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  • 优先权
    • 专利摘要:
    2,4-Disubstituted thiazole compounds of the formula or a pharmaceutically acceptable acid addition salt thereof wherein X is NH and Y is CH or N, or X is S and Y is CH; R1 is certain straight or branched chain alkyl groups, (R3)2C6H3, or (R3)Ar(CH2)n where n is an integer from 1 to 4, R3 is H or certain substituent groups and Ar is phenylene, naphthalene or the residue of certain heteroaromatic groups; R2 is H or (Ci-C4)alkyl; or R1 and R2 taken together with the nitrogen atom to which they are attached form certain heterocyclic groups; and R4 is H, (C1-C5)alkyl, NH2 or CH20H; a method for their use in treatment of gastric ulcers in mammals and pharmaceutical compositions containing said compounds.
    公开号:SU1400508A3
    申请号:SU864027210
    申请日:1986-04-02
    公开日:1988-05-30
    发明作者:Алан Рестер Лоренс
    申请人:Пфайзер Инк. (Фирма)；
    IPC主号:
    专利说明:


    about
    ate
    oo
    The invention relates to a process for the preparation of new chemical biological active compounds, specifically to a process for the preparation of aryl-thiazole-2- {N-substituted guanidino derivatives) (15 2,4-triazole-5-th) thiazols, which have the ability to block the action of histamine H-receptor Histamine-H receptor agonists), inhibit the secretion of acid, which is part of the gastric juice, and inhibit the formation of ulcers of the stomach, caused by alcohol. These compounds may be useful in preventing and treating increased gastric acidity and peptic ulcers.
    ; The aim of the invention is to obtain new derivatives of 2 (M-substituted guanidino) -4- (1,2,4-triazol-5-yl) -thiazoles, which can be used in medicine as an antagonist of histamine-H-, as well as having a new type of activity for a number of arylthiazoles - the ability to inhibit the formation of ulcers by the stomach, which causes alcohol.
    All temperatures are in degrees Celsius. Nuclear magnetic resonance spectra (NMR) were measured for solutions in deuterated hlot roforme. (CDCI3), deuterated methanol (CDjO) or deuterated dymetilsulfoksyde (DMBO-df,) and peak positions are given in x on the floor yl LYON in the downlink region from tetra- methylsilane. The following abbreviations are used for peak shapes: bS is a broad singlet; S is a singlet; d is a doublet; t is a triplet; q - quartet; m - multiplet ,,
    Example 1: Ethyl-2- (1-n-hexyl-3-guanidine) thiazole-4-carboxllate.
    A mixture of 1- (n-hexylguanil) thiocarb; | mida (4.09 g, 20 mmol), ethyl bromide ester of pyruvic acid (4.09 21) and 200 ml of ethanol is heated under reflux for 4 hours and cooled. The mixture is concentrated in vacuo to a yellow solid, which is treated with a complete solution of sodium hydrogencarbonate and extracted with chloroform. The dried extracts are concentrated in vacuo to an orange oil, which is cured by trituration with hexane. After re-crisplization from hexane mixture

    0 5
    0 5 0
    five
    0
    five
    with ethyl acetate, g (62%) of yellow crystals are obtained. Treatment of stock solutions gives an additional 1.20 g (20%) of the product. A sample for analysis is obtained by recrystallization from hexane with ethyl acetate, melting point 118-119 C.
    Mass spectrum (ha / e): 298 (); H - tR (CDCl1) fractions per 1 mln / s: 0., 6-1.8 (t, 14 N); 3.2 (t, 2 H) j 4.3 (q, 1 7 Hj, 2 H); 7.03 (S, pgaroky, 3 N); 7.41 (5, 1 H).
    Calculated,%: C 52,32 | H 7.43; N 18.78.
    Found: C 52.41; H 7.55; N 18.36.
    Example 2. 2- (1-n-hexyl-3-guanidino) thiazole-4-carboxylic acid hydrazide.
    A mixture of 3.36 g (11.3 mmol) of ethyl- -2- (1-n-Hexyl-3-guanidino) thiazole-4-carboxyl 1 and 6.5 mp (110 mol) of 38% hydrazine hydrate in 110 ml ethanol is heated under reflux for 24 hours. An additional 6.5 ml of hydrazine hydrate is added and continued: heating for another 24 hours. The resulting mixture is cooled, the solvent is evaporated in vacuo, the residual colorless solid is triturated with isopropanol and filtered. 2.32 g (78%) of a colorless powder are obtained. Pro (5y for analysis is obtained by recrystallization from isopropanol, melting point 136-137 ° C. Mass spectrum (m / e): 284. (); H-NMR (DMSO-d / CDsOD) parts per million (s /): 0.7-1.7 (t, 11H); 3.2. (T, 2H); 7.31 (s, 1H).
    Calculated,%: C 46.45; H 7.09; N 29.55.
    C h oNgOS
    Found,% g, C 46,10; H 7.18; N 29.93,
    Example 3. 2- (1-n-hexyl-3-guanidino) -4- (3-methyl-1H-1,2,4-triazol-5-yl) thiazole (I) /
    A mixture of 568 mg (2.0 mmol) of 2- (1-n-hexy-p-3-guanidino) thiazole-4-carboxylic acid hydrazide, 751 mg (MO mol) of thioacetamide in 20 ml of n-butanol is heated with reflux for 48 hours. The cooled reaction mixture is concentrated in vacuo and the residue is chromatographed on a silica gel column to give 241 mg (39%) of pure triazole as
    ten
    15
    20
    yellow sponge mass, melting point 207-209 ° C. Mass spectrum (ha / e): 307 (M); H - NMR (CDOD) parts per million (cg): 0.7-1.8 (t, 11 N); 2.43 (s, 3 H); 3.3 (t, 2 H); 7.22 (s, 1H).
    Calculated,%: C 49.34; H 7.01, - N 30.99.
    C, I-, 5 0.5N20
    Found,%: C 49.42; H 6.73; N 30.82.
    Example 4. 2- (1-n-hexyl-3-guanidino) -4- (3-amino-1H-1,2,4-triazol-5-yl) thiazole (11).
    A mixture of 852 mg (3.0 mmol) of 2- (1-n-hexyl-3-guanidino) -thiazole-4-carboxylic acid hydrazide, 835 mg (4.5 mmol) of S-methyl isothiuronium sulfate and 492 mg of sodium acetate and 30 ml of n-butanol are heated under reflux for 4 hours and cooled. The mixture was filtered, the filtrate was concentrated in vacuo and the residue was chromatographed twice on silica gel columns, first removed from the 85:15 adsorbent with chloroform / methanol, then with acetone, to give 491 mg (53%) of the title compound as a yellow solid. 30 of that substance, melting point 210-211 s. Mass spectrum (t / e) 308 (M); H - NMR (CDjOD) parts per million (S: 0.7-1.9 (t, 11 H); 3.2 (t, 2 H); 7.13 (S, 1 H) .. 35
    Calculated N 36,34.
    With jH joNgS
    Found,%: N 36.03.40
    Example 5. Activity in relation to resistance to histamine -N.
    The activity of the compounds according to the proposed invention, antagonizing histamine-Hj, is determined by the following method.
    The marine pigs are quickly killed by a blow to the head, the heart is removed, and the right artery is dissected so that it is free. The artery is suspended isometric in a temperature-controlled tissue bath (32i2 ° C; this bath (10 ml) contains oxgemone (95% 5% CO7) 55 buffer (pH 7.4) Krebs-Henseleit. Leave to stabilize for about 1 h. During this time, the tissue bath is washed several times with a strong structure.
    q 46.73; H 6.54;
    C 46.63; H 6.42;
    0
    five
    0
    0 5
    0
    five
    0 5
    her fluid. Separate abbreviations related to the atrium are tracked using a device that transmits displacement from the force connected to the cardiotachometer and the Grass polygraph. After obtaining a curve expressing the relationship between dose and histamine response, the bath containing each atrium is washed several times with a strong jet of fresh buffer and the atrium is equilibrated with the fundamental frequencies. After returning to the base frequency, test compounds are added at selected final concentrations and the histamine dose-response curve is determined again. The ratio of histamine concentration required to obtain half of the maximal stimulation in the presence or absence of the antagonist is determined and the constant 5 of the apparent dissociation of the H receptor antagonist p A is calculated. The test results are shown in Table 2.
    Example 6
    Inhibition of ST formation caused by ethanol in rats.
    The anti-ulcerative activity of the products according to the invention is also determined in a rat by checking the ulcers extracted by ethanol. In this test, male rats, fixed overnight, are given medicine (at 30 or 3 mg / kg) or water by ingestion through the mouth 15 minutes before ingesting absolute ethanol (1.0 ml) through the mouth. One hour after the ethanol call, animals (8 in the group) are killed and the stomach is examined for damage. Surgical treatment of the stomach is performed, and a hemostat is installed in the pylorus. A 6 ml 4% formaldehyde solution was injected into the stomach through a gastric probe, and a second trailing jaw was installed to lock the esophagus. The stomach is removed, opened along the highest curvature and examined for the formation of stars,
    The counting system used to determine the amount of damage caused by ethanol is given in Table 1.
    more than 2, point damage may be present
    : 5 Damage with bleeding
    For each group of animals, an index of stars is calculated, as shown below.
    The link index is (the amount of damage for each group) X (the sum of the number of links in each) x (the share in the group that has the link for any degree of development).
    Inhibition of the formation of stress, expressed in%, is given as follows:
    % inhibition of 100x (index zvM.u control) - (index of ulcers in those who delivered the drug)}: (index of ulcers at; control) about
    The test results on cytosafety are given in Table 2.
    Table 2 Activity against countermeasures; to histamine-H and cytoprotective activity of aryl thiazole and cymetidine derivatives
    og
    Th-
    7.0
    7.2
    7,8
    6.4
    1.21 0.90 0.8
    1.0
    21
    66
    ABOUT
    Not active
    respectfully take medication by mouth. Typically, compounds of formula (I) are to be administered orally at approximate dosages within
    O, D to 20 mg / kg body weight of the subject, which is treated per day, preferably from about 0.2 to 2.5 mg / kg per day in single or divided into several parts doses. If it is desirable to administer for the purpose of treatment, mine the digestive tract, then these compounds can be given in the form of total daily doses in the range of about 0.1 and 1.0 mg / kg body weight of the subject being treated.
    Thus, the compounds obtained by the proposed method have a low degree of toxicity to humans.
    35
    Formula and 3 about b ry te n and
    The method of obtaining derived arylthiazoles of General formula (I)
    V
    40s
    kgN jr- il HN NH2 H-CgH
    45
    tf.
    I i
    n
    50
    i
    where R is methyl or amino group; characterized in that an acid hydrazide of the formula
    $
    J-P
    II
    H-CeHia
    1 H CONHNHg
       1400508
    is reacted with .thioace-1.5, respectively, in butanol medium with tamid or S-methylisotiuro salt at its boiling point at a molar ratio of Is55 - a condenser.
    权利要求:
    Claims (1)
    [1]
    • Claim
    The method of obtaining derivatives of arylthiazopia of General formula (I)
    Connection No.
    Analogue
    Cimetidine
    Ant min-N pA 2 ~ 7 ~ 0 ~
    7.2
    7.8
    6.4 histagonism agonism
    Slope, growth on oblique agar
    G, 2 '
    0.90
    0.8
    Cytoprotection
    AU 5 about (% protection at
    30 mg (kg), orally
    With 1.0N-6N minutes
    R is methyl or l and ch, and where t is an acid hydrazide of the formula amino group;
    th with i that
    Inactive conhnh 2 is reacted with .thioacetamide or S-methylisothiuronium salt in a molar ratio of 1:55 -
    1.5, respectively, in butanol at boiling temperature with a reflux condenser.
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    法律状态:
    优先权:
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