NO160759B - MODULMOEBEL. - Google Patents

Description

Process for the production of new, therapeutically active chromone - 2 -carboxylic acid derivatives.

The invention relates to method

for the production of new chromone-2-carboxylic acid derivatives which have special activity as inhibitors of the antigen/antibody reaction, and have the formula:

as well as salts, esters and amides thereof, where R denotes an alkyl group containing up to 12 C atoms, preferably 2-8 C atoms, substituted by one or more

hydroxyl groups or with a carboxyl group; an alkyl or aralkyl group with up to 12 C atoms, preferably 2-10 C atoms, which groups are interrupted by one or more oxygen atoms and optionally substituted with one or more hydroxyl groups; a heterocyclic ring containing carbon and oxygen, e.g. a furfuryl, tetrahydrofurfuryl or dioxolanyl ring, which may be substituted with one or more hydroxyl groups or with one or more alkyl groups; or an alkyl group with up to 12 C atoms substituted with a heterocyclic ring containing carbon and oxygen, which ring may be substituted with one or more hydroxyl groups or with one or more alkyl groups; R1, R2 and

R3 are the same or different and each denotes a hydrogen atom or halogen atom, an alkyl group with up to 8 C atoms or a group OR where R has the above meaning, or R1 and R2 together with the adjacent carbon atoms form a saturated or unsaturated heterocyclic ring containing carbon and oxygen.

The Swiss patent document no. 375 021 deals with similar chromone derivatives, which, however, in experiments carried out by the patentee, have been shown not to have the same properties as compounds produced according to the present invention.

Preferred salts of the chromone-2-carboxylic acid derivatives include metal salts (especially alkali metal salts) and ammonium salts. Preferred esters are alkyl and hydroxyalkyl esters, such as methyl, ethyl and hydroxyethyl esters. When the group R contains one or more hydroxyl groups, such hydroxyl groups can be esterified, e.g. in the form of their acetates, hemisuccinates or carbonates.

When the group R contains a carboxyl group, this can be in the form of the same functional derivative as the carboxyl group in the 2-position. Thus, e.g. the carboxyl-substituted group R be in the form of an amide, while the carboxyl group in the 2-position is in the form of a salt, e.g. a sodium salt.

When the group R is an alkyl group substituted with one or more hydroxy groups, it is preferred that the alkyl group contains at least 2 carbon atoms and no more than 8 carbon atoms. Examples of hydroxyalkyl groups include hydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, dihydroxybutyl and trihydroxybutyl.

When the group R is an alkyl group, interrupted by one or more oxygen atoms, it is preferred that the alkyl group contains at least 2 carbon atoms, but not more than 10 carbon atoms. Examples of such groups include methoxymethyl, ethoxymethyl, ethoxyethyl, hydroxyethoxyethyl, ethoxypropyl and acetoxymethyl.

Examples of group R when this is a heterocyclic ring or alkyl group substituted with a heterocyclic ring include furfuryl, tetrahydrofurfuryl and dioxolanyl and substituted dioxolanyl, e.g. groups with the formula:

wherein R°, R<7> and R<8> are alkyl groups or hydrogen atoms, and n is 0 or an integer. The definition of R as a heterocyclic ring or alkyl group substituted with a heterocyclic ring is also intended to cover saccharide rings, e.g. when R is a glucosyl or ribosyl group.

Preferred compounds are:

5-(2-hydroxypropoxy)-chromone-2-carboxylic acid,

5-(2-phenoxyethoxy)-chromone-2-carboxylic acid,

5-(2-hydroxypropoxy)-7-methyl-chromone-2-carboxylic acid,

5-(2-ethoxyethoxy)-chromone-2-carboxylic acid,

5-(2-acetoxypropoxy)-chromone-2-carboxylic acid,

5-(tetrahydrofurfurylmethoxy)-chromone-2-carboxylic acid, 5-(4-1,3-dioxan-4-ylmethoxy)-chromone-2-carboxylic acid,

5,7-blis-(-2-ethoxyethoxy)-chromone-2-carboxylic acid, and 4-(2-ethoxyethoxy)-9-methoxy-5-oxo-5H-furo(3,2-g)-(l) -benzopyran-7-carboxylic acid.

The new chromone derivatives have been shown to inhibit the release of spasmogens (convulsion-causing compounds) that normally follow when specific antigens and antibodies are combined. In humans, the pathological effect that follows the administration of antigen to susceptible individuals is significantly prevented. These compounds are therefore of value in the treatment of any condition in which an "external" antigen combined with antibody is primarily responsible for disease such as asthma, hay fever, hives and the like.

The new chromone derivatives produced according to the present invention also have important therapeutic properties in conditions where "internal" antigen is combined with antibody. Consequently, they are of value in the treatment of auto-immune diseases, e.g. joint rheumatism, systemic lupus erythematosus and the like.

The new compounds are produced according to the invention by reacting an o-hydroxy-acetophenone with the formula:

where R1, R- and R<3> have the meaning given above, is reacted with a substituted dihaloacetic acid ester of the formula: in which R' and R" denote alkyl groups and X is a halogen atom, e.g. chlorine atom, or is reacted with a ester with the formula:

in which R' has the above meaning, such as e.g. ethoxalyl chloride, after which, if desired, the formed acid or ester is transferred to a salt ester or amide, or the formed ester is hydrolyzed to the free acid,

or, if desired, any free hydroxyl groups present are esterified.

When the new compounds are prepared by reacting o-hydroxy-acetophenone with substituted dihalo-acetic acid ester, the reaction is preferably carried out at an elevated temperature, and essentially equimolar amounts of the reactants are advantageously used and preferably in the presence of a catalyst sator as finely divided metallic platinum, palladium or ruthenium.

When the compounds are prepared by reacting o-hydroxy-acetophenone with an ester of the formula:

the reaction is preferably carried out in the presence of an acid-binding compound, e.g. an organic base such as pyridine, diethylamine or triethylamine. o-Hydroxy-acetophenone of formula III can be prepared by acetylation of a phenol of the formula:

followed by a Fries rearrangement to the corresponding compound of formula III.

The chromone-2-carboxylic acids obtained by the above-mentioned process can then be converted into their salts, esters or amides using known methods. Thus, salts of the acids can be prepared by reacting the acids with basic metal-ene ammonium compounds, such as alkali metal or ammonium hydroxide or carbonates. Esters can be prepared by direct reaction of the acid with the corresponding alcohol and amides by reaction of the acid with the corresponding amine. In general, it is preferred to use the acid in the form of salts, such as alkali metal salts or amides, in particular as complex amides with amino acids such as glycine. Such amides can be used as free bases as acid addition salts thereof.

In order for the invention to be easily understood, the following examples are given as an illustration of the invention. In the examples, all parts and percentages are given by weight, if nothing else is stated.

Example 1

5-(2-Ethoxyethoxy)chromon-2-karoonsylic acid.

A mixture of 45 parts of 2-hydroxy-6-(2-ethoxyethoxy) acetophenone and 51 parts by weight of ethyl oxydichloroacetate (80% purity) was heated at 150-170° C. for several hours. The thus prepared mixture, which contained the ethyl ester of the desired acid, was dissolved in 300 parts of acetic acid and 50 parts of concentrated hydrochloric acid. The solution was heated under reflux for 4 hours. After cooling, the solid was filtered off, washed, dried and crystallized from water, giving 5-(2-ethoxyethoxy)chromone-2-carboxylic acid with melting point 165=-166°C.

Analysis:

Example 2

Sodium - 5-( 2- e toxye toxy)- chromone-2- carooxylate.

To a mixture of 10 parts of 2-hydroxy-6-(2-ethoxyethoxy)acetophenone in 20 parts of pyridine, 13 parts of ethoxy-allyl chloride were carefully added. The mixture was heated at 100°C for 30 minutes. After cooling, the mixture was poured onto ice into concentrated hydrochloric acid, and an oil formed. The oil was extracted with chloroform and the extract dried over sodium sulfate. After filtration, the solution was removed and the residue was crystallized from ether and petroleum ether, and ethyl 5-(2-ethoxyethoxy)-chromone-2-carboxylate was obtained with a melting point of 62-63°C.

The ester was hydrolyzed to sodium 5-(2-ethoxyethoxy)-chromone carboxylate with sodium bicarbonate solution.

Example 3

Pharmacological anti-anaphylactic

results in vitro.

The inhibition of histamine release and the release of slow-reacting anaphylactic compound (SRS-A) has been determined using dissected, ovalbumin-sensitized guinea pig lung. The method as described by Mongar and Schild (J. Physiol. 1957, 135, 301-19) has been used, comprehensive analysis of SRS-A on isolated guinea pig small intestine.

All of the above-mentioned chromone-2-carboxylic acids and their sodium salts are sub-

thrown experiment, and it has been found that for-

the bonds to a considerable extent inhibit free-

making both histamine and SRS-A at a concentration of 200 [Ag/ml.

Example 4

The clinical examination of the follow-

end compounds were based on symptom-

induction by antigen inhalation.

Disodium 5-(1',4'-dioxa-5'-oxo-heptyl)-chromone-2,7'-dicarboxylate,

Sodium 5-(2-hydroxypropoxy)-chromone-2-carboxylate,

Sodium 5-(2-phenoxyethoxy)-chromone-

2-carboxylate,

Sodium 5-(2-hydroxypropoxy)-7-methyl-chromone-2-carboxylate,

Sodium 5-(2-ethoxyethoxy)-chromone-

2-carboxylate,

Sodium 5-(2-tetrahydrofurylmethoxy)-chromone-2-carboxylate.

The volunteer subjects who were

picked out for this purpose suffered from speci-

got allergic asthma. When these persons in-

inhaled an antigen to which they were specifically sensitive

faced, this normally resulted in an asthma attack on the subject. Gra-

that of the induced asthma attack in

according to this method, can be measured by re-

determined the airway resistance.

A suitable respirometer was used

for the measurement of the forced respiratory

volume for 1 second (TRVi.o), and hence for-

changes in airway resistance. A test compound's anti-allergic activity is determined from the difference between the maximum percentage TRVi.o reduction that was respectively due to control samples and test samples after the compounds were ad-

administered under identical experimental conditions:

The test results are expressed as a percentage

protection according to the formula:

According to this procedure, they gave

above mentioned compounds, when they were inha-

in the form of 0.5% aerosols, (calculated dose in the lungs below 1.0 mg) more than 70% be-

shooting when administered 10 min-

ter before the antigen. A be-

tractable protection for at least 2 hours.

Claims (1)

Process for the production of therapeutically effective chromon-2-carboxylic acids with the formula: as well as salts, esters and amides thereof, in which R denotes an alkyl group containing up to 12 C atoms, preferably 2-8 C atoms, substituted by one or more hydroxyl groups or with a carboxyl group; an alkyl or aralkyl group with up to 12 C atoms, preferably 2-10 C atoms, which groups are interrupted by one or more oxygen atoms and optionally substituted with one or more hydroxyl groups; a heterocyclic ring containing carbon and oxygen, e.g. a furfuryl, tetrahydrofurfuryl or dioxolanyl ring, which may be substituted with one or more hydroxyl groups or with one or more alkyl groups; or an alkyl group with up to 12 C atoms substituted with a heterocyclic ring containing carbon and oxygen, which ring may be substituted with one or more hydroxyl groups or with one or more alkyl groups; R1, R2 and R3 are the same or different and each represents a hydrogen atom or halogen atom, an alkyl group with up to 8 C atoms or a group OR where R has the above meaning, or R<1> and R2 together with the adjacent carbon atoms forms a saturated or unsaturated heterocyclic ring containing carbon and oxygen, characterized in that an o-hydroxy-acetophenone with the formula: in which R1, R2 and R<3> have the meaning given above, is reacted with a substituted dihaloacetic acid ester of the formula: in which R' and R" denote alkyl groups and X is a halogen atom, e.g. chlorine atom, or is reacted with an ester of the formula: in which R' has the above meaning, such as e.g. ethoxalyl chloride, after which, if desired, the formed acid or ester is transferred to a salt, ester or amide, or the formed ester is hydrolyzed to the free acid, or, if desired, any free hydroxyl groups present are esterified.