• 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:
    The invention relates to heterocyclic compounds, in particular to the preparation of thieno-1,2-ti-azole derivatives of the formula MY, where M is a compound of the formula r -SOax cl C iJkpX N Ugdeel of the formula -OHjCHjCOOF, R is a hydrogen atom or a lower al- and a fragment of X T means a group of qx which have pharmacological properties. The goal is to develop a method for obtaining new compounds. They are synthesized from a compound of the formula MH, where M is as indicated above, translated into its alkaline salt by treatment with a hydride, hydroxide or alkali metal alcoholate. The resulting alkaline salt is reacted with a 3-halopropionic acid lower alkyl ester of the formula Hal, where R is lower alkyl and Hal is a halogen atom, preferably R, is ethyl or tert-butyl and Hal is C1, Br, in an anhydrous di - methylformamide, dimethyl sulfoxide or dimethylacetamide at 95-110 ° C. The target product is isolated, where R is lower alkyl, or the target product, where R is tert-butyl, is heated in a medium of benzene, toluene or xylene in the presence of a catalytic amount of p-toluene, benzene or methane sulfonic acid to the boiling point the reaction mixture and the desired product is isolated, where R is a hydrogen atom. 1 hp f-ly, 1 tab. § ABOUT)
    公开号:SU1424738A3
    申请号:SU864027699
    申请日:1986-06-27
    公开日:1988-09-15
    发明作者:Биндер Дитер
    申请人:Хеми Линц Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method obtained1: new chemical compounds-Hi-tfl, namely, thieno-1,2-β-thiazole derivatives, which have pharmacological properties and can be used in medicine.
    The aim of the invention is to obtain novel thieno-1,2-thiazole derivatives having biological activity.
    The following examples illustrate the invention.
    Example 1. 10.0 g (0.053 mol of thieno- (2,3-d) -1.2-thiazol-3 (2H) -on--1,1-dioxide are suspended in 100 ml of dry dimethylformamide, mixed with 2.5A g (0.053 mol) washed with benzol 50% sodium hydride slurry, dissolved, constantly stirring, at 7G ° C for 10 min, cooled to 30 ° C, mixed with 12.16 g (0.058 mol of complex 1.1- 3-bromopropionic acid dimethyl ethyl ester and heated for 3 hours to 100 ° C. After that, evaporated in vacuo, the residue is distributed between NaHCO 3 solution and CH 4 Cl, the organic phase is separated, dried with and evaporated. of 1,1-dimethylethyl 2,3-dihydro-W-Oak sotieno- (2,3-d) -1,2-thiazole-propionate 1,1-dioxide can Vat recrystallized from diisopropyl ether.
    Yield: 11 g (65.5%); m.p. (diiso propyl ether): 66-6.7 ° C; colorless crystals.
    PRI mme R 2. 10.0 g (0.053 mol thieno (3.2-6) -1,2-thiazole-3 (2H) -one -1 -1-dioxide suspension is carried out in 100 mp of dry dimethyl sulfoxide , processing, as in example 1, for 4 h at 95 ° C.
    The yield of 1,1-dimestetyl-2,3-dihydro-3-oxo-thieno- (3,2-y) -1,2-thiazole-propionate-1,1-dioxide is 67%. M.p. (diisopropyl ether): 72-74 C.
    Example 3. South (0.053 mol) thieno- (3,4-d) -1,2-thiazole-3 (2H) -on--1,1-dioxide is suspended in 100 ml of dry dimethylacetamide and treated as indicated in the example 1 for 3 h at 110 ° C.
    The yield of 1,1-dimethylethyl 2,3-dihydro-3-oxo-thieno- (3,4-b) -1,2-thiazole-propionate-1,1-dioxide is 62%. M.p. (diisopropyl ether): 94-95 s.
    PRI me R 4. 10 g (0.045 mol) 2-chlorothieno (3,2-d) -1,2-thiazol-3 (2H) - -one-1,1-dioxide is reacted with 10.03 g (0,048 mol) of the complex 1,1-dimethylethyl ester of 3-bromopropionic acid, as indicated in example 1.
    The yield of 1,1-dimethylstil-5-chloro-2,3-dihydro-3-oxo-thieno- (3,2-e) -1,2-thiazole-propionate-1,1-dioxide is 60%. M.p.
    (diisopropyl ether): 115-116 ° C.
    I
    Example 5. South (0.053 mol) thieno- (2,3-d) -1,2-thiazol-3- (2H) -one is mixed with a solution of 2.12 g (0.053 mol) of sodium hydroxide in 150 ml of water and stirred until the precipitate is almost completely dissolved. A minor amount of undissolved particles is filtered off. By evaporation of water in vacuum, a dry residue is obtained - an alkaline salt, which is finely dispersed and dried to a constant weight in high vacuum. After that, the salt is suspended in 100 ml of dry dimethylformamide, dissolved at 80 ° C while stirring, cooled to 30 ° C, mixed with 7.92 g (0.058 mol) of 3-chloropropionic acid ethyl ester and heated for 4 hours and 15 minutes to.
    Further processing is carried out in the same way as in gigrimer 1.
    Ethyl 2,3-dihydro-3-oxo-thieno- (2,3-d) -1,2-thiazole-propionate--1,1-dioxide is obtained in 65% yield, mp, (diisopropyl ether ): 62-63 C,
    Example 6. South (0.053 mol) thieno (3,2-a) -1,2-thiazol-3 (2H) -one is mixed with a solution of 3.61 g (0.053 mol) of sodium ethylate in 120 ml of dry ethanol and Drink until a clear solution is obtained. By drying the solvent in vacuo a dry residue is obtained. The sodium salt thus obtained is finely dispersed, dried to a constant weight, then suspended in 100 ml of dry dimethylformamide, dissolved, stirring, at, cooled to 30 ° C, and mixed with 10.49 g (0.058 mol) of ethyl ester 3- bromopropionic acid. For complete conversion, the mixture is heated to 100 ° C for 3 hours. Further processing is carried out as in Example 1,
    Ethyl 2,3-dihydro-3-oxo-thieno- (3, 2 -d) -1,2-thiazol-propionate-1, 1-dioxide is obtained in 60% yield. M.p. (diieopropyl ether): 95-9b C,
    Example. The south (0.053 mol) thieno- (3,4-e) -1,2-thiazole-3 (2H) -one -1,1-dioxide is suspended in 100% dry dimethylacetamide, as in example 1, is treated with sodium hydride and within 2 hours 40 minutes, at 100 ° C., they are reacted with 10.49 g (0.058 mol) of 3-bromopropionic acid ethyl ester.
    Ethyl 2,3-dihydro-3-oxo-THeHo- (3,4-d) -1,2-thiazole-propionate -1.1-dioxide is obtained. Yield 65%. M.p. (di-isopropyl ether): SW-YuU S.
    Example 10.8 g of 1,1-dimethyl-ethyl-2,3-dihydro-3-oxo-thieno- (2,3-y) -1,2-thiazole-propionate-1,1-dioxide is dissolved in 110 ml of dry toluene and 113 mg of p-toluenesulfonic acid are added. The reaction mixture is heated for 90 minutes using reverse flow. After cooling, colorless crystals consisting of 2,3-dihydro-3-oxo-thieno- (2,3-d) -1,2-thiazole-propionic acid 1,1-dioxide are sucked off and recrystallized from ethanol.
    Yield: 79%. M.p. 133-135 s.
    Example9. In example 8, 1,1-dimethylethyl 2,3-dihydro-3-oxo-thieno- (3,2-d) -1, 2-thiazole-propionate -1.1-dioxide is heated in 120 ml and 5-llor-2 is obtained. , 3-leagues, fo-oxy-thieno- (3,2-d) -1,2-thiazole-propionic acid-1,1-dioxide. Yield 85%. M.p. (ethanol): 195-197 s.
    Experiments on animals have shown that compounds of the formula I contribute to a significant reduction in the level of cholesterol and triglyceride in the blood. Fortunately, the ability to reduce lipids can be used for treatment and prophylaxis, diseases in humans caused by high cholesterol and / or triglycerides in the blood 15 (cardiovascular diseases, thrombosis, atherosclerosis, myocardial infarction, as well as angina).
    The properties of the compounds of formula I are confirmed by laboratory tests, 20 in animal experiments, and in mammals, such as guinea pigs, mice, rats, cats, dogs or monkeys. The compounds can be administered enterally or parenterally 25 and, in the treatment of humans, orally.
    The following tests, in particular, were used to study the lipid-lowering properties of the compounds of formula I.
    The test substances were suspended in freshly prepared 1% carboxymethylcellulose and injected intraperitoneally into MbmiaM males (strain: OF 1, Switzerland, SPF, the weight at the beginning of the test was about 25 g) having
    When using benzene, using a 35 ° ° reverse access to a standard diet and
    flow.
    2,3-Dihydro-3-oxothie-Ho- (3,2-d) -1,2-thiazole-propionic acid 1,1-dioxide is obtained. Yield 85%. M.p. (water): 1AO-142 ° C.
    Example 10. 10.8 g of 1,1-dimethylethyl 2,3-dihydro-3-oxo-thieno- (3,4- -d) -1,2-thiazole-propionate-1,1-dioxide is dissolved in 100 ml of dry toluene and 110 mg of benzosulphate are added. The reaction mixture is heated for 95 minutes using a reverse flow. 2,3-Dihydro-3-oxo-thieno- (3,4-d) -1,2-thiazole-propionic acid-1,1-dioxd is obtained. The yield is 78%. M.p. (water): 173-176 C.
    Example 11. 8. g 1,1-dimethyl-ETSH1 5-chloro-2,3-dihydro-3-oxothio- Ho- (3,2-d) -1,2-thiazol-propionate-1,1 - - The dioxide is dissolved in 90 ml of dry xylene and 95 mg of methanesulfonic acid is added. The reaction mixture is heated to 115 ° C. with stirring for 105 minutes.
    5-lloro-2, 3-leagues, pho-ox-thiosieno (3,2-d) -1,2-thiazole-propionic acid-1,1-dioxide is obtained. Yield 85%. M.p. (ethanol): 195-197 s.
    Animal studies have shown that compounds of formula I contribute to a significant reduction in blood cholesterol and triglyceride levels. Due to the property of reducing lipids, these compounds can be used for the treatment and prophylaxis of diseases in humans caused by blood cholesterol and / or blood triglycerides (cardiovascular diseases, thrombosis, atherosclerosis, myocardial infarction, as well as stenocardi).
    The properties of the compounds of formula I are confirmed by laboratory tests, in animal experiments, of mammals such as guinea pigs, mice, rats, cats, dogs, or monkeys. The compounds can be administered enterally or parenterally, and in the treatment of humans, orally.
    The following tests, in particular, were used to study the lipid-lowering properties of the compounds of formula I.
    The test substances were suspended in freshly prepared 1% carboxymethylcellulose and injected intraperitoneally to MbmiaM males (strain: OF 1, Switzerland, SPF, the weight at the beginning of the test was about 25 g)
    drinking water once a day in the same doses (20 mg / kg with a constant volume of 10 ml / kg) for 14 days. The control group received only 10 cells / kg of 1% carboxymethylcellulose;
    4 hours after the last intake of the test substances or carboxymethylcellu oza of animals in the control
    Five groups were killed by bleeding through Aorta carotis. EDTA (ethylenediaminetetraacetic acid) plasma was used to determine the level of blood lipids in experimental animals.
    Q Methods of analysis.
    Cholesterol was determined both by the classic fy (Liberman-Burchard staining) and by the full enzymatic method (Tselekhrom cholesterine; test system: Cheniie Linz AG, diagnostics; Linz, Austria). Triglycerides were determined according to the fully enzymatic method (triglycerides of iodonitrotetrazolineunislets P1, test system: Chemie Linz AG, diagnosis} Linz, Austria).
    In tests, compounds of general formula I showed strong low-reducing properties. Hanpm tep, 2, 3-dihydro-3-oxothieno- (3, A-d) -1,2-thiazole-propionic acid-1-1 dioxide at a dose of 20 mg / kg i, p. a 9.2% reduction in cholesterol and a 7.8% reduction in thieno-1,2-thiazole of the general formula I triglyceride level in the blood are observed in comparison with the control group of animals.
    Compounds of general formula I can be used as therapeutic agents, for example pharmaceutical preparations, js which contain them in mixture with pharmaceuticals suitable for enteral or parenteral administration, organic or inorganic inert auxiliary and / or carrier materials, for example pharmaceutically suitable solvents, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, poly (25) alkylene glycols, petroleum jelly, and the like.
    Pharmaceutical preparations can be prepared in solid form, for example, in tablets, dragees, suppositories, capsules, as well as in the form of solutions of suspension or emulsions. If necessary, these drugs are sterilized, additives are added (preservatives, stabilizers or emulsifiers), salts to change the osmotic pressure, as well as other therapeutic agent compounds, which are of low toxicity making them promising in the creation of drugs used in medicine.
    权利要求:
    Claims (1)
    [1]
    Claim 1. Method for producing derivatives
    And jT Y-SNGNGSOOK,
    II Oh
    where R, is hydrogen or lower alkyl fragment means a group of general formula II a, II b or II in a responsible manner
    Wed: - Wasp
    where R is hydrogen or chlorine, characterized by the general formula III
    ,
    Oss /
    I
    about
    what
    where is a fragment of meaning
    about:
    has specified
    alkaline hydride.
    sol guide
    translated into it by processing
    An oxide of alkali metal or an alkali metal alcoholate formed by an alkaline salt of a compound of general formula III is reacted with a complex 3-halopropionic alkyl ester.
    action
    The compounds of the formula I are classified as low toxic. For example,
    50
    Ruddle compound of Example 10 LD
    but 1000-2000 mg / kg, i.e. this substance
    practically non-toxic.
    thieno-1,2-thiazole of general formula I
    The low toxicity of these compounds makes them promising for the development of drugs used in medicine.
    Claim 1. Method for producing derivatives
    thieno-1,2-thiazole of general formula I
    compound
    And jT Y-SNGNGSOOK,
    II Oh
    where R, is hydrogen or lower alkyl fragment means a group of general formula II a, II b or II c, respectively
    Wed: - Wasp
    compound
    where R is hydrogen or chlorine, characterized by the general formula III
    ,
    Oss /
    I
    about
    what
    where is a fragment of meaning
    about:
    has indicated
    alkaline hydride.
    salt is converted to it by treatment
    oxide or alkali metal alcoholate, the resulting alkali salt of a compound of the general formula III is reacted with a lower alkyl ester of 3-halopropionic acid of the general formula IV
    Hal CHjCH COOR ,, where R is lower alkyl; Hal is a halogen.
    in anhydrous dimethylformamide.
    For the study of acute toxic g-dimethyl sulfoxide or dimethyl cetti-1,1-dioxvd 2,3-dihydro-3-oxo-amide,
    Eno- (3,4-d) -1,2-thiazole-propionic acid was given to three mgamy-males of the genus NUMA, / YARE intraperitoneally in five dosages, its solution in 1% carboxymethylcellulose solution. Con50
    the product, where R is lower alkyl, or the target product, where R "is tert-butyl, is heated in benzene, toluene or xylene in the presence of a catalytic amount of p-toluene, benzene or methanesulfonic acid to the boiling point of the reaction mixture and target product is isolated, where R, is hydrogen.
    the floor group has only a solution of carboxymethylcellulose. Observation- led for seven days.
    The results are presented in the table.
    Thus, the proposed method allows obtaining new pharmacological properties of chemicals.
    five
    the product, where R is lower alkyl, or the target product, where R "is tert-butyl, is heated in benzene, toluene or xylene in the presence of a catalytic amount of p-toluene, benzene or methanesulfonic acid to the boiling point of the reaction mixture and target product is isolated, where R, is hydrogen.
    2, Pop.1 method, I distinguish. - y and i with g that take the compound of General formula IV, where R is ethyl or tert-butyl, Hal - chlorine or bromine.
    Data on the study of the acute toxicity of 2,3-dihydro-3-oxo-thieno- (3, A-d) -1,2-thiazolpropionic acid 1,1-dioxide
    Dose, mg / kg
    About (control)
    100
    500
    1000
    2000
    4,000
    Editor A.Makovska
    Compiled by Z. Latypova
    Tehred M.Didyk Proofreader A.Obruchar
    Order 4701/59
    Circulation 370
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    eight
    Fatalities per group (3 animals)
    after 24 h after 7 days
    h g
    0/3 0/3 0/3 0/3 3/3 3/3
    Subscription
    类似技术:
    公开号 | 公开日 | 专利标题
    FI75347B|1988-02-29|FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT VAERDEFULLA FURO- | -PYRIDINDERIVAT.
    CS241015B2|1986-03-13|Method of 2-benzyl-1,2-dihydro-1-oxophthalazine-4-ylacetic acid's derivatives production
    EP0269295A1|1988-06-01|Therapeutic agents
    SU1424738A3|1988-09-15|Method of producing derivatives of tieno-1,2-thiazole
    EP0074628B1|1986-05-28|Ascochlorin derivatives; process for preparing the same and pharmaceutical composition containing the same
    US3553234A|1971-01-05|Dibenzo|dioxocin-6-carboxylic acids, esters and salts
    CN110612288A|2019-12-24|Substituted imidazole salt compound, preparation method thereof, medicinal composition and application thereof
    EP0102175A1|1984-03-07|5-Oxo-5H-|benzopyrano|pyridine derivatives, their production and use
    PL105940B1|1979-11-30|METHOD OF MANUFACTURING NEW 2,6-DIMETHYL-3-METHOXYCARBONYLO-4- / 2'-NITROPHENYL / -1,4-DIHYDROPYRIDINE-5-CARBOXYLIC ACID ISOBUTYL ESTER
    US3894033A|1975-07-08|5-Aryltetrazoles
    PL110887B1|1980-08-30|Method of manufacture of novel 4-substituted 3-sulfamoyl-5-pyrrolylalkylbenzoic acids
    EP0034263B1|1984-09-26|Substituted benzonitriles and compositions for inhibiting viruses
    US4067873A|1978-01-10|Certain 1-amino-3-|oxy-2-propanol derivatives
    US3467676A|1969-09-16|5-hydroxy-2,2,7-trialkylchroman-4-ones and derivatives
    EP0175005A1|1986-03-26|5,6,7-Quinoline carbamates
    CA1300135C|1992-05-05|Substituted quinoxalines
    US3828073A|1974-08-06|4-hydroxy-2h-1-benzothiopyran-3-carboxamides and their corresponding s-oxides
    US3801578A|1974-04-02|7-|-propyl)-theophylline-2-|-isobutyrate
    US3346568A|1967-10-10|2-amino-5-sulfamyl-benzoic acid hydrazides
    US4076712A|1978-02-28|Derivatives of pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9|-one
    US4122083A|1978-10-24|1,2,3,4-Tetrahydropyrido[4',3':4.5]thiazolo-[3,2-a]benzimidazoles
    CA1296334C|1992-02-25|Substituted pyrimidoquinoxalines
    US4105791A|1978-08-08|Hypolipidemic cycloalkylaminobenzoic acids
    EP0197533B1|1991-08-14|Dioxolobenzisoxazole derivatives and process for preparing the same
    CS256395B2|1988-04-15|Method of n-substituted aziridine-2-carboxylic acid's derivatives preparation
    同族专利:
    公开号 | 公开日
    AT62489T|1991-04-15|
    EP0213295B1|1991-04-10|
    DD251557A5|1987-11-18|
    DK316486D0|1986-07-03|
    AU5945586A|1987-01-08|
    HUT41803A|1987-05-28|
    US4801591A|1989-01-31|
    NO862541D0|1986-06-24|
    CS465186A2|1988-03-15|
    FI862513A|1987-01-05|
    DE3678645D1|1991-05-16|
    EP0213295A1|1987-03-11|
    NZ216730A|1989-01-06|
    NO862541L|1987-01-05|
    FI862513A0|1986-06-12|
    ZA864765B|1987-02-25|
    AU586485B2|1989-07-13|
    ES2000458A6|1988-03-01|
    HU194254B|1988-01-28|
    JPS6210091A|1987-01-19|
    KR870001220A|1987-03-12|
    DK316486A|1987-01-05|
    CS259888B2|1988-11-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2957883A|1957-10-09|1960-10-25|Merck & Co Inc|Sulfamyl derivatives of certain saccharins and process|
    JPS4514897Y1|1965-09-08|1970-06-23|
    JPS47346U|1971-01-16|1972-08-01|
    BE793779A|1972-06-20|1973-05-02|Central Glass Co Ltd|PROCESS AND APPARATUS FOR CUTTING A FILM INTO PIECES TO BE INSERTED BETWEEN SHEETS OF GLASS OF A LAMINATE|
    DE2534689C3|1974-09-16|1979-10-18|Basf Ag, 6700 Ludwigshafen|
    JPS5441885Y2|1975-08-02|1979-12-06|
    JPS555765Y2|1976-07-03|1980-02-09|
    JPS569482B2|1976-09-06|1981-03-02|
    AT364852B|1977-11-05|1981-11-25|Thomae Gmbh Dr K|METHOD FOR PRODUCING CONDENSED ISOTHIAZOL-3 -ON-1,1-DIOXIDES AND THEIR SALTS|
    JPS54141104U|1978-03-24|1979-10-01|
    DK169255B1|1983-02-22|1994-09-26|American Home Prod|Analogous Process for the preparation of thieno-isothiazole-1,1-dioxide derivatives and pharmaceutically acceptable salts thereof|
    DE3242477A1|1982-11-18|1984-05-24|Basf Ag, 6700 Ludwigshafen|HETEROCYCLICALLY SUBSTITUTED NITRILES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS|
    JPS6166456U|1984-10-05|1986-05-07|ATA39088A|1988-02-18|1990-06-15|Binder Dieter Dr|BASICALLY SUBSTITUTED THIENOISOTHIAZOL-3-ON-1,1-DIOXIDES AND THEIR PHARMACEUTICALLY COMPATIBLE SALTS, METHOD FOR THE PRODUCTION AND THEIR USE|
    AT390060B|1988-05-02|1990-03-12|Cl Pharma|METHOD FOR PRODUCING 5-CHLORINE-3CHLORESULFONYL-2-THIOPHENICARBONIC ACID ESTERS|
    JP2525531Y2|1989-09-05|1997-02-12|京セラ株式会社|Output voltage limiting circuit|
    CN101186612B|2006-11-15|2012-10-03|天津和美生物技术有限公司|Pyrroline derivative capable of inhibiting cell to release tumor necrotic factor and its preparation and application|
    WO2009084501A1|2007-12-27|2009-07-09|Asahi Kasei Pharma Corporation|Sultam derivative|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    AT198885|1985-07-04|
    [返回顶部]