• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Compounds corresponding to the general formula I <CHEM> wherein: - R and R1, that may be different, represent a hydrogen atom, a halogen, an alkyl group, an alkoxy radical in which the alkyl group contains one to four carbon atoms, a nitro group, a cyano group, an amino group, an acetamino group, a sulfamidic or N-substituted sulfamidic group; R2 represents a hydrogen atom, a halogen, an alkoxy radical, an alkyl group, a phenyl group, a phenylalkyl group, in which the alkylen radical contains two to four carbon atoms, a nitro group, a cyano group, an amino group, an acetamino group, an N-substituted sulfamidic group; and R3 represents a hydrogen atom, an alkyl group, preferably containing one to three carbon atoms or a cyano group, are useful as antifungal and antibacterial agents.
    公开号:SU1600630A3
    申请号:SU874203231
    申请日:1987-08-12
    公开日:1990-10-15
    发明作者:Пестеллини Витторио；Гелардони Марио；Джаннотти Алессандро Джолитти Данило；Барзанти Адриано；Кьяппи Россела；Ортолани Карло
    申请人:А.Менарини Индастрие Фармасеитеке Риуните С.Р.П. (Фирма)；
    IPC主号:
    专利说明:

    05
    oo
    The invention relates to new compounds - (benzofuran-2-yl) -inazoles with antifungal and antibacterial activity that can be used in medicine.
    The purpose of the invention is new imidazole derivatives having both antibacterial and antifungal activity.
    The invention is illustrated by the following Examples.
    Example 1c, The hydrochloride is (5-. -Bromobenzofuran-2-yl) phenylmethyl J-1H-imide 3ol.
    28.1 g (5-bromobenzofuran-2-yl) phenylmethyl chloride in 200 ml of dioxane is added dropwise to 11.9 g of imidazole in 250 ml of dioxane at the temperature of reflux distillation and with strong stirring while maintaining the mixture at the temperature of reflux distillation. 5 h, then the mixture is cooled, filters
    they are washed and the mother water is evaporated to dryness. The residue is taken up again in ethyl ether, washed with first 2% sodium hydroxide solution and then with water; from ether solutions, the compound is extracted with a 5% hydrochloric acid solution, and then alkalinized with 5% sodium hydroxide, to give an oil, which is extracted with ethyl ether. The ether extract is dried, dried and brought to dryness to give a solid which is crystallized from isopropanol. That pl. 123-12А С „
    The product is dissolved in ethyl acetate, then gaseous HC1 is liberated; , dav51 precipitate, t „pl 173-174 С
    (acetone)"
    Example 2-hydrochloride i-L (5- -chlorobenzofuran-2-yl) - (o-chlorophenyl) -4methyl} -1I-imidazole. To 0.2 mol of imidazole in 200 ml of dioxane, 0.07 mol of I5-chlorobenzofuran-2-yl) - (o-chlorophenyl) methyl chloride in 1 O ml of dioxane is slowly added with stirring at the boiling point; After a period of 5 hours, the mixture is cooled, filtered, and the mother liquors are dried: under vacuum conditions. The oil thus obtained is extracted with ethyl ether, washed with 2% sodium hydroxide solution, water, and then extracted with 5% HCl solution. Alkalization with 5% sodium hydroxide gives a precipitate, which is extracted with ether, and the solution is pressed with gaseous HC1, the precipitate thus obtained is crystallized from acetone, mp. 1/8180 ° C.
    By dissolving the hydrochloride in water and by alkalizing, an oil is obtained which is extracted with ethyl ether, the solution is dehydrated, brought to dryness, and the base of the x-cris is lysed from hexane, t. 70-80 ° C
    (decomposed).
    Example 3c 1-G (benzofuran-2-yl) phenylmethyl-1H-imidazolo hydrochloride
    To 0.08 mol of imidazole in 70 ml of acetonitrile was added
    0.22 mol of thionyl chloride followed by holding for 1 h, and then 0.02 mol of (benzofuran-2-yl) phenylmethanol in 20 ml of acenitrile is added. The reaction mixture is maintained for 24 hours at a temperature of
    0
    five
    20
    25
    thirty
    35
    40
    45
    50
    55
    environment and then concentrated to dryness. The residue is extracted into ethyl ether, taken first with sodium hydrate solution and then with water; The hydrochloride is prepared from ethereal solutions using 5% hydrochloric acid, then an oil is obtained by alkalinization with 5% sodium hydroxide, which is extracted with ethyl ether. The ether extract is dried, dehydrated and treated with gaseous HC1, the precipitate thus obtained is crystallized from isopropanol, m.p. 205–207 ° С (decomposed).
    Example 4. (5-Bromobenzofuran-2-yl) - (p-chlorophenyl) methyl chloride.
    To 36.2 g of (5-bromobenzofuran-2-yl) - - (p-chlorophenyl) methanol dissolved in 50 ml of methylene chloride, 8.6 ml of thionyl chloride in 25 ml of cyclohexane is added dropwise with stirring. After allowing to stand for 4 hours, the solution is brought to dryness under vacuum. The residue is crystallized from petroleum ether, t pLo 8385 С o
    Example 5. (5,7-Dichlorobenzofuran-2-yl) - (p-chlorophenyl) methyl chloride ..
    to o, 35 mol of thionyl chloride in 300 ml of cyclohexane is added in portions of 0.31 mol (5,7-dichlorobenzofuran-2- -yl) - (p-chlorophenyl) carbinol, followed by 3 hours by stirring at ambient temperature, then the solution is concentrated , filtered and crystallized from cyclohexane, mp 72-74 ° C.
    Example 6, (5-Chloro Zenzofuran-2-yl) (2-chlorophenyl).
    1 g (65 mmol) of 5-chlorosalicylaldehyde is added to a solution containing 2.6 g (65 mmol) of NaOH in 75 ml of anhydrous ethanol. 9.4 g (65 mmol) of 2-chloro-B-bromoacetophenone are slowly added to the solution at temperature with about its displacement. The reaction mixture is heated under reflux for 8 hours, cooled, and the precipitate formed is collected by filtration. The solid is washed with ethanol, water, and dried in a drying cabinet. The yield is 62%, t, pl. 75-77 s.
    (5-Chlorobenzofura-2-yl) - (2-chlorophenyl) meth col „
    51600630
    The ketoi obtained earlier is dissolved in 50 ml of dioxane, followed by its reduction with 1.5 g (AO mmol) of NaBHi, at a lower temperature. The resulting solution was stirred for 6 hours, evaporated to a volume of 1/3 and diluted with water. The separated oil was extracted with ethyl ether, washed with water and dried over anhydrous magnesium sulfate. After evaporation, the residue was recrystallized from hexane in 89% yield , t. plo 90-91 C.
    (5-Chlorobenzofuran-2-yl) - (2-chlorophenyl) methyl chloride.
    A solution containing 10.4 g (3 mmol) (5-chlorobenzofuran-2-yl) - (2-chlorophenyl) methanol in 80 ml of chloroform is treated dropwise at room temperature with 3 ml (40 mmol) of SOCli. Then, the resulting solution is heated to 40 ° C for 1 hour, and after distilling off the excess of SOCl / g at vacuum together with the solvent, an oil is obtained, which is used in the next stage without further purification.
    1 - 1. (5-Chlorobenzofuran-2-yl) - (2-chlorophenyl) methyl, imidazole „
    7.5 g (110 mol) of imidazole is dissolved in 100 ml of boiling dioxane, and then 36 mmol (5-chlorobenzofuran-2-yl) - (2-chlorophenyl) methyl chloride, dissolved in 20 ml of dioxane, is slowly added. After boiling the reaction mixture for 5 hours under reflux, the solution is cooled, filtered and evaporated in vacuo. The resulting oil is taken up in ethyl ether, washed with water and extracted with a 2% HC1 solution. After basing the solution with 5% NaOH, a precipitate is obtained, which is extracted again with ethyl ether, followed by extracting HC1 gas. The precipitate obtained is filtered, dried over and crystallized from acetone (mp 178-180 ° C). TLC: chloroform / ethyl acetate, 4/1, Rf 0.45. The resulting hydrochloride is dissolved in water. Received free base when interacting
    ten
    f5
    20
    25
    thirty
    35
    40
    45
    to
    m m
    t h to
    d
    50
    is ism
    re price re 55 ko mr pi
    with NaHCOj, extract the prostapch with ether, dry and evaporate. The precipitate is crystallized from hexane, yield 45%, so pl. 78-80 ° (;. Elemental analysis for C, H, N.
    The target compounds are listed in Table. one.
    0
    five
    0
    five
    0
    five
    0
    five
    The melting points of these compounds are defined in open: capillaries, their values are uncorrected. IR spectra recorded on. spectrophotometer Parkin Elmer FT 1710 in the Nujol phase. H-NMR spectra were recorded on a Hitachi-Parkin Elmer R24 instrument, using trimethylsilane as the B1 standard. Elemental analysis was performed by the analytical 1-1M branch of the company Manarini Farmac ethical, which is within, 4% of the calculated values.
    Results.
    Biological test data
    In vitro tests.
    In vitro studies were carried out on 10 benzofuran-B imidazole derivatives of formula (I) to determine their antifungal activity against 70 strains of fungi by comparative analysis with 3 known imidazoles and the effect of griseofulvin on dermatophytes only.
    Very high inhibitory activity against dermatophytes was demonstrated by 5 of the indicated compounds of formula (I).
    Other hyphomycetes and yeasts showed a more noticeable variation in their susceptibility. However, the susceptibility of some isolates from Candida and other yeasts has been noted.
    It is known that imidazole derivatives have a broad spectrum of anti-mycotic action both in vitro and in vivo.
    For comparison, econazole, clotrimazole, bifonazole and griseofulvin were also tested against dermaphytes only.
    Experiments were performed in vitro. The yeast was agar dilution, while for
    50
    tests on the sensitivity of the test compounds to the fungal mold used broth dilution techniques ..
    All tested compounds were dissolved in DMSO at an initial concentration of 2560 µg / ml. The serial dilution method was used to determine the minimum inhibitory concentration 55 (MIC), in which, compared to the control compounds, no macroscopic fungicidal development was observed.
    71
    70 pathogenic and opportunistic strains, including AO yeast species, 20 dermatophytes and 10 hyphomycetes, were tested. Fungicidal strains were cultures isolated at the last stage of the disease or obtained from the laboratory collection of cultures.
    Yeast blastoconidia were obtained from an 18-hour culture at 37 ° C on Saburo dextrose agar, followed by suspending them in sterile saline and dispensing to a titer of I l cells, / ml. The first test was performed on modified Saburo agar (2% neo-peptone with 1 % gga-cose) at pH 6.5. The obtained data were calculated after incubation, for 18 hours at. Modified Saburo agar at pH 7 was used for the second test. Other parameters did not change.
    When using the agar dilution technique, serial dilutions of each BeniecTB test were prepared at a dose of 128-0.03 mcg / ml in 10 ml of sterile saline. Then, 2 ml of each dilution was taken and mixed with 18 ml of sterile modified agar Saburo, in the molten state, and then the resulting mixture was poured into Petri tongs. To each batch with different concentrations of the preparation in question, a cup with the same medium was added, but without the test substance, as a control. Each series of cups of each test substance was inoculated with a nail point inoculum.
    Dermatophyte inoculum was scraped off, observing asepsis, from a 7-day culture on Saburo's dextr agar, then suspended in sterile saline diluted to a final inoculum with a titer of 1-10 cells / ml. The test was performed in myocoflora broth at pH 7 , 0. 7-10 days after incubation at 30 ° C, the obtained data was calculated
    Other hyphomycetes were grown on Saburo agar for 72 h, and then harvested in sterile saline. The resulting suspension was adjusted to a titer of about 1 x 10 cells / ml.
    006308
    The test was performed in broth with mycoflora (pH 7.0).
    When using the dilution method in broth, serial dilutions of the tested substances were prepared.
    by two-fold dilution. The final concentration ranged from 128 to 0.03 µg / ml o. The indicated series, together with the control group containing no test drugs, were incubated at 37 ° C for 3-7 hours with the developmental characteristics
    fS
    20
    25
    thirty
    35
    0
    five
    0
    five
    According to these strains.
    Results.
    Yeast-.
    The data summarized in table. 2, obtained from the first series of experiments on Candida albleans at pH 6.5. Other types of yeast also showed a susceptibility to all 13 substances, except for derivatives 7, 8 and 9, which showed good activity against Crytococus neoformans. Unsatisfactory results forced the test conditions to be modified by raising the pH to 7.
    The obtained data of the second series of experiments on droyuk are presented in detail in Table 3 and 4 regarding C. albicans and other types of yeast, respectively. In tab. 5 shows the interval of the minimum inhibitory concentration (MIC), 50% MIC and 90% MIC for 26 strains of C. albicans.
    Some of these strains exhibit a high resistance to all of the tested drugs, including those from the controls shown by strain No. 2 of C. albi cans. Other isolates exhibited a range of relatively high sensitivity that strains 3, B5.19 / 11.23 / 12.26 / 13.29 / 15, 30/16, 31 / 17.34 / 20.35 / 21.38 / showed. 24, some of which were more susceptible to benzofuran imidazole No. 9 than at least one of the known imidazoles (strains No. 3, B5 19/11, 35/21).
    Other types of yeast showed significant variations in their susceptibility to the tested substances. In essence, the inhibitory ability of clotrimazole, econazole and bifanozole appears to be higher than that of benzofuran imidazoles. HP theme
    less significant is the activity of compounds nos. 2.8 and 9 on strain 24 C. pseudotropicalis. Compound No. 9 showed the highest activity against Torulopsis glabrata and Phodotarula species.
    The antimycotic activity of all tested drugs increased with an increase in pH from 6.5 to 7.0, which concerns Cr. neoformans, on the contrary, the highest results were obtained with a lower pH value of 6.5. Under these conditions, Cr. neoformans inhibited 0.5 µg / ml of Compound 9 and 1 µg / ml of Compounds 7 and 8, the data obtained showed similar nsto or higher activity compared with the results obtained using econazole, clothrymazole and bifonazole (Table 6 ).
    Dermatophytes.
    The results of these experiments are presented in Table. 7 and 8 “As can be seen from the data table. 7, the active drug itself is econazole, and all strains were inhibited with the indicated drug at a concentration of 0.25 µg / ml. The kenzofuran imidazoles were found to be highly active against
    dermatophytes, even if it is possible to observe a greater scatter of MIC values.
    For each compound, limit values of MIC for deformatites were calculated, which are listed in Table. 8o
    Almost all of the tested microorganisms showed a high susceptibility to compounds of 2.7.8, 10, and 9.
    The activity of these substances was similar to clotrimazole and higher than bifonazole and griseofulvin. Among the tested dermatophytes, the most sensitive species were Erichophyton rubnim, T. mentagrophytes, T. verrucosum, and Epidermophyton floccosum. The genus Microsporum, as it turned out, showed less similar sensitivity to clotrimazole, bifonazole, and griseofulvin, as well as the above indicated benzofura- nium imidazoles. The two isolated cultures from Microsporura canis were more sensitive to compounds 2.7.8 and 10 compared with clotrimazole, bifonazole, griseofulvin and compound 9. One of the isolates

     .
    ten
    15
    .
    0063010
    M, gypseum, which exhibited high resistance to bifonazole (MPTC-128 µg / ml), was inhibited by 5 benzofuran imidazoles (2.7.8.9 and 10) at low concentrations. Compound 9 activity against two strains M The audouinii was the same as that of econazole, clotrimazole or griseofulvin, and higher compared to other benzofuran imidazoles and bifonazole.
    Other types of fungi.
    These species included probiotic or conditionally pathogenic strains of the genus Aspergillus, Penicillium, J Geotrichmn, Trichoderma, and Aureobasidium. Their sensitivity to benzofukrovymi imidazoles is given in Table. 9. Compared with the lime antifungal substances included in this study, the activity of compounds 7,8,9 and 10 against Penicillium and, mainly, against Aspergillus / Geotrichum candidbm and Trichoderma viride is excellent, the most highly sensitive species of this group. However, one strain from G. candidum shows moderate susceptibility to compound 9.
    Discussion.
    Analysis of in vitro results obtained in this study20
    25
    thirty
    five
    0
    five
    0
    five
    It shows that benzofuran imidazoles exhibit a wide range of action and have a good inhibitory ability against many fungal pathogenic microorganisms, including yeast, dermatophytes and other monomorphic hyphomycetes.
    Similar to many other imidazole derivatives, their antimycotic action has been found to be significantly influenced by the test conditions, especially the pH of the cultured medium. However, most of the new drugs on offer demonstrate a wide range of their deist-VIA on families of the genus Candida; albicans species have been found to be more sensitive than non-albicans species. When testing compounds against pathogenic yeasts, such as Tonilopsis glabrata and Phodotorula, compound 9 was more active than clrtrimazole, econazole
    scrap and bifonazole. In addition, this compound showed the highest inhibitory activity relative to Cryptococcus in the first test at pH 6.5.
    It has been found that benzofuran imidazoles exhibit the highest inhibitory activity against dermatophytes. Their activity against dermatophytes in most cases was the same or higher than that of econazole and clotrimazole, and was mainly superior to activity than that of - Zeofulvina.
    Compounds 2,7,4,0,8 and 9 showed a strong effect on the most frequently encountered pathogenic microorganisms of this group gr. mentagrophytes, T. rubrum, M. canis, E, floccosms even when M, canis, as established, exhibits low sensitivity to compound 9.
    The susceptibility of monomorphic hyphomycetes, except for dermatophytes, to benzofuran imidazoles is relatively low.
    A moderate sensitivity to the indicated imidazoles of the species Aspergillus and Penicillium is noted.
     Since the in vitro activity of any antifungal drug cannot accurately reflect its potential therapeutic effect, most of the compounds of formula (I) should be selected for subsequent studies to evaluate the effectiveness of their biological properties about
    Table 10 lists the antibacterial activity of compounds of formula (I).
    The compound of formula (I) DLjj OS in the mouse was 500-1000 mg / kg (body weight, in the mouse ddt bifonazole and clotrimazole are 2629 mg / kg,
    Antibacterial activity.
    The experiments were performed in vitro (in a flask, in a test tube) by determining the minimum inhibitory concentrations (MIC) using the agar and broth dilution method.
    The results of this study were: 377 bacterial strains of clinical origin were obtained, of which 256 were gram-positive and 121 gram-negative.
    All tested substances were diluted in DMSO at an initial concentration of 2560 µg / ml. To implement
    00630.12
    The experiments were performed using the following dilutions obtained by doubling, µg / ml: 128.6A; 32; 16.8; BUT; 2; 1.0; 0.5; 0.25; 0.12; 0.06; 0.03. 5 Cultural environments.
    The following culture media were used: Muller-Hinton agar for enterobacteria, Pseudomonas, staphylococcus and Bacillus cereus; Rogoca agar for Lactobacillus; Todd-Hevitta for d-hemolytic streptococcus and enterococcus; liquid yew, glycollate for Trichomonas.
    Grafting material.
    ten
    15
    20
    25
    thirty
    35
    The 18-hour cultures at 37 ° C were diluted in sterile saline to a concentration in the order of 10 kloons / ml.
    Results.
    The results of the experiments, expressed in the MIC-range (μg / ml), are given in Table 10, the comparison was carried out with econazole, clotrimazole and bifonazole.
    Vyshody.
    From a study of the results obtained, it can be seen that the antibacterial activity of the imidazole derivatives of formula (I) as a whole is comparable with the antibacterial activity of zconazole and clotrimazole, and the complete absence of bifonazole activity.
    The results of biological tests show that compounds 2,7,8,9 and 10 are the most active, their LD "(through the mouth in mice) is
    The value of W gy 900 700 800 800. 750
    Connections 2 7 8 9
    ten
    权利要求:
    Claims (1)
    [1]
    Compounds are promising for use in medicine, the Invention Formula
    (Benzofuran-2-yl) -imidazoles of the general formula Ri-P-snX
    , Vv ™
    five
    where is rj. R,
    Nor R j - 2-C1; 5-C1 and R 2 - H; 5-Br and R. - H; 5-C1 and R - 2-C1
    or
    - 5.7-0. and R N,
    having antifungal and antibacterial activity.
    15
    60063С16
    Continued table. 2
    IngiSITN activity 13benone imidazoles
    Table 3
    Inhibitory activity of 10 benzofuran imidazoles against C. albicans MIC, mg / ml
    Inhibitory activity of 10 benzofuran imidazoles against Cryptococcus neoformans at 2 pH values
    Table 5
    Table
    160063024
    Table 8
    The boundary values of the activity of 10 benzofuran imidazoles against dermatophytes
    Antifungal drugs
    0.25.2
    Oo 25
    About about 25 about 128. Оо25 "16
    0.25-16 0.25.16
    Os25o4
    0.25.4
    0.25-16
    0.25-8 Oo25 „2
    0.25.2 0.25-8
    0.25 "4
    MIC, mg / ml
    类似技术:
    公开号 | 公开日 | 专利标题
    Ezabadi et al.2008|Sulfonamide-1, 2, 4-triazole derivatives as antifungal and antibacterial agents: Synthesis, biological evaluation, lipophilicity, and conformational studies
    US4328348A|1982-05-04|Novel benzylimidazole derivatives
    SU1600630A3|1990-10-15|-imidazols displaying bactericidal and fungicidal activity
    Mancuso et al.2017|Synthesis and antibacterial activity of polymerizable acryloyloxyalkyltriethyl ammonium salts
    Swetha et al.2019|Synthesis, characterization and antimicrobial evaluation of ferrocene–oxime ether benzyl 1 H-1, 2, 3-triazole hybrids
    Jafari et al.2017|Synthesis and antimicrobial evaluation of some 2, 5 disubstituted 1, 3, 4-oxadiazole derivatives
    FI85701B|1992-02-14|FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA TRIAZOLDERIVAT.
    Castellano et al.2003|Synthesis and antimicrobial properties of 3-aryl-1-|-2-| propanes as ‘carba-analogues’ of the N-arylmethyl-N-[|-4-ylmethyl])-1H-imidazol-1-amines, a new class of antifungal agents
    Vani et al.2021|Microwave assisted synthesis and antimicrobial and antioxidant activities of dimers of 1, 2, 3-triazole-benzofuran bearing alkyl spacer derivatives
    Li et al.2014|Synthesis and antibacterial activities of yanglingmycin analogues
    Reddy et al.2010|Synthesis, nematicidal and antimicrobial activity of 3-|-4-oxo-1, 3-thiazolan-3-yl]-1, 3, 4-thiadiazol-2-ylbenzo [b] furan-5-yl) methyl] benzo [b] furan-7-yl-1, 3, 4-thiadiazol-2-yl)-2-|-1, 3-thiazolan-4-one
    CN107056687B|2020-06-30|Pyridine group-containing 1, 4-pentadiene-3-ketoxime ester compound, preparation method and application
    US5460814A|1995-10-24|Fermentation broth and microorganisms which produce them
    FI89595C|1993-10-25|FREQUENCY REQUIREMENT FOR THERAPEUTIC ACTIVATION OF ACTIVE 2- | EECL-1H-IMIDAZOLDERIVAT
    Abdel-Hafez et al.2011|Synthesis of selenium-containing amino acid analogues and their biological study
    Abdel-Moty et al.2014|Synthesis and biological evaluation of some novel 1, 2, 3-Triazole-N-Arylidene Acetohydrazine incorporating Benzimidazole ring moiety as potential antimicrobial agents
    Siddiqui et al.2010|Synthesis, characterization and antimicrobial evaluation of some new 1, 3-thiazole-2, 4-diamine derivatives
    CN108440414B|2021-07-09|Pyrazolone amide antifungal drug and preparation method and application thereof
    Sharma et al.2013|Synthesis and Microbial Activity of some new Furfural Acrylamides
    CN107382988B|2020-10-09|2-substituted sulfenyl-5- | -1,3, 4-oxadiazole compound and application thereof
    KR100232859B1|1999-12-01|Novel amino acid amide derivatives
    CN104059011B|2016-06-29|A kind of substituted azole derivatives and its preparation method and application
    CN106234385B|2018-11-13|A kind of application of 1,2,4- triazole derivatives of the structure containing benzopyrazines as fungicide
    CHAUDHARY et al.2019|Synthesis and investigation of anthelmintic, antibacterial and antifungal activity of 3, 3-diphenyl propanamide derivatives
    KR100232856B1|1999-12-01|Novel amino acid amide derivatives
    同族专利:
    公开号 | 公开日
    AT56008T|1990-09-15|
    PL267298A1|1988-12-08|
    US4800208A|1989-01-24|
    DK418187D0|1987-08-11|
    YU150787A|1988-10-31|
    EP0257171B1|1990-08-29|
    CS597887A2|1990-03-14|
    DK166917B1|1993-08-02|
    HUT46910A|1988-12-28|
    DK418187A|1988-02-14|
    DD270305A5|1989-07-26|
    IT1216256B|1990-02-22|
    ES2037011T3|1993-06-16|
    NO873383D0|1987-08-12|
    YU46222B|1993-05-28|
    NO170085C|1992-09-09|
    PT85491B|1990-06-29|
    EP0257171A1|1988-03-02|
    HU202864B|1991-04-29|
    PL149009B1|1989-12-30|
    IT8609461D0|1986-08-13|
    JPS6372687A|1988-04-02|
    AR243181A1|1993-07-30|
    IE872153L|1988-02-13|
    ZA875908B|1988-02-12|
    AU604042B2|1990-12-06|
    AU7679987A|1988-02-18|
    DE3673822D1|1990-10-04|
    IE61019B1|1994-09-07|
    GR3000903T3|1991-12-10|
    PT85491A|1987-09-01|
    CA1325212C|1993-12-14|
    CS272226B2|1991-01-15|
    NO873383L|1988-02-15|
    NO170085B|1992-06-01|
    MX7723A|1993-12-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BR6915465D0|1969-03-07|1973-01-04|Bayer Ag|PROCESS TO PREPARE SUBSTITUTED N-BENZIMIDAZOLES IN THE ALPHA POSITION BY PENTA-MEMBER HETEROCYCLES WITH ANTIMYCOTIC ACTIVITY|
    DE2009020C3|1970-02-26|1979-09-13|Bayer Ag, 5090 Leverkusen|Process for the preparation of N- -methylazoles|
    US3928348A|1970-03-23|1975-12-23|Bayer Ag|N-methyl-imidazole derivatives and their production|
    IT1154888B|1980-11-12|1987-01-21|Menarini Sas|2-SUBSTITUTED BENZOFURAN DERIVATIVES AND RELATED METHODS OF PREPARATION|
    DE3049542A1|1980-12-31|1982-07-29|Basf Ag, 6700 Ludwigshafen|AZOLYLALKYL-2,3-DIHYDROBENZOFURANE, FUNGICIDES CONTAINING THEM AND METHOD FOR THE PRODUCTION THEREOF|
    ZA825413B|1981-08-26|1983-06-29|Pfizer|Thromboxane synthetase inhibitors, processes for their production, and pharmaceutical compositions comprising them|
    FI842502A|1983-06-27|1984-12-28|Ciba Geigy Ag|FRAMEWORK FOR FRAMSTAELLNING AV NYA 2-SUBSTITUERADE BENSOFURAN DERIVAT.|
    DE3413363A1|1984-04-09|1985-10-17|Merz + Co GmbH & Co, 6000 Frankfurt|Benzofuran-2-ylethylimidazole derivatives, process for their preparation, and pharmaceuticals|GB9212833D0|1992-06-17|1992-07-29|Glaxo Group Ltd|Chemical compounds|
    EP0574992A1|1992-06-17|1993-12-22|Glaxo Group Limited|5--3H-isobenzofuran-1-one derivatives, their preparation and use as aromatase inhibitors|
    US5426196A|1993-12-22|1995-06-20|Glaxo Inc.|Synthesis of diaryl methanes|
    IT1286866B1|1996-10-28|1998-07-17|Menarini Farma Ind|FURANO-HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND USE AS AROMATASE INHIBITORS|
    US6503935B1|1998-08-07|2003-01-07|Abbott Laboratories|Imidazoles and related compounds as α1A agonists|
    GB0223915D0|2002-10-15|2002-11-20|Univ Cardiff|Benzofuran derivatives formulations and uses thereof|
    EP2019691B1|2006-05-15|2020-08-12|Massachusetts Institute of Technology|Polymers for functional particles|
    MX2010003642A|2007-10-12|2010-08-09|Massachusetts Inst Technology|Vaccine nanotechnology.|
    US7762049B2|2008-12-31|2010-07-27|Black & Decker Inc.|Electric mower having two-motion activation system|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT8609461A|IT1216256B|1986-08-13|1986-08-13| IMIDAZOLI, WITH PHARMACOLOGICAL ACTIVITY, THEIR SALTS AND RELATED MANUFACTURING PROCEDURES.|
    [返回顶部]