• 专利附录
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    • 专利摘要:
    Thiazole derivatives of the formula: wherein each of R' and R independently represent hydrogen, C1-4 alkyl, benzyl or benzoyl, or, taken together with the adjacent nitrogen atom, form a saturated heterocyclic ring containing from 5 to 7 ring atoms, R3 is hydrogen or C1-4 alkyl, Z is 0, S, or CH2, n is 2 or 3 when Z is 0 or S and n is 1, 2 or 3 when Z is CH2, R5 is hydrogen or C1-4 alkyl, m is 1, 2 or 3, wherein A is N-CN, N-NO2, CH-NO2, S, 0, NH, N-SO2- aryl, N-SO2-C1-4 alkyl, N-CO-NH2, N-CO-C1-4 alkyl, N-CO2-C1-4 alkyl; CH-SO2-aryl or CH-SO2-C1-4 alkyl, wherein aryl is phenyl, halophenyl, C1-4 alkylphenyl or C1-4 alkoxyphenyl, and B is NRR6, wherein R and R6 are independently hydrogen, C1-5 alkyl, C3-6 cycloalkylmethyl, hydroxy C2-5 alkyl, C3.6 cycloalkyl, alkoxyalkyl or dialkyl-aminoalkyl wherein the total number of carbons is less than 8 and there is at least a two-carbon chain between the hetero atoms, or YR4, wherein Y is oxygen or sulfur and R4 is C1-5 alkyl, -CH2 C2-4 alkenyl or benzyl, or a pharmaceutically acceptable salt of a compound in which B is NRR6, have been found to possess activity as H2 antagonists and are therefore of value as antiulcer agents.
    公开号:SU1184443A3
    申请号:SU813344304
    申请日:1981-10-01
    公开日:1985-10-07
    发明作者:Пол Пьоч Ричард
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to organic chemistry, in particular, to a method for producing new thiazole derivatives, which are potential antagonists of Hj receptors and can be used in medicine, and ta1: the same as its variant. The purpose of the invention is to obtain new compounds that increase the efficiency of Hj receptor antagonists in a series of guanidine derivatives. Example 1. Preparation of N-methyl-N -2-G G2- (dimethylaminomethyl) -4-thia-I 7 V, methylthio-ethyl-m-cyanoguanidine. A solution is obtained from 3.07 g of dimeti cyanodithioimido carbonate and 35 ml of ethanol. A second solution containing 4.62 g (dimethylaminomethyl) -4-thiazole1 methylthio (ethylamine in 50 ml of ethanol, is added dropwise with stirring to the first solution for 1.5 hours. The resulting reaction mixture is stirred further 30 min, after which the volatile components are removed on a rotary evaporator. Chromatography of the residue on silica with gradient elution using ethyl acetate as the eluent, containing increasing amounts of methanol, gives fractions containing N-methyl (dimeshminaminomethyl) -4-thiazolyl methylthio This fraction is combined and the solvent is removed from the combined extractors on a rotary evaporator. The residue weighs 4.8 g and has a melting point of 75-77 C. after recrystallization from carbon tetrachloride. Found,%: C 43.66; H 5.71; N 20.98; S 29.15. Calculated,%: C 43.74; H 5.81; N 21.25; S 29.19. 2, 52 g of this thiophene is dissolved in 12 ml of methanol. 30 ml of a 35% strength solution (by weight) of methylamine in ethanol is added with stirring. After 5 hours, the solvent and the excess amine are removed by evaporation on a rotary evaporator. The residue is purified by chromatography on silica using an ethyl acetate-methanol mixture as eluent during gradient elution. The fractions containing N-methyl -N (dimethylaminrmethyl) -4-thiazolyl methylthio s ethyl-N in yanoguanidine -JJ, -r; -f formed by the above reaction, are combined and obtain 1.86 g of a glassy residue by evaporation of the solvent. Found,%: C 46.43; H 6.39; N 26.85. Calculated,%: C 46.13; H 6.45; N 26.90. NMR spectrum (CUClj, TMS as internal standard), S: 2.34 (singlet, 6H); 2.72 (triplet, 2H); 2.84 (doublet, SN); 3.42 (multiplet, 2H) -, 3.74 (singlet, 2H); 3.82 (singlet, 2H); 6.08 (multiplet, 1H); 6.22 (multiplet, 1H); 7.10 (singlet. 1H). Using the appropriate starting materials, N-ethyl-N-2- (2-dimethylaminomethyl) -4-thiazolyl methylthioethyl-N-cyanooguanidine is obtained. Found,%: C 48.05; H 7.01; N 25.51; S 19.33. C ,,, S2. Calculated,%: C, 47.82; H 6.79; N 25.74; S 19.64. The NMR spectrum (CDCl1, TMS as an internal standard) gives the following peaks, S: 1.22 (triplet, 3N); 2.34 (6H singlet); 2.72 (triplet, 2H) 3.1-3.55 (unresolved multiplets, 4H); 3.74 (singlet, 2H); 3.82 (singlet, 2H); 5.7 (wide line, 1H); 6.0 (wide line, 1H); 7.08 (singlet, 1H). K-Methyl-K-2 | 2- (dimethylaminomethyl) -4-thiazolyl methylthio ethyl-N -p-tolylsulfonylguanidine. Found,%: C 49.25; H 6.27; N 16.10; S 21.62. Calculated,%: C 48.95; H 6.16; N 15.86; S 21.78. . NMR spectrum (COCl3, TMS as an internal standard), o: 2.34 (singlet, 6H); 2.38 (singlet, SN); 2.62 (triplet, 2H); 2.80 (doublet, SN); 3.35-3.55 (multiplet, stronger than 2H); 3.72 (singlet, 2H), 3.74 (singlet, 2H), 7.06 (singlet, IH); 7.18 (doublet, 2H); 7.70 (doublet, 2H). H-methyl-y-2- 2- (dimethylaminomethyl) -4-thiazolyl-methylthio-1-ethyl-s-methanesulfonylguanidine, having, after recrystallization from ethyl acetate, mp. 95-97 C. Found,%: C 39.71; H 6.19; About 8.72. Calculated,%: C 39.43; H 6.34; About 8, -75. N-2-1 2- (Dimethylaminomethyl) -4-thiazolyl mettidoethyl-H - (2-methylethyl) -2-nitro-1,1-etheneamine, mp, 68 ,. Found,%: C 41.54; H 5.61; N 16.14; S 27.54. Calculated,%: C 41.36; H 5.78; N 16.08; S 27.60. NMR spectrum (CDC1., S: 2.36 (singlet, 6H) -, 3.1-3.65 (multiplet, 6H) -, 3.75 (singlet, 2H); 3.83 (singlet, 2H) ; 6.54 (1H singlet; 6.75 (wide signal, 1H); 7.08 (singlet, 1H); 10.35 (wide signal, 1H). N-2-1 L2- (Dimethylaminomethyl) -4 -thiazolyl1methylthio ethyl-S -cyclopropyl-2-11Itro-1, 1-etenediamine, mp 128.5-131, after recrystallization from a solvent mixture of methanol - ethyl acetate. Found: C 47.31; H 6; 12; N 19.35. Calculated,%: C 47.04; H 6.49; N 19.59. (Dimethylaminomethyl) - 4-thiazolyl methylthio-ethyl-N - (2-methylethyl) -2-nitro -1,1-etenediamine in the form of oil. Found,%: C 44.65; H 6.59; N 18.32. Calculated,%: C 44.78; H 6.71; N 18.65. NMR- spectrum (CDClj): 2.36 (singlet, .6H); 2.76 (triplet, 2H) 3.40 (singlet, 3N); 3.1-3.65 (mule tiplets, 6H); 3.75 ( singlet, 2H); 3.83 (singlet, 2H), 6.54 (singlet 1H); 10.35 (wide signal, 1H), 7.08 (singlet, 1H), 6.75 (wide signal, 1H) N-2-G 2- (Dimethylaminomethyl) -4-thiazolyl methylthio ethyl-3- (dimethylaminopropyl) -2-nitro-1,1-ete diamine (glass-like mass). Found,%: C 47.82; H 7.24; N 21.16. Calculated,%: C, 47.74; H 7.51; N 20.88. NMR spectrum (CDCl1) -, S: 1.77 (quintet, 2H); 2.33 (singlet, GN) 2.28 (singlet, GH); 2.36 (6H singlet); 2.23-2.28 (2H), 2.72 (triple 2H), 3.0-3.5 (multiplets, 4H), 3 (singlet, 2H); 3.84 (singlet, 2H) 6.50 and 6.53 (singlet, 1H total); 34 7.11 (singlet); 8.6 (broad signal, 1H); 10.2 (broad signal, 1H). N-2-G 2- (Dimethylaminomethyl) -4-thiazolyl-1-m-1-thio-ethyl, N-dimethyl-2-nitro-1, 1-etentenediamine (oily substance). Found,%: C 45.32; H 6.71; N 20.54. Calculated,%: C 45.19; H 6.71; N 20.27. (Dimethylaminomethyl) -4-thiazolyl methylthio ethyl-2-nitro-1, 1-etenediamine, m.p. 125-127 0 after purification by chromatography on silica with the use of solvent mixture 94: 5: 1 ethyl acetate-methanol-ammonium hydroxide as eluent. Found,%: C 41.38; H 6.21; N 21.87. Calculated,%: C 41.62; H 6.03; N 22.06. Example 2. Preparation of N-2- {2- (Dimethylaminomethyl) -4-thiazolyl methylthio-yethyl-N-methyl-2-nitro-1, 1-etenediamine. Trihydrobromide (dimethylaminomethyl) -4-thiazolyl-methylthio-ethylamine, obtained from 50-g of 2- (dimethylaminomet) -4-thiazolylmtanol, is dissolved in 150 ml of water. Then a solution (125 g) of potassium carbonate in 150 ml of water is carefully added. The water is removed by evaporation under vacuum. The resulting alkaline solution is triturated with ethanol and isopropanol and the alcohol is removed by evaporation. The resulting residue is extracted several times with hot isopropanol and the isopropanol extracts are filtered to remove inorganic salts. By evaporation of the solvent from the filtrate, a residue is obtained, which is dissolved in chloroform and the filter is one. Chloroform is removed from the filtrate on a rotary evaporator. The resulting residue, containing 2- 2- (dimeshminaminomesh1) -4-thiazolyl methylthioHethylamine as the free base, is dissolved in 250 ml of water. This solution is added with stirring to a suspension (40.7 g) of N-methyl-1-methylthio-2-nitroethylamine at 50 ° C. The solution is stirred at this temperature for 4 hours after the end of the addition. The water is then removed on a rotary evaporator under vacuum. The resulting residue is dissolved in
    ethanol and the solvent are removed by evaporation. The residue is crystallized from ethanol-acetonitrile and recrystallized from ethanol-ethyl acetate to obtain 49.5 g of N Methyl-N-2- 2- (dimethylaminomethyl) -4-thiazolium-IH methylthio1-ethyl-2-nitro-1, 1-etentenimine, water at m.p. t30-132 ° C.
    Found,%: C 43.66; H 6.40; N21.14.
    Calculated,%: C 43.48; H 6.39; N 21.13.
    The following compounds are prepared analogously:
    N-methyl-H-2- (methylaminomethyl) -4-thiazolylmethylthioch ethyl-2-nitro-1, 1-etenediamine, melting point after recrystallization from acetonitrile and subsequent recrystallization from ethanol 105-107 ° C,
    Found,%: C 41.79; H 6.10; N 21.80.
    Calculated,%: C 41.62; H 6.03; N 22.06.
    N-Ethyl-m-2-1 2- (dimethylaminomethyl) -4-thiazolyl | methylthioC ethyl-2-iitro-1, 1-etenediamine, m.p. 89-90 C.
    Found,%: C 45.32; H 6.70; N 20.44.
    C, H,.
    Calculated,%: C 45.19; H 6.71; N20.27. ,
    N-Methyl-N-2 | 2- (dimethylaminomethyl) -4-thiazolyl methylthioch ethylthiourea (glassy solid).
    Found,%: C 43.62; H 6.49; N 18.15.
    Calculated,%: C 43.39; H 6.62; N 18.40.
    H-Methyl-H -2- {2- (dimethyl метн мет мет) 4-thiazolyl methylthio ethyl urea, m.p. 56-59 0.
    Found,%; C 46.03; H 6.66; N 19.41.
    Calculated,%: C 45.81; H 6.99; N 19.42.
    N-Metsh1-Y-2- 2- (dimethylaminomethyl) -4-thiazolyl methylthioSethyl-N-nitroguanidine, so pl. 86.5-88 C.
    Found,%: C 39.92; H 5.89; N 25.15; S 19.49.
    Calculated,%: C 39.74; H 6.06; .N 25.28; S 19.29.
    N-2-G 2- (Dimethylaminomethyl) -4-tizolyl1-methylthio-1-ethyl-n-nitroanidine, melting point after
    recrystallization from ethyl acetate 104-105,5 ° C.
    Found,%: C 37.88; H 5.41; N 26.10.
    Calculated,%: C 37.72; H 5.70; N 26.39.
    {Etil-M -2- | 2- (dimethylaminomethyl) -5-methyl-4-thiazole1 | methylthio | ethyl-2-nitro-1, 1-etenediamine, m.p. 104-10bs.
    Found,%: C, 45.54; H 6.47; N 19.60.
    Calculated,%: C 45.19; H 6.71; N 20.27.
    N-4-1 2- (Dimethylaminomethyl) -4-thiazolyl butyl-N-methyl-2-nitro-1,1-ethylenediamine, m.p. 97-99 C. Found,%: C 49.56; H 7.25; N 22.15.
    Calculated,%: C 49.82; H 7.40; N 22.35.
    Mass spectral analysis of semi-. The following peaks are observed: m / e at 236; 212; 194; 178; 153; 126; 112; 97; 85; 71; 58; 42; 32 and 15.
    N-MeTHn-N -2- | 2- (morpholinomethyl) -4-thiazolyl methylthio ethyl-2-nitro 1, 1 ztenediamine, m.p. 151-153 ° C after recrystallization from methanol-ethyl acetate.
    Found,%: C 45.23; H 6.24; N 18,56.
     Calculated,%: C 45.02; H 6.21; N 18.75.
    N-Methyl-N-2 | Z- (1-pyrrolidinmethyl) -4-thiazolyl1-methylthio7 ethyl-2-nitro-151-etrandiamine, after recrystallization from methanol / ethyl acetate mixture, t. square 119-120 s.
    N-Methyl-H -2-1 2- (1-piperidinemethyl) -4-thiazolyl1 methylthio-1-2-nitro-1, -etenediamine, etc. 100 ... o
    103 C after recrystallization from methanol-ethyl acetate.
    Found,%: C 48.72; H 5.94; N 18.64.
    Calculated,%: C 48.49; H 6.78; N 18.85.
    N-Methyl-N-2- | 2- (methylethylamino methyl) -4-thiazolyl-methylthio (ethyl-2-nitro-1, 1-edendiamine, mp 114116 ° C.
    Found,%: C 45.48; H 6.80;
    N 19.98.
    Calculated,%: C 45.19; H 6.71; N 2P.27. N-2-f 2- (Dimethylaminomethyl) -4-thiol methylthio ethyl-N-cyanoganidine / R (a glassy product). NMR spectrum (CDCl1), S: 2.32 (singlet, 6H); 2.76 (triplet, 2H) J 3.50 (doublet, triplet, 2H); 3.74 (singlet, 211), 3.83 (singlet, 2H); 6.38. (Broad signal, 2H), 7.01 (siglet, 1H), 7.64 (wide signal, 1H Found,%: C 43.91; H 5.90; N 27.93.: Calculated ,%: C 44.27; H 6.08; N 28.16. H-3- | 2- (Dimethylaminomethyl) -4-thiazolylJ methyl ethyl thiolpropyl-N-methyl-2-nitro-1, 1-edendiamine. Found : C 45.25; H 6.51; N 19.99. Calculated,% g C 45.19; H 6.71; N 20.27. NMR spectrum (CDClj): 1.93 (quintet, 2H ), 2.42 (singlet, 6H); 2.65 (triplet, 2H); 2.92 (broad signal, 3N); 3.34 (multiplet, 2H) 3.81 (singlet, 2H) “, 3, 83 (singlet, 2H); 6.58 (singlet, 1H); 7.10 (singlet, 1H). The compounds obtained are potential antagonists of the Hj receptors and, therefore, means to combat the disease. The following procedure was used to block the activity of the Hj receptor. White females were treated with custron 24 hours before the start of the experiment. Then, the mice were sacrificed and parts of the uterus were removed, which were placed at room temperature in baths containing de Jalot solution After equilibration, strips of uterine tissue were placed in an aqueous solution of potassium chloride (50 mmol), which made it possible to maintain contraction. After a corresponding contraction of the uterus, histamine caused a dose-dependent relaxation of the Hj receptors. A control curve for histamine was also plotted for each tissue, depending on the dose. After thoroughly removing histamine after obtaining a control curve depending on the doses, the antagonists under study were administered for 30 minutes at a molar concentration of 10 Then the strips of uterine tissue were treated with an aqueous solution of potassium chloride in the presence of an antagonist and a second curve was obtained to histamine, depending on the dose. In the presence of the tested antagonist, the corresponding histamine curve shifts parallel to the right, depending on the dose, without lowering the position of the maximum relative to the control curve. The dose ratio (OD) is calculated for each of the concentrations of antagonist by dividing the ED5d for histamine in the presence of the test antagonist by the ED value for histamine. The dissociation constant (Kg) for the antagonist is calculated from the dose ratio of the Kg antagonist equation: (OD-1); Cimetidine was used as an internal standard. From the results obtained during the test according to the proposed method of N-metsh1-s (dstiylaminomethyl) -4-thiazolshG methylthio7 ethyl-2-nitro-1, 1-ethylenediamine, it follows that this compound has approximately 11 times more remedies for the receptors H, than cimetidine, N-methyl-N (dimethylaminomethyl) -4-thiazolyl methylthioJ3THn-N-cyanguanidine has an affinity for these receptors that is approximately 1.5 times higher than the affinity of cimetidine. For the first of these compounds, Kg in a nanomolar solution is 87 compared to Kg 871 for cimetidine, which corresponds to a relative affinity value of about 10: 1. The second experiment in studying the blocking activity of the compounds with respect to the H receptors is carried out on the separated mucous membrane of the stomach of a large marsh lushka (l hawqbyka). The experiment was carried out as follows. The mucous membrane of the stomach of a lamb of a bull was separated from the musculature of the same Ludka and placed between a pair of Jussing chambers made of lucite. The chambers were filled with Ringer's solution and stimulated the secretion of acid by adding histamine to the serous side of the mucosa at a final concentration. 10 mol / l. The amount of acid automatically titrates to pH 4.5. After establishing a stable response to 10 mol / l of histamine, the test antagonist is injected on the serous side of the chamber and the maximum degree of inhibition is recorded for each of the concentrations of the H, antagonist. From the corresponding dose-dependent curve, the ED, p, n value of the corresponding compound is obtained. The relative activity of each new antagonist is calculated by dividing the value of cimetidine by the ED of the test compound. At the same time, N-methyl-Y-2-G 2- (dimethylaminomers1) -4-tyazolyl methylthio-7-ethyl 2-nitro-1, 1-edendiamine has a relative activity of 17.78 compared with 1.0 for cimetidine. Experiments in vivo on the study of the anti-secretion effects of the test drugs were carried out using dogs' gastric fistula with vascular innervation of the gastric fistula and vascular denervation of the Heidendentine bag. According to this technique, sustained gastric secretion is caused by intravenous administration of histamine. Drugs with anti-secretion effects to be tested were administered either intravenously over a 30 minute period of time or orally 75 minutes before picking up gastric secretions 310 from the fistula. It was found that N-methyl-Y-2-G 2- (dimethylaminomethyl) -4 thiazolyl-methylthio1 ethyl-2-nitro-1, 1-etente-diamine is approximately 6.5 times more active than cymetidine when administered intravenously and about 11 times more active when administered orally. These latter results show that M-methyl-L (dimethylaminomethyl) -4-thiazolyl-methylthio ethyl-2-nitro-1,1-etrandiamine and other compounds according to the invention absorb the best cimetidine or any other known Hj antagonists by oral route of administration. histamine type. The indicated oral absorption by the oral route is also confirmed by the relatively higher toxicity (compared with the toxicity when administered intravenously) for the proposed compounds. The values for L-Durravny, respectively, for N-methyl N-2- 2- (dimethylaminomethyl) -4-thiazolyl-methylthio ethyl-2-nitro-1, 1-etenediamine LD are equal to those for intravenous administration of 265 mg / kg, for oral oral administration of 1685 mg / kg, for rats for intravenous administration - more than 300 mg / kg, for rats, for oral administration, 1680 mg / kg. LD 50 for cimetidine, respectively, is 150; 2600; 106 and 5000 mg / kg.
    权利要求:
    Claims (2)
    [1]
    1. The method of obtaining thiazole derivatives of the General formula, f = r 'CH 2 -S- (CH 2 ^ H “C-'N S-γΝ X ch 2 -n ^ Ki
    In 2 , where A ( and T < 2 are independently of each other C ( -C 4 ~ alkyl;
    R 3 and R 4 are independently hydrogen or C ( —C 4 -alkyl;
    X - = NCN or = CHNO 2 , characterized in that, the compound of the General formula where R and R 2 have the indicated meanings, are reacted with X, R 3 and R 4 have the indicated meanings;
    L, is a leaving group, such as an amino group in a polar solvent medium.
    [2]
    2. A method of obtaining derivatives of thiazole of the General formula
    CH 2 -S- (CH 2 1 2 NH-CN g = G
    CH 2 M R1 in
    Hg where R, and R 2 independently of one drugaS ^ -C ^ alkyl;
    Rj and R ^ are independently hydrogen or C {-C <|. Alkyl;
    X - = NCN or = CHN0 2 , characterized in that the compound of the general formula ^ CH 2 - S- (CH 2 ) 2 NH-C-L2 where R. <S R 2 and X have the indicated meanings;
    L 2 is a leaving group, such as a halogen atom, • is reacted with an amine of the general formula c-cm-nx X hnr 3 r 4 , where R 3 and R 4 are as defined, in a polar solvent.
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    GR75023B|1984-07-12|
    引用文献:
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    法律状态:
    优先权:
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