IL43761A - 1-(4-cyano-phenoxy)-2-hydroxy-3-(2-(5-1h-tetrazolyl)-chromon-5-yloxy)-propane and salts thereof their preparation and pharmaceutical compositions containing them - Google Patents

Description

This invention relates to pharmacologically active compounds useful in the treatment of allergic and matory particularly allergic asthma and hay Belgian Patent issued on May provides for compounds having the formula 1 2 3 4 7 in each of R R R R R and R can be phenyl alkoxy or alkyl with the condition that one or 1 2 3 7 more of group R R R and R is other than hydrogen or X is a hydrocarbon chain of from 2 to 4 carbon optionally substituted by and E is a carboxy or tetrazolyl This invention relates to and its pharmacologically a process for preparing that and compositions for the treatment of asthma comprising and its has the Pharmacologically salts of for the and hydroxymethylaminomethane Compound I is prepared by the following reacting in which R is an alkyl group of from 1 to 4 carbon with ammonia in a solvent such as or a at from to to obtain the corresponding CN dehydrating the amide at a temperature of from to with a reagent mixture such as fonyl or toluenesulfonyl in dimethyl formamide to obtain the corresponding reacting the nitrile with sodium azide and ammonium or sodium chloride in an organic solvent such as or dimethylacetamide to obtain a corresponding salt of a tetrazolyl wherein X is a or ammonium treating the tetrazolyl derivative with a dilute mineral acid to acidify the salt and to hydrolyze the group thereof to obtain compound Step of the process optionally may be carried out with an azide such as or lithium azide without ammonium or sodium in that in VIII is a or lithium Starting materials V are prepared as reacting 2 with in in the presence of benzyltrimethylanunonium hydroxide to obtain a recovering the and reacting it with diethyl oxalate to obtain an recovering the and reacting it with cyclization mixture such as concentrated hydrochloric i acid and a lower alcohol of 1 to 4 carbon thus compound Details of the preceding synthesis are available in Patent and are key intermediates in the synthesis of compound Compound I its salts possess properties that make them useful in treating and certain inflammatory those pounds may also be useful in treating autoimmune An effect is produced in an individual in need of such therapy by administration of an effective amount of compound I or a pharmacologically acceptable salt The term means a human being or an experimental animal used as a model The compounds may be administered by or other suitable routes of Effective doses range1 from to Succeeding example 5 provides details of the Compound I and its salts also have activity upon topical application to inflammed areas of the skin or of the For the treatment of compound I or a salt thereof may be in a form suitable for administration by That form can comprise a suspension or solution of the active ingredient in water or in a suitable alcohol for administration as an by means of a conventional that can comprise a sion or solution of the active ingredient in a conventional liquefied propellant to be administered as an aerosol from a pressurized The forms for administration can comprise the solid active ingredient in a solid diluent for administration from a powder inhalation Other routes of oral or buccal rectal parenteral or i intravenous can also be The form for administration can also in tion to compound X other active bronchodilating those of the such as or prenaline or The forms for administration can contain to by weight of compound or a salt If salbutamol or or sulphate are they are suitably present in a concentration of to by Example 1 2 in chloroform and ethanol were cooled at and saturated with The precipitated solid was washed with ethanol and dried to as a cream C H N C H N Example 2 1 2 5 FORMATE 1 and toluenesulphonyl chloride in pyridine and dimethylformamide were heated under reflux at with stirring for 90 then poured into water and acidified with The brown precipitate which formed was and washed with hot ethanol to as a pink formate C H N C H N Example 1 2 1 formate sodium azide ammonium chloride and dimethylformamide cooling and filtering solid the solution was poured into water and acidified to pH 1 with dilute hydrochloric acid and heated for one hour at The suspension was filtered to give a yellow solid which after crystallization from cream prisms of 2 5 C H N C H N Example SODIUM 1 3 2 was dissolved with warming in a solution of sodium hydrogen carbonate in water The resulting solution was filtered and to give a pale peach This was solved in ethanol and on standing a solid was This was filtered and dried to yield sodium 2 as white C Η N C Η N Example 5 ACTIVITY Compounds described in above examples 3 and 4 were evaluated for activity in the rat by the passive cutaneous anaphylaxis test utilizing egg albumin as the PCA is an experimentally allergic reaction which develops in the skin of test animals after venous injection of an The intensity of such PCA reactions is assessed by measuring the diameters of wheals which develop in the skin of the test Details of the PCA test can be found in the following 465 113 In the following ID50 is the dose which reduced the diameter of the wheal by in ected intravenously together with the LD50 is the intravenous dose that caused death in of the test Therapeutic index is the The reference compounds utilized disodium chromoglycate and sodium TABLE CED COM insufficientOCRQuality

Claims (7)

43761/4 CLAIMS:

1. A compound selected from the group consisting of 1- (4-cyano-phenoxy) -2-hydroxy-3- [2- (5-lff-tetrazolyl) - chromon-5-yloxy] -propane or a pharmacologically acceptable, non-toxic salt thereof.

2. The compound as in claim 1, 1- (4-cyano-phenoxy) - 2-hydroxy-3- [2- (5-l#-tetrazolyl) -chromon-5-yloxy] -propane.

3. The compound as in claim 1, sodium 1- (4-cyano-phenox) 2-hydroxy-3- [2- (5-li7-tetrazolyl) -chromon-5-yloxy) -propane .

4. A process for preparing 1- (4-cyano-phenoxy) -2- (hydroxy) -3- [2- (5-lff-tetrazolyl) -chromon-5-yloxy] -propane , which process comprises: reacting a compound having the formula wherein R is an alkyl · group of 1 to 4 carbon atoms, with . ammonia in a solvent selected from the group consisting of ethanol, chloroform, methanol, and a chloroform/methanol mixture to obtain an amide, 1- (4-cyano-phenoxy) -2-hydroxy-3- (2- carbamoyl-chromon-5-ylox )-propane, dehydrating the amide with a reagent selected'^rom the v group consisting of p-toluenesulfonyl chloride/pyridine , p-toluenesulfonyl chloride/lutidine , and p-toluenesulfonyl chloride/collidine in dimethylformamide, to obtain the corresponding nitrile formate, 1- (4-cyano-phenoxy) -2-formy- loxy) -3- (2-cyano-chromon-5-yloxy) -propane ; reacting the nitrile with sodium azide and ammonium chloride or lithium chloride in the presence of a second solvent selected from the group consisting of dimethylformamide, dimethylsulfoxide, and dimethylacetamide, to obtain a corresponding tetrazolyl salt selected from the group consisting of sodium, lithium, potassium, or ammonium 1- (4-cyano-phenoxy) - 2-hydroxy-3- [2- (5-l#-tetrazolyl) -chromon-5-yloxy] -propane formate; and acidifying the tetrazolyl salt with a dilute mineral acid to obtain the 1- (4-cyano-phenoxy) -2-hydroxy-3- [2- (5-lff-tetrazolyl) -chromon- 5-yloxy] -propane .

5. A composition for the treatment of asthma comprising: from 0.1% to 10% by weight of 1- (4-cyanophenoxy) -2-hydroxy- 3- [2- (5-1H- etrazolyl) chromon-5-yloxy]propane or a pharmacologically acceptable salt thereof and from 0.1 to 5% by weight of salbutamol in a pharmaceutically acceptable vehicle.

6. A composition for the treatment of asthma comprising: from 0.1% to 10% by weight of 1- (4-cyanophenoxy) -2-hydroxy- 3- [2- (5-lH-tetrazolyl) chromon-5-yloxy]propane or a pharmacologically acceptable salt thereof and from 0.1% to 5% by weight of isoprenaline sulfate in a pharmaceutically acceptable vehicle.

7. A composition for the treatment of asthma comprisings from 0.1% to 10% by weight of 1- (4-cyanophenoxy)-2-hydroxy-3- 12- (5-lH-tetrazolyl) chromon-5-yloxy] ropane or a pharmacologically acceptable salt thereof and from 0.1% to 5% by weight of orciprenaline sulfate in a pharmaceutically acceptable vehicle.