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    • 专利摘要:
    The object of the present invention are new pharmacologically active substituted guanidino heterocyclicphenylamidines of the following formula …<CHEM>… in which R, R1 and R2 which may be the same or different, each represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R3 represents a linear or branched alkyl group containing optionally heteroatoms such as oxygen, sulfur or nitrogen atom, a linear or branched alkenyl group, an alkynyl group, a cyano group, a cycloalkyl or cycloaliphatic alkyl group, a bicyclic group, an aryl group, a heterocyclic group or R3 and R2 together with the adiacent nitrogen atom represent a heterocyclic group, R4 represents a hydrogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms or a halogen atom, Het represents a substituted or unsubstituted heterocyclic group containing two or three heteroatoms and tautomers thereof and acid addition salts of the aforesaid compound. Processes for the preparation of the compounds of formula (I) as well as pharmaceutical compositions containing them are also object of this invention. The new compounds are H2- receptor blocking agents which inhibit gastric acid secretion, and are useful antiulcer agents.
    公开号:SU1251804A3
    申请号:SU833675010
    申请日:1983-12-05
    公开日:1986-08-15
    发明作者:Биетти Джузеппе；Цереда Энцо；Донетти Артуро；Дель Сольдато Пьеро；Джакетти Антонио；Михелетти Розамария
    申请人:Иституто Дэ Анджели С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    12
    The invention relates to a method for producing new pharmacological active derivatives of heterocycle-containing amidine, in particular, to a method for preparing derivatives of heterocycle-containing phenylamidine of the general formula
    Riw
    C l -HelHf

    3
    where R is hydrogen or methyl;
    RJ is hydrogen, methyl or ethyl;
    R, - C, -Cd-alkyl, allyl, unsubstituted or substituted by methyl. groups, propargyl, cyclopropyl-, cyclohexyl, norbonyl, phenyl, pyridyl, methoxyethyl, methylthioethyl, hydroxypropyl, cyanoethyl;
    RJ and R, together with the nitrogen atom, form a nirrolidine or morpholine ring;
    R. hydrogen, chlorine, methyl, methoxy;
    Het - thiazoldiyl, oxazoldiyl, 1,3,4-thiadiazolidyl, 1,2,4-thiadiazol-diyl, 1,2,4-oxliamidiyl, or their acid addition salts.
    The compounds of the general formula or their salts are a Hj receptor blocking agent that inhibits the secretion of gastric acid and a valuable anti-ulcer agent.
    The aim of the invention is to obtain new derivatives of heterocycle-containing pheNilamidine, exhibiting a higher antagonistic activity on the histamine receptors.
    The invention is illustrated by the following examples.
    Example 1. N-methyl-to-3- (2- -guanidino-thiazolyl) phenyl) -formamidine (compound I).
    4 g of H-cyaio-K (2-gianidino-4-thiazolyl) phenyl-formamidine are added in one portion to 40 ml of 35% methylamine in water. After a few minutes, the product is separated from the solution. This solid is filtered, washed with water and dried. 2.66 g of compound with m.p. 182 ° C (decomposition in the form of maleate from ethanol).
    Found,%: C 46,98; And 4.32; N 16.41.
    C, JI IlgOgS.
    Calculated,%: C 47.43; H 4.38; N 16.59.
    four
    The following compounds are obtained anapogically: N-ethyl-N-3- (2-guanidino-4-thiazolyl) phenyl-formamidine as a maleate (from ethanol) with m.p. 175-177 ° C (decomposition) (compound 2).
    Found,%: C 47.95; And 4.70; N 15.98.
    c ,, H5 ,.
    Calculated,%: C 48.46; H 4.65; N 16.14.
    N-ITropyl-N - 3- (2-guanidino-4-β-thiazolyl) phenyl-formamidine as a maleate (from ethanol) with m.p. 180 C (decomposition) (compound C),
    Found,%: C 49.43; H 4.88; N 15.59.
    Calculated,%: C 49.43; H 4.90; N 15.72.
    K-Isopropyl-K (2-guanidino-4-thiazolyl) phenyl-formamidine in the form of citrate (from zanolol) with m.p. 135 ° C (decomposition) (compound 4).
    Found,%: With 46.96; H 5.18;
    N 14.32.
    C..202.5,
    Calculated,%: C 46.78; H 5.12; N 14.23.
    N-Butyl-Y (2-guanidIno-4-thiazolyl) phenyl-formamidine in the form of maleate (from ethanol) with m.p. 196 C (decomposition) (compound 5).
    Found,%: C 49.86; H 5.03; N 15.21.
    C iiLNgOgS
    Calculated,%: C 50.36; H 5.14;
    N 15.32.
    N-Boro-Butyl-N (2-guanidino-4-thiazolyl) phenyl-formamidine as a maleate (from ethanol) with m.p. 190 ° C (decomposition) (compound 6).
    Found,%: C 49.81; H 5.18; N 15.02.
    (H NgOgS
    Calculated,%: C 50.36; H 5.14;
    N 15.32.
    N-isobutyl-n - 3- (2-guanidino-D-thiazolyl) phenyl-formamidine in the form of maleate (from ethanol) with so pl. 208 ° C (decomposition) (compound 7).
    Found,%: C 50.16; H 5.16; N 15.33.
    H ,, LOVES
    Calculated,%: C 50.36; H 5.14; N 15.32.
    N-Heopentil-N (2-guanidino-4-thiazolyl) phenyl-formamidine in vi3
    de maleate (from ethanol) with m.p. 188 190 ° C (decomposition) (compound 8). Calculated,%:
    Found,%: C 50.73; H 5.33; N 14.81.
    Calculated,%: C, 51.24; H 5.37; N 14.94,
    M-Hexyl-K (2-guanidino-4-zolyl) phenyl-formamidine in the wcde maleate (from ethanol) with m.p. 96 ° C. (decomposition) (compound 9).
    Found,%: C 51.71; H 5.65; N 14.70.
    CjjHj D Og S
    Calculated,%: C, 52.07; H 5.59; N 14.57.
    H-Octyl-H - 3- (2-guanidino-4-thia zolyl) phenyl-formamidine in the form of maleate (from ethanol) with m.p. 177-180 ° C (decomposition) (compound 10).
    Found,%: C 53.15; H 6.00; N 13.86.
    Calculated,%: C 53.63; H 6.00;
    N 13.89.
    K-Allyl-K (2-guanidino-4-thia zolyl) phenyl -formamindin as maleate (from ethanol) with m.p. 168-170 With (decomposition) (compound P).
    Found,%: C 49.19; H 4.47; By 15.50.
    ,
    Calculated,%: C 49.62; H 4.54;
    N 15.78.
    K-Dimetnpallil- - 3- (2-guakid - no-4-thiazolyl) phenyl-formamidine in the form of maleate (from ethanol) with tg. (decomposition) (compound 12).
    Found, Z: C 51.2; H 4.98; N 14.64.
    (, H S
    Calculated,%: C, 51.42; H 5.03; N 14.99.
    N-Propyl-N-N (2-gundin-4-thiazolcp) phenyl-formamidine in the form of maleate (from ethanol) with so pl. IJO C (decomposition) (compound 13).
    Found Z: C 49.06; H 4.12; N 15.89.
    Calculated,%: C 49.81; H 4.18;
    N 15.84.,
    K-Cyclopropylmethyl-H (2-guaidino-4-thiazolyl) phenyl-formamide in vce maleate (from ethanol) with m.p. 183-185 C (decomposition) (compound 14).
    518044
    Found,%: C 49.82; H 4.71; N 15.28.
    C / ij / JgOgS
    . Calculated,%: C 50.54; H 4.79; 5 N 15.38.
    N-Cyclohexyl-N - 3- (2-guanidino-4-thiazapl) -phenyl-formamindin in whole maleate (from ethanol) with m.p. 190 C (decomposition) (compound 15). 10Found,%: C 52.00; H 5.34;
    N 14.81.
    Calculated,%: C 52.26; H 5.26; N 14.63.,,
    15N-Hop6oHHn-N -13- (2-gundio-4-tnazolyl) fensh1-formamide in the form of maleate (from ethanol) with m.p. 196 C (decomposition) (compound 16).
    Found,%: C 53.15; H 5.22; W N 14.21.
    .Oes
    Calculated,%: C 53.23; H 5.15; N 14.33.
     N- (2-Metoseciethyl) -N - 3- (2-guanidino-4-thiazolyl) phenylformamidine as a maleate (from ethanol) with m.p. 182-184 C (decomposition) (compound 17).
    0 Found,%: C 47.67; H 4.71; N 15.15.
    Calculated,%: C 48.00; H 4.76;
    N 15.26.
    5N- (2-Iethylthioetip) -K (2-guanidino-4-thiazolyl) phenyl J-formamidine as a maleate (from ethanol) with mp. 180-183 ° C (decomposition) (compound 18).
    0Found%: C 46.13; H 4.57;
    N 14.71.
    Calculated,%: C 46.63; H 4.62;
    N 14.83.
    5N- (2-Tsnanoethe I) -N (2-gianidino-4-thiazolyl) -phenyl-formamidine in the form of maleate (from ethanol) with m.p. 160-164 ° C (decomposition) (compound 19).
    0 Found,%: C 48.03; H 4.16;
    N 18.15. . С „1у |, 0.8
    Calculated,%: C 48.44; H 4.25; N 17.97.
    5H- (3-hydroxypropyl) -G1 -P- (2-guanidino-4-thiazolyl) fench11-formamidine as a maleate (from ethanol) with m.p. 184 ° C (decomposition) (compound 20).
    Found,%: C 47.08; And 4.57; N 16.95.
    LL Oe S
    Calculated,%: C 46,98; H 4.66; N 17.06.
    K-Methyl-H (2-guanidino-4-thia eolyl) phenyl1-formamidine as hydrochloride (from ethanol) with m.p. 264 (decomposition) (compound 21).
    Found,%: C 41.25; H 4.55; N 24.31.
    SI. S
    Calculated,%: C 41.50; H 4.64; N 24.20.
    N-Ethyl-K (2 guanidino-4-thiazolyl) phenyl-formamidine as a fumarate (from ethanol) with m.p. 136 ° C (decomposition) (compound 22).
    Found,%: C 48.37; H 4.85; N 16.16.
    C ,, 11 ,,
    Calculated,%: C 48.46; H 4.65; N 16.14.
    HY1zopropyl-H -f4- (2-guanidino-4-thiazolyl) phenylZ-formamidine in free form with so pl. 249-250 ° C (decomposition) (compound 23).
    Found,%: C 56.07; H 6.04;
    N 27.32.
    qjT,
    Calculated,%: C 55.61; H 6.00; N 27.79.
    N-Ethyl-N (2-guanidino-4-thiaz lil) phenyl-formamidine in the form of tartar and ethanol with so pl. 110 C (decomposition) (compound 24).
    Found,%: C 44.03; H 5.14; N 16.67.
    ,, o, 3
    Calculated,%: C, 44.44; H 4.91; N 16.36.
    N-propyl-N (2-guanidino-4-zolyl) phenyl-formamidine in the form of tartrate (from ethanol) with m.p. 135 C (decomposition) (compound 25).
    Found,%: C 45,53; H 5.20; N 15.70.
    C, N, D, 0. "5,
    Calculated,%: C 45,53; H 5.16; N 15.93.
    K-Allyl-P-L2- (2-guanidino-4-zolyl) phenyl-formamidine in the form of tartrate (from ethanol) with m.p. 120 C (decomposition) (compound 26).
    Found,%: C, 45.51; H 4.68; N 16.12.
    C.
    Calculated,%: 45.71; H 4.79; N 15.99.
    M-Ethyl and (2-methylguanidino-4-thiazolyl) phenyl-formamidine in the form of maleate (from ethanol) with so pl. 183 s (decomposition) (compound 27).
    Found,%: C 49,12; H 4.94; N 15.59.
    0 s, d; o, s
    Calculated,%: C 49.43; H 4.90; N 15.72.
    N-Propyl-N-13- (2-methylguanidino-4-thiazolyl) phenyl-formamidine in the form of 5 maleate (from ethanol) with m.p. 172 ° C (decomposition) (compound 28).
    Found,%: C 50.51; H 5.1I; N 15.45.
    s, llo “2
    0 Calculated,%: C 50.36; H 5.14; N 15.32.
    K-Isopropyl-S - 3- (2-methylguanidino-4-thiazolyl) phenyl-formamidine in the form of maleate (from ethanol) with hg 95-5 ° C 5 (decomposition) (compound 29).
    Found,%: C 50.25; H 5.16; N 15.10.
    Chz GLS VZ
    Calculated,%: C 50.36; H 5.14; 0
    N, N-Dimethyl-N - (3- (2-guanidino-4-thiazolnl) phenyl-formamidine in the form of maleate (from ethanol) with mp 216 ° C (decomposition) (compound 30).
    Found,%: C 48.61; H 4.70; N 16.26.
    c ,, H,; j, OaS
    Calculated,%: C 48.46; H 4.65; N 16.15.
    K, N-Diethp-N (2-guanidino-4-thiazolyl) phenyl1-formamidine in the form of maleate (from ethanol) with so pl. 190-193 ° C (decomposition) (compound 31).
    Found,%: C 49.99; H 5.06; N 15.32.
    C, jH,
    Calculated,%: C 50.36; H 5.14; N 15.32.
    (2-Guanidino-4-thiazolyl) -phenyl-1-pyrrolidiylmethanimine as a maleate (from ethanol) with m.p. 197-199 C (decomposition) (compound 32).
    Found,%: C 50.87; H 4.86; N 15.08.
    WITH",
    Calculated,%: C 50.54; H 4.79; N 15.33.
    P-I3- (2-Guanidino-4-thiazolyl) phenylJ-4-morpholinylmethanine as
    five
    0
    five
    maleate (from ethanol) with m.p. 208-210 C (decomposition) (compound 33).
    Found,%: C 48.88; H 4.70; N 15.05,
     Oa s
    Included,%: C 49.10; H 4.66;
    N 14.94.
    N-propyl-N-methyl-N (2-guanid but-4-thiazolyl) phenyl-formamidine in a de-maleate (from ethanol) with m.p. 105 (decomposition) (compound 34).
    Found, Z: C 50.21; H 4.99; N 15.45.
     ° in
    Calculated,%: C 50.36; H 5.14; N 15.32.
    N- (2-Pyridyl) -N (2-guanidino-4-tyazolyl) phenyl-formamidine with m.p. (decomposition) (compound 35).
    Found,%: C 57.14; H 4.41; N 28.86.
    16 V S
    Calculated Z: C 56.96; H 4.48;
    N 29.06.
    H-Phenyl-K - 3- (2-guanidino-4-thia zolyl) phenyl-formamidine with m.p. 167 168 ° C (decomposition) (compound 36).
    Found,%: C 60.10; H 4.74; N 24.56.
     c ,, iyj, s
    Calculated,%: C 60.69; H 4.79; N 24.98.
    N-3THn-N- (3- (2-Indian-5-methyl-4-thiazolyl) -formamidine as a maleate (from ethanol) with mp (decomposition) (compound 37).
    Found Z: C 49.19; H 4.82; N 15.43.
    Cj.jH, NgOgS
    Calculated,%: C 49.43; H 4.90; N 15.72.
    K-Propyl-K (2-guanidino-5-methyl-4-thiazole) phenl-formamidine as a maleate (from ethanol) with mp 160 ° (decomposition) (compound 38).
    Found,%: C 49.86; H 4.93; N 15.52.
    C4 / l, OeS
    Calculated,%: C 50.36; H 5.14; N 15.32.
    M-Propnl-M - 6-methyl-3- (2-yanidino-4-thiazolt) phenyl} -formamidine in the form of maleate (from ethanol) with m.p. 204-207 ° C (decomposition) (compound 39).
    Found,%: C 50.00; H 5.25; N 15.45.
    .
    Calculated,%: C 50.36; H 5.15;
    N 15.32.
    N-Propyl-N-6-chloro-3- (2-guanidino-4-thiazolyl) phenyl-formamidine as a maleate (from ethanol) with mp 191-195 ° C. (decomposition) (compound 40).
    Found,%: C 46.74; H 4.51; , 0 N, 14.54.
    c; d ,,
    Included in%: C 46.44; H 4.43; N 14.77.
    and-Propyl-K -t6-methoxy-3- (2-gya- (5 nidino-4-thiazolyl-phenyl-formamidine as maleate (from ethanol) with mp 201-204 ° С (decomposition) (compound 41 ).
    Found,%: C 49.19; H 5.07; 20 N 14.74.
    GLL 9 S
    Calculated,%: C 48.93; H 4.99;
    N 14.89.
    K-Ethyl-Y-4- (2-guanidino-1,3,4-ty-25 adiazol-5-yl) phenyl1-formamidium in the form of maleate (from ethanol) with m.p. 182-183 C (decomposition) (compound 42).
    Found,%: C, 46.16; H 4.49; N 18.70.
    30C,
    Calculated,%: C 46.06; H 4.45; N 18.80.
    K-Isopropyl-14- (2-guanidino-I, 3,4-thiadiazol-5-yl) phenyl-forma- "Dean in the form of maleate (from ethanol)
    from m.p. (decomposition) (compound 43).
    Found,%: From 46.45; H 4.77; N 18.42.
    0
    Calculated,%: C 47.09; H 4.71; N 18.31.
    L-Isopropl-H (2-ryanidino- -l, 3, 4-thiadiazole-5-sh1) phenyl-forma-j din in the form of maleate (from acetone) with so pl. 166 ° C (decomposition) (compound 44).
    Found,%: C 46.75; H 4.68; N 18.35. 0C ,,, O.S
    Calculated,%: C 47.09; H 4.71; N 18.31. .
    N-Ethyl - 3- (5-guanidino-1,2,4-β-thiazolol-3-yl) phenyl-formamidine - in the form of maleate (from ethanol) with m.p. 173-175 s (decomposition) (compound 45).
    Found,%: C 45.92; H 4.50; N 18.69.
     D Og S
    Calculated,%: C 46.06; H 4, A5; N 18.80.
    N-Isopropyl-N-GZ- (5-guanidino--1,2,4-thiadiazol-3-yl) phenylJ-forms of din in the form of maleate (from ethanol) with so pl. (decomposition) (compound 46),
    Found,%: C 46.73; H 4.71; N 18.21.
    Yag
    Calculated,%: C 47.09; H 4.71;
    N 18.31.
    K-Ethyl-K-14- (5-guanidino-1,2,4-β-thiadiazol-3-yl) phenyl-formamidine as a maleate (from acetone) with m.p. 184 C (decomposition) (compound 47).
    Found,%: 45.70; H 4.39; N 18.68.
    c,
    Calculated,%: C 46.06; H 4.45; N 18.80.
    N-Propyl-N (5-guanidino -1,2,4-thiadiazol-3-Sh1) phenyl-formamidine in the form of maleate (from acetone) with m.p. 187 C (decomposition) (compound 48).
    Found,%: C 46.86; H 4.64; N 18.42.
    q, HJ}, OgS
    Calculated,%: C 47.09; H 4.71; N 18.31.
    N-Isopropyl-K - 4- (5-guanidino -1,2,4-thiadiazol-3-yl) phenyl: -form- amntion in the form of maleate (from acetone) with m.p. (decomposition) (compound 49).
    Found,%: From 46.45; H 4.66; N 18.27.
    q ,, oeS
    Calculated, 7 ,: C 47.09; H 4.71; N 18.31.
    N-Metsh1-N-GZ- (2-guanidino-4-oxazazolyl) feiyl-formamidine as hydrochloride (from ethanol) with mp 1.5 253 C (decomposition) (compound 50).
    Found Z: C 43.26; H 4.83; N 25.37.
    Cn4, Cl, N.O
    Calculated,%: C 43.51; H 4.87; N 25.37.
    N-Ethyl-H - (3- (2-guanidino-4-oxa znlp) phenyl-formamidium in the form of hydrochloride (from ethanol) with m.p. 1.254-255 C (decomposition) (compound 51).
    Found%: C 44.82; H 5.15; N 24.12.
    QiHie l N O
    Calculated,%: C 45.22; H 5.22; N 24.34.
    N-Hexyl-N-13- (2-guancin-4-oxazolyl) phenyl-formamidine as hydrochloride (from ethanol) with mp 237 238 s (decomposition) (compound 52).
    Found,%: C 50.17; H 6.57; N 21.09. C, DS1, H, 0
    Calculated,%: C 50.87; H 6.53; N 20.94. ,
    N-Methyl-H (2-gua 1NCINo-4-oxazazolyl) phenyl-formamidine as hydrochloride (from ethanesulfa) with m.p. 239- (decomposition) (compound 53).
    HaitaeHo, 2: C, 43.25; H 4.87; N 24.91.
    WITH,
    Calculated,%: C 43.51; H 4.87; N 25.37.
    M-Propyl-K (2-guanidino-4-oxazazolyl) phenyl-formamidine in the form of hydrochloride (from ethanol) with m.p. 232-23 C (decomposition) (compound 54).
    Found,%: C, 47.02; H 5.58; N 23.46.
      Ng o
    Calculus,%: C 46.80; H 5.61; N 23.39.
    K-Butyl-P- (4- (2-guanidino-4-oxazolyl) phenyl-formamidine as hydrochloride (from ethanol) with mp 233-235 ° C (decomposition) (compound 53). Found 7: C 48.41; H 5.99; N 22.14.
    .
    Calculated,%: C 48.26; H 5.94; .N 22.52.
    K-Allsh1-K (2-guanidino-4-oxazolyl) phenyl-formamidine in the form of fumarate (from ethanol) with m.p. 150-152 C (decomposition) (compound 56).
    Found,%: C 53.87; H 5.06; N 21.16.
    c ,, H,; i, o,
    Calculated,%: C, 53.99; H 5.04; N 20.99.
    N-isopropyl-N-G4- (5-guanidino, 4-oxadiazol-3-yl) phenyl1-formamidine in the form of maleate (from ethanol) with m. 189 ° C (decomposition) (compound 57) ..
    Found,%: C 48.10; H 4.86; N 18.61.
    with.,
    Calculated,%: C 48.55; H 4.85; N 18.87.
    %: C 48.96; H 4.85;
    N-Methyl-N - (.4- (5-guanedino-, 2, -oxadiazol-3-yl) pheny.t7-formaidine is a form of fumarate (from ethanol) with mp 186-187 ° С (decomposition) ( connection 58).
    Found,%: C 47.85; H 4.57; N 5.91.
    ,,
    Calculated,%: C 48.00; H 4.57;
    N 26.12.
    K-Isopropyl-K - 13- (5-guanidino--1,2,4-oxadiazol-3-yl) phenyl-form of midin in the form of maleate (. From zanol) with m.p. (decomposition) (compound 59).
    Found N, 19.05.
    h.
    Calculated,%: C 48.55; H 4.85; N 18.87.
    P-Methyl-H - 13- (5-guanidino-1,2,4-oxadiazol-3-ip) phenyl-formamidine in the form of nitrate (from methanol) with mp 215-216 C (time) (compound 60).
    Found,%: C 33.97; H 3.88; N 32.58.
    ,
    Calculated N 32,72.
    N-Allyl-H (5-guanidino-1,2,4-okskadiazol-3-yl) phenyl-formamidine in the form of maleate (from ethanol) with so pl. 160 ° C (decomposition) (compound 61).
    Found,%: C 48.21; H 4.48; N 18.80.
    C ,,,. OO
    Calculated,%: C 48.74; H 4.47; N 18.95.
    N-STOP-Butyl-M - 3- (5-guanidino-1, 2,4-oxadiazol-3-yl) phenyl} -for mamidine in the form of maleate (from ethanol) with m. (decomposition) (compound 62).
    Found,%: C 49.24; H 5.18; N 18,52.
    CHL.709
    Vyisleno,% N 18.38.
    C 34.28; H 3.92;
    C 49.53; H 5.10;
    Example 2. The histamine receptor antagonistic activity on H receptors is confirmed by in vitro experiments by inhibition of H-dependent biological effects, in particular, caused by histogram, positive (positive chronotropic effect and histamine-induced release of ventricular acid).
    five
    0
    five
    0
    fresh juice. The inhibition of the positive chronotropic effect of Isracids in the isolated atria of guinea pigs suspended in a 50 ml bath containing an oxidized (Oj 95%; CO 5%) Krebs-Genseleit solution, having a pH of 7.4 and a temperature of 32 ° C. The myocardial preparation with an isometric tension of 1 g was given time to stabilize for 60 minutes and myocardial contractions were recorded through an isothermal lever connected to the strain gauge, the beating was recorded using a cardiotachometer. After a two-fold control reaction for histamine (), the test compounds were added to the bath in the desired concentration and after 30 minutes the atria were treated again with histamine. The chronotropic reaction, which was obtained in the presence of an antagonist, was compared with the control reaction to histamine, and the percentage reduction in the reaction caused by histamine was determined from the data obtained. In addition, the mean effective concentration (EC) of the Hj antagonist was determined by known methods.
    Inhibition of histamine-induced tachycardia (in vitro) is presented in Table. one.
    Table 1
    Compound
    one
    EC
    So
    IO M
    one
    2
    3
    four
    five
    6
    7
    eleven
    13
    sixteen
    17
    3.3
    5.3
    2.8
    2, .o
    5.5
    3.0
    12.0
    3.3
    31.0
    10.0
    A, 8
    The ability of the studied compounds to inhibit the release of acid from the gastric juice caused by gnetamine was studied after intravenous or intraduodenal administration to rats in which perfusion was performed through the stomach. At the same time, a polyethylene tube was introduced into the aerofagnum and pyrolysis-antral zone of anesthetized animals (Gg / kg urethane, intraperitoneally) at a constant temperature. After flushing the stomach to remove food debris, a continuous gastric perfusion was started using 0.5 ml of saline temperature min. After 30 minutes after the start of perfusion, samples were collected every 30 minutes, which were titrated for acid content, expressed in mHeq I n. Sodium hydroxide After a constant acid content was reached, intravenous histamine perfusion (1 mg-kg h) began, which continued until the end of the experiment. After achieving a constant high degree of acid secretion, the compounds under study were injected intravenously in boiling doses in order to reveal the dose-response ratio. Then determined
    Effective dose (ED) by known methods. The compounds under study are of high antisecretory activity with intravenous administration at a dose of 100 µg / kg or less. The results of the experiment, in which all the tested compounds were used as a free base, are summarized in Table. 2
    Table 2 Antisecretory activity in the release of gastric acid acid caused by histamine (in vivo)
    Compound
    ED mg / kg (intravenous)
    I
    2
    3
    four
    five
    6
    7 II 13
    17 20 45 58
    Cimetidine (known)
    0.020 0.013 0.019 0.035 0.073 0.041 0.082 0.020 0.074
    0,050 0,028 0,051 0,090
    0.560
    The data table. I and 2 indicate that the proposed (new) compounds exhibit better activity than the known ones. The compounds listed in Table. I and 2, have the same toxicity as the known compound cimethium () 500 mg / kg, administered through the mouth (mppi).
    权利要求:
    Claims (1)
    [1]
    A method of obtaining derivatives of a heterocycle-containing phenylamidine of the general formula where R is hydrogen or methyl;
    R is hydrogen, methyl or ethyl;
    R 3 - C, -C g -alkyl, allyl, unsubstituted or substituted by methyl groups, propargyl, cyclopropylmethyl, cyclohexyl, norbonyl, phenyl, pyridyl, methoxyethyl, methylthioethyl, hydroxypropyl, cyanoethyl;
    R and R 3 together with the nitrogen atom form a pyrrolidine or morpholine ring;
    R 4 is hydrogen, chloro, methyl, methoxy;
    Het - thiazoldiyl, oxazoldiyl, 1,3,4-thiadiazoldiyl, 1,2,4-thiadiaoediyl, 1,2,4-oxadiazediyl, or their acid addition salts, characterized in that the compound of the general formula
    N = CH-NH-CN where R,, R ^ and Het have the indicated meanings, are reacted with a compound of the general formula
    SU <"1251804 where R T and Rj have the indicated meanings, followed by the inclusion of the target product in free form or in the form of an acid addition salt.
    >
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    引用文献:
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    EP0003640B1|1978-01-18|1982-01-27|Imperial Chemical Industries Plc|Antisecretory guanidine derivatives, processes for their manufacture and pharmaceutical compositions containing them|
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    GB9125970D0|1991-12-06|1992-02-05|Fujisawa Pharmaceutical Co|New compounds|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT20356/82A|IT1200371B|1982-03-24|1982-03-24|GUANIDINO ETEROCICLIFENILAMIDINE, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL USE|
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