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    • 专利摘要:
    Heretofore unavailable 2-guanidino-4-(2-substituted- amino-4-imidazolyl)thiazoles; a novel process therefor, also advantageous for the preparation of known antiulcer 2-guanidino-4-(2-substituted-amino-4-imidazolyl)thiazoles; intermediate compounds therefor; and a method for treatment of ulcers in mammals therewith.
    公开号:SU1195907A3
    申请号:SU833585699
    申请日:1983-05-03
    公开日:1985-11-30
    发明作者:Лоренс Ля Маттина Джон；Эндрю Липински Кристофер
    申请人:Пфайзер,Инк.(Фирма)；
    IPC主号:
    专利说明:


    H2N - C-1SH in acetone at the boiling point of the reaction mixture with the selection of the target product in free form or in the form of a crystalline hydrobromic salt.
    2, Method for producing acetylimidazole of formula III
    n
    N0 Y).
    SNS
    where R is a group of the formula NHR2 or
    NR3R4;
    lRJ () is alkyl, (C4-C5) -pyridylalkyl or (St-C) -phenylalkyl, possibly substituted by chlorine;
    1195907
    Rj and R are each independently - () -alkyl
    or taken together with the nitrogen atom to which they are attached form a pyrrspidine, piperidine or morpholine ring, which is also characterized by the fact that oxazole formula //
    N
    . H., N 0 5
    interact with an excess of amine of formula
    HjNR2 or HNRgR
    in water or in a mixture of water and isopropanol at the boiling point of the reaction mixture with the selection of the target product.
    The invention relates to a process for the preparation of both new and known 2-guanidino-4- (2-substituted amino4-imidazolyl) -thiazoles of the general formula
    N.
    / V
    , / VKH
     l
    {
    NH
    NS /
    H N-С- 1Н
    where R / 5 is the NHPj group or 5 K (C-C) -alkyl, (C4-Cd) -pyridylalkyl or (C -,) -phenylalkyl, possibly substituted with hi;
    Rj and R are each independently () alkyl or taken with the nitrogen atom to which they are attached to form a pyrrolidine, piperidine or morpholine ring, or their hydrobromic salts possessing biological activity and to a method for producing acetylimidazole of the general formula
    2
    H NRt
    /
    X .N
    CHr
    where R is the group NHP or NRsR .; R is () -alkksht, (C4-C8) -pi-1 ridylalkyl or (C-G) -phenylalkyl, possibly substituted by chlorine; . RJ and R are each independently () alkyl
    , or taken together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, an intermediate product for the synthesis of 2-guanidino-4- (2-for 1 amino-4-imidazolyl) -thiazoles, which have valuable properties.
    The purpose of the invention is to expand the range of imidazolylthiazoles and increase their yield.
    Example 1. 5-Acetyl-2-aminooxazole (IV). A mixture of 132.2 g (0.80 mol) of 2-bromo 1-hydroxy-3-oxo-1-butene, 120.1 g (2.0 mol) of urea and 1.85 l of acetone is refluxed at stirring for 1 h. The mixture is concentrated and the oily residue is treated with 600 ml of water, then basified with concentrated ammonium hydroxide. After stirring at room temperature for 0.5 hours, a precipitate formed. It is collected and dried in vacuo to give 61.1 g of a crude product. Filtrate Concentrate again and oil. The precipitate is treated with 50 ml of water is alkalinized again with concentrated ammonium hydroxide. After standing overnight, a second collection of crude product in an amount of 17.6 g was isolated. Both collections were combined and recrystallized from methanol to obtain 50.3 g (50%) of 5-acetyl-2-amino-oxazole, m.p. 214-215 C. And p. M. 2. General procedure for 2-substituted-amine C-5-acetylimidazoles (V). A mixture of 2.0 g (16 mmol) of 5-acetyl2-aminooxazole, 20 ml of the corresponding amine and 30 ml of water is heated under reflux for 396 hours (in the case of some lipophilic amines, iso-propanol must be added to obtain a homogeneous reaction mixture ). The mixture is concentrated (if necessary, it is distilled off to remove all traces of the amine), and the residue is then chromatographed on 60 g of silica gel using a 4: 1 mixture of ethyl acetate / hexane as eluant. As soon as all the less polar material (pyrimidine byproduct) is eluted, the column is quenched with 9: 1 chloroform / methanol to obtain a more polar imidazole product. Analytically pure imidazole is obtained by recrystallization from a suitable solvent. Thus, the 2-substituted amino-5-acetylimimazole presented in table. 1. E & C. 3. 3. General procedure for 2-substituted amino 5- (2-bromoacetyl) -imidazoles (VI). A solution of 1.0 g of a suitable ketone in 25 ml of concentrated hydrobromic acid is stirred at room temperature and a 5% molar excess of bromine is added dropwise over a period of 2 minutes. The mixture is then heated at 80 ° C (external heating) for 1 hour, during which time the color imparted by bromine disappears. The mixture is cooled, then concentrated. The precipitate is carefully ground with. in our solution bicar-. sodium bonate and collect the precipitate formed in this basic medium, wash it with water, then dry under vacuum and get 2-amino-5 (2-bromoacetyl) imidazoles (see table 2) as solid products, characterized by NMR spectra in dmsr-dt. PRI me R 4. General procedure for 2-guanidino-4- (2-substituted amino-4-imidazolyl) -thiazole hydrobromide (III. Br). A mixture of 1 g of bromoacetyl imidazole of Example 3, an equivalent amount of amidinodiourea and 50 mp of acetone is refluxed for 1 hour, during which time the product precipitates as its monobromide salt. This solid was collected, washed with acetone and dried in vacuo. It is then converted to its dichlorohydrate, as described in Example 5. EXAMPLE 5 General procedure for the preparation of 2-guanidino-4- (2-substituted amino-4-imidazolyl) -thiazoles (O (HC1)) dichlorohydrate ). The hydrobromide salt is stirred in 50 ml of saturated sodium bicarbonate solution for 1530 minutes. The solid product in the form of the free base is collected, washed with water, then dried in vacuo. This solid is dissolved in a minimum amount of methanol. The methanol solution is saturated with HC1 gas, then slowly diluted with ether. The resulting precipitate is collected, washed with ether, then dried in, get dihydrochloride, which is characterized by elemental analysis (burning) and / or spectral data. The yield of dihydrochloride crawled according to examples 4-5, the results of its elemental analysis and / or spectral data are given in table. 3. PRI me R 6. Antisecretory resistance to the allocation of gastric
    S
    Antisecretory activity to the secretion of gastric juice of the compounds of the invention was determined on overnight and conscious Haydenhain dogs. Pentagastrin (Pentavolon-Ayerst) is used to stimulate the release of acid with continuous infusion into the superficial leg vein with predetermined doses to stimulate close to the maximum release of gastric juice from the gastric sac. Gastric juice is collected at intervals of 30 minutes from the start of pentagastrin infusion and measured to the nearest 0.1 ml. During the experiment, make 10 charges from each dog. The acid concentration is determined by titration of 1.0 MP of gastric juice to pH 7.4 with 0.1 N sodium hydroxide using an automatic burette and a pH meter with a glass electrode (Radometer).
    The drug or vehicle is administered intravenously 90 minutes after the start of pentagastrin infusion at a dose of 1 mg / kg or less. The antisecretory effect on gastric juice excretion is calculated by comparing the lowest juice excretion after drug administration with the average juice content just prior to drug administration.
    Products h ,, n, g, and its example 3 at a dose of 1 mg / kg inhibit gastric secretion by at least 21%. Preferred products f - h and W inhibit gastric secretion by at least 97% at the same or lower dose. At a dose of 3 mg / kg, the compound yields 42% inhibition. At a dose of 0.1 mg / kg, the compound gives 72% inhibition.
    Example 7. Hj-Antagonistic activity in relation to histamine.
    H-Antagonistic activity in relation to histamine of the compounds of the invention is determined as follows.
    Guinea pigs are quickly killed by a blow to the head, the heart is extracted and the right atrium is dissected. The atrium is isothermally suspended in 10 ml of a temperature-controlled tissue bath (32 + 2 ° C) containing oxygenated (95% Oi, 5%
    959076
    The CO) Krebs-Henseleit buffer (pH 7.4) is allowed to stabilize for approximately 1 hour, during which time the tissue bath several times 5 is rinsed with a strong jet pressure. Individual atrial contractions follow a force-moved transducer connected to a cardio-tachometer and recording of the Grass polygraph O. After obtaining the dose-response curve for histamine, the bath containing each atrium is washed several times with a strong jet of fresh buffer, and the atrium of the again equilibrated to the base intensity. After returning to baseline intensity, test compounds are added at selected final concentrations and the histamine-dose response curve in the presence of an antagonist is determined again. The results are expressed as the dose ratio of the concentrations of histamine required to obtain half of the maximum stimulation in the presence and absence of the antagonist, and the apparent dissociation constant for the H-receptor of the pL2 antagonist is determined.
    Products a- t, n, os-bg of example 5 pAj values are at least 5.9. Preferred products f, i, p, S, t and W give pA 7.0 and above.
    PRI me R 8. Inhibition caused by ethanol stars in rats.
    5 The anti-stress activity of the products of the invention was also determined by testing an ethanol-induced starter in a rat. In this test, unfed during the night
    0 rats are given medicine (5 mg / kg) or water orally 15 minutes before oral administration of a dose of absolute ethanol (1.0 ml). An hour later, after the introduction of ethanol, animals are killed and their stomachs
    5 are examined for damage. After killing, the abdominal cavity is opened, and a hemostat is placed in the pylorus. Inject 6 ml of 4% formaldehyde solution into the stomach
    0 with a gastric supply tube and use a second locking hemostat to close the esophagus. The stomach is removed, opened along the greatest curvature and examined for ulcer.
    The evaluation system used for the amount of damage caused by ethanol is as follows: 7 Evaluation Definition 1 Normal stomach view 2 Damage to point sizes 3 Damage, 2 or less, may be point 4, Damage, more than 2, may be point-like, 5 Damage from bleeding . For each group of animals, the index of ulcers is calculated as follows: The index of ulcers (the sum of the group's estimates) X (cjTMMa number of stars in the group) X (fraction of the group having any random expressions).
    CHjNH
    CHj (CH,) 2NH
    CH3 (CH2) sSh
    Cti3 (CH2) 4NH
    sk (CE) t
    CE (
    CH () H
    CE.) Ntt
    CHj (CH2) gNH
    (CHj) CHNH
    C2H5 (SNZ) DREAM
    (СНз) 2СН (СН2) 2МН
    Cyclopropylamino
    Cyclopentilamino
    Cyclohexylamino 78 Percentage of inhibition of ss is calculated as follows:% inhibition, van 100 V (control index) - (drug treated index): (control index. At oral dose, products a-K, m, g - n, W, y, Z, vv and its example.a 5 show inhibition of at least 19% of ulcers caused by ethanol.At the same dose of the compound o, V, x and aa do not show significant activity, the compound n, p and g show 7–13% inhibition, compounds show 21–51% inhibition, and preferred Connections f-i, s, t and W indicate 86-100% inhibition. T a b l e 1
     CHjCCHp NH
    91
    CHj (CHj) NH
    85
    IH), 4.33 (singlet, 2H), 3.15 (quadruplet, 2H), 1.50 (multiplet, 2H), 0.87 (triplet, 3N)
    7.88 (singlet, 1H 7.0 (broad, IH), 4.43 (singlet, 2H), 3.27 (multiplet, 2H), 1.43 (multiplet, 4H), 0.87 (triplet, GH )
    7.67 (singlet, IH), 6.5 (wide, IH), 4.27 (singlet, 2H), 3.28 (multiplet, 2H), 1.38 (multiplet, 6H), 0.91 (triplet , ZN)
    eleven
    Output,
    Substituted amino group (R)
    CHjCCH-NH
    75
    CH j (CH2) iNH
    97
    SNZ (SN), W
    98
    CHgCCH gNH
    90
    CH3 (CH2) eKN
    99
    : CH3) iCHNH
    63
    C, H5j (CHj) CHNH
    60
    (SNE) oCH (CH) 1Sh
    80
    45
    Cyclopropylamino
    81
    Cyclonetilamino
    83
    Cyclohexylamino
    92
    12
    1195907 Continuation of table 2
    NMR (delta, ppm)
    7.65 (singlet, IH), 6.5 (wide, IH), 4.32 (singlet, 2H), 3.17 (cartoon, 2H), 1.31 (multislet, 8H), 0.83 (triZN )
    lash
    8.23 (singlet, IH), 4.56 (singlet, 2H), 3.30 (multiplet, 2H), 1.21 (broad singlet, YUN), 0.80 (triplet, G)
    8.22 (singlet, IH), 4.49 (singlet, 2H), 3.26 (multiplet, 2H), 1.22 (broad singlet, I2H), 0.84 (triplet, 3N)
    8.23 (singlet, IH), 4.58 (singlet, 2H), 3.27 (multiplet, 2H), 1.27 (broad singlet, I4H), 0.80 (triplet, 3N)
    8.06 (singlet, IH), 4.46 (singlet, 2H), 3.20 (broad, 2H), 1.26 (broad singlet 16H), 0.80 (triplet, 3N)
    7.75 (singlet, IH), 6.43 (broad doublet, IH), 4.38 (singlet, 2H), 3.90 (multiplet, IH), 1.19 (doublet, 6H)
    7.50 (singlet, IH), 5.4 (wide, IH 4.11 (singlet, 2H), 3.75 (multiplet 2n), 1.48 (multiplet, 2H), 1.2 (doublet, 3N) , 0.90 (triplet, ЗН)
    7.87 (singlet, IH), 6.9 (broad, IH), 4.42 (singlet, 2H), 3.28 (multiplet, 2H), 1.9-1.3 (multiplet, 3N), 0 , 92 (doublet, 6H)
    7.94 (singlet, IH), 5.4 (wide, IH), 4.47 (singlet, 2H), 0.9-0.4 (wide, 5H)
    7.97 (singlet, IH), 7.0 (wide, IH), 4.46 (singlet, 2H), 4.1 (wide, IH), 2.0-1.4 (wide, 8H)
    7.87 (singlet, IH), 6.9 (wide, IH), 4.42 (singlet, 2H), 3.5 (wide, IH), 2.0-1.0 (multiplet, YUN)
    7.95 (singlet, IH), 7.8 (broad, IH), 7.15 (singlet, 5H), 4.5 (singlet, and doublet, 4H)
    (CH2) NH
    84
    C (iif (cH) m
    76
    C (, l {(CE2) m
    75
    2- (4-Pyridyl) 91 ethylamino
    2- (2-Pyridyl)
    94 ethylamino
    4-Chlorophenyl Amino
    (
    53
    60
    62
    100
    47
    71
    7.73 (singlet, IH), 7.23 (singlet, 5H), 6.63 (broad, IH), 4.36 (singlet, 2H), 3.42 (triplet, 2H), 2.80 (triplet , 2H)
    7.67 (singlet, IH), 7.20 (singlet, 5H), 6.64 (broad, IH), 4.37 (singlet, 2H), 3.18 (triplet, 2H), 2.60 (triplet , 2H), 1.83 (multiplet, 2H)
    7.79 (singlet. III), 7.37 (singlet, 5H), 6.77 (broad, IH), 4.42 (siglet, 2H), 3.33 (multiplet, 2H), 1.9- 1.6 (multiplet, 6H)
    8.45 (doublet, 2H), 7.72 (singlet, IH), 7.23 (doublet, IH), 6.6 (broad, IH), 4.38 (singlet, 2H), 3.56 (multiplet , 2H), 2.85 (triplet, 2H)
    8.43 (doublet, IH), 7.951-7.6 (singlet and multiplet, 2H), 7.4-7.2 (multiplet, 2H), 6.75 (broad, IH), 4.34 (singlet, 2H), 3.60 (multiplet, 2H), 2.97 (triplet, 2H)
    7.76 (singlet, IH), 7.27 (singlet, 5H), 6.73 (broad, DN), 4.37 (singlet, 2H), 3.48 (multiplet, 2H),
    2.77 (triplet, 2H)
    (CC1) - 7.64 (singlet, IH), 4.13 (singlet, 2H), 3.20 (singlet, 6H)
    7.63 (singlet, IH), 4.23 (singlet, 2H), 3.29 (quadruplet, 2H), 2.86 (singlet, 3N), 0.93 (triplet, 3N)
    7.87 (singlet, .IH), 4.42 (singlet, 2H), 3.50 (quadruplet, 4H), 1.13 (triplet, 6H)
    7.83 (singlet, IH), 4.41 (singlet, 2H), 4.0-3.3 (multiplet, 8H)
    7.81 (singlet, IH), 4.37 (singlet, 2H), 3.40 (multiplet, 4H), 1.89 (multiplet, 4H)
    7.70 (singlet, IH), 4.28 (singlet, 2H), 3.3 (broad, 4H, 1.4 (broad, 6H)
    74
    a) CHgNH
    b) C, H-NH
    80
    X O
    c) CHj (CH5) 2NH
    59 d) CH, (CH2) 3NH e) CHjCCH NH f) CHj (CH) yNH g) CH (CH) NH
    h) CHj (CH) NH
    55
      2HC1 HgO
    280
    Calculated,%: C 29.27, H 4.60, N, 29.87.
    Found,%: C29,21,
    H 4.14- N 29.33-, S 9.17
      2HS1 -.
    275
    Vyisleno,%: C 44.34J
    .H 4.66; N 30, 9.89,
    Found,%: C32.93;
    H 5.1U N 29.39iS 9.64
    C, oV-.S.2HCr.
    27-229
    Calculated,%: C 35.50,
     5.07j n 28.99-s 9.48
    Found%: C35.28-,
    H 5.14; N 28.37; S 9.42.
    NMR (DMSO-d), delta (ppm): 8.47 (wide, 4H), 8.09 (wide IH), 7.93 (singlet, IH), 7.80 (singlet, IH), 3 , 50 (wide 2H), 1.9-1.1 (wide, I2H), 0.92 (triplet, 3N) 2HC1: Calculated,%: C, H 5.43; N 27.83-, S 9.10 Found; C: 37.44; H 5.48; N 26.53; S 8,34 C,. 2FC1 Calculated,%: C 37.49; H 6.03; N 25.51 S 8.34; Found: C, 37.71; H 5.71V N 23.86 S 7.80 - 2HC1. H-iO; Calculated,%: C 39.20V H 6.33-, N 24.61, S 8.05 Found,%: C 39.84, H 5.865 N 24.60; S 8.19. 2НС1 HjO Calculated,%: C 40.78; H 6.60i N 23.78-, S 7.78. Found%: H 6.13 N 23.20J S 7.72
    i) CHg (CHj) gNH
    43
    j) CH, (CH2) e # 1
    k) (CHj) 2CHNH42
    6) C, H5 (CH5) CHNH
    60
    m) (CHj), CH (CH2) 2NH18
    n) Cyclopropylamino
    42
    o) Cyclopentilamino
    21
    p) Cyclohexylamino
    38
    275
      2HC1 “% 0;
    Calculated,%; C 43.63 H H 7.09, - N 22.26; S 7.28.
    Found,%: C 43, 73; H 6.48; N 21.60, S 7.04,
    NMR (DMSO-dj), delta (million
    275 shares): 8.47 (broad, 4H); 8.06 (broad, IH), 7.93 (singlet, IH); 7.77 (singlet, IH), 3.46 (wide. 2H), 1.9-1.1 (wide, I6H) 0.90 (triplet, 3N)
    NMR (DMSO-d), delta (million
    07-210 shares): 8.38 (broad, 4H), 8.00 (broad, IH), 7.89 (singlet, IH), 7.67 (singlet IH), 3.9 (broad, IH), 1.26. (doublet, 6H)
    NMR (DMSO-db), delta (million
    93-294 fractions): 8.37 (broad, 4H), 7.90 (singlet, IH), 7.80 (broad, IH), 7.66 (singlet IH), 4.0 (wide, IH), 1.56 (multiplet, 2H), 1.23 (doublet, ZN), 0.98 (triplet, ZN).
    ,: 2NS1- HjO
    275
    Calculated,%: C 37,50-,
    H 6.03 N 25.51; S 8.34
    Found,%: C 37.83; H 5.75;
    N 25.17; S 8.00
    275
     2HC1
    Calculated,%: C 35.72; H 4.50; N 9.53
    Found,%: C 35.91; H 4.81; S 8.60.
    275
    C; j ,, H. ,, N, S, - 2HC1
    Calculated,%: C 37.70; H 5.54; N 25., 65; S 8.38,
    Found,%: C 37.28; H 5.30 N, 24.89; S 8,08, -.
    YAG-1R (DMSO-d), delta. (Million
    275. fractions): 8.19 (broad, 4H), 7.80 (broad, IH), 7.67 (singlet, IH), 7j48 (singlet, IH), 3.4 (multiplet, IH), .1.9 -1.0 (broad, IOH)
    40
    q) C4% CH2NH
    r) (CH2) 2NH
    58
    s), g (CH2) sSh
    58
    t) C HjCCH NH
    44
    u) 2- (4-pyridip) 48 ethylamino
    v) 2- (2-1b1ridyl) - 52 ethylamino
    w) 4 Chlorphenethyl- 60 amino
    x) (CH) jN66
     . 2HC1
    275
    Calculated,%: C 43,53i
    H 4.44i N 25.28 JS 8.30. Found,%: C42.95 {
    H 4.75; N 24.59j5.8.25
    NMR (DMSO-d), delta (million
    275 shares): 8.40 (broad, 4H), 8.04 (pshroka, IH), 7.83 (singlet, IH), 7.69 (singlet, IH), 7.30 (singlet, 5H), 3 , 7 (broad, 2H), 2.91 (triplet,
      2H) j
    53-255, jN7S; 2HC1 - HjO
    Calculated,%: C 44.44 | H 4.90i N 22.67i S 7.42.
    Found,%: C 44.00) H 4.64} N 21.83v S 7.14
    NMR (DMSO-d,), delta (million
    69-270 shares): 8.41 (broad, 4H)., 8.08 (broad, IH), 7.86 (singlet, IH), 7.70 (singlet, IH), 7.14 (singlet, 5H), 3.5 (broad, 2H), 2.66 (multiplet, 2H), 1.9-1.5 (broad, 4H)
    NMR (DMSO-d), delta (ppm): 8.89 (doublet, 2H), 8.43 (broad, 4H), 8.17 (doublet, 2H), 7.98 (singlet, IH) 7.73 (singlet, IH), 4.0 (broad, 2H), 3.36 (multiplet, 2H)
    05-209
    %% NgS - 3HCt
    C, 38.41; H, 4.37; N, 25.60; S, 7.32.
    Found,%: C 38.38; H 4.65; N 24.78; S 7.08qjH, SC1 -2HS1 "1 / 2H20 Calculated,%: C 40.60j
    H 4.32 | N 22., 09; .S 7.23 Found,%: C 40.74; H $ 4.32
    N 21.90i S 7.16
    285
    CjHijN S - 2HC1 H20
    Calculated,%: C, 31.58;
    H 5.01; N 28.64i S 9.37 ..
    Found,%: C 31.20-, H 5.22-,
    N 27.86i S 8.91
    u) C HjfCCHpN.
    61
    z) (
    61
    aa) morpholino
    45
    68
    BB) Pyrrolidino
    38
    cc) Piperidine
    dd) (CHj) jNH
    Prepared from C, H) j-NH according to the methods of examples 2-5,
    275
    ; j-S 2HC1 - HjO Calculated,%: C 33.71,
    H 5.38i N 27.52 j S 9.00
    Found,%: C 33.92-; H 4.90}
    N 27.45; S 9.19
      2HC1
    275
    Calculated,%: C 37.50; H 5.44; N 27.83 S 9.10.
    Found,%: C 37.37 H 5.41; N 26.43; S 8.80
    270
    . SiV-S 2HC1.
    . Calculated,%: C 36.07; H 4.68 N 26.77} S 8.75.
    Found,%: C 35.97; H 5.06; N 25.95; S 8,62
      2HC1 - 1 / 2H2.0
    280
    Calculated,%: C, 36.77;
    H 5.05; N $ 27.29 S 8.92 Found%: C 37.145,
    H 4.98; N 27.02; S 8.38.
      2HC1. 1 / 2h2.0
    250
    Calculated,%: C 38.61,
    H 5.40i N 26.27; S 8.59; Found: C 38.67;
    H N 26.05; S 8,71
    , S Hbr HC1
    .
    calculated,%: C 44.40 H 5.18; N 20.14; S 5.49.
    Found,%: C 44.00; H 4.97-, N 19.73; S 6.51
    权利要求:
    Claims (2)
    [1]
    , 1. A method for producing 2-guanidi : but-4- (2-substituted amino-4-imidazolyl) thiazoles of the general formula ί
    N. -D.
    where is the group NHR ^ or NR 3 R 4 ;
    - (C <| -C 1e ) -alkyl, (C ^ -Cp-pyr id yl-alkyl or (CjC ^) -phenyl alkyl optionally substituted with chlorine;
    R ^ and R ^ - each independently (C 4 -C fi ) alkyl or taken together with the nitrogen atom * to which they are attached, form a pyrrolidine, piperidine or morpholine ring, or their hydrogen bromide salts, which differs from the fact that, in order to expand the range of imidazolylthiazoles and increase their yield, oxazole of the formula C |. > sn g
    II 0 O is reacted with an excess of the amine of the formula
    H 2 NR 2 or HNRgR ^ where Rj, R 4 , R 2 are as defined above, in water or in a mixture of water and isopropyl; panol at the boiling point of the reaction mixture to obtain a 5-acetylimidazole of formula W sn 3 where R ·) 4 | is indicated above, imidazole of formula 0 is brominated with bromine in concentrated hydrobromic acid at a temperature of 80 ° C with the formation of bromoacetylim-dazole of formula IV
    N D
    CH 2 Br where R, j is indicated above,! And bromoacetylimidazole of the formula ξ * are reacted with a compound of the formula V>
    s
    II ^ NH
    HzN-C-lNH-cf x NH 2 in acetone at the boiling point of the reaction mixture with the isolation of the target product in free form or in the form of crystalline hydrobromic salt.
    [2]
    2. A method of producing acetylimidazole of the formula ΙΪΙ oyV 1 sn 3 where Rj is a group of the formula NHR 2 or _ NR3R4;
    IR 2 (C ^ -C ^ -alkyl, (C4-C d) -pyridylalkyl or (C 7 -C 1o ) -phenylalkyl optionally substituted with chlorine;
    R3 and R 4 are each independently - (C 4 C 6 ) -alkyl, or taken together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, characterized by the fact that the oxazole of formula fj is reacted with excess amine formula
    HjNRj- or HNRgR ^ in water or in a mixture of water and isopropanol at the boiling point of the reaction mixture with the release of the target product.
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    同族专利:
    公开号 | 公开日
    DD209828A5|1984-05-23|
    NO159932B|1988-11-14|
    AU3081584A|1984-11-08|
    ES522223A0|1984-08-16|
    CS318483A2|1987-02-12|
    PL141199B1|1987-07-31|
    EG17029A|1992-06-30|
    AT33649T|1988-05-15|
    PL241840A1|1985-01-16|
    GT198302123A|1984-10-27|
    IE831061L|1983-11-10|
    IL68630D0|1983-09-30|
    NZ204158A|1986-05-09|
    GR79279B|1984-10-22|
    CS252461B2|1987-09-17|
    JPS58206588A|1983-12-01|
    KR840004745A|1984-10-24|
    KR860000931B1|1986-07-19|
    YU42857B|1988-12-31|
    PT76662B|1986-04-16|
    IL68630A|1987-03-31|
    ES8407045A1|1984-08-16|
    ZA833286B|1984-12-24|
    DK205883A|1983-11-11|
    YU99683A|1986-02-28|
    DK163829B|1992-04-06|
    FI831595L|1983-11-11|
    FI831595A0|1983-05-09|
    DK205883D0|1983-05-09|
    AU539244B2|1984-09-20|
    NO831632L|1983-11-11|
    PT76662A|1983-06-01|
    FI78481B|1989-04-28|
    AU1436383A|1983-11-17|
    EP0094191A1|1983-11-16|
    HU196377B|1988-11-28|
    AU566755B2|1987-10-29|
    EP0094191B1|1988-04-20|
    FI78481C|1989-08-10|
    DE3376322D1|1988-05-26|
    NO159932C|1989-02-22|
    US4435396A|1984-03-06|
    IE55229B1|1990-07-04|
    HU190899B|1986-12-28|
    CA1201120A|1986-02-25|
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    US3519637A|1966-12-06|1970-07-07|Hoffmann La Roche|1-nitroimidazole derivatives|
    DE2142585A1|1971-08-20|1973-02-22|Schering Ag|2- BENZIMIDAZOLES|
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    WO1986003203A1|1984-11-22|1986-06-05|Yoshitomi Pharmaceutical Industries, Ltd.|Thienylthiazole derivatives|
    US4814341A|1986-08-26|1989-03-21|Reiter Lawrence A|2-guanidino-4- thiazoles as antiulcer agents|
    ES2031514T3|1986-08-29|1992-12-16|Pfizer Inc.|2-GUANIDINO-4-ARILTIAZOLES FOR THE TREATMENT OF PEPTIC ULCERS.|
    ES2054684T3|1986-10-29|1994-08-16|Pfizer|PROCEDURES FOR THE PREPARATION OF 2--4-THIAZOL AND CRYSTALLINE DIHYDROCHLORIDE OF THE SAME.|
    WO1994028898A1|1993-06-15|1994-12-22|Pfizer Inc.|H2-antagonists as immune stimulants in bacterial infections of cattle or swine|
    AU2009292931B2|2008-09-22|2014-09-11|Cayman Chemical Company, Incorporated|Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases|
    WO2022034121A1|2020-08-11|2022-02-17|Université De Strasbourg|H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/376,486|US4435396A|1982-05-10|1982-05-10|Antiulcer 2-guanidino-4-thiazoles and process therefor|
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