DE1643356A1 - New bis-chromonyl compounds and processes for their preparation - Google Patents

Description

1643335

dr. W. Schalk pipl-ing. p. Wirth piPL.-iNG. G. Dannenberg

DR. V. SCHMIED-K.OWARZIK DR. P. WEl N HOLD DR.D.GUDEL

6 FRANKFURT AM MAIN

CR. ESCHENHEIMER STRASSE 39

P 16 4-3 356.0-42 Wd / Bi : '■' ■■

Fisons Pharmaceuticals limited 12 Derby Road

Loughborou ^ h / Leicestershire ENGLAND

New. Bia-chromonyl compounds and process for their preparation.

The present invention relates to improvements with regard to new chemical compounds and to which they containing pharmaceutical preparations.

It has been found that certain new ones described below Bis-chromonyl compounds have an activity as inhibitors of the action of certain types of antigen-antibody reactions to have.

The present invention therefore relates to the new Bis-chromonyl compounds of the formula:

0 p

COOH

R "1

10982W2279

. ^ τ »ι α · κ« 2 No. 1 sentence 3 de «amendui« »fle8. V. '

New documents iAn.7iiAb8.2NM sa

and functional derivatives thereof, in which P, Q, R, l ^J

Q ₁ and R _{1 can be} identical or different and V / ater.: Substance, halogen, hydroxy, alkyl, alkoxy, alkenyl, alkenyloxy, substituted alkyl, alkoxy, alkenyl or alkenyloxy, nitro, amino and cyano can mean; and X is substituted or unsubstituted carbocyclic or heterocyclic; odor a £ orad <j or verzv / ei / jte, ^ esätti ^ 'e cd er \ ,.'. -; - üätti ^ tc, üubutituierte or unüubatituierte Kohleriv.'asserstoffkette, which can be interrupted by one or more carbocyclic or heterocyclic rings, oxygen atoms, sulfur atoms or nitrogen atoms or substituted sulfur or nitrogen atoms.

The substituents P, Q, R, -P--, Q ₁ and R ₁ do not all need to be the same and can be selected from several groups. Examples of suitable groups are alkyl groups with 1 to 8 carbon atoms, which are straight or branched (e.g. methyl, ethyl or isopropyl groups) and can contain one or more substituents, such as hydroxy, alkoxy or halogen groups, e.g. a hydroxymethyl, Hydroxypropyl, ethoxyethyl or chloromethyl group; alkoxy groups corresponding to the alkyl groups, for example an isopropoxy group, a hydroxypropoxy group or an ethoxyethoxy group; Alkenyl or alkenyloxy groups which correspond to the alkyl or alkoxy groups, for example an allyl or allyloxy group; Amino groups which can carry substituents such as a mono_ or M-lower alkylamino group; a hydroxy group; or a halogen atom such as chlorine, bromine or iodine.

Preferably no more than one of the groups P, Q and R has a meaning other than hydrogen and no more than one of the groups Pj fy and R ^ has a meaning other than hydrogen: appropriately all groups P, Q, R, P ₁ , Q are - and R- for hydrogen.

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BATH ORIGINAL

- 3 -

The group X can represent many different groups; it can, for example, be a carbocyclic or heterocyclic king (for example a cyclohexane, cyclopentane, benzene, furan _T , pyridine or pyran ring) which, as described above, can be unsubstituted or substituted.

Where the group X stands for a hydrocarbon chain, this can, as stated above, be substituted or unsubstituted and by a substituted or unsubstituted one carbocyclic ring be interrupted. Where the group is interrupted by a sulfur or nitrogen atom this can be substituted; i.e. the chain can be replaced by a group of the formula

-S0 _Q - -SO- or T

-H-

be interrupted, where T is hydrogen or a substituent other than hydrogen.

The groups X preferably stand for saturated or unsaturated straight or branched polymethylene chains, which one or more OH, alkoxy, halogen or carbonyl oxygen I can carry as substituents, and their chain through one or more oxygen or nitrogen atoms can be interrupted.

Examples of groups X include:

—CHp-CH-CH-CHρ_
-OH ₂ -CH ₂ -CH (CH ₅ ) -CH ₂ -CH ₂ - -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ - -CH ₂ -CO-CH ₂ -

109824/22 7 9

_ 4 - 1643356 -OH ₂ -OH (OO ₂ H ₅ ) -OH ₂ - -CH ₂ -CH (OH) -CH ₂ - CH ₂ OH ■ ·
CH ₂ -C-CH ₂ -
CH ₂ -Cl -CH ₂ - / 'VoH ₂ - CH ₉ -
r ~ \
0 0

-CHo

The term "functional derivatives" includes functional ones Derivatives of all reactive substituents present, e.g. functional derivatives of acidic groups, "basic Groups, hydroxyl groups and carbonyl groups (including those in the chromone rings).

Thus the acidic groups can be in the form of salts, e.g. Metal salts (such as alkali metal salts, such as sodium and potassium salts, and alkaline earth metal salts ^ such as calcium and magnesium salts) and salts with ammonia and organic bases (e.g. amine salts, such as piperidine, triethanolamine or diethylaminoethylamine salts) are present. The acidic groups present can also be in the form of esters (e.g. simpler Alkyl esters, such as methyl, ethyl, propyl esters, etc.) are present.

• Other functional derivatives of the acidic groups present include amides, such as amides with simple amines and amides with substituted amines (e.g., alkylamines, dialkylamines, amino acids, and arylamines); Ureals, hydrazides and (in the case of sulfonic acid groups) sulfonylureas.

The hydroxyl groups present can, for example, be in the form of esters, ethers or acetals; the carbonyl groups present

109824/2279

- 5 can e.g. be present in the form of their oximes.

The amino groups present can be in the form of quaternary salts, e.g. with a pharmaceutically acceptable acid, such as hydrochloric acid or succinic acid.

Compounds according to the invention in particular are, for example:

1,3-bis (2-carboxychromon-6-yl) propane; 1,5-bis (2-carboxychromon-6-yl) pentane; 1,6-bis (2-carboxychromon-6-yl) hexane;

1,5-bis (2-carboxychromon-6-yl) pentan-3-ol; Ä

1,5-bis (2-carboxychromon-6-yl) pent-2-ene; and their functional derivatives.

The novel compounds according to the invention inhibit the release and / or action of toxic products resulting from the Combination of certain types of antibodies and special antigens e.g. the combination of reaginic antibodies with specific antigen. The new compounds are therefore valuable in the treatment of diseases for which the antigen-antibody reaction are responsible.

According to a further feature of the present invention, g

pharmaceutical preparations are therefore created which contain a bis-chromonyl compound according to the invention, preferably in In the form of a salt, in association with a pharmaceutical carrier or diluent. According to the invention there is also provided a method of manufacturing the pharmaceutical preparations by mixing a bis-chromonyl compound labeled with a carrier or diluent.

The nature of the preparation and the pharmaceutical carrier or diluent depend of course on the desired mode of administration, i.e. orally, parenterally or by inhalation.

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For example, the preparations may be in a form suitable for administration by inhalation. So a Suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer include. The preparations can also be a suspension or solution of the active ingredient in a conventional, liquefied one Propellants to be administered from a pressurized container. You can continue to use the fixed one active ingredient diluted with a solid diluent, e.g. lactose, for administration from a powder inhalation device include.

The pharmaceutical preparations can also contain other active ingredients. It was found that in particular the addition of a bronchodilator is of value if the preparation is to be administered by inhalation.

According to a further feature of the present invention, there is therefore provided a pharmaceutical preparation that a bronchodilator and a bis-chromonyl compound according to the invention contains. These preparations are then usually in one described above for administration by inhalation suitable form.

Any bronchodilator can be used in the new preparations according to the invention such as isoprenaline, adrenaline, orciprenaline, isoetharine and derivatives thereof, where Isoprenaline sulfate is preferred.

The bronchodilator is suitably used in a smaller amount than the bis-chroraonyl compounds, e.g. in a Amount of 0.1-10% by weight of the bis-chromonyl compound.

The present invention also includes a method for Inhibiting the action of antigen-antibody reactions,

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which is characterized in that one therapeutically effective in the field of the antigen-antibody mechanism Applying amount of a bis-chromonyl compound according to the invention.

The new compounds according to the invention can be prepared are obtained by treating the compounds of the formula:

"1 / ¹ ^ / Vy ^{1 R} 1

(in which, P, Q, R, P-, Q- and X have the above values; Z is a hydroxyl group and Y is a hydrogen atom, a group -CO'CH, or a group -COOR ¹ (where R ^{1 is} represents an alkyl group) or Y and Z together represent a chain -CO-CH = C (V) -O- or a chain -CO-CH ₂ -CHW-O- (where W is a COOH group or a derivative thereof or a group V which can be converted into a COOH group or a derivative thereof; and Y ¹ · and Z 'together form the chain -CO-CH = C (COOH) -O- or a derivative thereof or for the group pair X and Z stand, which can have the meaning given above) in which in one or more stages the pair or pairs of groups Y and z 'and / or Y ¹ and Z ^{1 are converted} into the desired -CO-CH =C (COOH ) -O-chain or a derivative thereof.

The conversion can be carried out in one or more stages, depending on ^{the nature of Y and Z and Y 1} and Z ^1. Therefore, if Y and Z are equal to Y 'and Z ¹ , both group pairs can • simultaneously' by the same reaction or reactions

10982472279

. ■ 1643358.

are converted into the same desired chain, while if Y and Z and Y ¹ and Z 'are different, or if Y ünä Z and Y ¹ and Z' are to be converted into different chains, separate conversion steps are necessary. In general, it is preferred to work with only one conversion stage.

The conversion of compounds in which Y stands for a. Group -COr-CH, and Z represents a hydroxyl group and / or Y ^{1 represents} a group -CO-CH, and Z ^{1 represents} a hydroxyl group, ie o-hydroxyacetophenone compounds which comprise the group

-OH

included in compounds that make up the group

usually occurs through condensation of the o-Hydroxyacetophenone with a compound of the formula

W-COOR

or a functional derivative thereof, in which W is the desired COOH group or a derivative thereof or is a group convertible to this and R represents an alkyl group, followed by cyclization

109824/2279

of the condensation product. For example, the 2-methyl-chromonyl compound are produced by the condensation of deso-hydroxyacetophenone with ethyl acetate and then converted to the desired 2-carboxy chromone, or the 2-carboxy chromone can directly through condensation with diethyloxjilat getting produced.

The preparation of the compounds preferred according to the invention, i.e. the 2-carboxychromones, from o-hydroxyacetophenone can be done in different ways.

A preferred method consists in the reaction of o-hydroxyacetophenone in an oxalic acid derivative of the formula i

GOR ²⁴

R ²⁵ -C -R ²⁷
R ²⁶

in which R ^ is a halogenator or a group -OR ¹ (where R ^{1 is} an alkyl group); R and E are

27 25

in each case halogen atoms and R is a group OR 'or R and R together represent an oxygen atom (= 0) and R is a halogenator or a group OR '.

Thus, a particularly preferred method is by reaction of the o-hydroxyacetophenone with a dialkyl oxalate, such as diethyloxp.lat, preferably in the presence of a compensating agent, such as an alkali metal alkoxide, e.g. sodium ethoxide, Sodium amide, metallic sodium or sodium hydride, and expediently in the presence of an organic solvent, such as Ether, dioxane, ethanol or benzene. This process takes place via an intermediate product of the form -.- ■ '■ -

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BAD ORiGINAL

- ίο -

in which R 'stands for the alkyl group of the dialkyl oxalate; this intermediate product can be cyclized immediately by heating and isolated and by heating in a suitable Solvent in the presence of a cyclizing agent such as an acid, can be cyclized.

If the oxalic acid derivative has the formula: .. ·

R'-0-C (HaI) 2-COOR "

where R "stands for an alkyl group, e.g. ethyl ethoxydichloroacetate, so the reactants are expediently used in practically equimolar proportions, and the reaction is expediently carried out in the presence of a metallic catalyst, such as finely divided metallic platinum or palladium or ruthenium. Does the oxalic acid derivative have the formula:

Shark - CO - COOR

e.g. Ethyloxalyl chloride, the reaction is expediently carried out in the presence of an acid binding agent. Is the oxalate derivative an oxalyl halide, such as oxalyl chloride, does the. ™ Reaction expediently in the presence of an organic solvent and an acid binding agent.

The o-hydroxyacetophenone can also with an ester of Glyoxalic acid to a compound of the formula:

CO-C

Oh? ^H ■ ''. ·. COOR «~""

condensed and then oxidatively converted into the desired chromium

10982A / 22M ^ - ο ^ m

mon-2-carboxylic acid are cyclized. The non-oxidative cyclization results in the corresponding auromanon, that in .below described '/, "can also be converted into the Chromo.n.

Another method of forming the desired chromanyl compound takes place with conversion of Y and Z (if Y for -COCH, and Z stand for -OH) in an intermediate product of Formula:

, 0

t. ■. . "; ■■." '.: ■'. ■■■; ■

where V stands for a group convertible into the carbonic acid or a derivative thereof, and subsequent conversion of group V into a carboxylic acid group or a functional one Derivative of the same.

The group V can be, for example, the nitrile group which can be hydrolyzed to a carboxylic acid group, or groups such as methyl, hydroxymethyl, halomethyl (e.g. chloromethyl, bromomethyl, dichloromethyl, trichloromethyl), formyl, acetyl , Vinyl and styryl groups ^ which can be oxidized or hydrolyzed into a carboxylic acid group, Ä

The 2-methylchromone can pass from the o-hydroxyacetophenone Condensation with an alkyl acetate in that for the dialkyl oxalate described manner.

The 2-methylchromone also serves as an intermediate in the Manufacture of numerous other, oxidizable derivatives. Thus the 2-methylchromone can be converted into the corresponding 2-halomethylchromone be converted by using hydrogen chloride and manganese dioxide in boiling acetic acid to form of a 2-chloromethylchromone or by reaction with Bromine in acetic acid to form 2-bromomethylohromone.

109824/2279
OfiJGfWAi. ''

- 12 -. . . ; . ■; ■. . ■■■

The 2-halomethylchromone can be used with potassium permanganate, for example corresponding ghromone-2-carboxylic acid oxidized or under.Use of moist silver oxide to ^ -hydroxymethylchrotaan hydrolyzed, which is then, for example, using chromium trioxide as an oxidizing agent in the presence of acetic acid and to the chromo-2-carboxylic acid at room temperature or below can be converted or oxidized.

The 2-methylchromone can be combined with p-nitrosodimethylaniline implemented and the reaction product rait dilute mineral acid to be hydrolyzed to the corresponding 2-formylchromone, the

then using chromium trioxide as a reagent for the corresponding Chromon-2-carboxylic acid can be oxidized.

The condensation of 2-methylchromone with a benzaldehyde

in the presence of a condensation calculator this gives

2-styrylchromone made using potassium permanganai;

can be oxidized into the corresponding chromone-2-carboxylic acid.

Numerous chromone derivatives other than 2 — methylchromone, the can be converted into the chromone-2-carboxylic acid can be prepared directly from the o-hydroxyacetophenone.

The 2-formylchromone can be produced by condensation of a dialkoxyacetate of the formula!

(RO) ₂ OH-COOR "

where R 'and R "have the meaning given above, for example ethyidiethoxyacetate, with the o-hydroxyacetophenone to form an acetal, which can then be _{hydrolyzed to the aldehyde, for example with dilute mineral acid 8} , and the latter can be oxidized to the carboxylic acid.

* ■

The 2-Formylch ^ roraon also serves as the starting material for the production of 2-Cyanchromon. So can the 2-formylchromon; Hydroxylamine can be set to the 2-0ximinochromone ^ that also

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BAD ORIOlNAt

643356

sura 2-cyanochromone can be dehydrated? the latter can then under acidic conditions to 01ιτοΐηοη-2-carboxylic acid or the amide of the same are hydrolyzed «,

The 2- styrylchromoη can be prepared from the o-hydroxyacetophenone by reaction with sodium tinamate and cinnamic anhydride (ie, by Kostanecki reaction) or by reaction with an Oinnamoy halide _a z «B. Ginnaraoylchlorid, in the presence of an acid binding agent to form the girinamate ester of o-hydroxyacetophenone and subsequent treatment with a base, ζ.B ₀ potassium carbonate _t in the presence of an inert solvent such as toluene or benzene, to an .X-diketone of the formula §.

ÖO-GH

OH? ⁰
C.

the aesole flowing either back-direct heating, or-heating. can be cyclized in the presence of a CyclisierungsiBitisl (Bakpr ¥ enkataraiisa ⁱ reaction) »

The 2- ¥ inylofe, roiBoa can be made from & ®m. Q

Ithylaerylate can be hedged ^

for

The connections, in

and / or T °

stand ,, & A * connection

the formal

erstoff mod % and 2 » for

can be converted into compounds with the grouping:

by using a cL, ß-unsaturated carboxylic acid of the formula ι

H ²⁴ H ²⁵ .

“J

W-C = G- COOR "

in which W has the above meaning and R ^ and "BT are identical or different and each represent a hydrogen or halogen atom or together represent a carbon-carbon bond.

For example, can the Chroraon-2-carboxylic acid be produced by reacting the acetylenedicarboxylic acid or a dialkyl • ester of the same? For example, diethyl acetylenedioarboxylate _s with the phenol or with an alkali metal phenate of the same.

Where the acetylenedicarboxylic acid or an ester thereof is reacted with the alkali metal phosphate, ie * the verbiodination of the formula ι ■ - ·

in which M stands for an alkali metal atom, the reaction is expediently carried out in the presence of an inert organic solvent or diluent to form a fumarate tea . . *.

109 82

43356

C.

then, optionally after hydrolysis, e.g. by. Treatment with a cyclization catalyst such as sulfuric acid » is cyclized to the desired chromone-2-carbonic acid. In A modification of this process is acetylenedicarboxylic acid or the ester thereof by a halofumaric acid or an ester thereof, e.g. diethyl chloride fumarate, or by a dihalosuccinic acid or an ester the same replaced.

The chromone-2-carboxylic acid can also consist of your phenol by reaction with a compound such as prepared Äthyläthoxyallylacetat werden.- _f

In another process, the phenol, e.g. with ethyl ethoxalyl chloride, to an ester of iOrmels

O ₂ C-CO ₂ -O ₂ H ₅

esterified, which is then in the presence of acetic acid or a derivative thereof (e.g. ethyl acetate or acetyl Chloride) cyclized to the desired chromone-2-carboxylic acid can be.

The phenol can also be mixed with maleic anhydride to form a compound of the formula j

_ 00
"^^ y ^" ^0H CH * CO ₂ E

24/2279

BAD ORIO (NAl.

1643358

- 16 -

are condensed, which then oxidatively to the desired ghromone 2-carboxylic acid can be cyclized. The non-oxidative cyclization gives the corresponding chromanone, which then as below can be converted to the chromone.

The conversion of compounds in which Y is a group -COOR 'and Z is a hydroxyl group and / or Y ^{1 is} a group -COOR ¹ and Z' is a hydroxyl group, ie compounds with a "grouping of the formula:

in Chromony! compounds with a grouping of the formula:

can be obtained by condensation with a compound of the formula

OH- CO'-COOR '

take place,

So the substituted salicylic acid ester of the formula 5

by reaction with a pyruvate ester of the formula:

CH ₃ -CO-COOR '

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BATH

1843356

optionally in the presence of a condensing agent such as an alkali metal alkoxide, e.g. ITatriuraethoxide, sodium amide, FietallisGh.es sodium or sodium hydride, and preferably in Presence of an organic solvent such as ethanol or Bioxane, converted to the desired ghromone-2-carboxylic acid will. "■" "-" .-

If Y and Z together form a chain -CO-OHp-CH (W) -O- ₈ doho a chroraanone compound ₉ this can go through. Dehydration ύοτ or after conversion of the W group to the desired one

Gliromone to be converted. -j (j

The dehydration of a compound of the formula

irs which W has the values given above _a using "selenium dioxide or other suitable dehydrating agents such as palladiura black or ohloranil, take place"

The dehydrogenation can also be carried out indirectly by bromination and subsequent dehydrobromination ₀ For example, the ghromanone can be obtained using IC-bromosuccinimide in an inert solvent or by treatment with pyridinium perbromide; in an inert solvent such as chloroform ₉ in the presence of a free radical catalyst such as bensoyl peroxide for the 3- ~ Brora ° can be broraized * which can then be dehydrobrorated. .- ■ - ■. "■."; .: -, .-

The compounds according to the invention can also be prepared by linking two C-hromone nuclei that have already been formed ₀ BIa, nucleus linking can be produced using a large number of

BATH -

conventional methods that are used for making the desired linking group X are suitable.

The methods described above usually lead to Formation of the Ohromon-2-carboxylic acids per se or in the form their esters. These can easily be converted into other functional parts Derivatives, e.g. salts or amides, are converted, which takes place according to conventional methods.

The compounds of formula II are also new compounds, and the invention therefore also relates to compounds of the formula.

Q and their derivatives, in which P, Q, R, P-.i ^ nd R _{1 are} identical or different and are each hydrogen, halogen, hydroxy, alkyl, alkoxy, alkenyl, alkenyloxy, substituted alkyl, alkoxy, alkenyl,

or can be alkenyloxy, nitro, amino or cyano; X is a substituted or unsubscribed, carbocyclic or heterocyclic ring or a straight or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbon chain, which is interrupted by one or more carbocyclic or heterocyclic rings ₉ oxygen atoms, sulfur atoms, nitrogen atoms or substituted sulfur or nitrogen atoms can? Y ' ^s and Z ¹ ' either together form a chain -CO-CH = C (GOOH) -O- or a derivative thereof or form • the group pair Y ' ^os and Z ^IS % the -OH and -H or -GOJ ₅ -H and -OG (W) = CHCOOH or -OCOGOOR '' or together

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BADORfGlAi ^ O

a chain -GO-CH ₂ -GH (W) -O- or -CO-CH = C (V) -O- can form, where J is -CII ₃ , -0R ^f , -CH ₂ GOW or -CH = CHW and W stand for a COOH group or a derivative thereof or a group V which can be converted into a COOH group or a derivative thereof. ". ■

The following examples illustrate the present invention without limiting it.

example 1

a) 1,5-bis (2-carboxychromon-6-yl) pentane M.

To a sodium ethoxide solution (prepared from 0.46 parts of sodium and 20 parts of ethanol) 2.5 parts of 5-di- (o-hydroxyphenyl) pentane were added with stirring and the solution was then evaporated, giving the sodium salt of phenol as a white solid stayed behind. This was suspended in 50 parts of refluxing dry bioxane, and 4.13 parts of ethyl chlorofuraarat were added. The mixture was refluxed for a further hour, then 20 parts of 10% sodium hydroxide solution were added and the mixture was refluxed for a further hour. The dioxane was evaporated and the residue diluted with water and extracted with ether. The aqueous solution was then acidified with hydrochloric acid 10 $ ä and extracted with ether. The essential extracts were extracted with a sodium bicarbonate solution, and this aqueous solution was then acidified and extracted with ether. This essential solution was evaporated to give 3 parts of a red oil which was 15 minutes with 20 parts of cold conc. Sulfuric acid was triturated until dissolved. The viscous ^: red solution was then poured onto crushed ice and gave an oily pest. The supernatant liquid was decanted off and the oil was recrystallized from ethanol; in this way, 0.3 parts of 1,5-bis- (2-carboxychromon-6-yl) pentane were obtained as a white solid with a melting point of 265-267 ° O (with decarboxylation),

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BATH

- 20 - ■ ■ ',

Analysis for C ₂ 5 ^H 20 ° 8

calc .: - C ₍ 66.96 H $ 4.50

Found: C 66.4 H 4.68 <f ₀

t>) 1.5-bis (2-ethoxycarbonylchromon-6-yl) pentane

0.6 part of 1,5-bis- (2-carboxychromon-6-yl) -pentane was added to a solution of 50 parts of ethanol saturated with hydrogen chloride, and the mixture was refluxed for 2 hours. The acid slowly dissolved, and after cooling the solution was added 0.45 parts of 1,5-bis (2-ethoxycarbonyl · - chromone-6-yl) pentane as white needles having a melting point of 162-164 ⁰ C. .
Analysis for-GggHggOg

calc .: C 69.04 H 5.59 1 °
found: 0 69.6. H 5.61 %

c) 1,5-bis (2-carboxychromon-6-yl) pentedine sodium salt

A mixture of 0.45 parts of 1,5-bis (2-ethoxycarbonyl- chromon-6-yl) pentane and 1.92 parts 0.92981T sodium hydroxide in ethanol was refluxed for 2 hours and then evaporated to a white solid. This was in Dissolve 50 parts of water and give the 1,5-bis- (2-carboxychromon-6-yl) pentane salt freeze-dried as a white powder.

Example 2

a) 1,6-bis (4-methoxyphenyl) hexane

A mixture of 20 parts of zinc wool, 2 parts of mercury chloride, 32 parts of water and 2.4 parts of conc. Hydrochloric acid was shaken for 5 minutes. The liquid was decanted off, and 8.5 parts of water, 26 parts of conc. Hydrochloric acid, 9 parts of toluene and 5 parts of 1,6-bis- (4-methoxyphenyl) -hexa-1,6-dione were added.
The mixture was refluxed for 60 hours and gradually

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ia43356

the first 6 hours a further 13 parts were concentrated. hydrochloric acid admitted. After cooling and separating the solid residue, the organic layer was separated and the aqueous layer extracted with ether. The United

Toluene and ether solutions were washed, dried and the solvents removed. The yellow residue was urnkristallisiert from Petrol.äther to give 3 ', 4 parts of 1,6-bis (4-methoxyphenyl) hexane having a melting point of 7O ⁰ C.

Analysis for C ₂ 0 ^H 26 ° 2
calc .: C 80.6 H8.74 $> |

Found: C 81.56 H 8.7 f

The structure was determined by IR and nuclear magnetic resonance spectrometry confirmed.

b) 1,6-bis (3-acetyl - 4-hydroxyphenyl) hexane

A mixture of 29.8 parts of 1,6-bis (4-metiioxyphenyl) hexane and 23.5 parts of acetyl chloride in 80 parts of tetrachloroethane was stirred in an ice bath; Then 83 parts of aluminum chloride were added, the temperature was kept below ■ 15 ⁰ O. The mixture was stirred overnight.

to remove the solvent with V / water vapor distilled -ä and the product was extracted with ether, dried and the ether removed. The remaining brown oil solidified and was recrystallized from petroleum ether; it gave 15.5 parts of 1,6-bis (3-acetyl-4-hydroxyphenyl) -he! xan with a P. 97-98 ⁰ C. The structure was confirmed by analysis and nuclear magnetic resonance spectrum.

Analysis for G ₂ 2 ^H 26 ° 4

calc. ί C 74.5 H 7.04 . f> _

Found: 0 74.0 H 7.44 1 * "\ J

-o) 1, ö-bis-CS'-ethoxycarbonylchrOraon-ö-yl) -hexane

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A sodium ethoxide solution was prepared from 5.52 parts of sodium and 90 parts of ethanol. A mixture of 10.7 parts of 1,6-bis- (3-acetyl-4 ^ hydroxyphenyl) · hexane, 21.9 parts of diethyl oxalate and 75 parts of dry ether was added to this and the mixture was kept at about 40 ° C. for 3.5 hours heated. After cooling, it was poured into water, acidified and the solution extracted with ethyl acetate. The extract was washed, dried and the solvent removed. The remaining oil was concentrated with 135 parts of ethanol and 19.5 parts. Hydrochloric acid heated for 10 minutes and after cooling gave a white solid which was filtered off and dried. It was recrystallized from ethanol and gave 3.2 parts of pure 1,6-bis- (2-ethoxycarbonylchromon-6-yl) -hexane with a melting point of 16O ⁰ O.

Analysis for 03 ₀ ^H 30 ° 8 '' calc .: 0 69.4 H 5.8 ^ t

found: C 69.7 H 6.1.7 #

ι '

d) 1,6-BIs- (2-carboxychromon-6-yl) -hexane

A mixture of 1.5 parts of 1,6-bis (2-äthoxycarbonylchromon-6-yl) hexane and 20 parts of saturated Natriumbiearbonatlösung was added with stirring over flattens to Cloo ⁰ C, cooled, filtered and the filtrate is acidified; Thus, 1,6-bis (2-carboxyehromon-6- # l) hexane obtained which gave the pure compound with a P. von 249-251 ⁰ C (with decomposition,) after recrystallization from dioxane.

Analysis for ^G 26 ^H 22 ° 8
calc.s C 67.5 H 4.76, $
Found i C 67.1 H 4.86? δ

e) 1,6-bia- (2-carboxychromon-6-yl) -hexanine triutn salt

0.2 parts of 1,6-bis- (2-oarboxychromon * 6-yl) -hexane were with

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.0.070 parts of sodium bicarbonate in water treated the obtained solution filtered and in the usual way for Disodium salt of 1,6-bis- (2-carboxy-rotnon-6-yl) -hexane freeze dried.

Example 3

a) 1,3-bis (3-acetyl-4-hydroxyphenyl) propane

A solution of 20 parts of 1,3-bis (p-raethoxyphenyl) propane and 12.4 parts of acetyl chloride in 500 parts of tetrachloroethane was cooled to below 15 ° and stirred while adding 54 parts of anhydrous aluminum chloride. The mixture was stirred at room temperature for 18 hours and then ^{heated to 50 °} C. for one hour before being poured onto 1000 parts of crushed ice and 25 parts of conc. Hydrochloric acid was poured. The tetrachloroethane was removed by steam distillation and the residue was extracted with ether. The extracts were dried, treated with charcoal and evaporated, would result in a Peststoff, after recrystallisation from ethanol, 14 parts of 1,3-bis (3-äcetyl-4-hydroxyphenyl) propane as white platelets having a melting point of 112 ⁰ C delivered.

Analysis for C ^ H ^ O ^

ber *: C 73.06 H 6.45 #
found: C 72.88 H 6.55 #

b) 1,3-bis (2-ethoxycarbonylchromon-6-yl) propane

A sodium ethoxy solution prepared from 2.95 parts of sodium and 100 parts of ethanol was added with stirring Solution of 5 parts of 1,3-bis (3-acetyl-4-hydroxyphenyl) propane in 11.7 parts of diethyl oxalate and 50 parts of ether are added, the mixture is refluxed for 4 hours, cooled, diluted with ether and extracted with water. ' The aqueous extracts were acidified with hydrochloric acid and extracted with chloroform. Evaporation of the chloroform! -

109824/2279

- 24 - ■ .. ■ ""

extracts gave a red solid, which in 100 parts of boiling ethanol, which 3 parts of conc. Hydrochloric acid had been added, was dissolved. It turned out a "brownish powder which after recrystallization from ethanol (charcoal) 1.8 parts of 1,3-bis (2-äthöxycarbonylchromon-6-yl) -propane as ~ needles P. von 190-192 ⁰ C revealed.

Analysis for C ₂₇ H ₂₄ O ₈

Calculated: C 68.06 H $ 5.08
found: C 67.58 H 5.11 %

c) 1,3-bis- (2-carboxy-chroinon-6-yl) -propandine sodium salt

A solution of 1.2 parts of 1,3-bis (2-ethoxycarbonylchromon-6-yl) propane and 0.424 parts of sodium bicarbonate in 40 parts of ethanol and 20 parts of water was stirred with a Heated on the steam bath for an hour. The solution was with Treated animal charcoal, evaporated to remove ethanol 'and the aqueous solution to 1.1 parts of 1,3-bis- (2-carboxychromon-6-yl) propane sodium salt freeze-dried as a white powder.

The structure was determined by nuclear magnetic resonance spectroscopy confirmed.

Example 4

a) 1,5-bis (p-methoxyphenyl) pent-3-yl acetate

54.5 parts of 1,5-bis (p-methoxyphenyl) pentane-3-oil were mixed with 218 parts of acetic anhydride, whereupon 0.5 »Parts conc. Sulfuric acid were added. The mixture was left to stand at room temperature for 72 hours, in 1000 parts of water were poured and the solution was extracted with ether. The extracts were washed with cold sodium hydroxide solution and then washed with water, dried and evaporated5 55 parts of a pale yellow oil were obtained in this way

1 0982-4 / 2279

~ 25 - '

Distillation 4-9 parts of 1,5-bis (p-methoxyphenyl) pent-3-yl acetate as a colorless liquid with a Kp.q * c yielded 203-206 ⁰ C. . ■ '

Analysis for G21 ^H 26 ° 4 "

calc .: C 73.66 H 7.66 fo , ■ found: 0 73.86 H 7.45>

b) 1,5-bis (3-acetyl-4-hydroxyphenyl) pent-3-yl acetate

To a cooled solution of 23 parts of 1,5-bis (p-methoxy- ^ phenyl) pent-3-yl acetate and 17.4 parts of acetyl chloride in 450 parts of nitrobenzene and 50 parts of tetrachloroethane were stirred with 54 parts of anhydrous Alurainium chloride was added at such a rate that the temperature of the mixture remained below 15 ⁰ C. After completion of the addition the mixture was heated for 3 hours at 5O ⁰ C and held for 18 hours at room temperature before "poured onto 3000 crushed ice. The mixture was .extrahiert with chloroform and distilled the extracts with water vapor. The residual oil was taken up in ether , the solution dried, treated with charcoal and evaporated to give 22 parts of 1,5-bis (3-acetyl-4-hydroxyphenyl) pent-3-yl-acetate as a colorless oil the purity was determined by Dünnschichtchroraato- \ chromatography. and the structure determined by mass spectrometry.

c) 1,5-bis- (2-ethoxycarbonylchromon-6-yl) -pentan-3-ol

A sodium ethoxide solution was added with stirring to a sodium ethoxide solution prepared from 5.26 parts of sodium and 200 parts of ethanol Solution of 21.9 parts of diethyl oxalate and 10 parts of 1,5-bis (3-acetyl-4-hydroxyl phenyl) pent-3-yl acetate added in 150 parts of ether; the mixture became after the addition was complete Heated to reflux for 3 hours, 18 hours at room temperature held and poured into a chloroform and water mixture. The aqueous layer was separated with

1098 24/2 279

2N hydrochloric acid acidified and extracted with chloroform. The extracts were dried, treated with animal charcoal and evaporated; the first oil was concentrated in 20 parts of ethanol and 1 part for one hour. Hydrochloric acid heated. After evaporation of the ethanol, 2.15 parts of a solid were obtained which, after recrystallization from ethanol, 1.4 parts of 1,5-bis- (2-ethoxycarbonylchromon-6-yl) -pentan-3-ol as a yellow powder with an F. . of 172-175 ⁰ .

Analysis for C ₂ QH ₂₈ Og

b'er .: C 66.9 H 5 »42 $
Found: C 66.9 H $ 5.36>

d) 1,5-bis (2-caEboxychromon-6-yl) pentan-3-ol disodium salt

A solution of 1.374 parts of 1, S-Bis - ^ - äthoxycarbonylchromono-yl ^ pentan ^ -ol in 25 parts of methanol was heated to reflux with 5.61 parts of 0.941N-methanolic sodium hydroxide; after half an hour the solvent was evaporated and the residue dried by azeotroping with benzene and recrystallized from ethanol; so 1.1 parts of egg, 5-bis- (2-carboxychromon-6-yl) -pentan-3-ol-disodium salt became obtain.

e) 1,5-bis (2-carboxychroraon-6-yl) pentan-3-ol

A solution of 1.9 parts of 1, S-bis - ^ - äthoxycarbonyichromonö-yl ^ pentan - ^ - ol in 50 parts of ethanol was refluxed for one hour with 1 part of sodium hydrogen carbonate in 30 parts of water. The ethanol was evaporated and the aqueous solution acidified with 2N hydrochloric acid; it gave 1.4 parts of 1,5-bis- (2-carboxychroraon-6-yl) -pentan-3-ol as an off-white. Powder with a F .. of 240 ⁰ C (with decarboxylation).

Example 5

a) 1,5-Bi3- (3-acetyl-4-hydroxyphenyl) -pentan-3-ol 14 parts of 1,5-bis (3-acetyl-4-hydroxyphenyl) pent-3-yl acetate were with 20 parts of 1Obiger sodium hydroxide solution for one hour warmed up. The ethanol was evaporated and the aqueous back

10982 4/22 79

was acidified with 1 above hydrochloric acid to an oil, which in Ether absorbed, dried, treated with animal charcoal and freed from the solvent by evaporation; so were * 10 parts 1,5-bis- (3 * -acetyl-4-hydroxyphenyl) -pentan-3-ol obtained as a low melting solid. Its structure,. was confirmed by mass spectrometry.

b) 1,5-bis (3-acetyl-4-hydroxyphenyl) pent-2-eη

A mixture of 30 parts of potassium hydrogen sulfate and 10 parts of 1,5-bis (3-acetyl-4-hydroxyphenyl) pentane-3-ol was heated for one hour at 200 C ^10. The tar was partitioned between water and chloroform £, which was separated Chloroformschieht), dried, treated with charcoal and evaporated to a dark oil. This was extracted with petroleum ether and the extracts gave, after evaporation, 1,5-bis- (3-acetyl-4-hydroxyphenyl} -pent-2-ene as a colorless oil.

Analysis for ^G 21 ^ 22 ^ 4

Calculated: C 74.5 H 6.55 $>
Found: C 74.7 H 6.82 1 <>

o) 1,5-bis (2-carboxychromon-6-yl) -pent-2-ene

To a solution of sodium ethoxide (made from 1.19 parts | Sodium in 75 parts of ethanol) became a solution of 2.2 parts of 1,5-bis- (3-aGetyl-4-hydroxyphenyl) -pent-2-ene with stirring and 4.75 parts of diethyloxalate in 30 parts of ether were added. The mixture was gently refluxed for 2 hours, Left to stand for 18 hours at room temperature and then closed a mixture of 100 parts of water and 100 parts of ether given. The aqueous layer was separated with 1 oil 'Hydrochloric acid acidified and'extracted with chloroform. The , . Extracts were dried, treated with animal charcoal and evaporated to an oil with a solution of part sodium bicarbonate heated in 25 parts of water and 25 parts of ethanol until clear. The ethanol was evaporated and the aqueous solution acidified to give a gum which

109824/2279

after unicrystallization from a mixture of chloroform and petroleum ether, 0.5 part of 1,5-bis- (2-carboxychromon-6-yl) -pent-2-ene was obtained as a yellow powder with a F. of 178-18O ⁰ C.

Analysis for C ₂ cH ₁₈ 0g »H ₂ 0

calc .: C 64.7 H 4.32 <fo
found C 65.2 H 4.38 </ o

d) 1,5-bis (2-carboxychromon_6-yl) -pent-2-ene-disodium salt

To a solution of 0.145 parts of sodium bicarbonate in 5 parts 0.385 parts of 1,5-bis- (2 "carboxychromon-6-yl) -pent-2-ene were added to water added and the mixture warmed to homogeneity. Then the solution was treated with animal charcoal, filtered and the piltrate in 0.350 parts of 1,5-bis- (2-carboxychromon-6-yl) -pent-2-ene-disodium salt freeze-dried as a fine white powder. -

10982 A / 22 7 9-

Claims (1)

and functional derivatives thereof, in which P, Q _s ... ^ P ₁ , Q ₁ and R _{1 can be the} same or different and ■ hydrogen, halogen, hydroxy, alkyl, alkoxy, alkenyl, alkenyloxy, substituted alkyl, alkoxy, alkenyl or alkenyloxy, nitro, amino and cyano and X is a substituted or unsubstituted carbocyclic or heterocyclic ring or a straight or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbon chain, which is replaced by one or more carbocyclic or heterocyclic rings, oxygen atoms, sulfur atoms , Nitrogen atoms or substituted sulfur or nitrogen. - ' atoms can be interrupted. ™ 2. Compounds according to claim 1, characterized in that no more than ^ iner of the substituents P, Q and R and no more than one of the substituents P ₁ , Q ₁ and R _{1 has} a meaning other than hydrogen. 3. Compounds according to claim 1, characterized in that that all substituents P, Q, R, P ₁ , Q ₁ and R _{1 are} hydrogen. 4 »The new connections: ' 1,3 ^ BiS- (2-carbOxyehromon-6-yl) propane, Documents {Art 7 g I Abe. 2 No. 1 sentence 3 de »Anderuitleflea.». 4. ΐ. th> ». 109824/2 27 9 "- 30 - T, 5-bis (2-carboxychromon-6-yl) pentane, 1,6-bis- (2-carboxychromon-6-yl) -hexane, 1,5-bis- (2-carboxychrQmQn-6-yl) -pentan-3-ol, 1,5-bis (2-carboxychromon-6-yl) pent-2-ene and functional derivatives thereof. ' 5. Compounds according to claim 1 to 4 in the form of their salts. 6 * = compounds according to claim 5 »in the form of their ammonium or amine salts. 7. Compounds according to claim 5 in the form of their alkali metal or alkaline earth metal salts. 8. Compounds according to claim 1 to 4 in the form of their esters. 9. Compounds according to claim 1 to 4 in the form of their amides. 10. A pharmaceutical preparation containing a bis-chromonyl compound according to claim 1 to 9 in connection with a pharmaceutical carrier or diluent or. other active ingredient. 11. Pharmaceutical preparation according to claim 10, characterized characterized in that the bis-chromonyl compound in In the form of a salt. . T 12. Pharmaceutical preparation according to claim 10 and 11, characterized in that it is in one for administration is in a suitable form by inhalation. 13. A pharmaceutical preparation according to claim 12, containing a solution or suspension of the active ingredient in water. 109824/2279 14. A pharmaceutical preparation according to claim 12, containing a solution or suspension of the active ingredient in a liquefied propellant. · 15. A pharmaceutical preparation according to claim 12, containing the solid active ingredient diluted with a solid diluent, 16. A pharmaceutical preparation according to claim 15 ». through this characterized in that the solid diluent Is lactose. 17. Pharmaceutical preparation according to claim 10 to 16, characterized in that there are still other active ones Contains ingredients. (| 18. Pharmaceutical preparation according to claim 16, characterized characterized as containing a bronchodilator. 19 »Pharmaceutical preparation according to claim 18, characterized in that ^ ■ Indicates that the bronchodilator isoprenaline, Is adrenaline, orciprenaline, isoetharine or a salt thereof 20. Pharmaceutical preparation according to claim 19 »thereby characterized in that the bronchodilator isoprena ^ insulfate is. 21. Pharmaceutical preparation according to claim 18 to 20, . characterized in that - that the bronchodilator in one Amount of 0.1-10% by weight of the bis-chromonyl compound is used· ' 2 "2. Method of Inhibiting the Effect of Antigen / Antibody Reactions, characterized in that one in the field of antigen / antibody reactions 10982Λ / 7779 therapeutically effective amount of a compound or of a preparation according to Claims 1 to 21. 23. The method according to claim 22, characterized in that the bis-chromonyl compound is in the form of a salt is used. 24. Method for the relief "of asthma, characterized in that that after the patient a therapeutically effective amount of a compound or preparation Claim 1 administered bia 21. 25. The method according to claim 24, characterized in that 1-50 mg of the bis-chromonyl compound are used. 26 * Method according to claims 24 and 25, characterized in that that the bis-chromonyl compound is used in the form of a salt. 27..Compounds of the formula or a derivative thereof, wherein P, Q, R, P ₁ , Q ₁ and R _{1 are the} same or different and are each hydrogen, halogen, hydroxy, alkyl, alkoxy, alkenyl, alkenyloxy, substituted alkyl, alkoxy, alkenyl or alkenyloxy, nitro, Can mean amino or cyano; X is a substituted or unsubstituted carbocyclic or heterocyclic ring or a straight ^ or Ίο. in / mi Ϊ43356 branched, saturated or unsaturated, substituted or unsubstituted hydrocarbon chain which can be interrupted by one or more carbocyclic or heterocyclic rings, oxygen atoms, sulfur atoms, nitrogen atoms or substituted sulfur or nitrogen atoms; Y ¹ - ¹ and Z ¹ 'either together form a chain -GO-OH = C (COOH) -O- or a derivative thereof or form the group pair Y ¹ "and Z ¹ ", the -OH and -H or -COJ, -H and -OC (W) = CHCOOH or -OCOCOOR ¹ or together a chain -CO-CH ₂ -CH (W) -O- or -CO-CH = C (V) -O- can form, where J is -CH ₅ , -ORS-GH ₂ COW or -CH = CHW and W is a group V which can be converted into a COOH group or a derivative thereof. 28. Process for the preparation of bis-ohromonyl compounds the formula 0 " ⁰⁰ 2 ^H and their derivatives, · characterized in that a compound of the formula -γι -V wherein P, Q, R, P ₁ , Q ₁ and R _{1 are} identical or different and are each hydrogen, halogen, hydroxy, alkyl, alkoxy, alkenyl, alkenyloxy, substituted alkyl, 109824/2279 Alkoxy, alkenyl or alkenyloxy, nitro, amino or cyano "; X is a substituted or unsubstituted earbocyclic or heterocyclic ring or a straight or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbon chain, which is replaced by one or more carbocyclic or heterocyclic rings, Oxygen atoms, sulfur atoms, nitrogen atoms or substituted sulfur or nitrogen atoms can be interrupted; Z stands for a hydroxyl group and Y for a hydrogen atom, the group -GOCH, or a group -COOR ¹ (where R ^{1 is} an alkyl group), or Y and Z stand together a chain -CO-CH = C (V) -O- or a chain -CO-CH ₂ -CH (W) -O- (WObCi W a carboxyl group or a derivative thereof or one which can be converted into a carboxyl group or a derivative thereof Group V means) mean, and Y ¹ and Z ¹ together form a chain -CO-CH = C (COOH) -O- or a derivative thereof or are a group pair which each of the ob en can have the meaning given, treated so that in one of the several stages the group pair or the group pairs Y and Z and / or Y ¹ and Z ¹ in the desired -CO-CH = C (COOH) -O chain or a derivative the same are converted. 109824/2279