• 专利附录
  • 专利说明
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    • 专利摘要:
    The invention relates to imidazolium salts which are effective in lowering blood glucose levels in mammals. In particular, there is provided a compound of formula (I) which is useful in lowering blood glucose levels: …<CHEM>… in which:… R<1> is C1-C4 alkyl;… R<2> and R<3>, independently, are hydrogen or C1-C4 alkyl;… each R<4>, independently is, -OR<5>, -NR<6>R<7>, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, or C1-C4 alkylthio; ……R<5> is hydrogen or -@-R<8>; ……R<6> is hydrogen, C1-C4 alkyl, or -@-R<8>;… R<7> is hydrogen or C1-C4 alkyl;… each R<8>, independently, is C1-C4 alkyl or phenyl;… Z is oxygen or sulfur;… X is a therapeutically acceptable anion; and… m is 0, 1 or 2.
    公开号:SU1424733A3
    申请号:SU853972626
    申请日:1985-11-11
    公开日:1988-09-15
    发明作者:Джеймс Доминиани Самуэль；Т.Т.Йен Теренс
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

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    The invention relates to a process for the preparation of new salts of imidazole, which can be used for the treatment of diabetes.
    The purpose of the invention is to obtain new salts of imidazole, which, unlike the structural analogue, have a hypoglycemic effect.
    Example 1. 1-Methyl-3-G2- (A-methylphenyl) -2-oxoethyl -1H-imidazol-bromide.
    To a solution of 10.6 g (0.05 mol) of 1-bromo-2- (A-methylphenyl) -2-oxoethane in 150 ml of distillate ether is introduced 4.18 g (0.051 mol) of 1-methyl-imidazole. The reaction mixture is stirred for about 3 hours at room temperature and the precipitated solid is recovered by filtration. The nony4etrHoe hygroscopic solid is recrystallized from methanol-ethyl acetate to obtain 4.82 g of 1-methyl-3-G2- (4-methylphenyl) -2-oxo-ethyl-1H-imidazol bromide as a solid. A second portion of the product is obtained from the filtrate, and the additional yield of this product is 5.8 g.
    Yield 72%, so pl. 148-15GS.
    Calculated,%: C, 52.90; H 5.12; N 9.49.
    C ,,, H jBrNjO.
    Found,%: C 52.73; H 4.95; N 9.26.
    Example 2, 1-Methyl-3-G2 (-3-methoxyphenyl) -2-oxoethyl -1 H-imidazol bromide.
    A solution of 4.58 g (0.02 mol) of 1-bromo -2- (3-methoxyphenyl) -2-oxoethane in 100 ml of diethyl ether is filtered, the filtrate is treated with 1.82 g (0.022 mol) of 1, -methyl, zazola The resulting reaction mixture is stirred at room temperature for approximately 19 hours, after which the solution is decanted and the precipitate is washed with diethyl ether. This precipitate is dissolved in hot acetonitrile and, after cooling, dark needles precipitate from the solution. The resulting solid is recovered and recrystallized twice from acetonitrile / ethyl acetate, resulting in 2.1 g of 1-methyl-3-2- (3-methoxyphenyl) -2-oxoethyl -1H-imidazol bromide as white needles.
    Yield 34%, so pl. 1b7-17Gs.
    g
    5 0 5 0
    0 5
    five
    0
    five
    Calculated,%: C 50.18; H 4.86; N 9.00; Br 25.68.
    C, ZN, BrN, Oj.
    Found,%: C 49.89; H 4.75; N 8.98; Вг 25,56.
    H.M.I. 3. 1-Metsh1-3-G2 (3-ethoxyphenyl) -2-oxoethylJ-1H imidazol-bromide.
    A solution of 2.9 g (0.012 mol) of 1-5throm-2- (3-ethoxyphenyl) -2-oxoethane in 20 ml of acetoyl acetate is mixed with 1, 03 g (0.013 mol) of 1-methylimidazole and the resulting mixture is stirred at room temperature to approximately 18 h. The mixture is diluted with methanol and the volatiles are evaporated under reduced pressure to a volume of about 15%. The solution was diluted with ethyl acetate and the solid brown precipitate was recovered by filtration. The removed solid is washed with ethyl acetate and dissolved in acetonitrile. The mixture is purified with charcoal, and after cooling, the solid is recovered. This solid is recrystallized from acetonitrile / diethyl ether, and two portions are obtained, which are mixed and recrystallized three times. From isopropyl alcohol, D to give 0.27 g of 1-methyl-3-H2- (3-ethoxyphenyl). ) -2-oxoethyl - 1H-imidazol bromide as pale yellow flakes.
    Yield 7%, so pl. 137-138 ° C.,
    Calculated,%: C, 51.71; H 5.27; N 8.61; Br 24.57.
    С Н Н п BrN 0.
    Found,%: C 51, 54; H 5.01; . N 8.40; Br 24.80.
    Example 4. | -Methyl-3- (1,1-dimethyl-2-phenyl-2-oxoethyl) -1H-imidazol bromide.
    A solution of 4.6 g (0.02 mol) with -bromo-isobutyrophenone and 1.8 g (0.022 mol) of 1-methylimidazole in 30 ml of diethyl ether is stirred at room temperature for about 48 hours. The solvent is decanted and the resulting oil is suspended in ethyl acetate . The solvent is decanted again and the residue is dissolved in acetonitrile prior to the introduction of a small amount of ethyl acetate. The resulting white precipitate is recovered by filtration and the crystals are recrystallized from methanol / ethyl acetate, resulting in 3.88 g of 1-methyl-3- (151-dimethyl-2 da in the form of glitter white white flakes.
    Output 63%, so pl. 137-140 ° C.
    Calculated,%: C 54.38; II 5.54; N 9.06; Br 25.84.
    C ,, H ,,.
    Found,%: C 54.25; H 5.82; N 8.87; Br 25.67.
    Example 5. 1-Methyl-3-G2- (4-ethylfeiyl) -2-oxoethyl -1H-imidazol-bromide.
    A solution of 4.41 g (0.019 mol) of 1-bromo 2- (4-ethylphenyl) -2-oxoethane and 1.65 g (0.02 mol) of 1-methylimidazole in 40 ml of diethyl ether is stirred at room temperature for approximately 18 hours The solvent of the reaction mixture is decanted and the precipitate is washed with diethyl ether and dissolved in a small amount of acetonitrile. The resulting solution is diluted with a small amount of ethyl acetate, after which a brown precipitate is formed. The solid is recovered and the lysohydrate is recrystallized from acetonitrile / ethyl-1-acetate, resulting in 2.26 g of 1-methyl-3-.2- (4-ethyl-propyl -2-oxo-ethyl -1H-imidazol bromide in the form of thin yellow brown needles.
    Exit 38%, so pl. 177 -: 79 S.
    Calculated,%: C 54.38; H 5.54; N 9.06; Br 25.54.
    C ,, H ,, Br
    Found,%: C 5.13; H 5.81; N 9.04; Br 26.05.
    Example 6. 1-Methyl-3- 2- (2-methylphenyl) -2-oxoeth1 J-1B-imidazole-bromide.
    A solution of 4.22 g (0.02 mol) of 1-bromo, 2-2-methyl-phenyl-2-oxoethane, 2.64 (0.032 mol) of 1-methyl 1-1-dibasyl and 60m of diethyl ether is stirred at room temperature for about 17 hours. The solvent the reaction mixture is decanted and the precipitate is washed with diethyl ether. This precipitate is dissolved in hot acetonitrile and the resulting solution is cooled and diluted with diethyl ether. The solid product is recovered and recrystallized twice from acetonitrile / diethyl ether to give 1.99 g of 1-methyl-3- 2 - (2-methylphenyl) -2-oxoethyl} -1H-imidazol bromide as white needles.
    Yield 34%, so pl. 152-154 p.
    N 9.49; Br 27.07.
     .
    Found,%: C 52.82; H 5.28; N 9.54; Br 27.14.
    Example 7. 1-Methyl-3- (1-methyl-2-phenyl-2-oxoethyl) -1H-imidazol bromide,
    0 A solution of 8 ml (0.047 mol) of 90% pure 1-phenyl-l-OKCo-2-bromopropane and 4.25 g (0.052 mol) of 1-methylimidazole in 100 ml of diethyl ether are stirred at room temperature. about 24 hours. The precipitated solid is recovered by filtration, washed with diethyl ether and dissolved in methanol. This solution was diluted with Q diethyl ether and the resulting white solid was recovered by filtration. This solid is recrystallized from methanol / simple diethyl ether to give
    7.65 g of 1-methyl-3- (1-methyl-2-phenyl-2-oxo-ethyl) -1H-imidazol bromide as white crystals.
    Yield 55%, so pl. 1b7-170 ° C.
    Calculated,%: C, 52.90; H 5.12;
    0
    N 9.49.
    C, H
    0
    1 15
    Found,%: C 52.73; H 4.95; N 9.26.
    Example 8. 1-Methyl-3-P-methyl-2- (4-methylphenyl) -2-oxoethyl - 1H-imidazol bromide.
    A solution of 2.24 g (0.01 mol) of 1- (4-methylphenyl) -1-oxo-2-bromopropane and 0.9 g (0.011 mol) of 1-methylimidazole in 50 ml of diethyl ether is stirred at room temperature for approximately 18 The solvent of the reaction mixture is decanted and the precipitate is washed with diethyl ether and dissolved in acetonitrile. The resulting solution is diluted with diethyl ether, and the precipitated solid is recovered by means of a filter. This solid was recrystallized from acetonitrile / diethyl ether, and 0.33 g of 1-methyl-3-1-methyl-2- (4-methylphenyl) -2-oxo- / eth11l 1H-imidazolbromide was obtained as a solid. - 5 of this substance.
    Yield 11%, so pl. 175-177 ° C.
    Calculated,%: C 54.38; H 5.54; N 9.06.
    five
    0
    C, N ,,.
    Found,%: C 54.09; H 5.54;
    N 9.17.
    A second portion of the product is obtained from the filtrate, and the additional yield of this product is 0.4 g. T. pl. 174-178 C.
    Example 9. 1-Methyl-3- 2- (2,4 dimethylphenyl) -2-oxoethyl -1H imide-eolbromide,
    A solution of 4.76 g (0.021 mol) of 1-bromo 2- (2,4-dimethylphenyl) -2-oxoethane and 1.76 g (0.021 mol) of 1-methyllimidazole in 50 ml of diethyl ether is stirred at room temperature for about 21 hours. The reaction solvent is decanted. The precipitate is washed with simple diethyl ether. This precipitate is recrystallized from acetonitrile / ethyl acetate. 3.32 g of the expected product are obtained in the form of white crystals.
    Yield 51%, so pl. 179-18GS.
    Calculated,%: C 54.38; H 5.54; N 9.09; Br 25.84.
    C, H,. ,
    Found,%: C 54.18; H 5.46; N 8.86; Br 25.96.
    Example 10. 1-Methyl-3- 2- (3-methylphenyl) -2-oxo-trans-1H-imidazole-bromide.
    A solution of 5.16 g (0.024 mol) of 1-bromo 2- (3-methylphenyl) -2-oxostan and 2.15 (0.026 mol) of 1-methylimidazole in about 30 ml of diethyl ether is stirred at room temperature for about 19 hours. The solvent the reaction mixture is decanted. The obtained brown precipitate is washed with simple diztile ether. This precipitate is washed with hot acetonitrile and recrystallized twice from acetonitrile / diethyl ether, resulting in 1.74 g of 1-methyl-3-2- (3-methylphenyl) -2-oxoethyl -1H-im1Hdazolbromida in the form of white needles.
    Yield 25%, temperature pl. 185-187 C.
    Calculated,%: C, 52.90; H 5.12; N 9.49; Br 27.07.
    C iiH,.
    Found,%: C 53.11; H 5.08; N 9.43; Br 26.96.
    The following examples illustrate additional compounds used in the invention, which give
    4247336
    conventional described method, 1MI.
    11. 1-Methyl-3-G2 Example with (2,5-dimethoxyphenyl) -2-oxo-ethnl J-1H-imidazol bromide, m.p. 207-210 C (with decomposition).
    Calculated,%: C 49.28; H 5.02; N 8.21; Br 23.42. 10 0.4 Hi ,.
    Found,%: C 49.05; H 4.98; N 8.08; Br 23.14.
    Example 12. 1-n-prop 1-3- (2-phenyl-2-oxo-ethyl) -1H-imidazol chloride, 15 tons pl. 143-150 ° C.
    Calculated,%: C 63.51; H 6.47; N 10.58.
    Found,%: C 64.81; H 6.77; 20 N 9.86.
    Examples;) 13. 1-Methyl-3-C2- (2-methoxyphenyl) -2-oxoethyl - 1H-imidazol bromide, t. Rin. 165-167 C.
    Calculated,%: C 50.18; H 4.86; 25 N 9.00; Br 25.68.
    C 1 H, 5BrN202.
    Found,%: C 49.95; H 4.97; N 8.78; Br 25.92.
    Example 14. 1-Methyl-3-C2-30 (3,5-dimethoxyphenyl) -2-oxo-ethyl -1H-imidazol bromide, mp. 239-241 ° С (with decomposition).
    Calculated,%: C 49.28; H 5.02; N 8.21; Br 23.42.
    С14Н „ВГЫ20з.
    Found,%: C 49.33; H 4.98; R 7.97; Br 23.34.
    Example 15. 1-Methyl-3-C2- (4-ethoxyphenyl) -2-oxoethyl -1H-imidazol-bromide, m.p. 143-146 C.
    Calculated,%: C, 51.71; H 5.27; N 8.61; Br 24.57.
    Ci4H nBrNjOt
    Found,%: C 51.49; H 5.39; N 8.42; Br 24.45.
    Example 16. 1-Methyl-3-G2- (3,4-dimethylphene1) -2-oxoethyl 1-1H-imidazolbromide, so pl. 163-165 C.
    Calculated,%: C 54.38; H 5.54; N 9.09; Br 25.84.
    C H BrNiO
    Found,%: C 54.61; H 5.49; N 9.17; Br 25.90.
    Example 17. 1-Methyl-3- 2- (4-methoxyphensh1) -2-oxoethyl-1H-imidazol-bromide, m.p. 156-159 s.
    Calculated,%: C 50.18; H 4.86; N 9.00; Br 25.68.
    Cn, H, jBrNjO35
    40
    45
    50
    Found: C, 49.98; And 5.11; N 8.82; Br 25.95.
    Example. 18. 1-Methyl-3- (2-phenyl-2-oxo-ethyl) -1H-imidazol chloride, t. 104-108 S.
    Calculated ,, C, 60.89; And 5.53; N 11.84; C1 14.98.
    Found,%: C 59.63; And 5.35; N 11.37; C1 14.33,
    Example 19. 1- (1-methyl-ethyl) - (3-methoxypheni.p) -2-oxo-methyl J-1 H imide 3 alba r omide.
    This compound is made when the following procedure exists. A mixed solution of 1- (3-methoxy-phenyl) imidazole (1.08 g) in 20 ml of acetonitrile is treated with 2-bromopropane at room temperature for seven days. The solvent is removed in vacuo and the residual product, which is a brown glassy substance, is stirred by trituration with tetrahydrofuran, and a whitish powder is obtained. After recrystallization from methanol-tetrahydrofuran mixture, the product is obtained as thin white needles with m. 177-179 C (with decomposition).
    Calculated,%: C 53.11; And 5.65; N 8.26.
    With ijH .iBr
    Found,%: C 52.91; And 5.39; N 8.35.
    The process was carried out in this manner to obtain the products of Examples 20 and 21.
    Example 20. 1-Methyl-3-C2 - (3 hydroxyphenyl) -2-oxoethyl -1H-imidazol-4 methylbenzenesulfonate, so pl. 96-98 C (s. Decomposition).
    Calculated,%: C 58.75; And 5.19; N 7.21; S 8.25.
    C HioNcjOsS
    Found,%: C 58.54; H 4.91; N 7.22; S 8.02.
    Example 21 1-Methyl-3- 2- (3-trifluoromethylphenyl) -2-oxo-ethyl-1H-imidazolyodide, m.p. 184-186 C (with decomposition).
    Calculated,%: C 39.41; H 3.05; N 7.07.
    With ijiioi N-iOF
    Found,%: with 39.65; H 3.26; N 7.02.
    The invention encompasses a method of lowering blood glucose in a mammal of C1-1x animals, comprising an effective amount of a new imidazole compound in the body of a mammal. Under
    By the term effective amount is meant the amount of a compound necessary to achieve a hypo tic effect after ingestion of the preparation, preferably into the organism of mammals with diabetes in adulthood.
    These active compounds are effective over a wide range of doses. For example, daily doses range from 0.5 to 500 mg / kg pesa. With
    For adults, the preferred dose limit is about 0.5 to 500 mg / kg body weight and is administered as a single or divided dose. However, the amount of compound actually injected into the body must be determined by the attending physician and this is related to circumstances such as the condition of the patient being treated, the choice of compound to be administered: to the body, age, weight of the patient, reaction of each patient, the severity of the symptom of the patient, the selected method of drug administration
    into the body. Therefore, the limits of this dose do not limit the scope of the invention. Although the compounds of the proposed method are preferably administered orally to reduce the glucose content in the blood of mammals, these compounds can also be administered in various other ways, for example, transdermally, subcutaneously, in the nose, intramuscularly, intravenously.
    The compounds used according to the inventive method act differently from the sulfonylurea and increase insulin resistance. Therefore, the compounds of the proposed method are most suitable for the treatment of type II diabetes, diabetes, manifested in people of a ripe age, since many patients have sufficiently good circulating insulin but are insulin resistant. However, the exact mechanism by which these compounds function is still unknown and the invention is not
    limited by some principle of action.
    The compounds according to the inventive method are administered orally to the patient. Although you can enter connect91424
    not according to izo retenny teploposstpsino without cooking recipes, however, their use is in the form of a pharmaceutical preparation, including pharmaceutically suitable
    Tel, the diluent or excipient compound, from 11 ° 11; its invention. These compositions contain from about 0.1% to about 90% of the compound.
    When formulating compositions according to the inventive method, the active ingredient is usually mixed with a carrier or diluted with a carrier, or coated with a carrier, which may be in the form of capsules, vials, paper wrappers and another form. When the carrier serves as a diluent quality 13, it may be a solid, semi-solid, l-liquid substance that acts as a carrier, excipient, or medium for the active ingredient. Thus, the composition may be in the form of tablets.
    , powders, pellets, vials of capsules, elixirs, emulsions, solutions, sirogg, suspensions, aerosols (both in solid and in liquid medium and soft and hard gelatin capsules,
    Examples of suitable carriers for this purpose, excipients ij, diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphite, gliginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, calcium :: lulose, a syrup, a syllose, a syllable gelatin, syrup, methylcellulose, methyl and propyl oxybenzoates, talc, magnesium stearate, water and mineral oil. These formulations could include wetting agents, emulsifying and suspending agents (preservatives, sweeteners or flavoring agents. Formulations according to the invention can be prepared in a way that provides quick, continuous or replaceable release of the active ingredient after entering the body of the pathogen through the use of already known methods.
    For oral administration to the body, the compound according to the invention can be ideally mixed with carriers and diluents and can be molded into tablets in a gelatin capsule.
    The long-term compositions are preferably from single unit dosage form, and each single dose contains 500 mg, usually
    It lives from about 1 to about 5 to 300 mg of the active ingredient. Under the concept of a unit dose form are meant physically discrete unit drugs, suitable as unitary doses for entry into humans and other mammals, and such each unit drug contains a predetermined amount of active material, calculated in such a way that
    would achieve the desired therapeutic effect when combined with a pharmaceutical carrier,
    The hypoglycemic activity1; The strength of the compounds according to the invention is determined by testing the effectiveness of formulations, including these compounds, under conditions that are not wine for viable yellow diamonds that are obese. The method of testing is described by Hiime.
    Conduct an experiment.
    The test recipes are prepared by dissolving the compound to be tested in a saline solution containing 2% emulsifier (surfactant; a substance that is polyoxyethylated vegetable oil supplied by GAF CORP), so that the dosage form is em 100 mg / kg. Each test formulation is injected into the body of six viable yellow mice that are obese from diabetes by force-feeding. Blood glucose was determined after 0, 2 and 4 hours after the administration of the formulation. We took the average of six trials.
    The data presented in the table. one,
    Some of these compounds have also been shown to be used for the effect against type II diabetes in rats and animals. They are also able to lower the blood glucose content of these animals.
    Comparison of the proposed. Ix compounds with similar by known compounds are given in table. 2
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing imidazole salts is of general formula
    T
    1 1 / 2Д733
    Continuation of table 1
    3 ::: znzi:
    about 100
    283 + 9
    A101 + 11
    O100
    290t5
    A108 + 5
    O100
    278 ± 9
    4103 + 5
    Compound
    Suggested compounds for example
    one
    2 3 4 5 6 7
    9 10 11 12
    Continued table. I
    one
    100
    83 + A
    95 ± D
    100
    79 ± 3
    93 + 7
    100
    74 + 4
    71 + 7
    table 2
    The percentage of glucose in the blood after 2 hours after administration
    2
    80 + 3 63 + 4 66 + 9 84 + 5 77 + 5 93 + 6 70 + 6 75 + 5 77 + 4 78 + 5 78 + 5 79 + 7
    K ssng-s
    N N-CH2-C-4O - HC1
    H3C-N N-CH2-C- Q
    122 + 7
    118 + 4 107 + 8
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    同族专利:
    公开号 | 公开日
    DK164547C|1992-11-30|
    KR880001231B1|1988-07-12|
    IE59093B1|1994-01-12|
    ZA858499B|1987-06-24|
    HU195490B|1988-05-30|
    KR860004029A|1986-06-16|
    NZ214088A|1988-09-29|
    EP0182533B1|1989-09-20|
    DK515285A|1986-05-14|
    PT81439A|1985-12-01|
    JPS61122212A|1986-06-10|
    ES8702370A1|1987-01-01|
    IE852822L|1986-05-13|
    AR244671A1|1993-11-30|
    CA1266673A|1990-03-13|
    DK164547B|1992-07-13|
    EP0182533A2|1986-05-28|
    AU574532B2|1988-07-07|
    PT81439B|1988-03-03|
    GR852707B|1986-03-10|
    US4609670A|1986-09-02|
    EG17707A|1990-08-30|
    CN85108115A|1986-07-30|
    PH21656A|1988-01-13|
    EP0182533A3|1987-06-03|
    CN1013444B|1991-08-07|
    DE3573114D1|1989-10-26|
    JPH0647576B2|1994-06-22|
    ES548797A0|1987-01-01|
    DK515285D0|1985-11-08|
    AT46505T|1989-10-15|
    AU4973785A|1986-05-22|
    HUT39164A|1986-08-28|
    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/670,776|US4609670A|1984-11-13|1984-11-13|Imidazolium hypoglycemic agents|
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