• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:

    公开号:SU904521A3
    申请号:SU792774403
    申请日:1979-06-15
    公开日:1982-02-07
    发明作者:Хаас Джорж；Роси Альберто；А.Егги Кнут；Зеле Алекс
    申请人:Циба-Гейги Аг (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING DERIVATIVES OF BENZOPIRANE
    one
    This invention relates to a process for the preparation of new compounds of benzopyran derivatives of the general formula 1

    A NH-C-R (I) Ph T
    OK,
    where Ph is 1,2-phenylene unsubstituted or substituted by lower alkyl, lower alkylene and / or halogen atom, R is hydroxymethyl and RI is a hydrogen atom
    These compounds have valuable bio-active properties.
    The method is based on the reaction of reacting a carboxylic acid or its derivative with a primary amine, followed by the preparation of amide 1.

    The purpose of the invention is to obtain new benzopyran derivatives possessing pharmacological activity. This goal is achieved in that according to the method, a compound of the formula L
    , Rl t. ,
    where Ph and RI have the meanings indicated, are reacted with a compound of the Formula RX or X | -X, where R has the meaning indicated, X is a carboxy or halogencarboxy group, and Xj is esterified to ester with a lower alkanol carboxylic acid hydroxymethyl group or g9l15 genomethyl, and the desired product of formula I is isolated, where R is hydroxymethyl, or in the resulting compound of Formula 3
    Ooh
    20A / NH-ii-XV jn
    Ph t
    ,
    权利要求:
    Claims (6)
    [1]
    where Ph, RI and X are as defined above, 25 group X) is hydrolyzed to oxymethyl at 39 temperature of 20-200 ° C, followed by isolation of the desired product. The compounds of the formula J and RX react or are carried out in the presence of a water-binding agent, for example acid anhydride, phosphorus pentoxide or dicyclohexylcarbodsylmide or acidic or basic Koi-sensation, such as mineral acid, for example hydrochloric acid or alkali metal hydroxide or alkali carbonate metal, e.g. sodium hydroxide or calcium, or in the presence of an organic nitrogen base, e.g. triethylamine or pyridine. When interacting with the acid anhydride, the preferred organic nitrogenous nitrogen is used as a condensation agent. The reaction with carboxylic acids, for example, glycolic acid, is preferably carried out in the presence of a water-binding agent that affects the dehydration of the initially formed substituted aMMOiiMn PCHI acid condensation agent. If necessary, the process is conducted in an inert solvent or diluent, for example a hydrocarbon, toluene, M, N-di-lower alkyl chloride, for example dimethylformamide or chloroform or methylene chloride, in a closed vessel and / or in an inert gas atmosphere, HanpiiMep in a nitrogen atmosphere. Hydrolysis group X | in hydroxymethyl is carried out in the usual way, if necessary in the presence of a base or in the presence of an acidic hydrolytic agent, e.g. a need for a polar solvent, e.g. a lower alkanol, ketone or ether, e.g. ethanol, acetone or dioxane, and / i.p. upon cooling or heating from 20 ° C to 200 ° C Compounds of formula I possess single pharmacological properties. In particular, they have an antiallergic effect, which can be demonstrated, for example, in rats with oral doses of from 3 to 100 mg / kg when administered intravenously in doses of 0.3 to 10 ml, in a passive skin anaflex test (PCA). ). The compounds of formula I or their pharmaceutically acceptable salts are intended for topical and local, as well as general, for example oral or rectal, as well as parenteral use and for warm-blooded inhalation, which contain only one pharmacologically active substance or active substance together with a pharmaceutically acceptable carrier. . The dosage of the active ingredient depends on the type of warm-blooded age and the individual condition of the patient, as well as the method of application. New pharmaceutical preparations contain, for example, 10-95%, preferably 2090% of the active, ingredients. The pharmaceutical preparations according to the invention can be made in the form of aerosols or spray formulations, or in a dosage form, such as dragees, tablets, suppositories, and also in the form of ampoules. Example 1. K6g 3-amino-4-oxo-4, 6, 7, 8-tetrahydro cyclopenta (d) -1-benzopyra added 7 g of glycolic acid. The reaction mixture is heated to 120 ° C for one hour. It is then cooled to room temperature, extracted with water, filtered, evaporated and recrystallized from 400 ml of ethanol, and then from a small amount of ethyl ester of acetic acid. By; Tuchayu ;, 3-glycoloylamino-Foxo-4, 6, 7, 8-tetrahydrocyclopenta (d) -1-bepzopyran with so pl. 199-200 ° C. PRI me R
    [2]
    2. Tablets containing 0, β glycoloylamino-4-oxo-4, 6, 7, 8-tetrahydrocyclopenta (d) -1-benzopyraia are prepared as follows: Composition (for 1000 tablets), g: 3-Ch11 Coloyl-4-oxo -4, 6, 7, 8-tetragidroglikotsenta (d) -1-beizopiran100 Laktoza50 Pshetgishy krahmal73 colloidal silicic kislota13 stearate mapsheet 2 Talk12 VodaNeobhodimoe number 3 Glikoloilamino-4-oxo-4, 6, 7, 8-tetragidro1shklopenta (d) - -benzopyran is mixed with a portion of pure starch, lactose and colloidal silicic acid, and the mixture is rubbed through a sieve. The rest of the starch is klesterized in a water bath, adding five times the amount of water, and the above powder mixture is kneaded with this paste to obtain a weak plastic mass. The plastic mass is forced through a sieve with a magnitude of cells of approximately 3 mm, dried, and the dry granulate is again rubbed through the sieve. The rest of the wheat starch, talc and magnesium stearate interfere with this and the mixture is pressed into tablets of 0.25 g. PRI me R
    [3]
    3. Suitable dp inhalation 2% aqueous solution of the active vein is prepared as follows: 5 Composition, mg; 3-Glycolonl-amino-4-oxo-4, 6, 7, 8-tetrahydroiocyclopenta (d) -1-benzopyran2000 Stabilizer, for example ethylenediamine acetic acid salt 10 Preservative 10 Freshly distilled water 100 The active substance is dissolved in freshly distilled water. A preservative and a stabilizer are then added. PRI me R
    [4]
    4. Suitable for insufflation, containing 25 mg of active at the beginning, capsules are obtained as follows Composition, mg: 3- Glycoloylamino-4-oxo-4, 6, 7, 8-tetrahydrocyclopenta (d) -1-benzopyran25 Fine grinding lactose 25 Active ingredient and lac1; ozu pretty k tram. The resulting powder is sieved through a sieve and 1000 wish-filled capsules of 50 mg each are filled. . . In a similar manner, 6-chloro-8-methyl-3-gpicoloylamino-4-oxo-4H-1-benzopyran is also obtained with m.p. 178-182 ° C, 6-chloro-3-glyc-clooylamino-4-oxo-4H-1-beisopyran with m. Pl. 206 ° C, 5,7-dimethyl-3-glycoloylamino-4-oxo-4H-1-benzopyran with t. Pl. 193-195 ° C. PRI me R
    [5]
    5. Similarly to the method described in example 2, tablets are obtained containing 0.1 g each: 3-glycolpylamino-4-oxo-4H -1 - benzopyran, 6-chloro-3-glycoloylamino-4-oxO-4H-1-benzopyran, 6 , 7-trimethylene-3-glycoloylamino-4-cc-4H- - benzopyran, 5,7-di methyl-3-glycoloylamio-4-oxo-4H-1-benzopyran 6-chloro-7-metsh-3- glycoloylamin1So-4H-benzopyran; 6-chloro-8-methyl-3-glycoloylamino-4H-1-1-benzopyran. PRI me R
    [6]
    6. Analogously to the method described in example 3, the following 2% aqueous solutions for inhalation are obtained: 3-glycoloylamino-4-pkso-4H-1-benzopyran, 6-chloro-3-g and choloylamino-4-oxo-4H- 1-benzopyran, 6,7-trimethylene-3-glycoloylamino-4-oxo-4H-1-benzopyran, 5,7-domegyl-3-glycoloyl NO-4-OXO-4H-1-benzopyran, 6-chloro 7-methyl-3-glycoloylamino-4H-1-benzopyran; 6-chloro-2-8-metsh-3-glycoloylamino-4H-1-benzopyran. EXAMPLE 7 2.7 g of 3-acetoxy-acegylamino-4-oxo-4H-1-benzopyran are dissolved in 25 ml of ethanol and 5 ml of 2 are added. solution of caustic soda. The mixture is then stirred for approximately 10 hours at room temperature, the solvent is removed in vacuo and recrystallized from ethanol 16. (petroleum ether. 3-glycopoylamino-4-oxo-4H-1-benzopyran is obtained with a melting point of 216-218 ° C. A similar method is obtained from 3-acetoxy acetylamino-4-oxo-4, 6, 7, 8-tetrahydrocyclopenta (d) - 1-benzopyran 3-glycoloylamino-4-oxo-4, 6, 7, 8-tetrahydrocyclone (d) -1-benzopyran with mp 199-200 ° C. PRI me R 8 To 2.4 g of 3-chloroacetylamino-6-chloro-7-methyl-4-oxo-4H-1-benzopyran, add 3 ml of methanolic sodium acetate solution: and transfer, then heat for about 2 hours to 180 ° C. The reaction mixture is recrystallized from ethanol / petroleum ether, to obtain 6-chloro {-7-methyl-3-glycoloyl-1ino-4-oxo-4H-1-benzopyran are melted with mp 266-268 ° C. The starting material is prepared as follows: K 3 g 3-amino-6-chloro -7-methyl-4-oxo-4H-1-benzopyran was added 2.3 g of chloroacetic acid chloride (or 2.1 g of chloroacetic acid) and the reaction mixture was heated for approximately 2 hours to 100 ° C. Was filtered, dried and the reaction mixture (my mixture is directly subjected to subsequent interaction. EXAMPLE 9. In a similar way to the method described in example 4, capsules for insufflation containing 25 mg each in each of the following methods are also semi-salted: -oxo-4H-1-benzopyran, 6,7-trimethylene-3-glycoloylamino-4-OXO-4H-1-benzopyran, 5,7-dimethyl-3-gt1coloylamino-4-OXO-4H-1-benzopyran, 6 -chloro-7-methyl-3-glycoloylamino-4H-1-benzopyran, 6-chloro-8-metip-3-glycoloylamino-4H-1-benzopyran .. Claim formula Method for producing 1 benzy benzopyran derivatives of the formula PA A Pb T where Ph - unmixed or mixed with lower alkyl, lower alkyl ohm and / or halogen atom 1,2-phenylene; R is hydroxymethyl; RI is a hydrogen atom, characterized in that the compound of the general formula P, Ph T, where Ph and RI have the values indicated above, is reacted with a compound of the formula RX or Xi-X, where r.e has the above value, X represents a carboxy or halogencarboxy group and Xi is an oxymethyl group or a halomethyl esterified to an ester by a lower alkaiolcarboxylic acid, and the desired product of formula 1 is isolated, where R is oximethpl, or in the compound of formula 3 Oo, Pb phCh where and X) is as above, the group is hydrolyzed hydroxymethyl at that erature 20-200 C followed vschelekiem desired product. Sources of information taken into account in the examination 1. Bgoler K., Pearson D. Organic syntheses. M., Mir, 1973, p. 384.
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