NO124994B - - Google Patents

Description

Analogy method for the production of new,

therapeutically active bis-chromonyl compounds.

The present invention relates to a method for the production of new, therapeutically effective bis-chromonyl fluoride compounds with the formula:

12 3 4 5 6

where R,R,R,R,RogR are the same or different groups and are hydrogen, halogen or lower alkyl, preferably all groups-12 3 4 5 6

neat R , R , R , R , R and R are hydrogen, X is a straight chain or

branched alkylene or alkenylene residue with 2-12 carbon atoms which is optionally interrupted by a phenylene residue or one or more oxygen atoms and/or substituted with one or more hydroxy or lower alkoxy groups and/or containing one or more carbonyl groups, and M is an alkali metal .

This method is characterized by the fact that a compound with the formula:

12 3 4 5 6

where R , R , R , R , R and R and X have the same meaning as stated above, R is hydrogen or an alcohol residue, is reacted with an alkali metal compound.

It is preferred that the alkali metal compound is sodium hydroxide or sodium bicarbonate. Furthermore, it is preferred that X is 2-hydroxypropane. Specific examples of the group X are groups with the formulas:

-CCH2)5-

-CH2-CH=CH-CH2-

-CH2CH2CH-(CH )-CH2CH2-

-CG2CH2OCH2CH2-

-CH2COCH2-

-CH2-CH(OC2H5)-CH2-

-CH2CHOHCH2-

-CH2CHOHCH2OCH2CHOHCH2-

The group X is preferably a straight or branched alkylene or alkenylene residue which may be broken by one or more oxygen atoms, and which contains from 3 to 7 carbon atoms. It is desirable that such a chain is substituted with one or more hydroxyl groups, particularly preferred is the 2-hydroxytrimethylene chain with the formula (-CH2.CHOHCH2-).

Preferred compounds are thus bis-chromonyl compounds of the formula:

The chain -0-X-O- can connect different or corresponding positions in the chromone molecules.

A particularly preferred compound because of its activity is alkali metal salts of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane of the formula:

where M has the above meaning..

With regard to the production of the output compounds used in the present method, reference can be made, for example, to application 162.258..

The new bis-chromonyl compounds produced according to the present invention have been shown to inhibit the release and/or the action of toxic products, which arise from the combination of certain types of antibody and specific antigen, e.g. the combination of reaginic antibody with specific antigen. In humans, it has been found that both subjective and objective changes, which occur when a specific antigen is inhaled in sensitive persons, are markedly inhibited if the persons have taken the new bis-chromonyl compounds. The new compounds are thus of great value in the treatment of extrinsic allergic asthma. It has also been found that the new bis-chromonyl compounds have value in the treatment of so-called "intrinsic" asthma (where no sensitivity to extrinsic antigen can be demonstrated).

In in vitro tests, the bis-chromonyl compounds have been shown to reduce the release of pharmacologically active compounds from sensitive human lung tissue after exposure to specific antigen, using a modification of an in vitro technique, as reported by Mongar et al. Schild (J.L. Mongar and H.O. Schild, J. Physiol, Vol.

150 (1960), pp. 5^6-564). The new bis-chromonyl compounds may also be of value in the treatment of other conditions where the antigen-antibody reaction is the cause of the disease, e.g. hay fever, urticaria and autoimmune diseases. It has also been found that in certain virus/antibody neutralization systems, the new bis-chromonyl compounds increase the antiserum's neutralization capacity, and said new compounds can thus be used in the treatment of viral infections.

In pharmaceutical preparations, the alkali metal salts of the bis-chromonyl compounds are used together with a pharmaceutical carrier or diluent. The nature of the preparations and the pharmaceutical carrier or diluent will naturally depend on the desired method of administration, be it oral, parenteral or by inhalation.

When treating asthma, the preparations should

be in a form suitable for inhalation. The preparations can thus consist of a suspension or a solution of the active ingredient in water for administration by means of an ordinary nebuliser. Alternatively, the preparations can consist of a suspension or a solution of the active ingredient in a common liquid propellant, which can be supplied from an aerosol bottle. The preparations can also consist of a solid active ingredient diluted with a solid diluent, e.g. lactose, for delivery from a powder inhalation device.

The pharmaceutical preparations may also contain other active ingredients and it has been found in particular that the addition of a bronchodilator is of value when the preparation is to be taken by inhalation.

Any known bronchodilator can be used in the pharmaceutical preparations. Examples of bronchodilators are isoprenaline, adrenaline, orciprenaline, isotarin and derivatives thereof, of which isoprenaline sulfate is particularly preferred.

The bronchodilator is preferably used in a smaller amount than the bis-chromonyl compound, e.g. in an amount from

0.1-10% by weight of the bis-chromonyl compound.

The novel compounds prepared are particularly useful for the relief or prevention of allergic respiratory disorders, whereby the patient is given a therapeutically effective amount (eg 1-50 mg) at suitable intervals of an alkali metal salt of a bis-chromonyl compound.

The following examples are given, so that one can get a better understanding of the invention and also include the production of used output connections.

Example 1.

(a) 1,3-bis(2-acetyl-3-hydroxyphenoxy) propane.

A mixture of 30.4 parts of 2,6-dihydroxyacetophenone, 20.2 parts of 1,3-dibromopropane and 12.8 parts of powdered potassium carbonate was heated under reflux in 200 parts by volume of acetone for 72 hours. The acetone solution was filtered and the solid residue was washed first with acetone and then with water. The total amount of acetone was evaporated, leaving an oil, which, on boiling with ether, gave pale yellow crystals. These were combined with the first solid obtained and extracted with refluxing isopropanol in a Soxhlet extractor for several days to give 16.1 parts of 1,3-bis(2-acetyl-3-hydroxyphenoxy)propane as nearly colorless crystals , which melted between 184 and 185°C.

Analysis:

Fuir.<p>t C, 65.4, H, 5.6855

<C>19<H>20°6 requires: c> 66>2> H> 5>8l5S

(b) Diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)propane.

A solution of 6.9 parts of 1,3-bis(2-acetyl-3-hydroxyphenoxy)propane in 15 parts by volume of ethyl oxalate was added to a solution of 3 parts of sodium in 30 parts by volume of ethanol and 50 parts by volume of benzene, and the mixture was gently heated under reflux for 20 hours. It was then poured into a larger volume of ether and the precipitated solid was filtered, washed with ester and dried. It was then dissolved in water and acidified to a sticky solid. This substance was then boiled for approx. 10 minutes with 50 parts ethanol to which had been added a catalytic amount of hydrochloric acid, after which crystals began to form. The solution was cooled and filtered, and the yield was 7.4 parts of a solid melting between 178 and 180°C. This compound was recrystallized from 200 parts by volume of a 1:2 mixture of benzene and ethanol, whereby a yield of

4.5 parts of the diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)

propane, which melted between 182 and 183°C.

Analysis:

Found: C 63.2, H 4.60f,

C27H24°10 requires: c 63>7, H 4.72$. (c) The disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)propane.

A suspension of 3 parts of the diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)propane in 50 parts by volume of boiling ethanol was treated with 11.6 parts by volume of 1.015 N aqueous sodium hydroxide. Water was added until a clear solution was obtained. This was treated with activated charcoal, filtered and concentrated by boiling, besides adding more ethanol now and then. On cooling, 2.2 parts of colorless crystals of the disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)propane monohydrate were obtained.

Analysis:

Found in: C, 54.1, H, 2.86$

<C>23<H>l4<Na>2<O>l0<H2O>

requires: C, 53.7, H, 3.11$.

Example 2.

$a) 1, 3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane.

In the method from example 1 (a), 10 parts of 2,6 dihydroxyacetophenone, 4.6 parts of potassium carbonate and 7.15 parts of 1,3-dibromopropan-2-ol were reacted in acetone, and 3 parts of pure 1,3-bis were obtained (2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane. as colorless crystals melting between 165 and 166°C.

Analysis:

Found: C, 63.5, H, 5.86%

C19H20°7 requires: c> 63>3, H> 5, 56%.

(b) 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane.

To a solution of 970 parts of 2,6-dihydroxyacetophenone and 325 parts of epichlorohydrin in 2,500 parts of hot isopropanol, a solution of 233 parts of Q5% KOH in 2,500 parts of isopropanol and sufficient water (about 100 parts ) to dissolve the solid. The mixture was heated under stirring and reflux for 48 hours. Half of the solvent was distilled off and 5000 parts of water were added. The mixture was cooled and the solid was filtered off, washed with water and ether. It was then recrystallized from 12,500 parts of isopropanol and a first yield of 380 parts was obtained and a second yield after concentration, of 300 parts of 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane identical to what was obtained in example 2 (a). (c) Diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane.

In the method from example 1 (b), 4.6 parts of 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane were reacted with diethyl oxalate, and the product obtained was ring-closed, after which 4.4 parts of the pure diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane as pale yellow crystals from a mixture of benzene and petroleum ether. The crystals melted between 180 and 182°C.

Analysis:

Found: C, 6l.5, H, 4.6l% <C>27<H>24°11 requires: c> 6l.8, H> ^, 57%. (d) The disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane.

By the method from example 1 (c), was

4 parts of the diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane saponified and 3j2 parts of the disodium salt tetrahydrate were obtained as colorless crystals from aqueous alcohol.

Analysis:

Found: C, 47.8, H, 3.8, Na, 7.755 <C>23<H>ll|Na20114H20 requires: C, 47.3, H, 3.79, Na, 7, 7%.

Example 3.

(a) 1,4-bis(2-acetyl-3-hydroxyphenoxy)but-2-ene.

In the procedure from Example 1 (a), 15.2 parts of 2,6-dihydroxy-acetophenone were condensed with 10.7 parts of 1,4-dibromobut-2-ene, whereupon 6 parts of 1,4-bis(2- acetyl-3-hydroxyphenoxy)-but-2-ene which melted between 145 and 146°C. (b) The disodium salt of 1,4-bis(2-carboxychromon-5-yloxy)but-2-ene.

By the method from example 1 (b), was

5 parts of 1,4-bis(2-acetyl-3-hydroxyphenoxy)but-2-ene condensed with diethyl oxalate, whereupon 3 parts of the diethyl ester of 1,4-bis(2-carboxychromon-5-yloxy)but-2 were obtained -one as yellow crystals from ethanol. The melting point was between 215 and 217°C.

Analysis:

Found: C, 64.1, H, 4.69/5

C28H24°11 requires: C, 64.6, H, 4.6%.

Saponification of 2 parts of the diethyl ester of 1,4-bis(2-carboxychromon-5-yloxy)but-2-ene by the method from example 1 (c) gave 1.5 parts of the disodium salt.

Example 4.

Disodium salt- the tetrahydrate of 1, 12- bis(2- carboxychromon-5- yloxy)-2, 11- dihydroxy- 4, 9- dioxadodecane.

A solution of 10 parts of 2,6-dihydroxyacetophenone, 5.6 parts of butane-1,4-diol diglycidyl ether and 0.1 part of a 40% aqueous solution of benzyltrimethylammonium hydroxide in 14 parts of dioxane was kept heated at 100°C in a closed vessel for 60 hours. The dioxane was removed under reduced pressure leaving a thick yellow oil. This oil was extracted several times with boiling ester,

and the combined extracts were fractionally precipitated with petroleum ether. The first faction, which was approx. 5 parts of a clear yellow oil, could not be crystallized or distilled, but had an infrared spectrum consistent with what would be expected for 1,12-bis(2-acetyl-3-hydroxyphenoxy)-2,11-dihydroxy- 4,9-dioxadodecane.

The oil was condensed with diethyl oxalate by the method from example 1 (b) and 3 parts of the diethyl ester of 1,12-bis(2-carboxychromon-5-yloxy)-2,11-dihydroxy-4,9-dioxadodecane were obtained, as a oil. This oil was stirred and heated with a saturated aqueous solution

of sodium bicarbonate until dissolved. The solution was then filtered and acidified with dilute hydrochloric acid. The precipitate was dissolved in ethanol and ethyl acetate, treated with activated charcoal, filtered and precipitated with petroleum ether, after which the solid was recrystallized from acetone and ether, and one part of the pure 1,12-bis(2-carboxychromone-5- yloxy)-2,11-dihydroxy-4,9-dioxadodecanedihydrate as colorless crystals which melted with decomposition at 80°C. Analysis: Found: C, 55.3, H, 5.24% <C>30<H>30<O>lI}2H20 requires: C, 55.3, H, 5, 22%

1,12-bis(2-carboxychromon-5-yloxy)-2,11-dihydroxy-4,9-dioxadodecanedihydrate (0.325 parts) was dissolved in a solution of 0.084 parts sodium bicarbonate in 100 parts water. The solution was filtered and freeze-dried, and 0.3 parts of the disodium salt tetrahydrate were obtained.

Analysis:

Found; C, 48.7, H, 4.75% <C>30<H>28Na2O1i|4H2O requires: C, 49.3, H, 4.9%.

Example 5- (a) 1,4-bis(2-acetyl-3-hydroxyphenoxy)butane. ^

In the method from example 1 (a), 2,6-dihydroxyacetophenone was reacted with 1,4-dibromobutane, and 1,4-bis(2-acetyl-3-hydroxyphenoxy)butane was obtained, which melted between 219 and 221°C.

Analysis:

Found: C, 66.0, H, 6.0%

C20H22°6 requires: c> 67.0, H 6.2%

(b) The diethyl ester of 1,4-bis(2-carboxychromon-5-yloxy)butane.

In the procedure from example 1 (b), 1,4-bis(2-acetyl-3-hydroxypheoxy)butane was condensed with diethyl oxalate and formed the diethyl ester of 1,4-bis(2-carboxychromon-5~yloxy)butane, which was crystallized from ethyl acetate and isopropanol, and which melted between 195 and 199°C.

Analysis:

Found: C, 62.4, H, 5.1%

<C>28<H>26°10H2° requires: c> 62>3, H, 5.2% (c) The disodium salt of 1, 4- bis( 2- carboxychromon- 5~ yloxy) butane.

The diethyl ester of 1,4-bis(2-carboxychromon-5-yloxy)butane was hydrolyzed by heating with aqueous sodium bicarbonate until the compound dissolved, after which the solution was filtered and acidified. The precipitate was recrystallized from methanol, and pure 1,4-bis(2-carboxychromon-5-yloxy)butane monohydrate was obtained which melted between 228 and 230°C.

Analysis:

Found: C, 58.6, -H, 3.95%

<C>24<H>l8°10H2° requires: C, 59.5, H, 4.2%

This acid was dissolved in an equivalent amount of sodium bicarbonate solution and freeze-dried to prepare the disodium salt.

Example 6.

The disodium salt of 1, 5~ bis( 2~ carboxychromon- 5~ yloxy) pentane.

2,6-dihydroxyacetophenone was reacted with 1,5-dibromopentane as in example 1(a), and 1,5_bis(2-acetyl-3-hydroxyphenoxy)pentane was produced which melted between 131 and 133°C Analysis:

Found: C, 67.4, H, 6.3%

C21H2406 requires: C, 67.7, H, 6.5%

This diketone with diethoxalate as in example 1 (b) was to prepare the diethyl ester of 1,5-bis(2-carboxy-chromon-5-yloxy)pentane, which was crystallized from ethanol and melted between 150 and 152°C.

Analysis:

Found: C, 64.6, H, 5.3%

C29<H>28°10 requires: c> 64>8> E> 5.3%

The ester was hydrolysed as in Example 5 (c) and the acid was crystallized as a monohydrate from ethanol, melting between 226 and 228°C.

Analysis:

Found: C, 60.3, H, 4.7%

<C>25<H>20<O>10H2° requires: c> 60.2, H, 4.4%

The acid was then converted to the disodium salt by the method from example 5 (c).

Example 7»

The disodium salt of 1,6-bis(2-carboxychromon-5-yloxy)hexane.

2,6-Dihydroxyacetophenone was reacted with 1,6-dibromohexane as in example 1 (a), and 1,6-bis(2-acetyl-3-hydroxyphenoxy)hexane was produced, which was crystallized from ethanol and melted between 147, 5 and 148.5°C.

Analysis:

Found: C, 68.1, H, 6.7%

C22H26°6 requires: c> 68.4, H, 6.8%

This diketone was condensed with diethoxylate by the method of example 1 (b) to obtain the diethyl ester of 1,6-bis(2Carboxychromon-5-yloxy)hexane, which was crystallized from ethanol and melted between 15°C and 155°C.

Analysis:

Found: C, 60.2, H, 4.9%

C26H22°10<H>2° requires: c> 6o>9, H, 4.7%

The disodium salt of the acid was then prepared as in Example 5 (c).

Example 8.

The disodium salt of 1,10-bis(2-carboxychromon-5-yloxy)decane.

2,6-dihydroxyacetophenone was condensed with 1,10-dibromodecane as in example 1 (a) to produce 1,10-bis(2-acetyl-3-hydroxyphenoxy)decane which after crystallization from ethyl acetate melted between 102.5 and 104 °C.

Analysis:

Found: C, 70.0, H, 7.4*

C26H35°6 ^ ever: C, 70.6, H, 7.7%

This diketone was reacted with diethyl oxalate as in example 1 (b) to produce the diethyl ester of 1,10-bis(2-carboxychromon-5-yloxy)decane, which after crystallization from ethanol and dioxane melted between 146.5 and 148°C .

Analysis:

Found: C, 67.4, H, 6.4%

<C>34<H>38°10 requires: c> 67.3, H, 6.3%

The ester was hydrolysed by boiling with aqueous sodium bicarbonate, and the slightly soluble disodium salt was obtained, which was recrystallized from water.

Analysis:

Found: C, 61.0, H, 5.2%

<C>30H28Na2°10 requires: C, 60.6, H, 4.7%

Example 9»

The disodium salt of 1,7-bis(2-carboxychromon-5-yloxy)-2,6-dihydroxy-4-oxaheptane.

2,6-dihydroxyacetophenone was reacted with diglycidyl ether as in example 4, and 1,7-bis(2-acetyl~3-hydroxypheoxy)2,6-dihydroxy-4-oxaheptane was obtained which, after crystallization from ethyl acetate and petroleum ether, melted between 129 and 131°C.

Analysis:

Found: C, 60.4, H, 6.3%

C22H26°9 requires: c> 60.8, H, 6.0%

This diketone was reacted with diethyl oxalate, and the bischromonide ethyl ester was obtained as an oil which did not crystallize. This ester was hydrolyzed as in example 5 (c), and 1,7-bis(2-carboxychromon-5-yloxy)-2,6-dihydroxy-4-oxaheptane monohydrate was obtained, which melted between 216 and 218°C.

Analysis:

Found: C, 55.5, H, 3.4%

<C>26<H>22°13H2° requires: c> 55.7, H, 4.3%

The disodium salt was then prepared as

in Example 5 (c).

Example 10.

The disodium salt of 1, 5-bis(2-carboxychromon-5-yloxy)~ 3-oxapentane.

2,6-dihydroxyacetophenone was condensed with 2,2'-dibromodiethylether as in example 1 (a), and 1,5_bis was obtained

(2-acetyl-3-hydroxyphenoxy)-3-oxapentane, which after crystallization from methanol melted between 120.5 and 121.5°C.

Analysis:

Found: C, 63.5, H, 5.1%

C22G22°7 requires: C, 64.1, H, 5.9%

This compound was condensed with diethyl oxalate as in example 1 (b), and the diethyl ester of 1,5-bis(2-carboxychromon-5-yloxy)-3-oxapentane was obtained, which after crystallization from methanol melted between 129 and 131.5°C..

Analysis:

Found: C, 62.3* H, 4.9%

C28<H>26°11 requires: C, 62.4^ H, 4.9%

The ester was hydrolyzed as in example 5 (c), whereupon the acid was obtained which melted between 219 and 220°C after crystallization from ethanol and dioxane.

Analysis:

Found: C, 59.8, H, 3.9%

C25H18°11 requires: c> 59.8, H, 3.8%

The disodium salt of the acid was then prepared as in Example 5 (c).

Example 11.

The disodium salt of 1,4-bis(2-carboxychromon-5-yloxy)-2,3-dihydroxy-butane.

The 2,6-dihydroxyacetophenone was reacted with 1,2:3,4-bisepoxybutane as in Example 4, whereupon 14,-bis(2-acetyl-3~hydroxyphenoxy)-2,3-dihydroxybutane was obtained, which melted between 211 and 212°C after crystallization from dioxane.

Analysis:

Found: C, 6l.0, H, 5.7%

C20H22°8 requires: c> 61.5, H, 5.7%

This compound was condensed with diethyl oxalate as in example 1 (b), whereupon the diethyl ester of 1,4-bis(2-carboxychromon-5-yloxy)-2,3-dihydroxybutane was obtained, which melted between 224 and 226°C.

Analysis:

Found: C, 59.2, H, 4.6%

<C>28<H>26°12 requires: c> 60.6, H, 4.7%

This compound was hydrolyzed as in example 5 (c), and the acid was obtained as a dihydrate, which melted between 124994 260 and 262°C.

Analysis:

Found: C, 54.0, H, 3.7%

<C>24<H>l8°122H2° requires: C, 54.0, H, 4.1%

This dihydrate was then converted to the disodium salt as in example 5 (c).

Example 12.

The disodium salt of 1,4-bis(2-carboxychromon-5-yloxy)-2-hydroxybutane.

2,6-Dihydroxyacetophenone was condensed with l-bromo-3,4-epoxybutane by boiling acetone in the presence of potassium carbonate, and 1,4-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxybutane was obtained which melted between 207.5 and 208.5°C after crystallization from methanol.

Analysis:

Found: C, 63.4, H, 5.8%

C20H22°7 requires: c> 64.2, H, 5.9%

This compound was condensed with diethyl oxalate as in example 1 (b), whereupon the diethyl ester of 1,4-bis(2-carboxychromon-5-yloxy)-2-hydroxybutane was obtained, which melted between 216 and 217°C, after crystallization from a mixture of chloroform, ethyl acetate and petroleum ether.

Analysis:

Found: C, 62.7 H, 5.2%

C28H26°11 requires: c> 62.4, H, 4.9%

This compound was hydrolysed as in example 5 (c), and the acid was obtained as a monohydrate, which melted between 226 and 227°C.

Analysis:

Found: C, 57.1, H, 3.9%

C24Hl8°llH2° requires: c> 57.6, H, 4.0%

This compound was then converted into the disodium salt as in Example 5 (c).

Example 13.

The disodium salt of 1,5~ bis(2-carboxychromen-7-yloxy) pentane.

The ethyl 7-hydroxychromon-2-carboxylate was condensed with half an equivalent of 1,5-dibromopentane by heating in acetone in the presence of potassium carbonate, and the diethyl ester of 1,5-bis(2-carboxychromon-7-yloxy)pentane was obtained melting between 148 and 150°C after crystallization from ethanol.

Analysis:

Found: C, 64.6, H, 5.3%

C29<H>28°10 requires: c> 64'8> H> 5.3$

This ester was hydrolyzed as in Example

5 (c), and the acid obtained melted between 283 and 284°C.

Analysis:

Found: C, 6l,8, H, 4.2%

C25<H>20°10 requires: c> 62.4, H> 4>2^

The acid was then converted to the disodium salt as in Example 5 (c).

Example 14.

The disodium salt of 1,5-bis(2-carboxy-8-chlorochromon-5-yloxy)pentane.

A mixture of 4.62 parts of 1,5-bis(2-acetyl-3-3-hydroxyphenoxy)pentane (from Example 6) and 2.7 parts of sulfuryl chloride in 300 parts of dry ether was stirred for 7 hours at room temperature. The solution was filtered and evaporated to dryness, leaving a yellow solid. This was recrystallized from ether, and 2.36 parts of 1,5-bis(2-acetyl-4-chloro-3-hydroxyphenoxy)pentane were obtained as pale yellow prisms, which melted at 96°C.

This compound was condensed with diethyl oxalate as in example 1 (b), and the obtained diethyl ester of 1,5-bis(2-carboxy-8-chlorochromon-5-yloxy)pentane melted between 162 and 164°C after crystallization from ethanol.

Analysis:

Found: C, 57.7, H, 4.3%

<C>29<H>26C12°10 requires: c> 57.5, H, 4.3%

The ester was hydrolyzed as in Example 5 (c), and the resulting acid melted at 244°C after crystallization from ethanol.

Analysis:

Found: C, 54.2, H, 4.6, Cl, 12.9% <C>25<H>l8Cl2010 required: C, 54.7, H, 3.28, Cl, 12.9?

The acid was converted into the disodium salt which

in example 5 (c).

Example 15-

(a) 2-(2,3-epoxypropoxy)-6-hydroxyaceto^phenone.

A mixture of 5.68 parts of 2,6-dihydroxyacetophenone, 10.3 parts of epichlorohydrin and 3 parts (by volume) of ethanol which was stirred and gently refluxed was slowly added to a solution of 2.58 parts of potassium hydroxide in 7 parts by volume of ethanol and 1 volume part water.

The mixture was then stirred and refluxed for 1 hour, then cooled

and added an excess of water, and the product was extracted into ether, whereupon the solution was dried over sodium sulfate. After the desiccant and solvent had been removed, there remained 5 parts of a crude

oil. This oil was extracted using hot petroleum ether (boiling

point 40-60°C), and on cooling yellow crystals of 2-(2,3-epoxypropoxy)-6-hydroxyacetophenone, melting point 6l-63°C, precipitated.

Analysis:

Found: C, 63.5, H, 5.75?

C11H12°4 requires: c> 63.45, H, 5.8%

( b) 1-( 2- acetyl- 3~ hydroxyphenoxy)~ 3~( 4- acetyl- 3~ hydroxyphenoxy) 2-hydroxypropane.

A mixture of 5 parts 2-(2,3_epoxypropoxy)

-6-Hydroxyacetophenone, 3.8 parts of resacetophenone, 20 parts by volume of dioxane and 5 drops of a trimethylbenzylammonium hydroxide solution were kept heated at 100°C in a closed bottle overnight. When cooling out

the product precipitated, and after recrystallization from dioxene, 2 parts of 1-(2-acetyl-3-hydroxyphenoxy)~3~(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane were obtained, melting at 182 to 185°C .

Analysis:

Found: C, 62.8, H, 5.4%

C19H20°7 requires: c> 63.3, H, 5.6%

( c ) 2-( 3~ chloro-2- hydroxypropoxy)- 6- hydroxyacetophenone■

A mixture of 10 parts of 2,6-dihydroxyacetophenone, 7 parts of epichlorohydrin in 18 parts by volume of dioxane and 5 drops of "Triton B" was kept heated at 100°C in a closed vessel for 2 days. The solvent was then removed under reduced pressure, and an excess of ether was added to the residue. The ether solution was decanted from the insoluble, washed with water (2 x 50 parts) and 2N sodium carbonate (3 x 25 parts). The solvent was removed after drying over sodium sulfate, and the residue was purified by chromatography using an alumina column and ether as eluent. The oil was distilled to give 2-(3-chloro-2-hydroxypropoxy)-6-hydroxyacetophenine (6 parts)

as a yellow oil, boiling point l66-l68°C at 1.5 ™.

Analysis:

Found: C, 53.7, H, 5.26%

C11H13C104 requires: c' 54.0, H, 5.32%

( d) • 1-( 2- acetyl- 3- hydroxyphenoxy)~ 3~( 4- acetyl~ 3- hydroxyphenoxy)-2- hydroxypropane.

To the above chlorohydrin (6 parts) were added 3.8 parts of resacetonephenone, 3.5 parts of anhydrous potassium carbonate and 50 parts by volume of dry acetone. This mixture was refluxed for 2 days. The insoluble material was filtered off and, after cooling, stirred in water to remove inorganic compounds. The recrystallization of the residue from dioxane gave 0.7 parts of 1-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane which melted between 182 and 185°C and was identical with the product from (b) above. A further 2 parts of this product were obtained from the acetone filtrate.

(e) 1-(2-ethoxycarbonylchromon-5-yloxy)~3~(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane.

In the procedure from example 1 (b), 1-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane was condensed with diethyl oxalate, and the obtained 1-(2-ethoxycarbonylchromone- 5-yloxy)-(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane melted between 193 and 194.5°C after crystallization from ethanol and dioxane.

Analysis:

Found: C, 62.0, H, 4.3%

C27H24°11 requires: c> 6l>8> H, 4.6%

(f) the disodium salt of 1-(2-carboxychromon-5-yloxy)~3~(2-carboxychromon-7~yloxy-2-hydroxypropane).

The ester from (e) above was hydrolyzed as

in Example 5 (c) and the acid obtained melted between 194 and 200°C with a prior softening.

Analysis:

Found: C, 55.2, H, 3.96%

<C>23<H>l6°llH2° requires: C, 54.7, H, 3.9%

This acid was dissolved in an equivalent amount of sodium bicarbonate solution and freeze-dried to prepare the disodium salt.

Example 16.

a) 1-(2-acetyl-3-hydroxyphenoxy)-5-(4-acetyl-3-hydroxyphenoxy) pentane.

. A mixture of 5.1 parts of 2,6-dihydroxyacetophenone, 7.7 parts of 1,5-dibromopentane and 2.3 parts of anhydrous potassium carbonate in 100 parts by volume of anhydrous acetone was refluxed for 20 hours. In an investigation using thin-layer chromatography, unchanged 2,6-

dihydroxyacetophenone, 1,5-bis(2-acetyl-3-hydroxyphenoxy)pentane and some thought to be 2-(5-bromopentyloxy)-6-hydroxyacetophenone. The acetone solution was concentrated to half its volume, and the residue was removed by filtration. After washing with water, this residue gave 1.9 parts of 1,5-bis(2-acetyl-3-hydroxyphenoxy)pentane. The filtrate was dried completely and chromatographed on an alumina column using ether as eluent. 2-(5-bromopentyloxy)-6-hydroxyacetophenone appeared in the first fraction, as confirmed by thin layer chromatography. Evaporation of the combined fractions gave 5 parts of an oil, which was used further without further purification. 2.4 parts of this crude oil, 1.2 parts of reacetophenone, 1 part of anhydrous potassium carbonate and 40 parts by volume of dry acetone were then refluxed for 20 hours. After cooling, the acetone solution was filtered off and evaporated to dryness. The residue was crystallized from methanol/water, and obtained 1.85 parts of 1-(2-acetyl-3-hydroxyphenoxy)-5-(4-acetyl-3-hydroxyphenoxy)pentane, mp 91 to 91J5°C

Analysis:

Found: C, 67.3, H, 6.7%

C21H24°6 requires: c> 67.7, H, 6.5%

(b) 1-(2-ethoxycarbonylchromon-5-yloxy)-5-(2-ethoxycarbonylchromon-7-yloxy)pentane.

In the procedure from example 1 (b), 1-(2-acetyl-3-hydroxyphenoxy)-5-(4-acetyl-3-hydroxyphenoxy)pentane was condensed with diethyl oxalate, and the desired product obtained melted between 149 and 152°C after crystallization from ethanol.

Analysis:

Found: C, 63.1, H, 5.3%

C29H28°10 requires: c> 64>9, H, 5.3%

(c) the disodium salt of 1-(2-carboxychromon-5-yloxy)~5~(2-carboxychromon-7-yloxy)pentane.

To 1.0012 parts of the above-mentioned bis-ester i

30 parts by volume of methanol, an amount of 0.969 N sodium hydroxide in methanol was added, just sufficient for the ester hydrolysis. The mixture was then heated on a steam bath for approx. J hour, after which the solvent was distilled off and the residue was taken up in water and filtered, after which the filtrate was acidified in hydrochloric acid. The precipitated solid was difficult to filter, and it was therefore separated from the liquid by means of centrifugation, washed twice with water and recentrifuged. 1-(2-carboxychromon-5-yloxy)~ 5~(2-carboxychromon-7-yloxy)pentane (0.25 parts) was crystallized from ethanol and had a melting point between 249 and

Analysis:

Found: C, 60.3, H, 4.4%

C25<H>20°10<H>2° C> 6°>2 H> h>h5%

This acid was dissolved in an equivalent amount of sodium bicarbonate solution and freeze-dried to prepare the disodium salt.

Example 17.

a) 1, 3- bis(2- acetyl- 3~ hydroxy- 5- methylphenoxy)- 2- hydroxypropane.

A solution of sodium ethoxide in ethanol (from

0.83 parts of sodium and 20 parts by volume of ethanol) was added to a solution of 12 parts of 2,6-dihydroxy-4-methylacetophenone and 3}34 parts of epichlorohydrin in 10 parts by volume of ethanol. The resulting mixture was stirred and refluxed for 4 hours, after which 250 parts of cooling water were added, and the solid was isolated by filtration. The crystallization from ethanol gave 4.15 parts of 1,3-bis(2-acetyl-3_hydroxy-5-methylphenoxy)-2-hydroxypropane, melting point 185-186°C.

Analysis:

Found: C, 64.1 H, 6.3%

<C>21<H>24°7 requires: c> 61j'9 H> 6>2%

b) the disodium salt of 1,3-bis(2-carboxy-7-methylchromon-5-yloxy)-2-hydroxypropane.

By the method of Example 1 (b), the above compound was condensed with diethyl oxalate, and the obtained 1,3-bis(2-ethoxycarbonyl-1-7-methylchromon-5-yloxy)-2-hydroxypropane crystallized from ethanol as colorless needles, m.p. 194-195°C The ester was hydrolysed as in example 5 (c), and acids were obtained as the monohydrate, melting point 240-241°C after crystallization from aqueous dioxane.

Analysis:

Found: C, 58.3 H, 4.4%

C25<H>20°11<H>2° requires: c> 58.4 H, 4.3% . The acid was then converted to the disodium salt as in Example 5 (c).

EXAMPLE 18.

(a) 1,3-bis(2-acetyl-4-ethyl-3-hydroxyphenoxy)-2-hydroxypropane.

2,6-Hydroxy-3-ethylacetophenone was condensed with epichlorohydrin as in Example 18 (a), and the resulting lá3~bis(2-acetyl-4-ethyl-3-hydroxyphenoxy)-2-hydroxypropane melted between 135

and 137°C (from ethanol).

Analysis:

Found: C, 66.7 H, 6.9%

<C>23<H>28°7 requires: c> 66>3 H, 6.8%

(b) the disodium salt of 1,3-bis(2-carboxy-8-ethylchromon-5-yloxy)-2-hydroxypropane.

The above compound was condensed with diethyl oxalate as in Example 1 (b), and it obtained 1,3-bis(2-ethoxy-carbonyl-8-ethylchromon-5-yloxy)-2-hydroxypropane melted between 159

and 161°C after crystallization from ethanol.

This ester was hydrolyzed as in Example

5 (c) to prepare the acid as the dihydrate, melting point 193-194°C after crystallization from ethanol.

Analysis:

Found: C, 57.5 H, 4.9%

<C>27<H>24°112H2° requires: c> 57.85 H, 5.0%

The disodium salt was prepared as in Example 5 (c).

Example 19.

The disodium salt of 1-(2-carboxychromon-5-yloxy)-3~(2-carboxy-8-ethylchromon-5-yloxy)-2-hydroxypropane.

2,6-Dihydroxy-3-ethylacetophenone was condensed with 2-(2,3-epoxypropoxy)-6-hydroxyacetophenone as in Example 15 (b) and the obtained 1-(2-acetyl-3~hydroxyphenoxy)-3_(2 -acetyl-4-ethyl-3~ hydroxyphenoxy)-2-hydroxypropane melted between 102 and 103°C after crystallization from aqueous ethanol.

Analysis:

Found: C, 64.8 H, 6.3%

C21H24°7 requires: c> 6i}>9 H, 6.2%

This diketone was condensed with diethyl oxalate using the procedure of Example 1 (b) to obtain 1-(2-ethoxycarbonylchromon-5-yloxy)-3-(2-ethoxycarbonyl-8-ethylchromon-5-yloxy)-2-hydroxypropane melted between 166 and 166.5°C after crystallization from ethanol.

Analysis:

Found: C, 62.6 H, 4.95%

<C>29<H>28°11 requires: c> 63.0 H, 5.1%

The ester was hydrolysed as in example 5 (c), and the acid dihydrate was obtained, melting point 190-192 oC after crystallization from ethanol.

Analysis:

Found: C, 56.8 H, 4.4%

C25<H>20°112H2° requires: c> 56.4 H, 4.5%

The disodium salt was prepared as in Example 5 (c).

Example 20.

The disodium salt of 1,5-bis(2-carboxychromon-8-yloxy)pentane.

2.3-Dihydroxyacetophenone was condensed with 1,5-dibromopentane using the procedure of Example 1 (a) to yield 1,5-bis(2-hydroxy-3-acetylphenoxy)pentane, melting between 103.5 and 104.5°C after crystallization from ethanol.

Analysis:

Found: C, 67.7 H, 6.9%

C21H24°6 requires: c> 67.7 H, 6.5%

This ketone was condensed with diethyl oxalate as in example 1 (b), and one obtained 1,5-bis(2-ethoxycarbonylchromon-8-yloxy)pentane, melting point 128-130°C from ethanol.

Analysis:

Found: C, 64.5 H, 5.4%

C29^28°10 requires: c> 64>9 H, 5.3%

As in example 5 (c), this ester was hydrolyzed to the acid monohydrate, melting point 237-238°C from ethanol. Analysis:

Found: C, 59.9 H, 4.3%

<C>25H20°10H2° requires: c> 60.2 H, 4.45%

This acid was then converted to the disodium salt as in example 5 (c).

Example 21.

The disodium salt of 1,5-bis(2-carboxy-8-methylchromon-7-yloxy) nicely an.

2.4-Dihydrosky-3-methylacetophenone was condensed with 1,5-dibromopentane using the procedure from Example 1 (a) and 1,5-bis(4-acetyl-3-hydroxy-2-methylphenoxy)pentane was obtained which melted between 116 and 117°C from ethanol.

Analysis:

Found: C, 68.4 H, 7.3%

<C>23H28°6 requires: G> 69.0 H, 7.05%

This product was condensed with diethyl oxalate as described in example 1 (b), and after crystallization from dioxane and ethanol, 1,5-bis(2-ethoxycarbonyl-8-methylchromon-7-yloxy)pnetane was obtained, which melted between 196 and 197°C

Analysis:

Found: C, 65.7 H, 6.05%

C31<H>32°10 requires: c> 65.95 H, 5.65%

The ester was hydrolyzed using the procedure of Example 5 (c), and the resulting acid melted between 274 and 176°C after crystallization from dioxane.

Analysis:

Found: C, 63.9 H, 5.0%

C27H2it01Q requires: C, 63.8 H, 4.8%

The disodium salt of this acid was prepared as in Example 5 (c).

Example 22.

The disodium salt of 1,3-bis(2-carboxy-8-methylchromon-7-yloxy)-2-hydroxypropane.

2,4-dihydroxy-3~niethylacetophenone was condensed with prichlorohydrin by the method from example 18 (a) and after crystallization from ethanol, 1,3-bis(4-acetyl-3~hydroxy-2-methylphenoxy)-2-hydroxypropane was obtained which melted between 151 and 153°C. Analysis:

Found: C, 64.5 H, 6.25%

C21H24°7 requires: C, 64.9 H, 6.2%

This ketone was then condensed with diethyl oxalate as described in example 1 (b), and it obtained 1,3-bis(2-ethoxy-carbonyl-8-methylchromon-7-yloxy)-2-hydroxypropane melting between 191 and 193°C after crystallization from dioxane and ethanol.

Analysis:

Found: C, 63.0 H, 5.24%

<C>29H28°11 requires: c» 63.0 H, 5.1%

The above ester was hydrolysed as in Example 5 (c) and gave 1,3-bis(2-carboxy-8-methylchromon-7-yloxy)-2-hydroxypropane dihydrate which melted between 272 and 275°C.

Analysis:

Found: C, 56.7 H, 4.35*

C25H20°112H2° requires: c> 56.4 H, 4.5%

The disodium salt of the acid was prepared as

in Example 5 (c).

Example 23.

The disodium salt of 1,5-bis(2-carboxychromon-5-yloxy)-3-methylpentane.

2,6-Dihydroxyacetophenone was condensed with 1,5-dibromo-3-methylpentane in the same manner as in Example 1 (a), and the

obtained 1,5~bis(2-acetyl-3_hydroxyphenoxy)-3~methylpentane melted

o

between 123 and 124 C after crystallization from ethanol.

Analysis:

Found: C,' 68.8 H, 6.9%

C22H26°6 requires: c> 68.4 H, 6.8%

The ketone was then condensed with diethyl oxalate as in example 1 (b) and gave after crystallization from ethanol 1,5-bis(2-acetyl-3-hydroxyphenoxy)-3-methylpentane melted between 123 and 124°C after crystallization from ethanol.

Analysis:

Found: C, 65.3 H, 5.4%

<C>30<H>30<0>10 requires: C, 65.4 H, 5.5%

Hydrolysis of the above-mentioned ester by the method described in example 5 (c) gave, after crystallization from aqueous ethanol, 1,5-bis(2-carboxychromon-5-yloxy)-3-methylpentamonohydrate, melting point 215-217°C.

Analysis:

Found: C, 6l.6H, 4.8%

C, 60.9 H, 4.7%

This acid was converted to the disodium salt in the same way as described in example 5 (c).

Example 24.

The disodium salt of 1, 3~ bis (2- carboxyl-6- k' lorchromon-7~ yloxy )- 2- hydroxypropane.

2,4-dihydroxy-5-chloroacetophenone is condensed with epichlorohydrin using the procedure described in Example 17 (a) and after crystallization from n-propanol, 1,3-bis(4-acetyl-2-chloro-5 hydroxyphenoxy)-2-hydroxypropane, melting point 19 7 - 199°C.

Analysis:

Found: C, 52.6 H, 4.7%

C19Hl8C12°7 requires: c > 53.1 H, 4.2%

The ketone was condensed with diethyl oxalate as described in example 1 (b), and after crystallization from ethanol gave 1,3-bis(2-ethoxycarbonyl-6-chlorochromon-7-yloxy)-2-hydroxypropane, melting point 199-202°C.

Analysis:

Found: C, 54.7 H, 3.6%

<C>27H22C12°11 requires: c> 54.6 H, 3.7%

This ester was hydrolyzed using the procedure described in Example 1 (c) and the disodium salt of 1,3-bis(2-carboxy-6-chlorochromon-7-yloxy)-2-hydroxypropane tetrahydrate was obtained from aqueous ethanol.

Example 25.

The disodium salt of 1-(2-carboxychromon-5-yloxy)~3~(2-carboxy-6-chlorochromon-7-yloxy)-2-hydroxypropane.

2,4-dihydroxy-5-chloroacetophenone was condensed with 2-(2,3-epoxypropoxy)-6-hydroxyacetophenone as in Example 15 (b) to give 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane, melting point 139-140°C.

This diketone was condensed with diethyl oxalate as described in Example 1 (b) and, after crystallization from ethanol, gave 1-(2-ethoxycarbonylchromon-5-yloxy)~3_(2-ethoxycarbonyl-6-chloro-chromon-7-yloxy)-2-hydroxypropane which melted between 166 and l68°C. Analysis:

Found: C, 57.4 H, 4.3%

<C>27<H>23C1 °ll requires>: c, 58.0 H, 4.1%

This ester was converted to the disodium salt using the procedure described in Example 1 (c) and, after crystallization from aqueous ethanol, gave the disodium salt of 1-(2-carboxychromon-5-yloxy)-3-(2-carboxy-6-chlorochromone) -7-yloxy)-2-hydroxypropane tetrahydrate.

Analysis:

Found: C, 45.5 H, 2.9%

C23H13C1Na2°ll<1>|H20 requires: C, 44.6 H, 3.4%

Example 26.

The disodium salt of 1,5-bis-(2-carboxychromon-6-yloxy)pentane.

Quinacetophenone was condensed with 1,5-dibromopentane as described in example 1 (a) and the resulting 1,5-bis(3-acetyl-4-hydroxypheoxy)pentane melted between 107 and 109°C after crystallization from ethanol.

Analysis:

Found: C, 67.8 H, 6.8%

C21H24°6 requires: c» 6?.7 H, 6.5%

The diketone was condensed using the procedure of Example 1 (b) with diethyl oxalate to give 1,5-bis(2-ethoxycarbonylchromon-6-yloxy)pentane.

Analysis:

Found: C, 64.7 H, 5.5%

C29<H>28°10 requires: c><g>4.9 H> 5.3%

The diketone was hydrolysed using the procedure described in Example 5 (c) and on crystallization from dioxane gave 1,5-bis(2-carboxychromon-6-yloxy)pentane melting between 275 and 277°C.

Analysis: .

Found: C, 62.6 H, 4.5%

<C>25<H>20°10 requires: C> 62'5 H, 4.2%

This acid was converted to the disodium salt by the method described in example 5 (c).

Example 27.

The disodium salt of 1, 3~ bis(2-carboxychromon-7-yloxy)-2-hydroxypropane.

Resacetophenone was condensed with epichlorohydrin as in example 18 (a) and gave 1,3-bia(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane, which melted between 152 and 154°C after crystallization from ethanol.

Analysis:

Found: C, 63.5 H, 6.2%

<C>19<H>20°7 requires: c> 63.3 H, 5.6%

1,3-bis(4-acetyl-3_hydroxyphenoxy)-2-hydroxypropane was condensed with diethyl oxalate as described in Example 1 (b) and the obtained 1,3-bis(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane melted between 178 and 180°C after crystallization from aqueous dioxane.

Analysis:

Found: C, 62.2 H, 4.5%

<C>27<H>24°11 requires: c> 61.8 H, 4.6%

The ester was hydrolyzed as in Example 5 (c) and after crystallization gave dioxane-water 1,3-bis(2-carboxychromon-7-yloxy)-2-hydroxypropane monohydrate which melted between 155 and 165°C. Analysis:

Found: C, 56.8 H, 3.7%

<C>23<H>l6°llH2° requires: c>- 56.8 H, 3.7%

The disodium salt of this acid was prepared as in Example 5 (c).

Example 28.

The disodium salt of 1,2-bis(2-carboxychromon-5-yloxymethyl)benzene.

1,2-bis(bromomethyl)benzene was condensed with

2,6-dihydroxyacetophenone as described in example 1 (a) and gave after crystallization from ethanol 1,2-bis(acetyl-3-hydroxyphenoxymethyl)benzene, melting point 148-153°C.

Analysis:

Found: C, 70.5 H, 5.4%

C24H22°6 requires: c> 70.9 H, 5.5%

The diketone was condensed with diethyl oxalate as in Example 1 (b) to give 1,2-bis(2-ethoxycarbonylchromon~5-yloxymethyl)benzene melting between 204 and 20.6°C.

Analysis:

Found: C, 68.1 H, 4.55%

C32<H>26°10 requires: c><g>7.4 H, 4.6%

The ester was saponified in the same way as described in example 1 (c) and the disodium salt was obtained as the tetrahydrate.

Analysis:

Found: C, 54.0 H, 3.3%

<C>28<H>l6Na2°10<l>jH20 requires: c> 53.3 H, 3.8%

Example 29-

The dinium salt of 1, 3~ bis(2-carboxychromon-6-yloxy)-2-hydroxypropane.

Quinacetophenone was condensed with epichlorohydrin as described in example 17 (a) and after crystallization from aqueous methanol gave 1,3-bis(3-acetyl-4-hydroxyphenoxy)-2-hydroxypropane, melting point 127-129°C.

Analysis:

Found: C, 62.6 H, 5.7%

C19H20°7 requires: c><g>3.3 H, 5.6%

The ketone was condensed as described in example 1 (b) with diethyl oxalate, and gave 1,3-bis(2-ethoxycarbonylchromon-6-6yloxy)-2-hydroxypropane, melting point 187-189°C after crystallization from ethanol-dioxane-water.

Analysis:

Found: C, 62.0 H, 4.3%

G27H24°11 requires: C' 61.8 E' ^

Hydrolysis of this ester as described in example 17 (c) gave 1,3-bis(s-carboxychromon-6-yloxy)-2-hydroxypropane dihydrate, melting point 268-270°C (from ethanol-dioxane-water).

Analysis:

Found: C, 55.0 H, 3.3%

<C>23<H>l6°ll2H2° requires: c» 54.7 H, 3.9%

The disodium saltate of this acid was prepared as described in Example 5 (c).

Example 30-

The disodium salt of 1-(2-carboxychromon-5-yloxy)-J>-(2-carboxychromon-6-yloxy)-2-hydroxypropane.

Quinacetophenone was condensed with epichlorohydrin as described in Example 15 (a) and gave after crystallization from petroleum ether (boiling point 60-80°C) 5-(2,3-epoxypropoxy)-2-hydroxyacetophenone, melting point 76-69°C.

Analysis:

Found: C, 64.0 H, 5.6%

<C>11<H>12°4 requires: C, 63.45 H, 5.8%

This epoxide was condensed with 2,6-dihydroxyacetophenone as described in Example 15 (b) to give 1-(2-acetyl-3-hydroxyphenoxy)-3-(3-acetyl-4-hydroxyphenoxy)-2-hydroxypropane, mp 185 and 186°C after crystallization from ethanol.

Analysis:

Found: C, 63.5 H, 5.6%

C19H20°7 requires: C' 63j3 Hj 5' 6%

This compound was condensed with diethyl oxalate as described in example 1 (b) and after crystallization from ethanol one obtained 11(2-ethoxycarbonylchromon-5-yloxy-)-3-(2-ethoxycarbonylchromon-6-yloxy_)-2-hydroxypropane, m.p. 164-166°C. Analysis:

Found: C, 62.4 H, 4.5%

<C>27<H>24°11 requires: c> 61.8 H, 4.6%

This ester was hydrolyzed to the disodium salt using the procedure of Example 1 (c).

Example 31-

The disodium salt of 1-(.2-carboxychromon-5-yloxy)-3~(2-carboxychromon-8-yloxy)-2-hydroxypropane.

2-(2,3-epoxypropoxy)-6-hydroxyacetophenone was condensed with 2,3-dihydroxyacetophenone as described in example 15 (b) and gave after crystallization from ethanol and dioxane 1-(2-acetyl-3-hydroxyphenoxy) -3~(3-acetyl-2-hydroxyphenoxy)-2-hydroxypropane which melted between 166 and 169°C.

Analysis:

Found: C, 63.6 H, 5.7%

CigH2007 requires: C, 63.3 H, 5.6%

After condensation with diethyl oxalate, as described in Example 1 (b), this compound gave 1-(2-ethoxycarbonyl-chromon-5-yloxy)-J>-(2-ethoxycarbonylchromon-8-yloxy)-2-hydroxypropane which melted between 162 and 165°C after crystallization from ethanol. Analysis:

Found: C, 6l.6H, 4.75%

C27H24°11 requires: c> 6l>8 H> h, >^ °

This ester was saponified as described in example 1 (c), and the disodium salt was obtained.

Example 32.

The disodium salt of 1,8-bis(2-carboxychromon-5-yloxy)octane.

2,6-Dihydroxyacetophenone was condensed with 1,8-dibromooctane as described in example 1 (a) and gave after crystallization from benzene 1,8-bis(2-acetyl-3-hydroxyphenoxy)octane, melting point 107-109°C.

Analysis:

Found: C, 69.6 H, 7 .255?

<C>24<H>30°6 requires: c><g>9>5 H, 7.3%

This diketone was reacted with diethyl oxalate

in the usual way (Example 1 (b)) and after crystallization from ethanol, 1,8-bis(2-ethoxycarbonylchromon-5-yloxy)octane was obtained, melting point 139-141°C

Analysis: ,

Found: C, 66.0 H, 6.0%

C32<H>3l|010 requires: C, 66.4 H, 5.9%

Hydrolysis of this ester as described in example 5 (c) gave 1,8-bis(2-carboxychromon-5-yloxy)octane monohydrate with an undetermined melting point.

Analysis:

Found: C, 61.1 H, 5.4%

<C>28<H>26°10H2° requires: c> 62>2 H» 5.2%

The disodium salt of this compound was prepared as described in Example 5 (c).

Example 33-

The disodium salt of 1,9-bis(2-carboxychromon-5-yloxy)nonane.

2,6-dihydroxyacetophenone was condensed with 1,9-dibromononane as described in example 1 (a) and gave after crystallization from ethanol 1,9~bis(2-acetyl-3-hydroxyphenoxy)nonane, melting point 55-59°C

Analysis:

Found: C, 69.7 H, 7.5%

C25<H>32°6 requires: c> 70.1 H, 7.5%

This diketone was condensed with diethyl oxalate as described in example 1 (b), and after crystallization from ethanol gave a 1,9-bis(2-ethoxycarbonylchromon-5-yloxy)ninane which melted between 128 and 129°C.

Analysis:

Found: C, 66.4 H, 5.2%

<C>33<H>36°10 requires: c~ > 66>9 H, 6.1%

Hydrolysis of this ester as described in example 5 (c) gave 1,9 bis(2-carboxychromon-5-yloxy)nonane which after crystalline precipitation gave dioxane and petroleum ether (boiling point 60-80°C), had a melting point between 123 and 127°C.

Analysis:

Found: C, 64.5 H, 5.7%

C29<H>28°10 requires>: c> 64»9 H, 5.3%

The disodium salt of this acid was prepared as described in Example 5 (c).

Example 34.

The disodium salt of 1, 2-bis(2-carboxychromon-5-yloxy)ethane.

2,6-dihydroxyacetophenone was condensed with 12,-dibromoethane as described in example 1 (a), and 1,2-bis(2-acetyl-3-hydroxyphenoxy)ethane was obtained, which melted between 188 and 189°C after crystallization from acetic acid.

Analysis:

Found: C, 65.7 H, 5.4%

Cl8Hl8°6 requires: c» 65.4 H, 5.5%

Condensation of this compound with diethyl oxalate was carried out as described in Example 1 (b) and after crystallization from dioxane gave 1,2-bis(2-ethoxycarbonylchromon-9-yloxy)ethane melting between 264 and 265°C

Analysis:

Found: C, 63.0 H, 4.7%

Q26<H>22°10 requires: • c> 63>15 H, 4.5%

This ester was hydrolyzed as described in Example 17 (c) to give 1,2-bis(2-carboxychromon-5-yloxy)ethane, which melted between 262 and 263°C.

Analysis:

Found: C, 59.6 H, 3.1%

<C>22<H>l4°10 requires>: c> 60.3 H, 3.2%

The disodium salt of this acid was prepared as described in Example 5 (c).

Investigation of the therapeutic properties of manufactured compounds.

The activity of the new bis chromonyl compounds has been assessed by antigen inhalation test on volunteer patients suffering from specific allergic asthma. The degree of asthma induced by the inhalation of an antigen to which the volunteers were sensitive can be measured by repeated assessment of the increase in airway resistance.

A suitable spirometer was used to measure the forced expiratory volume in one second (F.E.V.^ q) and consequently also the change in airway resistance. A compound's anti-allergic activity was estimated from the difference between the maximum percent F.E.V.^ Q reduction that followed control and test trials after drug administration under identical experimental conditions.

Thus:

The compounds to be tested were supplied as an aerosol by inhalation for 5 minutes. 2 hours before the experiment was carried out. The compounds were dissolved in sterile water at a concentration of 0.5% and were aerosolized from a Wright nebulizer, the air flow of which was 10 liters/minute, and which propelled a total of 5 mg of the compound. The following table shows the protection achieved with a wide range of the new bis-chromonyl compounds.

Clinical studies with 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane in the form of its disodium salt, hereinafter referred to as compound A, have been conducted on volunteers with clinical evidence of allergic asthma. In some of the volunteers, the asthma was identified as extrinsic asthma, i.e. it was induced by specific antigen. However, the majority of the volunteers suffered from intrinsic asthma, i.e. no results were obtained from a wide range of skin and aerosol tests.

In those cases where each of the volunteers suffered from extrinsic asthma, it was possible to determine the degree of protection quantitatively, using the test procedure described below.

In those suffering from intrinsic asthma, the therapeutic effect of compound A could be determined subjectively as well as by objective tests of lung function.

The results of the clinical investigations can be summarized as follows: (1) Inhalation of compound A in doses of 1-20 ml repeated at 4-8 hour intervals is very well tolerated, no side effects or other signs of toxicity could be observed during a continuous trial period in 5 months. (2) The therapeutic effect of compound A is evident within 4 hours, but increases over several days of continuous therapy, reaching a maximum within 1 to 2 weeks. A dose of 2-6 mg every 4 to 6 hours produces a significant improvement, which can be confirmed by objective tests of lung function in mild cases.

In more severe cases, doses of up to 20 mg every 4 to 6 hours are required to produce a significant improvement.

In quantitative objective tests, it has been found that compound A, administered at a dose of 20 mg, provides up to 84% protection 2 hours after administration, up to 70% protection 4 hours after administration and noticeable protection, e.g. about. 20% protection 18 hours after application.

Subjective improvement usually involves:

(a) Reduction of chest tightness,

(b) Increased tolerance to exercise, and (c) Reduced sputum volume and cough.

A stoppage of treatment with compound A was followed by a relapse within 48 hours in more severe cases, or after 7 to 14 days in milder cases.

The acute in vivo toxicity of compound

A in rats is very low, i.e. the LD^Q is at least 1000 mg/kg.

Claims (2)

1. Analogy method for the production of new, therapeutically active bis-chromonyl compounds with the formula: 1 2 3 4 5 6 where R , R , R , R , R and R are the same or different groups and are hydrogen, halogen or lower alkyl, preferably all groups R , R , R , R , r and R are hydrogen . and M is an alkali metal, characterized in that a compound with the formula: where R, R2, R^, R, R5, R^ and X have the same meaning as stated above, R 14 is hydrogen or an alcohol residue, is reacted with an alkali metal compound. 2. Process according to claim 1, characterized in that starting compounds are used where R"*" R are all hydrogen, X is 2-hydroxy-trimethylene and the group -O-X-O- is bound to the 5-positions in the chromium parts.