• 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:
    Hydantoin compounds are described, having the following formula wherein Ar is phenyl optionally substituted by up to three radicals selected from the group comprising C1-6 alkoxy, halogen, 1,3-dioxol-2-yl, hydroxy C1-4 alkoxy C1-4 alkyl, phenyl, hydroxyl, nitrile, C1-4 haloalkyl, C1-4 alkyl, C2-4 alkenyloxy, C1-4 alkoxycarbonyl or phenoxy optionally substituted by C1-4 haloalkyl, C1-4 alkoxy or halogen; or is thiophene optionally substituted by phenyl or by one or two C1-4 alkyl groups; R' and R2 are independently hydrogen or taken together represent a chemical bond; R3 is hydrogen, C1-6 alkyl or C2-4 alkenyl; and R4 is C1-6 alkyl, C2-4 alkenyl, phenyl or benzyl; provided that R3 cannot be hydrogen when Ar is unsubstituted phenyl and R4 is n-butyl. The compounds are useful in the prophylactic treatment of asthma in mammals.
    公开号:SU988190A3
    申请号:SU802955865
    申请日:1980-08-13
    公开日:1983-01-07
    发明作者:Боффей Джемиесон Вильям；Джеймс Росс Вильям；Джордж Симмондс Робин；Помфрет Верд Джон
    申请人:Лилли Индастриз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of new hydantoin derivatives of the general AgCHC of R where r is unsubstituted phenyl or mono- or dihalo substituted phenyl, unsubstituted thiophene or thiophene, substituted by phenyl or С С alkyl. alkyl or phenyl, provided that if Agphenyl, then R cannot be H - butyl (which have pharmacological autonomy for the prophylactic treatment of asthma in mammals. There is a known method for preparing 3-substituted gvdantins from alkyl- or arylisocyanates and amino acids 1 The aim of the invention is a method for producing novel hydantoin derivatives of formula 1, which are effective drugs for the prevention of asthma in mammals. The goal is achieved by the described method for producing hydantoin derivatives The general formula 1, which consists in the fact that the amino acid of the general formula ArCHgCHKH where Dg has the indicated values, is reacted with the isopyanate of the general formula RNCO (III), where Ar has the indicated values, with the selection of the target product. for the prophylactic treatment of asthma in mammals. This kind of activity has been shown in guinea pigs using the Thercoheimer test or in marine animals procured for testing lung. The compounds have low toxicity. The test of Turksheimer is based on the allergic bronchospasm caused in guinea pigs, which is near HanoMifflaex asthma in humans. Mediators (mediators) that cause bronchospasm are very similar to those that are released when sensitizing human tissue. the lung is caused by an antigen. Although the anti body in guinea pigs includes -iJqpQ, and in humans, Jc B, both antibodies are homoshtotrophic and bind strongly to tissue. The resulting compounds of general formula 1 exhibit activity in testing p6 by Herxeimer with dosages S ranging from 25-200 mg / kg. The compounds of general formula 1 may be administered for therapeutic purposes in various ways, therefore they can be incorporated into various dosage forms, although oral administration. is preferred. In addition to the oral intake, compounds of the general form 1 can be administered through the rectum, topically, the gastrointestinal tract, for example, by injection, or in the form of tablets, lozenges, tablets for resorption under the tongue (sublingual Compounds can also be introduced into Sots, sachets, dry spirits or dry fragrances, wafers or capsules for taking medicines, elixirs, suspensions, aerosols, ointments, lipsticks, rubbing, soaps, for example, 1-10% by weight of the active compound in the composition of a suitable base, soft or hard gelaty new capsules, suppositories, solutions for injections and suspensions in a physiologically suitable medium, in which sterile packaged powders adsorbed on the carrier material, for preparing solutions for injection, I. It is desirable that the formulations be prepared in unit dosage form and that our dosage contained 5-5OOO m (5.0 -. 50 mg in the case of the introduction, a minute of the nasopharynx tract, 5.0 - 50 mg in the inhalation and 25 - 5OO mg when taken by mouth or injected through the rectum) General formula 1. For treatment it is possible to take a dose About, 5 - ZOO mg / kg per day, preferably 1 2 O mg / kg of the active component. At the same time, the amount of the compound of general formula 1 to be used in the form of drugs should be determined by the attending physician, taking into account the condition of the patient, the choice of compound administered for therapeutic purposes, the choice of route of administration. The unit dosage form is an isologically discrete unit, the content is a single amount of the active co-part, usually in a mixture with a pharmaceutical diluent for it, or, in other words, in combination with a pharmaceutical carrier, the amount of the active ingredient being such that The overall therapeutic treatment required from one to several unit dosages. In the use of splittable unit dosages, such as tablets, provided with grooves to facilitate breaking, at least one portion, for example half or a quarter of the unitable unit dosage, should be used for therapeutic purposes. Formulations should usually contain at least one a compound of general formula 1, mixed with a carrier or diluent, or enclosed or encapsulated by means of a swallowed carrier in the form of capsules, sachets, dry perfume, dry flavored, eschestv, paper or other carriers, or as a single dosage for use, for example. The carrier or diluent may be a solid, semi-solid, or liquid material that serves as a binder for the corresponding component of the drug or the medium of the active drug substance. Some examples of extenders or carriers that may be used in the pharmaceutical compositions of the proposed preparations are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin white carbon black (silica), microfocal cellulose, calcium silicate, silica gel, psashv nkp / pyrrolidone, cetostearyl alcohol, the collapse is small, modified starches, acacia gum, calcium phosphate, cocoa butter, ethoxylated puffs, rum oil, peanut oil, algin you, tragacanth, gelatin, syrup BP, metiltsellSyu Oz monolaurate. polyoxyethylene sorbitan, etshshakat, methyl- and propyloxybenzoate, sorbitan trioleate, sorbitol and sesquoleate and openl alcohol; also aerosol promoting agents, such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoromethane. In the case of tabl & current can introduce a lubricant. prevents the formation of powdery ingredients in the soils of the mold and the punch of the tablet machine. For this purpose, for example, aluminum, aluminum or calcium stearates, talc or mineral oil may be used. Example. 3- f yTHn-5 (thiophenyl 2-methyl) gadantin. DU - p - - {5-M0gylthiophenyl-2) alanine (4, 1g; 0, O22 mol) is dissolved in a 2N solution of sodium oshsi hydrate (11 ml; O, O22 mol), cooled to m-tiLiocyanate (3 , 75 ml} 0, RPZ mol) is added gradually, maintaining the temperature of the growth, for 2 hours. The mixture is left to warm to room temperature and stirred overnight. The mixture is filtered off (solid off the blend from) into the filtrate is treated with ether. The washed filtrate is acidified with concentrated hydrochloric acid. (11 ml) and heated on a steam bath for 1 hour. After cooling to room temperature, the solid obtained is separated by filtration, interrupted with water and dried. Recrystallization from ethyladetate gives the desired product. The output of 4.2 g (72%), so PP. . The following compounds were prepared in a similar manner: 3 "-n-Butch1--5 (thiofesh1A2-methyl) hydantoin, m.p. 150 ° C, 3-in Butyl - (3-methylthiophenyl-2-methyl) g danthoin, so pl. 94 ° Cj W-and-Butip-5- (5-phenyltZofenvl-2-methyl) hydanto n, t. Yush. 3-n-Butyl-5- (4-chlorobenzel) hydantoin, so l. 5- (2-Brombenaip) -Z-n-butylgvdanthoia, m. 127.Cj 3-nbutyl-5- (3g 4-dichlorobenzyl) hydrophenyl, t. Sh1. 149Cj B-Benzsh & 3-methylgvdantoin t. Pl. 5-Bensh1-ZTs) Eg1gidaa-Toin t. Pl. 5-Benzyl. 3-n-hexsch1gvdan tons, so pl. 126 ° C. EXAMPLE 2. Soft gelatin-type capsules are PREPARED using the following components, mg / capsule; Active connection 2O. The proshgallat0.03 fractionated BFK70 coking oil. The indicated ingredients are sewn into the mixture by means of a mixture of soft iron capsules, in which the main constituents of the shell are alc-gelatin and glycerin. EXAMPLE EXAMPLE 3 Solid zhepatvnovye capsules are prepared with approx HAND following components, mg / capsule Active soedinenie25 silicon dioxide (kollovdalna) .25 LaktozaEO Butvlsch) ovanny hydroxyanisole BF0,02 BytshIIpov yishy oksianvzop dissolved aktishsoy part and pacTBqp obtained in this way is adsorbed on Cregella colloidal dioxide. Then add lactose and lactose and all together. Finally, the mixture is filled into hard gelatin capsules. - PRI me R 4. The ointment is prepared from a sl & ) 5 component parts weight,%: .- Active Soydia & 2: Buttered balancing oxyanisole BF0, O4 White soft paraffin To 1OO, the oxyanosol is dissolved in molten i paraffin, then the active compound is added and the cMetai is allowed to cool. . EXAMPLE 5 A topical cream containing 1% of the compound (PREPARED as follows: Active compound 1 Cetomacrogon 10003 Cetostearyl alcohol 1 O. Liquid paraffin (vaseline oil) 7 Butylated hydroxy anisole BF O, O4 Distilled water Up to 10 O, O Active the compound is mixed with oi & anisole and suspended in vaseline oil. Cetostearyl alcohol is added and the mixture is heated until the procedure is completed, then Cetoshkrogol 1OOO is placed in 6O g of water heated to 7NF. The compound is poured into the aqueous solution of Cmaturus Hop 10OO with stirring and stirring is continued until iqpeM is cold. After this, the cr & n is added to the required weight by adding water, and passed through a colloid mill; steel, at azor O, 38 mm (15/10 in.). Example 6. Suppositories containing 60 mg of Ds in 60 mg are prepared as follows: Take 3g of active compound and 97g Ggaokel. The active compound is mixed with a Gev kel base, which is preliminarily melted using the least possible amount of heat. Then the mixture is inserted.
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of producing hydantoin of the general formula 1 wherein Dg is unsubstituted phenyl or mono- or dihalogenated substituted phenyl, unsubstituted thiophene or thiophene substituted with phenyl or —C 4 -alkyl;
    R — C — C β — alkyl or phenyl, provided that, if Ag is phenyl, then R cannot be H-butyl, characterized in that the amino acid is of the general formula 2 agsn 2 annn 2 salt / where the values of Ag are indicated above, subjected to interaction with an isocyanate of the general formula
    RNC.0 t · where R has the indicated values, with the release of the target product.
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    引用文献:
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    FR910275A|1944-11-14|1946-06-03|Novel hydantoins and their preparation process|
    US2479065A|1945-09-06|1949-08-16|Du Pont|Preparation of 5-benzylhydantoin|
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    GB846601A|1958-01-13|1960-08-31|British Oxygen Res And Dev Ltd|Vinyl hydantoins|
    NL131665C|1964-05-18|
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    JPS5136332B1|1970-12-09|1976-10-07|
    US3847933A|1970-12-09|1974-11-12|Exxon Research Engineering Co|Acid catalyzed alkylation of hydantoin|
    US3932449A|1973-10-09|1976-01-13|Morton-Norwich Products, Inc.|5- hydantoin|
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    US4431656A|1981-02-05|1984-02-14|Kanegafuchi Chemical Industry Company Limited|3,5-di-Tert-butylstyrene derivatives, salts thereof, and pharmaceutical compositions containing the same as an active ingredient|
    US4684735A|1985-07-01|1987-08-04|Stauffer Chemical Company|Promotion of raney nickel hydrogenation catalyst|
    JPS6317864A|1986-07-11|1988-01-25|Mitsui Toatsu Chem Inc|Production of hydantoins|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
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