrous xylene.
    Cooled, filtered and washed
    40 is benzene solid and the washed solid is separated. The filtrate is dried. The residue is purified by chromatography on a silica column. Thus, mp 196-197 ° C (acetonitrile).
    Analysis, NjOj-2HC1.
    Calculated,%: C 58.72; H 7.07; N 8.93; C1 15.07.
    Found,%: C 58.29; H 6.83; N 8.44i C1 15.01.50
    Dichlorohydrate of (4-chlorophenyl) phenylmethyl -1-piperazinyl ethoxytoxy acetamide is also prepared according to the described method.
    This compound is recrystallized in isopropyl alcohol with one solvent molecule.
    Yield 11%. Melting point 100-102 C.
    40
    45
    mid.
    2.3 g (0.0057 mol) of methyl (4-chlorophenyl) fensch1metx13-1 -1-piperidinylJethoxycetate is dissolved in 100 ml of anhydrous methanol. This solution is cooled to 5-10 ° C and ammonia is introduced into it for 20 hours. The solvent is charged under vacuum, the residue is triturated in ether and left to crystallize. 1.2 g of 2- (4-chlorophenyl) phenylmethyl -1-Sh1perazinyl7ethoxyacetamide are obtained.
    Yield 54%. Melting point 109-110 ° C.
    Analysis of Cj HjgClN, 0.
    Calculated,%: C 65.02; H 6.7G, N 10.83; C1 9.14.
    Found,%: with b5,13; H 6.59; N 10.95; C1 9.54.
    Methyl (4-chlorophenyl) -enyl-methyl-1-piperazinyl ethoxy is used as the starting product.
    Acetate is prepared as follows. A mixture of 87 g (0.30 mol) of 1- and (4-chlorophenyl) phenylmethyl-piperazine is heated under reflux for 40 hours with good stirring.
    58 g (0.38 mol) of methyl (2-chloro ethoxy) acetate and 40.3 g (0.38 mol) of sodium carbonate in 500 ml of anhydrous xylene.
    Cooled, filtered and washed
    the solid is benzene and the washed solid is separated. The filtrate is dried. The residue is purified by chromatography on a silica column. Thus, 34 g (yield 27.8%) of the desired methyl ester are obtained.
    Analysis,.
    Calculated,%: C 65.60; H 6.70; N 6.95.
    Found,%: C 63.87; H 6.55; N 6.59.
    Also obtained two additive slie.
    Dichlorohydrate (melting point 123-125 ° C).
    Analysis .- 2EC.
    Calculated,%: C 55.50; H 6.10; N 5.89; C1 14.92.
    51
    Found,%: C 55.20; .n b, 23;
    N 5.65; C1 13.2.
    Dimepeat (melting point 128-130 ° C).
    C H gClN-jO analysis.
    Calculated,%: C 56.70, H 5.51; N 4.41.
    Found,%: C 57.01; H 5.22; N 4.45.
    Example 2. Preparation of acids of formula I (in OH).
    2.1. (-chlorophenol) phenyl methyl -1-piperazinyl-ethoxy and J-yccyc- acid.
    Dissolve 16.8 g (0.0417 mol) of methyl (4-chlorophenyl) phenylmethyl -1-piperazinylZ ethoxyacetate (prepared according to Example 1.3) in 65 ml of absolute ethanol, Adds - 42 ml of IN ethanol solution potassium hydroxide. The mixture was heated under reflux for 4 hours. The mixture was cooled and the precipitate was removed by filtration after washing with ethyl ether. The filtrate is evaporated to dryness. The powder is dissolved in ethyl ether and allowed to crystallize. 10.5 g of (4-chlorophenyl) phenyl-Imethyl-1-piperazinyl-J-hydroxy-potassium J-acetate (hygroscopic) are obtained.
    Yield 59%. Melting point 161-163 ° C.
    Analysis C.
    Calculated,%: C 59.0; H 5.63; N 6.56.
    Found,%: C 57.97; H 5.77, N 6.48.
    Dissolve the potassium containing salt in 100 ml of water and neutralize with 10% hydrochloric acid to. The solution is extracted with chloroorm and dried over magnesium sulphate. Evaporate to dryness. The residue is triturated in ethyl ether and left to crystallize. 7.5 g of 2- (4-chlorophenyl) phenylmethyl -1-piperazinyl ethoxy-acetic acid are obtained.
    Yield 81%. Melting point 110-115 C.
    Analysis C, H jgClN O 3.
    Calculated,%: C 64.80; H 6.48; N 7.20.
    Found,%: C 62.3; H 6.48; N 6.92.
    Corresponding dihydrochloride, obtained in toluene with a yield of 80%
    Wits at 225 C.
    76
    Analysis C ,,, H. jyClN O, - 2HC1. Calculated,%: € 54.60; H 5.85; N 6.07; C1 15.38 ClOB, 23.07.
    Found,%: C 54.42; H 5.60; N 6, or, С115,29; C1 „bc 23.08.
    2.2. (Diffusion Metals) I-1-piperazinyl) Ethoxy-ycyclic acid.
    A mixture of 19 g (0.054 mol) 2-G2-4- (diphenylmethyl) -1-piperazinyl ethoxy-acetamide (prepared according to Example 1.1) in 200 ml of ethanol and 27 ml of an aqueous solution of sodium hydroxide 4N is heated under reflux for 3 hours. Neutralize 29.7 ml of hydrochloric acid (3.6IN) to pH 6.3. Ethanol is emptied under vacuum. Filter the precipitate. After evaporation of the solvent, 17.4 g of (diphenylmethyl) -1-piperazinyl ethoxy-acetic acid are obtained.
    Yield 91%. Melting point 100 ° C. C-HjgNzOi analysis. Calculated,%: C 71.1; H 7.39; N 7.90. Found,%: C 69.1; H 7.07; N 7.12.
    Dichlorohydrate, melting point 217-218 ° C (isopropanol alcohol). Analysis With ,,,, -2НС1. Calculated,%: C 59.02; H 6.60, N 6.55; C1 16.59.
    Found,%: C 58.83; H 6.94; fN N 6.33; C1 15.90.
    According to the described method, the following new compounds. Dichlorohydrate (diphenyl) - mbtilj 1-pilerasin-ethoxy-ethoxy - acetic acid.
    Yield 57%. Melting point 85 ° C (lyophilized; decomposition). Analysis ,, gN. 2HC1.
    Calculated,%: C 58.60; H 6.84; N 5.94 s C1 15.04.
    Found,%: C 56.82; H 7.82; N 6.02; C1 16.76.
    (4-Chlorophenyl) phenylmethyl -1-pylerasinyl ethoxyCethoxy3-acetic acid dihydrochloride.
    Yield 82%. Melting point 112 ° C (lyophilized).
    Analysis C, H „ClNj.04-2S1. Calculated,%: C 54.6; H 5.78i; . N 5.54, C1, e ,, 21.03.
    Found,%: C 52.48; H 6.10; 5.72; Slovov22,19.
    Hydrate is (4-fluorophenyl) phenylmethyl-piperazinyl ethoxyJ-acetic acid.
    The yield is 100%. When melting, the product gradually softens, starting at 70 ° C.
    Analysis With ,,, -3 / 2 HjO.
    Calculated,%: C 63.1; H 7.0; N 7.0.
    Found,%: C 63.7; H 7.6 N 6.9.
    2- 2-C2-4-bis (4-fluorophenyl) methyl -1 -1-piperazinyl ethoxy ethoxy acetic acid dihydrohydrate.
    Yield 40%. Melting point 181-183 s (acetonitrile).
    Analysis C Hz8F N 04 2HCl.
    Calculated,%: C 54.54; H 5.95; N 5.52; C1 13.3.
    Found,%: C 54.26; H 6.13; N 5.57; C1 15.29.
    The following products are subject to pharmacological tests, the result of which is given below.
    2- 2- (Diphenylme dichlorohydrate 40
    ----, -,, - - piperazinyl acetic acid (about piperazinyl ethoxy acetamide (pro 3), (4-chlorophenyl) phenyl-. G methyl -1 piperazinyl acetic acid- 1.3); (4-fluorophenyl) phenylme- (product 4).
    Thyl -1-piperazinyl ethoxy-acetamide Antispasmodic and antihistamine- (product C, obtained in Example 1.1) 30 "aa activity. . 2- 2- 4- (4-methoxyphenyl) phenylmethyl -1-piperazinyl-ethoxy (β-acetanide) dihydrochloride (product D, prepared as in Example 1.1); 2- L4- (diphenylmethyl) -1 -piperazinyltoxy ethoxy-acetamide dihydrochloride (product E prepared in Example 1.2); 2- 2- (4-chlorophenyl) -phenylmethyl -1-piperazinyl-ethoxy ethoxy-acetamide dihydrochloride (product F, prepared in Example 1.2); (4-chlorophenyl) phenylmethyl -1-piperazinyl ethoxy-potassium acetate (product G, prepared in Example 2.1); injections, respectively, of serotoni- - ((4-chlorophenyl) phenylmethyl -1-piperazine-5-ethoxy-acetic acid (product H, creep according to example 2.1); (4-chlorophenyl) phenylmethyl -1-piperazinium ethoxy-acetic acid dihydrochloride (product 1, prepared as in Example 2.1); (diphenylmethyl) -1-piperazinyltoxyacetic acid (product I obtained in Example 2.2); 2- - | 2- (diphenylmethyl) -1-piperazinyl ethoxy ethoxy-acetic acid dihydrohydrate (product k, prepared in Example 2.2); 2- 2- 2- 4- t (4-chlorphenyl) phenylmethyl -1-piperazinyl ethoxy chichlorohydrate
     This activity was measured on guinea pigs according to the method of G. Konzet and R. Roessler (Haunyn-Schmidibergs Arch exp. Path. Pharmacol 195 (1940), 71-35 74) and compared with the activity of theophylline.
    Guinea pig under the influence of anesthesia and under the nerve exposure is artificially ventilated. Endotracheal pressure was measured. Repeated bronchial spasms are caused by sequential and gradual intravenous
    on and histamine.
    Substances to be examined were also administered intravenously.
    The table below shows the doses of products (DI 50 in mmol / kg), which inhibit in all animals an average of 50% of the administered bronchospasms.
    55
    ethoxy-acetic acid (product L, obtained according to example 2.2), hydrate (4-fluorophenyl) phenylmethyl -1-piperazinyl ethoxy-acetic acid (product M, obtained according to example 2.2); Dihydrofluorhydrate (trifluormetsh1) phenylmethyl-1-piperazinyl ethoxy ethoxy-acetamide (product N, prepared according to Example 1.1) dihydrochloride 2- (bis (4-fluorophenyl) methyl -1-piperazinyl ethoxy ethoxy-acetamide (product O, obtained according to example 1.1) J (4-fluorophenyl) methyl-1-piperazinyl-ethoxy ethoxy-acetic acid dihydrochloride (product P, obtained in example 2.2).
    The following known structural analogues are subject to the same pharmacological tests: (di
    phenylmethyl) -1-piperazinyl acetamide (product 1); (4-chlorophenyl) fer
    Antispasmodic and antihistamine activity.
    injections, respectively serotoni-
     This activity was measured on guinea pigs according to the method of G. Konzet and R. Rösler (Haunyn-Schmidibergs Arch, exp. Path. Pharmacol 195 (1940), 71-74) and compared with the activity of theophylline.
    Guinea pig under the influence of anesthesia and under the nerve exposure artificially ventilated. Endotracheal pressure was measured. Repeated bronchial spasms are caused by sequential and gradual intravenous
    injections, respectively serotoni-
    on and histamine.
    Substances to be examined were also administered intravenously.
    The table below shows the doses of products (DI 50 in mmol / kg), which are slowed down in all animals by an average of 50% of the administered bronchospasms.
    five
    55
    91310397JO
    Continuation of the table of prolonged antihistamine activity. Thus, for example, product 1, administered to a guinea pig at a dose of 1 mmol / kg by intravenous route, after 5 hours still retains an activity equal to 100%.
    Toxicity in mice (Irwin test). This toxicity has been tested.
    Irwin IQ (SIRWIN, General philosophy and a multidimensional approach), Aug 3-7 (1959) at Colby Junior
    | r College-New London).
    Gradual doses of the test product are administered through the peritoneum to groups of three male mice (weighing from 18 to 22 g).
    2Q Fatal doses (two of three animals) for the proposed products and for products 1, 2, 3 and 4 (not in accordance with the invention, m 0) are as follows:
    The proposed compounds are devoid of
    cholinergic activity. From this table it follows that these products have excellent activity with respect to bronchospasm, caused by serotonin and histamine, with a more pronounced selectivity in relation to the latter. Conversely, products 1, 2, 3, and 4 (inconsistent with the invention, m 0) are significantly less active.
    In addition, this test reveals that certain compounds administered in a single dose possess

    Products
    A B C D E F G H I J C L M N O P
    Fatal dose, mg / kg
    255
    232
    386
    456
    282
    339
    277
    116
    138
    708
    9D2
    505
    372
    161.5
    506
    507
    11131039712
    1927 Fatal dose (DL 50).
    The toxicity offered is weak.
    21030 products were confirmed by measuring DL 50, with the introduction of per os.
     .620 5 So, for product 1 in a rat, it
    is 703 mg / kg for a rat sam-68.8 cs and 865 mg / kg for a rat females.
    For the MGM for the same test, the toxicity of the DL 50 product, respectively, of the products being compounded appears to be very 600 mg / kg (male mouse) and 752 mg / kg weak. (Female).
    权利要求:
    Claims (1)
    [1]
    4 68,8
    In this test, the toxicity of the products on offer is very weak.
    Lethal dose (ΏΣ 50).
    Low toxicity offered
    products was confirmed by measuring Ώί, 50, with the introduction of reg.
    So, for product 1 in a rat, it is 703 mg / kg for the male rat and 865 mg / kg for the female rat.
    For a mouse for the same product, DL 50 is 600 mg / kg (male mouse) and 752 mg / kg (female mouse), respectively.
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    申请号 | 申请日 | 专利标题
    GB8103768|1981-02-06|LV930358A| LV5494A3|1981-02-06|1993-05-17|2-U4--1-piperazinyl-ethicabs or their amides or their non-toxic pharmaceutically acceptable islands with spasmolytic and antihistaminic activity|
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