DE2163869A1 - New connections and their creation - Google Patents

Description

PATENT LAWYERS

dr. W. Schalk dipl.-inc. P. Wjrth · dipl.-ing. G. Dan ν en berg DR-V-SCHMIED-KOWARZIK ■ DR. P. WEI NHOLD · DR. D. GUDEL

6 FRANKFURT AM MAIN CR. ESCHENHEIMER STRASSE

SK / Eh

B.A. 61915/70

Fisons Limited Harvest House, Felixstowe, Suffolk / England

New connections and their creation

The present invention relates to new compounds and their "Manufacture as well as preparations that contain these compounds.

The compounds according to the invention can be represented by the formula I. will*

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in which an adjacent pair of the groups P, Q, R and T and an adjacent pair of the groups Pa, Qa, Ra and Ta each form a chain -COCH-C (COOH) -O- which is linked to the naphthalene core in any way can be, where the other groups P, Q, R, T, Pa, Qa, Ra and Ta can have the same or different meanings and each represent hydrogen, an alkyl, alkoxy, alkenyl or alkenyloxy group, a substituted alkyl, An alkoxy, alkenyl or alkenyloxy group having a hydroxy, alkoxy or halogen substituent, an ψ acyl group, a hydroxy group or halogen, the present compound also includes pharmaceutically usable derivatives of these compounds.

Furthermore, the present invention provides a process for the preparation of a compound of the formula I or a pharmaceutically acceptable derivative of this compound, which is characterized in that:
a) a compound of the formula II below cyclizedx

Bg-f ^^ l'N-Bb

Be vol

in which an adjacent pair of groups Ba, Bb, Bc and Bd and an adjacent pair of groups Be, Bf, Bg and Bh, respectively

stands for a group pair Aa and Ab; each pair of the groups Aa and Ab for a chain -CO-CH-C (COOH) -O- or for Ao and Ad

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stands, but at least one pair of groups Aa and ATa die Groups Ac and Ad means which stand for the following group pairs ζ

i) -COCH ₂ COCOR ¹¹ and -OM or ii) -H and -0-C (COOM) = CH-COOM,

in which R "is a group -OH or a group which can be hydrolyzed to -OH, and M is hydrogen or an alkali; the remaining groups Ba to Bh can be the same or different and have the same meanings as those mentioned above remaining groups F, Q, R, T, Pa, Qa, Ra and Ta; and, if desired or necessary, the group R "is hydrolyzed; b) a compound of the formula III selectively hydrolyzed or oxidized:
III | ^p ψ

Bo- ^^ f ^ r- ^B j

Jm Bl

in this formula there is an adjacent pair of the groups Bi bis Bl and an adjacent pair of groups Bm to Bp each for a chain Ae; each chain Ae is a chain -CO-CH = C (COOH) -O-

or -CO-CH-CD-O-, but with at least one of the chains Ae must stand for a chain -CO-CH = CD-O- and D is a group, which can be oxidized or hydrolyzed to a group -COOH; and the remaining groups Bi to Bp can be the same or different be and have the same meanings as the other groups P, Q, R, T, Pa, Qa, Ra and Ta mentioned above; or

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c) a compound of the formula IV is dehydrated: IV

Bu Bt
in this formula there is an “adjacent pair of groups Bq to Bt

and an adjacent pair of groups Bu to Bx each for a chain Afj and each chain Af is a chain -CO-CH = C (COOH) -O- or fe -CO-CH ₂ -CH (COOH) -O-, where but at least one of the chains Af is a chain -CO-CH ₂ -CH (COOH) -O-}

whereupon the compound of formula I thus obtained is converted into one of its pharmaceutically usable derivatives or the other way around.

The cyclization of process a) i) can be carried out by heating or under basic or neutral conditions. However, the cyclization is preferably carried out in the presence of an acid, such as, for example, hydrochloric acid, and in a solvent which is inert under the reaction conditions, such as, for example, ethanol. The Eeaktion can be carried out at a temperature between about 20 ° and I50 ^0th The group -COR "is preferably an ester group, where R" can be, for example, a lower alkoxy group.

The cyclization of process a) ii) can be carried out by the suitable compound of formula II with a cyclizing agent, for example a dehydrating agent such as chlorosulfonic, polyphosphorous or

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Sulfuric acid. The reaction is preferably carried out under anhydrous Conditions and at a temperature between about 0 and 100 carried out. Cyclization is also achieved by using the free carhoxy groups of the compound of formula II in acyl halide groups and the acyl halide thus obtained is subjected to an intramolecular Friedel-Crafts reaction.

In method b), the group D can be, for example, an ester, acid halide, Be amide or nitrile group, which can be hydrolyzed to a group -COOH. The hydrolysis is carried out by known methods, e.g. under slightly basic conditions by adding sodium carbonate, sodium hydroxide or sodium bicarbonate is used, or under acidic conditions, e.g. a mixture of aqueous dioxane and hydrochloric acid or hydrogen bromide in acetic acid is used. The hydrolysis temperature depends on the compound used and is between about 25 and 120. The group D can also be an alkyl group, e.g. - lower alkyl group such as a methyl group; an aralkenyl group, e.g. a styryl group; an acyl group, e.g. a lower alkanoyl group such as an acetyl group, or an aldehyde group such as a formyl group. Known processes that use the molecule

do not otherwise modify; in this way an alkyl group can be oxidized by using selenium oxide e.g. under reflux in aqueous dioxane or chromic acid e.g. under reflux in aqueous acetic acid ο aralkenyl » groups are oxidized by adding neutral or alkaline substances Potassium permanganate in aqueous ethanol destroys and oxidizes

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Acyl groups are suitable e.g. chromic acid or an aqueous hypochlorite, like sodium hypochlorite. Aldehyde groups can be oxidized e.g. with chromic acid or silver oxide.

The dehydration of process c) is carried out by using a mild oxidizing agent such as selenium dioxide, palladium black or chloranil, lead tetraacetate or triphenylmethyl perchlorate. The dehydration can also be carried out indirectly by halogenation and subsequent dehydrohalogenation, e.g. by treatment with N-bromosuccinimide or pyridine bromide perbromide to give the 3-bromo derivative which is then dehydrobrominated. The reaction can be carried out in a solvent which is inert under the reaction conditions, e.g. in halogenated hydrocarbon, xylene or glacial acetic acid. The reaction takes place at an elevated temperature between e.g. 25 and 150.

-The compounds of formulas II, III and IV can be prepared from known starting materials can be obtained by methods known for the production of similar compounds (see e.g. Dutch Auslegeschrift 68 11 740).

The compounds of formula I and the intermediates are means known methods isolated from the reaction mixtures.

Pharmaceutically usable derivatives of the compounds of the form · 1 I sißd

including the pharmaceutically acceptable salts _t esters and amides

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the 2-carboxylic acid group. Suitable salts are ammonium salts, alkali salts, such as sodium, potassium and lithium salts5 alkaline earth salts, such as Calcium or magnesium salts; and salts with suitable organic bases, e.g. salts with lower alkyl amines such as methylamine or Ethylamine with substituted lower alkylamines such as hydroxy-substituted Alkylamines, or with simple monocyclic nitrogen-containing heterocyclic compounds, e.g. piperidine or morpholine, • Suitable esters are simple lower alkyl esters from alcohols, which contain lower basic groups, e.g. di-lower-alkyl-amino-substituted Alkanols; and acyloxyalkyl esters, e.g. a lower acyl lower alkyl ester, or a bis-ester of a dihydroxy compound, e.g., a di (hydroxy-lower-alkyl) ester. The pharmaceutically useful ones Salts of the basic esters, e.g. the hydrochloride, can also be used -be used. The esters can be prepared by known methods be, e.g. by. Esterification, transesterification or reaction of the Acid or one of its salts with a suitable compound which contains a good removable group.

The present invention thus also provides a method of manufacture a pharmaceutically acceptable salt of a compound of

Formula I, which is characterized in that a compound of Formula I, a salt of this compound or an ester or an amide thereof is treated with a suitable base or a salt. That The pharmaceutically acceptable salt is preferably the disodium salt.

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The compounds of the formula I and their pharmaceutically useful derivatives show good pharmacological activity in animals; they are particularly useful as they inhibit the release and / or action of pharmacological mediators produced by a combination certain types of antibodies and specific antigens are produced, e.g. the combination of reactive antibodies with specific ones Antigens (see example A). By following these new connections, people can be both subjective and objective Changes are prevented that are otherwise caused in sensitized patients by inhalation of certain antigens. The new Compounds are therefore suitable for the treatment of asthma, e.g. allergic asthma, and also for the treatment of the so-called . "intrinsic" asthma in which there is no sensitivity to external Antigens can be detected. They are valuable resources too for the treatment of other diseases caused by antigen-antibody-beak- • events, such as the treatment of hay fever, Urticaria and other allergic skin diseases.

The dosage of the active ingredient in such treatments depends on the compound used, the type of application and the desired "treatment." As can be seen from the experiment in example A, however, generally achieved satisfactory results when the

in the test according to Example A.
Dosage / between 0.1 and 50 Jng per kg of body weight of the test animal. In humans, the amount administered daily is between about 1 mg and 3,500 mg and is based on 1 to 6 ingestions daily

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distributed or entered in a form in which the active ingredient only is gradually released. Dosages suitable for administration (by inhalation or oesophageal) range from 0.17 mg to 600 mg the compound in admixture with a solid or liquid pharmaceutical useful diluents, carriers or auxiliaries.

The preferred compounds of the formula I and their pharmaceutically acceptable derivatives (in particular the salts, such as, for example, the alkali salts) have the advantage that they are absox-bated and effective even when administered oesophageally.

The present invention thus also creates pharmaceutical preparations which consist of a preferably small amount of a compound of the formula I or one of its pharmaceutically usable derivatives and a pharmaceutically usable auxiliary, diluent or carrier. Examples of such auxiliaries, carriers and diluents are: in the case of tablets and dragees - lactose, starch, talc or stearic acid; for capsules - tartaric acid or lactose; in the case of suppoitories - natural or hydrogenated oils or waxes; in the case of inhalation preparations - coarse lactose. When used in inhalation preparations, the compound of the formula I or its pharmaceutically acceptable derivative preferably has a particle size of 0.01 to 10 AA . The preparations can also contain suitable preservatives

agents, stabilizers and wetting agents, solubilizing agents, sweeteners, Contains colorants and flavorings. If desired, they can also be made into a preparation with long-term effects.

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Optionally, in addition to the compound of the formula I other active ingredients are also added, e.g. a bronchodilator, such as isoprenaline or its salts, especially the sulfate. This other Active ingredients are generally present in minor amounts, for example in an amount from 0.1 to 10% by weight, based on the weight of the compound of formula I.

The groups P, Q, R, T, Pa, Qa, Ra and Ta, which do not form a chain -CH-CH-C (COOH) -O-, can represent hydrogen; for alkyl groups having 1 to 8 carbon atoms, e.g., methyl groups; for alkoxy groups having 1 to 8 carbon atoms, e.g., methoxy groups; for alkenyi groups having 2 to 8 carbon atoms, e.g., allyl groups; for alkenyloxy groups having 2 to 8 carbon atoms, e.g., allyloxy groups; for Hydroxy or chloroalkyl groups or for hydroxy or chloroalkoxy groups with 1 to 8 carbon atoms, e.g. hydroxymethoxy groups; for Hydroxyl or chloralkenyl groups or for hydroxyl or chloralkenylbxy groups having 2 to 8 carbon atoms, e.g., 2-bromoallyloxy groups; for alkoxy-alkyl groups in which both the alkyl and the alkoxy group Contains 1 to 8 carbon atoms, e.g. ethoxy-ethyl groups; for Alkoxy-alkoxy groups in which both alkoxy groups have 1 to 8 carbon atoms contain, e.g. ethoxy-ethoxy groups; for alkoxy-alkenyl or Alkoxy-alkenyloxy groups in which the alkoxy group has 1 to 8 carbon atoms and the alkenyl or alkenyloxy group is 2 to 8 carbon atoms

contains; for acyl groups with 2 to 8 carbon atoms; for hydroxyl groups or for chlorine or bromine.

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Alkyl or alkoxy groups with 1-4 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, η-butyl, isobutyl or tert-butyl group, or the methoxy, ethojy group, are preferred , Propoxy, isopropoxy, _S n-butoxy, isobutoxy and tert-butoxy groups. In the same way, the substituted ·. Alkyl, alkoxy, alkoxyalkyl or "alkoxyalkoxy groups, preferably in each case 1-4 carbon atoms in the respective alkyl or alkoxy groups". 4 carbon atoms. UL's acyl groups are preferred to those with 2-4 carbon atoms, eg those derived from acetic, propionic or butyric acid »

The groups P, Q, R, T, Pa ₅ Qs, Ea and Ta, which do not form a chain -CO-CH ^ C (COOH) -O-, are preferably hydrogen or an acyl group, for example; an alkanoyl group. It is also preferred that

none of the groups P, Q, E, T, Pa, Qa, Ha and Ta contains more than β carbon atoms.

The present invention is further illustrated by the following examples —Explains. Unless otherwise stated, all known parts are available and percentages for parts by weight feezw. Wt .- ^?

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Example 1: 2.8

benzopyran hemihydrate

a) 1, 5 - diacetyl-2,6-dlhydroxynaphthalene

An intimate mixture of 5 parts of 2,6-diacetoxynaphthalene, 5 parts Sodium chloride and 25 parts of anhydrous aluminum chloride was added for 4 hours heated to 140. "After cooling, the mixture was made with ice and Hydrolyzed hydrochloric acid.

m The thus obtained Peststoff was filtered, washed with water and dissolved in a dilute sodium hydroxide solution. The alkaline solution was filtered and acidified with hydrochloric acid, yielding a solid which was filtered off, washed with water, dried and crystallized from ethanol; 2.1 parts of a yellow solid (F «254-256) were obtained, which consisted of 1,5-diacetyl-2,6-dihydric naphthalene.

Analysis C ^ B ^ O. » Ber. Found 14—1 ^ —4—

C 68.85 fo 68.9 f °

H 4i92 io 4.95 10o

The structure was determined by the NMR spectrum and mass spectroscopy confirmed.

b) 2,8-DicaΓboxy-4 ^ 10-dioxo-4H ^ 10H-1-benzop.yΓan- ₎ /5t5-f7-1-benzop.yran diethyl ester hemihydrate

To a solution of 5.8 parts of sodium in 100 parts of dry ethanol became a 5 part slurry with stirring at room temperature

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1,5-diacetyl-2,6-dihydroxynaphthalene in 15 parts of diethyloxalate and Given 200 parts of dioxane. The mixture was stirred for 4 hours and heated to reflux, cooled and poured into water. Then the solution was extracted with diethyl ether and the aqueous phase became acidified with hydrochloric acid and extracted with diethyl ether.

The ether extracts were washed with water, dried and evaporated to an oil to which ethanol was added. A small amount Pest was filtered off, and the ethanol solution became a half Heated to boiling with 1 part hydrochloric acid for an hour. The precipitated solid was filtered off and crystallized from dioxane and yielded 1.1 parts of 2,8-dicarboxy-4,10-dioxo-4H, 10H-1-benzopyran- / 5,5 ~ f7-1-loenzopyran diethyl ester hemihydrate (F ■ »277)»

Analysis C "^ H ^ 0 ^ .i / 2 H " 0: Ber "^ Gef.

"- di - I DU '' t ~" * "■ = ——" = "-"

C 63.3 % 63.0

H 4.07 ίο 3.84

The structure was confirmed by mass spectroscopy.

c) 2,8-dicarboxy-4,10-dioxo-4H, 10H-1-benzopyran- ^ 5j5 hemihydrate , ",

To a solution of 0.5 parts of 2 ₃ 8-Diearboxy-4,1G »dioxo-4H} 10H-1-

ⁱⁿ 50 parts

Dioxane were given 0 * 21 parts of sodium bicarbonate »Then was water was added to the boiling mixture until a solution was obtained The solution was heated to boiling point for 1 hour and then to dryness

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evaporated. The solid thus obtained was dissolved in water and filtered. The filtrate was acidified with hydrochloric acid and gave a white solid which was filtered off, washed with water and dried; 0.4 parts of 2,8-dicarboxy-4,10-dioxo-4H, 10H-1-benzopyran- ^ fi>, 5-f7-1-benzopyranheinihydrate were obtained (F ^ -300 ⁰ ). Analysis C , "H" 0 " .i / 2 H" Ot Ber. Found

C 59.8 io 59.5 # H 2.49 io 2.14 io

d) 2,8-Picarboxy-4 »10-dioxo-4H, 10H-1-benzop.yran - ^ o '_> 5-f 7-1- benzopyran disodium salt

To a solution of 0.13 part of sodium hydrogen carbonate "in 50 parts Water was added 0.28 part of 2,8-dicarboxy-4,10-dioxo-4H, 10H, 1-benzopyran- ^ S, 5-f / -1-benzopyran hemihydrate. The solution thus obtained was "filtered and freeze-dried to give 2,8-dicarboxy-4,10-dioxo-4H, 10H-1-benzopyran- ^ 5,5-f7-1-benzopyran as disodium salt.

Example 2i 3,10-dicarboxy-i, 8-dioxo-1H, 8H-1-benzopyran- / 7,6-f7-1- benzopyran

a} ... 1> 6-diacetyl-2,7-dihydroxynaphthalene

An intimate mixture of 5 parts of 2,7-Diacetoxynagthalin, 5 parts of 'sodium chloride and 25 parts of anhydrous aluminum chloride was heated for 2 hours at 145 his 155th After cooling, the mixture was hydrolyzed with ice and hydrochloric acid and the solid thus obtained was filtered off and dissolved in a dilute sodium hydroxide solution.

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The alkaline solution was filtered and acidified with hydrochloric acid; the solid obtained in this way was filtered off, washed with water, dried and crystallized from ethanol and yielded 2.6 parts a yellow solid obtained from 1,6-diacetyl-2,7-dihydroxynaphthalene consisted (F - 264-265 °).

Analysis C , H ^ O .: Ber. Found

"14—12—4 ~ -—

C 68.85 i » 69.3 i» Ή 4.92 % 4.75 1 *

The structure was determined by the NMR spectrum and mass spectroscopy confirmed.

b) 3,1Q-dicarboxy-1,8-dioxo-1H, 8H-1-benzopyran- ^ 7,6-f 7-1-benzopyran- . diethyl ester

- Became a solution of 3.8 parts of sodium in 100 parts of ethanol with stirring at room temperature a slurry of 5 parts of 1,6-diacetyl-2,7-dihydroxynaphthalene in 15 parts of diethyloxalate and Given 200 parts of dioxane. The mixture was refluxed for 20 hours.

After cooling, the mixture was poured into water and the like obtained solution extracted with diethyl ether. The aqueous extracts were acidified with hydrochloric acid and extracted with diethyl ether. the Ether extracts were washed with water, dried over sodium sulfate and evaporated to an oil. The oil was dissolved in ethanol and boil the solution with 1 part of concentrated hydrochloric acid for 1 hour

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2,63869

heats. After the solution has stood for several days at room temperature a solid was precipitated which was filtered off in a. , Sodium hydrogen carbonate solution. dissolved and again with hydrochloric acid has failed. It was esterified by using it for 18 hours 100 parts of ethanol and 1 part of concentrated sulfuric acid heated to reflux, and gave 0.4 part of 5,10-dicarboxy-1,8-dioxo-1H, 8H-1-benzopyran- ^ 7 »6-f / -1-benzopyran diethyl ester in the form of a yellow solid (F = 270 ° with decomposition).

_Ber . Found

C 64.7 1 ° 65.3 Io

H 5.92 io 4.25 #

The structure was confirmed by mass spectroscopy.

c) 3 »10-dicarboxy-1,8-dioxo-1H, 8H-1-benzopyran - / 7> 6-f 7-1-benzopyran - 0.2 parts of 3-, 10-dicarboxy-i, 8 -dioxo-1H, 8H-1-benzopyran- / f, 6-f7-1-benzopyran diethyl ester suspended in 100 parts of boiling ethanol fc. Then 0.14 part of atrium hydrogen carbonate and water were added until a solution was obtained. The solution was heated to boiling for half an hour, after which the ethanol was distilled off in vacuo. The aqueous solution was acidified with hydrochloric acid and yielded 0.15 part of a solid consisting of 5,10-dicarboxy-1,8-dioxo-1H, 8H-1-benzopyran- ^ 7,6-f7 ~ 1-benzopyran ( F 7 300 °).

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216386S

d) 3.1Q-M cart? oxy-1,8-dioxo-1H, 8H-1 -benzopyran - / ?, 6-f 7-1 -benzopyran disodium salt

To a solution of 0.047 part of sodium hydrogen carbonate in 50 parts of water, 0.09 part of 3,10-dicarboxy-i, 8-dioxo-1H, 8H-1-benzopyran- / j, G-fJ-'i-beazo ^ yran given. The solution was filtered and freeze-dried to give 3 »10-dicarboxy-1,8-dioxo-1H, 8H-1-benzopyran , 6-fJ-1 -benzopyrin sodium salt as a contaminant.

Example 5? 5-acetyl-3 »9-dicarboxy-1,7-dioxo-1H, 7H-1-benzopyran-

a) 1,5-pihydroxy-2,6,8-triacetylnaphthalene An intimate mixture of 5 parts of 1,5-diacetoxynaphthalene, 5 parts of sodium chloride and 25 parts of anhydrous aluminum chloride was heated to 155 ° for 3 hours. After cooling, the mixture was hydrolyzed with ice and hydrochloric acid to give a solid which was filtered off, washed with water and dissolved in a dilute sodium hydroxide solution. Acidification of the alkaline solution with hydrochloric acid gave a brown solid which was filtered off, washed, dried and extracted with benzene in a Soxhlet apparatus. Evaporation of the benzene solution gave a solid which, after

Crystallization from ethanol gave 0.5 part of a yellow solid which consisted of 1,5-dihydroxy-2,6,8-triacetylnaphthalene (F - 244-246 °).

Analysis C .JL £ ^ x Eer. G ef.

C 67.1 # 67.2 fa H 4.95 1 » 4» 9O %

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- 18 -

The structure was determined by the NMR spectrum and mass spectroscopy confirmed.

b) 5-acetyl-3,9-dicarboxy-1, 7-dioxo-1H, 7H-1 -benzopyran - ^ 8,7 -b. 7-1-benzopyran

To a solution of 1 _f 84 parts of sodium in 50 parts of ethanol was added with stirring at room temperature a slurry of 2.3 parts of?, S-dihydroxy-Zjoje triacetylnaphthalin added to 8.76 parts of diethyl oxalate and 50 parts of dioxane.

The mixture was refluxed for 5 hours, cooled and with Diluted diethyl ether. The sodium salt thus obtained was filtered off, washed with diethyl ether, dissolved in water and filtered.

-The aqueous solution was acidified with dilute hydrochloric acid and with Diethyl ether extracted. The ether solution was washed with water, dried over sodium sulfate and evaporated to an oil.

3 drops of concentrated hydrochloric acid were added to a solution of the oil in ethanol given. Then the solution was heated to boiling for 15 minutes. The yellow solid precipitated in this way was filtered off. Investigation of the solid by thin layer chromatography Made out a mixture of chromonic acid and chromonic acid. To a A suspension of 0.55 part of the solid in 100 parts of boiling ethanol was added to 0.3 part of sodium bicarbonate. Then became water added when a clear solution was obtained. The solution became a

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-19- 2! 63869

Heated to the boil for half an hour and the ethanol evaporated. Acidification of the aqueous solution with hydrochloric acid gave 0.45 part of 5-acetyl-3,9-dicarboxy-1 ^ -dioxo-IH ^ Hi-benzopyran- ^ e ^ -hj ^ -i-benzopyran in the form of a solid (F. = 309-310 ⁰ ).

c) 5-acetyl-5t9-dicarboxy-1 _r 7-dioxo-1H, 7H-1-benzopyran- / 8,7-h 7-1-benzopyran diethyl ester monohydrate

- A mixture of 0.25 parts of 5-acetyl-3> 9- <ii ^e a ^r b ° xy-t _r 7 - "<liO3co-1H» 7H-1-benzopyran- ^ 8.7- ^ 7-1 Benzopyran, 50 parts of ethanol and 2 parts of concentrated sulfuric acid were refluxed for 12 hours .. After partial evaporation and subsequent cooling, 0.2 part of a pale yellow solid was obtained, which is composed of 5-acetyl-3,9- <iicarboxy-1,7 -dioxo-1H, 7H-1-benzopyran- ^ 8,7-h7-1-benzopyran diethyl ester monohydrate (F * 212 ° with decomposition).

Ber. Qef

c 61.5 io 61.9 io

Ά -4.30 io -3.9 io The structure was confirmed by mass spectroscopy.

d) 5-Acetyl-3,9-dicarboxy-1,7-dioxo-1H, 7H-1-benzopyran - / §, 7-h 7-1- benzopyrinine sodium salt

To a solution of 0.11 part of sodium hydrogen carbonate in 50 parts Water was 0.26 part of 5-acetyl-3,9-dicarboxy-1,7-dioxo-1H, 7H-1-benzopyran- ^ 8,7-h7-1-benzopyran given. The solution obtained was

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2 i 6 3 8 6 9

filtered and freeze-dried to give 5-acetyl-3f9-dicarboxy-i »7-dioxo-1H, 7H-1-benzopyran- ^ 8,7-h7-1-benzopyran in the form of a pale yellow disodium salt.

Example A.

The procedure described below was used to determine effectiveness to determine a compound in inhibiting the release of pharmacological mediators of anaphylaxis.

This experiment determined the effectiveness of the compounds in inhibiting passive anaphylactic skin reactions in rats. Es it has been proven that this test form provides reliable qualitative conclusions about the ability of the test compounds to inhibit - Antibody-antigen reactions allowed in humans.

During the test series, male and female rats (bred by Charles River France / Fisons) with a body weight of 100 to 150 g at weekly intervals subcutaneously with K. brasiliensis larvae infected, the doses of about 2000 larvae per animal were increased to about 12,000 larvae per animal. After 8 weeks were

the rats were veined by cardiac puncture, and it was from each Animal collected about 15 to 20 ecm of blood. The blood samples were JO minutes at 3500 rpm, centrifuged to remove the blood cells from the blood plasma to remove. The plasma was collected and yielded a serum containing H. brasiliensis antibodies. Now a basic sensitivity

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2 i 638B9

Test performed to determine the minimum amount of serum required is to show a skin swelling of 2 cm in the control animals Cause diameter. It has been found that the optimal sensitivity is achieved in rats with a body weight of 100 to 130 g using a serum diluted with 8 parts of physiological saline. This diluted solution is called the antibody serum A denotes.

The antigen needed to react with the antibodies in Serum A. was made by removing the N. braziliensis worms from the intestines of the infected rats removed the homogenate centrifuged and collected the supernatant fluid. This liquid became diluted with saline to a protein content of 1 mg / ccm - and referred to as serum B.

Rats (bred by Charles River France / Fisons) with a body weight from 100 to 130 g were injected intradermally with 0.1 ecm des Serum A sensitized in the right flank. The sensitivity was allowed to develop for 24 hours; then the rats were given 1 cc / 100 g intravenously Body weight of a mixture of Serum B (0.25 ecm), Evans Blue dye

substance solution (0.25 ecm) and solution of the test compound (0.5 ecm with varying percentage of active ingredient). Insoluble compounds were given as a separate intraperitoneal injection 5 minutes before intravenous administration of solution B and de3 Evans blue toffee given. For each percentage of the drug in the solution, 5 rats were given used. In addition, 5 control animals were used in each experiment.

2 0 9 8 3 0/1165

The dosages of the test compounds were chosen so that a Range of inhibition values.

Thirty minutes after the solution B was injected, the rats were sacrificed and their skins stripped off and turned over. The intensity of the anaphylactic reaction was determined by looking at the size of the characteristic blue swelling caused by spread of Evans blue toffee is formed from the sensitization point, with the size of the fe compared swelling in the control animals. The size of the swelling was from 0 (no noticeable swelling, i.e. 100 ^ ige inhibition) up to 4 (no difference in swelling size, i.e. no inhibition) and the percent inhibition for each dosage according to calculated using the following equation:

_ # _T .... (control group value - value of the treated group) χ

% Inhibition » ^{v B} -" -—-— rrz * ■ * - ^l

¹ control group value

- The percent inhibition of each dose was determined for each -Test connection shown graphically. The dosage required for a 50 $ inhibition (ID5O) can be read from these curves. is needed.

The efficacy of the compounds when administered intestinally and gastricly was also determined in the manner described above.

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Claims (2)

Claims: 1. Process for the preparation of a compound of the formula I: R ^ T Ta
in which an adjacent pair of the groups P, Q, R and T and an adjacent pair of the groups Pa, Qa, Ra and Ta each form a chain -COCH = C (COOH) -O- which is linked to the naphthalene nucleus in any way can be, and the remaining groups P, Q, R, T, Pa, Qa, Ra and Ta, can have the same or different meanings, for hydrogen; Alkyl groups; Alkoxy groups; Alkenyl groups; Alkenyloxy groups; substituted alkyl, alkoxy, alkenyl or alkenyloxy groups with a hydroxy, alkoxy or halogen substituent; Acyl groups, hydroxyl groups or halogen; or a pharmaceutically acceptable derivative of this compound, characterized in that: a) a compound of formula II cyclizes: II Bra 209830/1165 in which an adjacent pair of groups Ba, Bb, Bc and Bd and an adjacent pair of groups Be, Bf, Bg and Bh, respectively for the group pair Aa and Ab} each group pair Aa and Ab is a chain -CO-CH-C (COOH) -O- or a group pair Ac and Ad forms, but at least one of the group pairs Aa and Ab is a group pair Ac and Ad istj and Ac and Ad for the group pairs i) -COCH ₂ COCOR ¹¹ and -OM or
ii) -H and -0-C (COOM) = CH-COOM stand, where E "is a group -OH or a group -OH is hydrolyzable group and M is hydrogen or an alkali; and the remaining groups Ba to Bh the same. or can be different and have the same meanings as the 'other groups P, Q, R, T, Pa, Qa, Ra and Taf and optionally the group R "hydrolyzed! b) selectively hydrolyzes or oxidizes a compound of the formula III; III bp Bi »Bo - ^^ Yf ^ V B j ^Bn \ / V ^ ^Bk Bm Bl ' in which an adjacent pair of groups Bi to Bl and an adjacent pair of groups Bm to Bp each represent a chain Ae; each chain Ae a chain -CO-CH «C (COOH) -O- or -CO-CH = CB-O-, but at least one of the chains Ae is a chain -CO-CH = CD-O-, where D is a group which leads to 209830/1 185 a group -COOH can be oxidized or hydrolyzed; and the remaining groups Bi to Bp are the same or different can be and have the same meanings as the remaining groups P, Q, R, T, Pa, Qa, Ra, Ta; or c) a compound of the formula IV is dehydrated: IV Bx Bq Bu Bt in which an adjacent pair of groups Bq to Bt and an adjacent pair of groups Bu to Bx each represent a chain Af; each chain Af is a chain -CO-CH = C (COOH) -O- or -CO-CH ₂ - CH (COOH) -O-, but at least one of the chains Af is a chain -CO-CH ₂ -CH (COOH) -O-} and optionally converting the compound of formula I into one of its pharmaceutically acceptable derivatives. 209830/1165 2. A compound of the formula I according to claim 1 or a pharmaceutical useful derivative of this compound. 3 «Compound according to claim 2, characterized in that the groups P, Q, R, T, Pa, Qa, Ea and Ta, which do not form a chain -CO-CH = C (COOH) -O-, represent hydrogen or the following Groups are: alkyl groups with 1 to 8 carbon atoms; Alkoxy groups of 1 to 8 carbon atoms; Alkenyl groups of 2 to 8 carbon atoms; Alkenyloxy groups of 2 to 8 carbon atoms; Hydroxy or chloroalkyl groups or hydroxy or chloroalkoxy groups having 1 to 8 carbon atoms; Hydroxy or chloro-alkenyl groups or hydroxy or chloro-alkenyloxy groups having 2 to 8 carbon atoms; Alkoxy-alkyl groups in which both the alkyl and the alkoxy group have 1 to 8 carbon atoms; Alkoxy-alkoxy groups in which both alkoxy groups contain 1 to 8 carbon atoms; Alkoxy .alkenylgruppen or alkoxy alkenyloxy groups in which the alkoxy group has from 1 to 8 carbon atoms and 2 contains the alkenyl or alkenyloxy group ψ to 8 carbon atoms; Acyl groups of 2 to 8 carbon atoms; Hydroxyl groups or chlorine or bromine. 4. A compound according to claim 2 and 3, characterized in that the Groups P, Q, R, T, Pa, Qa, Ra and Ta, which do not form a chain -CO-CH-C (COOH) -O-, for hydrogen or alkanoyl groups stand. 209 8 30 / 11-6 5 5. 2,8-Μcarboxy ~ 4 »10-dioxo-4H, 1ΟΗ-1-benzopyran- ^ δ, 5-f7" "1-benzopyran, 3,1O-dicarboxy-1,8-dioxo-1H, 8Η-1-benzopyran- ^ 7,6-f7-1-benzopyran, 5-acetyl-5,9-dicarboxy-1,7-dioxo-1H, 7H-1-benzopyran- / 8,7 ~ h7-1-benzopyran or a pharmaceutically acceptable derivative of these compounds. 6. The compound of claim 2 to 5 i ⁿ the form of a pharmaceutically acceptable salt. 7. Compounds of the formulas II, III or IV according to claim 1. 8. Medicaments containing a compound according to claims 2 to 6 and a pharmaceutically acceptable carrier and / or diluent and / or excipient. The patent attorney! 2 0 9 8 3 0/1168