• 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:
    Novel [5(6) (1H-azole-1-ylmethyl)benzimidazole]carbamates having the formula <CHEM> wherein R is C1-6alkyl, C3-6cycloalkyl, thienyl or substituted phenyl; R<1> is C1-6alkyl; R<2> is hydrogen or C1-6alkyl; Q is N or CH; pharmaceutical compositions containing said compounds as active ingredient; methods of preparing said compounds and compositions.
    公开号:SU1706389A3
    申请号:SU894613388
    申请日:1989-02-10
    公开日:1992-01-15
    发明作者:Херман Маргарета Реймакерс Альфонс；Ян Эдгард Фрейн Эдди
    申请人:Жансен Фармасетика Н.В.(Фирма)；
    IPC主号:
    专利说明:

    mo-en / 1a ol and, as antihelminthic drugs.
    The purpose of the invention is the synthesis of new benzimidazole-carbamates using the known method of forming the Penzimidazole cycle, which has a higher anthelmintic activity than the structural analogue of the same purpose.
    The goal is achieved by the proposed method of obtaining compounds of formula I, namely, that the cyclization of benzyldiamine of general formula II is carried out
    .N
    V
    NH,
    RfCH-NH7
    where R2 has the indicated meanings, or an acid addition salt thereof by reacting with isourea or isothiourea of the general formula
    X-CH3
    RS-NH-C-K-.COOR,
    where R, - C (-C6-alkyl;
    R 3 hydrogen or group - COOR ,; X - at ohm S and li 0,
    in an inert solvent medium in the presence of an acid and, if necessary, convert the compound of formula I to an addition salt of a non-toxic therapeutic active acid by treating with this acid or, conversely, converting the acid salt to the free base form by treating with an alkali.
    Preparation of Intermediates
    PRI and e p 1.
    A. To a stirred solution of 20 parts of (α-amino-3-nitrophenyl) - (-fluorophenyl) methanol in 1GS hours, metanols are added 3.8 hours. te ra t hydrobort sodium. The mass is stirred for 3 minutes at room temperature. 12 parts of acetic acid are added and the mixture is stirred for 15 minutes. After evaporation, water is added to the residue. The product is extracted with 2,2-oxy-bispropane. The extract is dried, filtered, and evaporated to give 20 parts (99%) -amino-alpha - (- fluorophenyl) 3 nitrobenzenemethanol as evaporation residue (intermediate compound 1) B. To a stirred solution of 2P parts of C-amino-epf-C4-fluorophenyl) -3c
    five
    0
    five
    0
    35 0
    45 50 55
    nitrobenzylmethane, dispersions of sodium hydride and 135 parts of tetrahydro) uranium are added 16 parts of 1,1 -carbonylbis- (1H-imidazole). The mass is stirred and refluxed for 2 hours. The solvent is removed. Water is added to the residue. The oil layer was separated, dissolved in dichloromethane, dried, filtered and evaporated. The residue is crystallized from a mixture of 65 parts of dichloromethane and 45 parts of benzene. The residue is filtered off and the filtrate is evaporated. The residue is purified on a chromatographic silica gel column using a mixture of ethyl acetate and methanol (90: 1 and vol.) As eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 52 parts of dichloromethane and 51 parts of benzene. The product is filtered off and dried, yielding 5.1 parts of (21, /.%) k- ((4-fluorophenyl) - (1H-imidazol-1-yl) -methyl) -2-nitrobenzenamine; m.p. , ° C (intermediate compound 2).
    B. A mixture of 6.2 parts of - ((1-fluorophenyl) - (1H-imidazol-1-yl) -methyl) -2-nitrobenzolamine, 1-, 4-thio-Oen solution in methanol and 200 hours Methanol is hydrogenated under atmospheric pressure and at room temperature in the presence of 2 parts of catalyst with 5% llatin-on-charcoal. After a calculated amount of hydrogen was added, the catalyst was filtered off and the filtrate was evaporated to give 5.5 m. K - ((- fluorophenyl) - (1H-imidazol-1 -yl) -methyl) -1,2-benzyldiamine in as residue (intermediate compound h).
    Similarly, k - ((1H-imidazol-1-yl) phenylmethyl) -1, 2t benzenediamine as a residue was obtained (intermediate compound O; A- ((1H-imidazole-1-) - (2-thienyl) ) -methyl) -1, 2-benzene-diamine as residue (intermediate 5); - ((3-lorofen) - (1H-imide of zolyl-1) -methyl) -1, 2-benzenediamine as residue (intermediate compound 6).
    Getting targeted compounds.
    PRI mme R 2. A solution of 8.3 h. K-. ((3 Chlorophenyl) - (1H-imidazolyl-1) -methyl) -1, 2-benzenediamine and, 8 parts of methyl- (iminomethoxymethyl) -carbamate in a mixture of 150 parts of trichloromethane and 10 parts of acetic acid are stirred for three days at reflux temperature. After lapping to room temperature, the reaction mixture is poured onto crushed ice. The whole mass is neutralized with ammonium hydroxide. The organic layer is dried, filtered and evaporated. The residue is purified chromatographically on a column of silica gel using a mixture of dichloromethane and methanol (9B: 2 vol.) As eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propacone and 1,1-oxybisethane. The resulting product is filtered off and dried to give 2.9 parts of (28.7) methyl- (5 - ((3-chlorophenyl) - (1H-imidazol-1) methyl) -1H-benzimidazolyl-2-) -carbamate, t .pl. 168.5 ° C (compound 1).
    Similarly receive: methyl- (5 ((1H-imidazolyl-1) -phenyl) -methyl) -1H-benzimidazolyl-2 -) - carbemate, so pl. 7.86, P ° C; methyl- (5 ((1H-imidazolyl-1) - (2-thienyl) -methyl) -1H-benzimide zolyl-2) carbamate, mp. 19.7 ° C (compound 3); methyl- (5 ((- fluorophenyl) - (lH-imidazolyl-1 -) - methyl) -1H-bsnimimidazolyl-2) carbamate, m.p. 211.1 C (compound M; methyl 5- (1 - (1H-imidazolyl-1) -butyl) -1H-benzimidazolyl-2-) carbemate, mp. 230, C (compound 5 methyl- (5 ((- phtopc Ј nyl) - (2-methyl-1 H - im id and sols l) -1 -) methyl} -1 H-benzim dazolyl-2) -carbamate , mp. (Compound 6); methyl-5 ((- fluorophenyl) - (-methyl-1H-imidazolyl-1) -methyl) -1H-benzimidazolyl-2) -carbamate, mp. , E ° C (compound 7); methyl- (5- (C "- fluorophenyl) - (5-methyl-1H-imidazolyl-1) -methyl or -1H-benzimidazolyl-2) -carbamate, mp. 300 C, decomp. (compound 8); methyl- (5- ((-fluorophenyl) - (1H-1, 2, -tri azolyl-1) -methyl) -1H-benzimidazol-1-yl) -carbamate, so pl. 250, P ° C (compound 9) and methyl- (5 (cyclopropyl) - (1H-imidazol-1-yl) -methyl) -1H-benzimidazole 2-yl) carbamate, mp. 217.8 ° C (compound 10).
    PRI me R 3. A mixture of 5 parts methyl- (5 - ((- fluorophenyl) - (1H-imidazol-1-yl) methyl) -1H-benzimidazol-2-yl) carbamate 10 parts of hydrochloric solution acids in 2-propanol and 00 hours. 2-propanol is stirred overnight at reflux temperature. After cooling to room temperature, the product is filtered off and dried, yielding 5.6 parts (87.1 $) methyl- (5
    0
    five
    0
    five
    YU
    15
    40
    15
    50
    five
    i (1 -lt 1rfenn l) - (1 I -, 1st g,: 1 -yl) -mo-tyl) -1H-G-neimidazol-2-yl) mat chac-r in lire hydrochloride hydrate m.p. PPi, (compound 2).
    Example. A mixture of 5.6 and. - (FluoroOenyl) (1H-imide sol-1-yl) -methyl-J 1, 2-benzenediamine with a 3-methyl-methyl (iminomethoxymethyl) carbamate, 12J parts of trichloromethane and 5 parts of acetic acid are mixed for 7 hours at reflux temperature. Then the reaction mixture is evaporated. The residue is dissolved in water and treated with ammonium hydroxide solution. The precipitated product is filtered off, washed with methyl benzene and 2,2-oxy-bis-propane and dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The organic solution is dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column using first a mixture of trichloromethane and methanol in a volume ratio of 90: 10, then a mixture of ethyl acetate, methanol and ammonia-saturated methanol (90: 5: 5 by volume) and finally mixtures of trichloromethane, methanol and saturated ammonia methanol (90: 5: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethyl acetate. The product is filtered and dried, the floor is 1, 1 hour (yield 1 5, C%) methyl 5 - (- Fluoro-Phenyl. (1 H-them and sol-1-and l-methyl) -1 H- benzimidazol-2-yl) -carbzmata with so pl. 21 1.1 ° C (compound M.
    Pr im p 5. A. A mixture of 6h. L- (1H-imidazol-1-yl) (2-thienyl) -methyl - 1, L-benol diamine hydrochloride with 3, part of (iminometoxymethyl) -carbamate, 12C of trichloromethane and 6 parts of acetic acid are stirred for 76 hours at reflux temperature. Then the reaction mixture is evaporated. The residue is dissolved in water and treated with concentrated ammonium hydroxide solution. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified on a silica gel chromatography column using a mixture of trichloromethane and methanol in a volume ratio of 90:10 as eluent. The second fraction is collected and the eluent is evaporated from it. The residue is crystallized from 56 parts of methanol. The product is filtered and dried,
    halftime t, 6 p. (yield / 2,6-) methyl-F5 (1H-imidl sol-1-yl) (2-thienyl) -methyl, -1 2-6eH3HMHf, a3on-2-k J -kchrblmata with so-called Heb, 7 ° Ј.
    B. A mixture of 5 parts of methyl 5 - ((-fluorophenyl) / 1H-imidazol-1-yl / -methyl) -1H-benzimidazol-2-yl / -carbamate (compound 0 from 7.8 parts 2 -propanol, saturated with hydrochloric acid, and 395 parts of 2-propanone are stirred overnight at reflux temperature. After cooling, the product is filtered and dried, yielding 5.6 hours (yield 91) methyl- / 5- ( A-fluorophenyl (1H-imidazol-1 -yl) -methyl) -1H-benzimilazol-2-yl / -carbamate dihydrochloride hemihydrate with mp 280, C.
    Biological examples. PRI me R 1. The test on rats artificially infected with Hymenolepis diminuta.
    Hyrnenolepis diminuta eggs are harvested from adult tapeworms in rats by macerating pregnant proglottids on moistened filter paper. The Fri-boliura confusum fly bug is bred as an intermediate host for H. di.mi.nuta. After the six-day fasting of the bugs, they are placed on filter paper to feed them on the egg of the tapeworm. 17 days after eating, the infected bugs were euthanized and macerated to collect ciscerceroid (blister) larvae from the abdominal cavity.
    Young rats are infected orally, giving them 10 ciscercoids. The larvae developed into adult worms in 2 weeks. Prior to a single dose of a compound of formula T, rats are collected from feces samples to ensure that they are infected.
    9 days after oral administration, the compounds of the formula I of the rats are opened to count the worms. The effectiveness of the drug is assessed.
    the number of worms in the rats that received the medicine, with the number of worms in the rats from the control lot that did not receive the medicine.
    For example, compounds 2 and U show 100% parasite damage at a dose of 20 mg / kg.
    EXAMPLE 5 - Test on dogs artificially infected with Taenia pisiformis.
    0
    5 0 5
    Q
    Proglottids of Taenia pisiforrais are harvested from feces of infected dogs. After maceration and washing in running water, the eggs are collected by passing a suspension of proglottids through a sieve with 53 µm holes. Count the number of eggs and ck. 1000 eggs are given to young rabbits.
    After 5 weeks, rabbits are infected with Cysticericum pisiformis in the abdominal cavity. After the rabbits are opened, cysticerci is harvested and orally given in the form of gelatin capsules to young hound breed dogs. Dose: 15 cysticersi.
    Two months after artificial infection, the dogs are put in isolated cages with a wire floor to ascertain their infection with tapeworms by testing feces.
    After a single dose of the compounds of the formula I by these dogs, feces are collected every four days. Decreased proglottids and skoko-facies. 7 days after the oral administration of the compounds of the formula I, the dogs are opened and the effectiveness of the compounds is determined based on the presence (or absence) of scolites in the intestine.
    For example, compounds 3 and show parasite damage when used at a dose of 2.5 mg / kg.
    Comparative data presented below show a stronger effect of the proposed compounds against tapeworms, in particular Hymenolepsis, in experiments on rats and more valuable - on dogs.
    The compounds of the invention are low toxic and are administered to the rat at doses of 0 mg / kg. No lethality is observed for compounds 1-5. Thus, the LDgp value for these compounds turned out to be significantly higher than 0 mg / kg of live weight.
    Comparative biological data.
    Hymenolepisdiminutay artificially infected rats. The two proposed compounds 2 and k are compared with two well-known widely used antihelminthic drugs, mebene dazole and flubendazole in accordance with Example 1.
    1OP percent effect achieved using a single dose, mg / kg
    Known About
    At least V 16 °
    O-C-UONll-C-O-CH,
    O mi least
    K C-CX M1K-0-CH1M6P
    - / N 5
    20
    Offered
    d
    V NH 9
    , CH-OS NS- ° CHS
    ™ --a
    2.5
    ,, / NIIC 0-C1I, N O
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 5 (6) - (1H-azol-1-yl-methyl) -benzimidazolecarbamate of General formula I
    tf "
    v NH-C-0-R,
    I'm about
    Taenia pisiformis in artificially infected dogs.
    The proposed compounds 3 are also compared with anthelmintic mebeidazole and slubenezole in accordance with Example 5.
    35
    1 00% effect achieved after two doses for five times a day, JQ mg / kg
    Famous About - NH
    I
    O-c-kX N -c-o-CH3
    xn 9
    FO-C-OC -C-0SI,
    ten
    100% effect achieved using single phase, mg / kg
    where R is —C — C — alkyl;
    R is phenyl, fluorophenyl or thienyl, and the 1H-aol-1-yl methyl part of the molecule is in the 5 or 6 position of the benzimidazole ring,
    or their salts of the addition of pharmaceutically acceptable acids, characterized in that it is the cyclization of benzyldiamine of the general formula II-VT
    II
    five
    0
    five
    where R2 has the indicated values. or an acid addition salt thereof by reaction with isourea or isothiourea of the general formula
    X - СН - I R 3 - Ш - С N - COOR
    where R is C-C-alkyl; .
    R is hydrogen or a group is COOR,
    X - S or O,
    in an inert solvent medium in the presence of an acid and, if necessary, convert the compound of the total (Jurmula I to the non-toxic therapeutically active acid addition salt by treating with this acid or, conversely, convert the acid salt to the free base form by alkali treatment.
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    同族专利:
    公开号 | 公开日
    NO890579D0|1989-02-10|
    CN1036014A|1989-10-04|
    NZ227801A|1990-10-26|
    EP0328203A3|1990-03-14|
    NO890579L|1989-08-14|
    EP0328203A2|1989-08-16|
    DK64089D0|1989-02-10|
    DK64089A|1989-08-13|
    FI890654A|1989-08-13|
    PT89659A|1989-10-04|
    NO172438C|1993-07-21|
    MA21493A1|1989-10-01|
    AU605406B2|1991-01-10|
    FI890654A0|1989-02-10|
    JPH01228986A|1989-09-12|
    AU2966589A|1989-08-17|
    PT89659B|1994-02-28|
    IL89249A|1993-03-15|
    US4826862A|1989-05-02|
    TNSN89015A1|1991-02-04|
    PH27056A|1993-02-01|
    NO172438B|1993-04-13|
    IL89249D0|1989-09-10|
    MY104979A|1994-07-30|
    ZA891079B|1990-10-31|
    CN1022245C|1993-09-29|
    引用文献:
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    US3969526A|1973-05-29|1976-07-13|Smithkline Corporation|Anthelmintic 5-heterocycliothio and oxy-2-carbalkoxyaminobenzimidazles|
    US4512998A|1980-10-20|1985-04-23|Schering Corporation|Anthelmintic benzimidazole carbamates|
    NZ221729A|1986-09-15|1989-07-27|Janssen Pharmaceutica Nv|Imidazolyl methyl-substituted benzimidazole derivatives and pharmaceutical compositions|US4943574A|1987-06-01|1990-07-24|Janssen Pharmaceutica N.V.| substituted benzotriazole derivatives and pharmaceutical compositions containing them|
    US5039677A|1987-06-01|1991-08-13|Janssen Pharmaceutica N.V.|6--1--1H benzotriazoles|
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    PH31175A|1990-10-31|1998-03-20|Squibb & Sons Inc|Indole and benzimi-dazole-substituted imidazole and benzimidazole derivatives.|
    US5374615A|1990-10-31|1994-12-20|E. R. Squibb & Sons, Inc.|Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives|
    GB9115272D0|1991-07-15|1991-08-28|Pfizer Ltd|Benzimidazole anthelmintics|
    GB9115273D0|1991-07-15|1991-08-28|Pfizer Ltd|Benzimidazole anthelmintics|
    DE4142731A1|1991-12-21|1993-06-24|Hoechst Ag|BIOCIDAL POLYMERISATES AND POLYMERISATE DISPERSIONS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE|
    GB9205368D0|1992-03-12|1992-04-22|Pfizer Ltd|Benzimidozole anthelmintic agents|
    US5278181A|1992-05-12|1994-01-11|Board Of Regents Acting On Behalf Of The University Of Michigan|Soluble alkyl[5-[amino methyl]-1H-benzimidazol-2-yl] carbamate anthelmintics|
    US20040170735A2|2002-04-05|2004-09-02|Mcneil-Ppc, Inc.|Methods and compositions for altering the sweetness delivery profile of sucralose|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US07/155,464|US4826862A|1988-02-12|1988-02-12|Anthelminthic [ benzimidazole]carbamates|
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