• 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:
    New benzopyrane derivatives of the general formula <IMAGE> (I) in which R is free, esterified or amidated carboxyl, Ph is 1,2-phenylene which contains the group R-CO-NR3- and is otherwise unsubstituted or is substituted, X is a group of the formula -CO-CR1=CR2-, in which R1 and R2 independently of one another are hydrogen, acyl or a substituted or unsubstituted hydrocarbon radical or a hetero-analogue thereof, or conjointly are 3-membered to 5-membered lower alkylene, and R2 can also be free or etherified hydroxyl or hydroxyl etherified by an organic carboxylic acid, and R3 is hydrogen or lower alkyl, are useful as anti-allergic agents.
    公开号:SU786897A3
    申请号:SU782658398
    申请日:1978-09-04
    公开日:1980-12-07
    发明作者:Джорджо Феррини Пиер
    申请人:Циба-Гейги Аг (Фирма)；
    IPC主号:
    专利说明:

    one
    This invention relates to a process for the preparation of new compounds, derivatives of benzopyran of the general formula I, R & D institute R - (-) alkyl, phenyl, pyridyl or hydroxy group f R - hydrogen or lower alkyl; R, - hydrogen, lower alkyl, lower alkoxy or oxy group, or their salts, when the R-carboxy group, which have biological activity and can be used in medicine 30
    权利要求:
    Claims (4)
    [1]
    The benzo-pyrone derivatives of the general formula are known where R R 2 is alkyl having physiological activity, which is obtained by reacting the corresponding 7-methoxy-8-chloromethyl chromone-2-carboxylic ester with the amine of the total FORMULA R i and RO where k and R g have the aforementioned signs . , in the medium of an organic solvent, in the presence of triethylamine at the boiling point of the reaction mixture. The aim of the invention is to obtain new compounds of the formula I or il, expanding the range of compounds that can be used as biologically active substances. A method is proposed for producing compounds of formula 1 or II, which consists in the fact that the compound of the formula lCN- j (01} U where R, R o, and R, j have the above values Yi-rpynna CRg-CRj-Y or -CO- CR, and Y. - in the appropriate case, the hydroxy group esterified to an ether or ester or YI is hydrogen, and Yg is the group -0-CRj-CRJ. -Yo-OR-0-CO-CR.J. CR2-Y4, or YI - the group -CO-R / j, and Y - the group -0-CO-CHy -Rj, or Yj - the group -CO-CH Rj, and Yj - the group -O-CO-Rg, and RJ and Rrt have the above values, Ya - in the corresponding case, a functionally modified carboxy group, and Y4 in the corresponding case. The hydroxy group or its tautomer, which has been certified to ether or ester, is subjected to intramolecular cyclization, and the compound of formula I, where R is carboxy, is isolated as a free acid or salt. Cyclization of a compound of formula is Y where Y is CR2 or CO-CR-CR2 .-Y, and Y2 - in the appropriate case, hydroxy group or YJ esterified in simple or ester, and Y; 5 group -0-CO-CRi CR (2-Y4, or Yj - group -CO-CHgR and Y2 - the group -0-CO-R2, or the Y group -COR2 and Y. - the group -O-CO-CH is preferably carried out in the presence of the main condensation means. Cyclization of a compound of formula II where YJ is a group -CRj2 CR4-Y2 OR CO-CR -CR -Y, and Ul — if appropriate, an hydroxy esterified ester or ester or YJ; - hydrogen and Y2 - the group -0-CO-CRj (or -0-CR2, preferably carried out in the presence of an acidic condensation agent. The process is preferably carried out in an organic solvent, such as kai lower alkanoic acid, lower alkanol, lower alkyl or lower Alkylene ether or dizzyne alkyl ketone, Pro4cess is preferably carried out at a temperature of from -25 to +125 C. Compounds of the formula I or 11 have valuable pharmacological properties. In particular, they have antiallergic effect, for example, in the case of rats is at dose x from about 1 to 100 mg / kg when administered orally when performing a test for passive skin anaphylaxis. In addition, they cause inhibition of immunologically induced release of histamine, for example, from the peritoneal cells infested by NippostronguEus brasi iensis in a test tube of rats. Further, they have great activity in various models of bronchus, as it can be shown, for example, in doses of about 1 to 3 mg / g (intravenously) on FgE-induced compression of the bronchi of rats and in doses of less than about 1 mg / g (intravenously ) on antibody-induced compression of the bronchus of guinea pigs. For this reason, the relevant compounds of formula I can be used as inhibitors of allergic reactions, for example, in the treatment and prevention of allergic diseases such as asthma (caused by external factors or congenital), and in the treatment of allergic diseases such as senna fever, inflammation of conjunctiva, nettle fever and eczema. Example 1.5.8 g of m-methoxy oxalyl-aminophenol is suspended in 50 ml of a 33% solution of hydrogen bromide in acetic acid. To (at the prepared suspension, 4.6 g of ethyl acetoacetate is added within 5 minutes. After the reaction has quenched, accompanied by a weak exothermic effect, the reaction mixture is stirred for 5 hours and 30 minutes at room temperature and 1 hour and 30 minutes at 30-4 hours , 0 ° C. It is then poured into ice-cold water, filtered off under suction and washed with cold water to give 7-methoxy oxalyl-amino-4-methylcoumarin, mp 248-251 0. The starting product can be obtained as follows, 5.45 g m-aminophenol is dissolved in 40 ml of ethyl acetate 55 C. At 40 ° C, 8 g of oxalic acid chloride monomethyl ester is quickly added dropwise, and the temperature inside the reaction mixture rises to 60 ° C. Then the reaction mixture is heated under reflux for 5 minutes and stirred for 3 hours at room temperature. filtered overnight and suspended in 2N hydrochloric acid solution.After stirring for 45 minutes at room temperature, the reaction mixture was again filtered under suction and dried in vacuo. The m-methoxy oxalyl-aminophenol is obtained, m.p. 228-230s. Example 2. Zg of 7-methoxy oxalyl-amino-4-methylcoumarin is suspended in 50 ml of 1N. sodium hydroxide solution and the resulting suspension is stirred for 2 hours 30 minutes at 30-35 0. The reaction results in a clear solution, which is acidified with a dilute solution of hydrochloric acid. The resulting precipitate was filtered off under suction, after which the product was recrystallized from acetone. Thus, 2,6 4-methyl-7-oxaloaminocoumarin are obtained, mp 236-238 ° C. (with decomposition). The sodium salt of the resulting compound is melted at 300 ° C. Example 3. 6.7 g of 5-methoxy oxalylamine salicylic aldehyde (obtained from 5-nitrosalicylic aldehyde by reducing the nitro group and condensing oxalic acid chloride monomethyl ether) in 65 ml of absolute ethanol is mixed with 4 g of 2-pyridyl glucose methyl acetate. 4 g of piperidine and heated for 3 hours under reflux. The reaction mixture is cooled to and filtered under suction. 6-methoxy oxalylamino.-3- (2-pyridyl) coumarin is obtained, m.p. 240242 ° C (with decomp.). Example 4. 1.4 g is introduced into 60 ml of tetrahydrofuran. Then 9 g of acetoacetic acid methyl ester are slowly added. The temperature inside the mixture at the same time increases (up to 52 ° C. Then it is stirred for 2 hours at 40 ° C until the sodium is completely dissolved. To the dark red cloudy solution, 6 g of 2-acetoxy-4 is added dropwise within 15 minutes -methoxyoxalylaminobenzoyl chloride in 50 ml of tetrahydrofuran and heated for 18 hours under reflux.The suspension is then cooled, filtered under suction and the residue on the filter is dissolved in ice-water.The solution is slightly acidified with 1N hydrochloric acid and filtered over suction the precipitate formed. The resulting yellow product is treated with meta. This is obtained using 3-acetyl-4-hydroxy-7-methoxy oxalylaminocoumarin, mp 205-206 ° C. The starting material can be obtained as follows: 41.4 g of 4-aminosalicylic acid is dissolved in 420 ml of acetone While cooling the ice to the prepared solution, 18.3 monomethyl ether of oxalic acid chloride in 120 ml of acetone is added dropwise to the solution. The suspension of the milky form is heated under reflux for 1 hour, cooled and poured into 300 ml of icy water, then filtered on suction and dried. 31.2 g of this 4-methoxy-oxo-aminosalicylic acid (mp. 229 23lc) are heated under reflux for 4 hours with 600 ml of benzene and 300 ml of acetic anhydride. The solution is evaporated in vacuo to dryness and the residue is recrystallized from a mixture of dichloromethane-diethyl ether and from methanol. The 2-acetoxy-4-methoxy oxyalylaminobenzoic acid thus obtained is converted to the acid chloride by reacting dioxane with phosphorus tetrachloride. Example 5. 4.25 g of 2-hydroxy-4-methoxy-oxalylaminopropiophenone, prepared from 2-hydroxy-4-acetylaminopropiophenone by saponification with hydrogen chloride in acetic acid and condensation with oxalic acid chloride monomethyl ether, are heated under reflux condenser for 8 h for 8 h, and the mixture is refluxed for 4 h, and the mixture is cooled in an hour for 4 h, and the mixture is cooled in an hour for 4 hours, followed by heating for 8 h, followed by heating for 8 h, refluxing the mixture for 8 h. , 4 g of benzoyl chloride and 17 g of potassium carbonate in 380 ml of acetone. The acetone is distilled off in vacuo and ice water is added to the residue. . The undissolved product is filtered off under suction, washed with successively cooled with ice, diluted with caustic soda and water, and dried in vacuo. 7-methoxy oxalyl-amino-2-phenyl-3-methyl-4-oxobenzopyran is obtained, m.p. . Example 6 1.5 g of sodium are dissolved in 50 ml of methanol. The latter is removed in vacuo. The remaining methyl sodium is suspended in 15 ml of dimethyl formamide and added to the solution. 13.24 g of 2-methoxy-4-methoxy-oxalyl; aminopropiophenone (prepared from 2-hydroxy-4-methoxy-oxalylaminopropiophenone, and methyl iodide) in 130 ml of dimethylformamide. The reaction mixture is stirred for 15 minutes at room temperature, then 3.7 g of ethyl acetate in 10 ml of dimethylformade is added dropwise at 5 ° C and stirred overnight at room temperature. The mixture is poured onto ice, lightly acidified and filtered on suction. This product is dissolved in hydroiodic acid, heated under reflux for 2 hours, poured into a small amount of ice water, brought to an alkaline reaction by means of concentrated sodium hydroxide solution and then stirred for 3 hours Cook at room temperature. The separated sodium salt of 2,3-dimethyl-7-oxaloamino-4-oxo-4H-benzopyran is sucked off and dried in vacuo. Its melting point is above 290 ° C. Example 7. Similar to the methods described in Examples 1-6, the following compounds can be prepared: 7-methoxy-oxo-oxylamino-4,6-dimethylcoumarin, m.p. 222-225s; 7-oxaloamino-4-methyl-coumarin, m.p. 236-238 ° C (with decomp.) .; sodium salt, so pl. above 300 C; 7-methoxy oxyalylamino-3-phenylcoumarin, m.p. 250-252 ° C; 6-methoxy oxalylaminocoumarin, m.p. 239-241C; 7-methoxy oxalylamino-3, 4-dimethylcoumarin, so pl. 258-260 ° C; 7-ethoxyoxalylamino-4-methylcumrin, mp. 218-220®C; 7-ethoxyoxalylamino-5-methylcumrin, so pl. 218-2200С; 7-oxaloamino-3; 4-dimethylcoumarin m.p. 233 ° C; 7- (4-methylcoumarin-7) -amino-oxalino-4-methylcoumarin, m.p. above 300 ° C; 7-methoxy-oxyallylamino-4-methyl-N-ethylcoumarin. Mp. 13b-138c; 7-oxaloamino-4-methyl-M-ethylcum ryn, m.p. 142 ° C; 7-methoxy oxyallamino-4-methylcoumarin, mp 164-1: 5 ° C; 7-oxaloamino-4-dimethylcoumarin, m.p. 1b2-164 ° C; 8-methoxy oxalylamino-4-methyl-7-methoxycoumarin, m.p. 228-229 ° C; b-methoxy oxalimino-4-methyl-7-hydroxycoumarin, so pl. higher than 6-oxalylamino-4-methyl-7-hydroxycoumarin, mp. higher than 7-oxaloamino-4, 5-dimethyl cumyl; 250-251s; 7-methoxy oxyalylamino-3, 4-tetra 1-tethylencoumarin, m.p. 231-232 ° C; 7-oxaloamino-3; 4-tetramethylene marin, m.p. 235s (with decomp.); 6-oxaloamino-3- (2-pyridyl) -cumrin, m.p. dihydrate, (c. 8-methoxy oxalyl-aminocoumarin, T.PL. 222-223 C; 8-oxaloamino-4-methyl-7-methoxy-coumarin, mp 221-222 C; b-oxaloaminocoumarin; 7-oxyacetylamino-4- methylcoumarin m.p. 253-254 ° C .; 7-methoxyacetylamino-4-methylcoumarin, m.p. 1b8-171C; b-methoxy-oxalylamino-2,3-dimethyl-4-oxo-4H-1-benzopyran, t. pl 242 2440c; b-oxaloamino-2, 3-dimethyl-4-ox-4H-1-6enzopyran, mp above 7-methoxyoxalimino-2,3-dimethyl-4-oxo-4H 1-6enzopyran, t mp 228-229 C; 7-oxaloamino-2, 3-dimethyl-4-ox-4H-1-benzopyran, mp 234-240 ° C; 7-oxaloamino-2-phenyl-3-meth -4-oxo-4H-1-benzopyra1-, mp 243 ° C Invention formula and 1. A method for producing a derivative of nzopyran B of the general formula where R is carboxy, lower alkoxycarbonyl, oxymethyl or lower alkoxymethyl, K is hydrogen, lower alkyl, phenyl, pyridyl or lower alkanoyl, R, 2 is hydrogen, lower alkyl, phenyl, pyridyl or hydroxy; R is hydrogen or lower alkyl; R is hydrogen, lower alkyl, lower alkoxy or hydroxy; or salts thereof, when R is a carboxy group, characterized in that the compound of the general formula where R, R and R have the above values; YJ- is -CR CR j-Yg or -CO-C R J - CR Y, and if appropriate, hydroxy or hydroxy esterified in ether or ester, and Y / J is -0-CR2 CRj-Yp or -0-CO-CRj. sCRg-Y,, or Yj is a group —CO-R / 2., and Y. is a group —O — CO — CH Rj, or YJ. - the group -CO-CH / jRj, and Y / j the group -0-CO-R, with Rj and R having the above values, Y - in the appropriate case, a functionally modified carboxy group, and Y - in the appropriate case, esterified in an ether or ester the hydroxy group or tautomer thereof is subjected to intramolecular cyclization and the compound of formula 1, where R is carboxy group, is isolated in the form of a free acid or salt.
    [2]
    2 .. The method according to claim 1, wherein the cyclization of the compound of the formula 1GG, where Y is a group or -CO-CRjzCR2.-Y4, and Y, 2 in an appropriate case, hydroxy or esterified into an ether or ester or Y and Y, 2 is the -O-CO-CR iCRo-Y j group, or YJ is the -CO-CHy2R4 group, and Y-2 is the -O-CO-Rg group, or YI is the -COR group and Yg -O group -CO-CH jR, carried out in the presence of fixed assets — a condensation.
    [3]
    3. The method according to claim 1, is different from and with the fact that the cyclization of a compound of the formula GP, where Y is a group. un i: -CO-Cf {Cf-, and if appropriate, the esterified ester or ester hydroxy group; or - Y - hydrogen and Yg group - -0-CO-CR CR2-Y4 or -0-CR are carried out B. PRESENTATION sour condensation agent.
    [4]
    4. Method according to claims.-. 1-3, of which it is assumed that the process is carried out in an organic solvent, such as a lower alkane alkanol, a lower alkyl or lower alkylene ether, or a diborical alkyl keto. with f, -,. S. method according to claims. 1-4, which is based on the fact that the process is carried out at a temperature of -25 db +125 s "-" sources of information taken into account in r (1 "spertiz 1. USSR author's certificate j 405885, class C 07 O 311/24, 1971.
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    法律状态:
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    LU75688A|LU75688A1|1976-08-31|1976-08-31|
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