DE2461670A1 - 5,6-BENZO-GAMMA-PYRONE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE IN PHARMACEUTICAL PREPARATIONS - Google Patents

Description

49 731 - BR

Applicant: Carlo Erba S.p.A., Via Carlo Imbonati 24-. 20159 Milan / Italy

5,6-Benzo-y-pyrone derivatives, process for their preparation and their use in pharmaceutical preparations

The invention relates to new 5 »6-benzo-y-pyrone derivatives, processes for their production and pharmaceutical preparations containing them.

The invention relates to new 5 »6-benzo-y-pyrone derivatives. the general formula

where mean:

509828/1051

η the number 0 or 1; η, * the number 0 or 1 ;.

J R (a) cyano, carboxy or the rest,

; (b) -CORq, where R _Q -NHOH or the radical -N ^

can mean, where R ^ q and R ^ In each case hydrogen or C ^ -Cg-alkyl or, if

β hydrogen, Rv _{1 Λ} the remainder

¹¹ -o

or the group -CH-COOH can mean in which

Itjp is hydrogen or C ^ -Cg-alkyl, or R ^ ₀ and R ^^ B together with the nitrogen atom mean an N-pyrrolidinyl, piperidino or morpholino radical,

(c) COOR ^ j ₅ , wherein R ^, a C ^ -C ^ -'- Okya or -alkenyl group, which is unsubstituted or by one or more substituents from the group halogen, carboxy, hydroxy, -OR ^ and -OCOR / i ^ may be substituted, in which R ^ C ^ -Cg-alkyl, substituted or unsubstituted phenyl ·, -

-H, where R _-1 Q and R ^ ^ those given above

Have meanings, or can mean one of the following radicals

B09828 / 1051

wherein R _{1 has} the meanings given above;

and R £, which are the same or different from one another, each hydrogen or methyl;

, and R ^ ,, which are the same or different from each other, respectively Hydrogen or C ^ -Cg

Er, Rg, Rr ₇ and Rg, which are the same or different from one another, each _Ώ

a ¹ ) hydrogen, halogen, hydroxy, nitro, - ^

wherein R ₁ Q and R ₁₁ .. have the meanings given above,

V) the radical - (O) _1n ^- R ₁ Xi in which m = zero or 1 and E _{1 has} the meanings given above,

c ¹ ) .the radical -0-CO-R ₁₁ -, in which R ₁ C can have the meanings given above for R _{1, or the group}

y ^R 10

-N denotes in which R ₁ Q and R _{11 have} the above

have given meanings,

d ¹ ) the radical -SE ₁ ,, in which R _{1 has} the meanings given above; . -

or R _n and R ₀ . if they are on adjacent carbon atoms / o ⁷

are, together a methylenedioxy, ethylenedioxy or propylenedioxy group;

509828/1051

ι ., · ■ "■ ■

X phenyl or a heteromonocyclic radical with 5 or 6 atoms, the at least one double bond and one or two heteroatoms from the group nitrogen,

Ij contains sulfur and oxygen, and when X is a nitrogen-containing radical, a nitrogen atom can be bonded to an oxygen atom to form

/ of the N-oxide;

S.
W ^ C - O, ^ C = S or ^ C i ^CH 2 ^ n » ^{where n} * ^the

Number 2 or 3 and the remainder R- (C) -

ι η

in the £ or 7 position of the benzopyrone ring can be located

ι '■

with the exception of the compounds in which —if at the same time X = phenyl, W is the group -CO-, η and n ^ = zero, Rc, Rg, Ry is hydrogen and R, which is in the 6-position, is carboxy - Rg Denotes hydrogen or, if Rg is in the 3 ¹ - or 4 'position of the phenyl, denotes hydroxy, methoxy, chlorine, bromine, iodine, and with the exception of the following

Links:

6-carboxy-3 ', 4 ¹ -methylenedioxy-f lavone; 6-carboxy-7-hydroxy-flavone;
6-carboxy-5-ethoxy-4-methoxy-flavone; 7-carboxy-flavone;
6- (7 | 4 ^f -dimethoxy) -flavonylacetic acid.

The invention also relates to the salts of the compounds of the general formula I given above, in particular the

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pharmaceutically acceptable salts of these compounds. The new compounds according to the invention also include all possible stereoisomers and their mixtures.

7th
In the case of the compounds according to the invention, if (a) X

Phenyl means the following numbering applied ":

(b) X is a heteromonoeyelic radical with 5 atoms, the following numbering is used:

• V 2 ·

where Z is the heteroatom from which the counting is usually started, - --- can mean a single or double bond,,

(c) X is a heteromonoeyelic residue with 6 atoms, using the following numbering: \ . V 6 ' ' 2 I '3 2!

where Z and the symbol lhi_l. are as defined above.

In the compounds according to the invention, the alkyl, Alkenyl and alkoxy groups branched; chain or straight chain

50982Ö / 1051

(unbranched). If X is a heteromonocyclic radical, it is preferably furyl, thienyl, pyridyl, pyrazinyl, imiazolyl. When "R ₁ ," means an alkyl group substituted by a phenyl group, may

this phenyl group in turn preferably by one or more substituents from the group consisting of hydroxy, alkyl, alkoxy, Alkenyl, acetyl may be substituted.

Particularly preferred among the new compounds according to the invention are those of the general formula I given above, in which:
η the number zero,
U _{1 is} the number zero or 1,

R is a carboxy group or the group -CONHCH ₂ COOh or the group -COOR ^, - ,. wherein R ^, C "-C ^ -alkyl.

. CpH, - / - \

-CH ₀ -CH ₀ N ^ ^ ^ -CH ₀ -CH ₀ -N 0, -CH ₀ -COOH or

2 2 v. _r τι, 2 2 \ / '■ 2

C ₂ H ₅ .

CH,
ι Ο

-CH ₂ -O-CO-C-CH, means
CH ₃

R, hydrogen or methyl,

R ^ hydrogen,

Hr hydrogen, allyl or propyl,

Rg hydrogen,

R “ and Rq, which are identical to or different from one another, are each (a) hydrogen, (b) the remainder

, wherein R ^ ₀ or R _{11 are} each hydrogen or

503828/1051

Mean alkyl, (c) den. Remainder - {θ) -Rxi * »where m is the number Zero or 1 and R ^, a C ^ -C ^ alkyl group which is unsubstituted or substituted by hydroxy or a C 1 -C 6 alkoxy group can mean

X -Phenyl or a furyl, pyridyl or pyrazinyl radical, W / C = O,
with the exception of the following connections:

6-carboxy-flavone
6-carboxy-3 ^f -methoxy-flavone
6-carboxy-4'-methoxy-flavone.

If in the compounds of the formula IR ₁ - denotes propyl or allyl, the propyl or allyl group is preferably in the 8-position. If X denotes phenyl, n, denotes the number zero and Rg and R denote hydrogen, R ″ is preferably different from hydrogen and is preferably in the 2 'position of phenyl. If m is the number zero, R ^, preferably a CL-CU-alkyl group, if m = 1, R ^, preferably a C ^ rC-alkyl group, in particular a propyl, isopropyl, butyl, 1-methylpropyl - and 2-methylpropyl group. When R 1 - is a substituted alkyl group, the substituent is preferably a hydroxy or ethoxy group.

Examples of pharmaceutically acceptable salts are the sodium salts and the salts with 2-amihoethanol and 2-amino-2-hydroxymethyl-1,3-propanediol.

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The invention also relates to pharmaceutical preparations which contain a suitable carrier and / or a suitable diluent and, as active ingredient, at least one compound of the general formula I, in which n, ή, ρ R, R ^, R ₂ , R ^, R / j. " Rr, R ₆ , R ₁ - ,, Rg, X and W have the meanings given above, but without excluding the above-mentioned compounds.

Examples of preferred compounds according to the invention and for preferred active substances of the pharmaceutical according to the invention Preparations are the following:

6-carboxy-2 * -isopropoxy-flavone
6-carboxy-2'-propoxy-flavone
6-carboxy-2'-butoxy-flavone
6-carboxy-2 '- (2-methyl-propoxy) -flavone 6-carboxy-2' - (1-methyl-propoxy) -flavone 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone 6- Carboxy-4- '- (2-ethoxy-ethoxy) -f lavone 6-carboxy-2' - (2-hydroxy-propoxy) -flavone 6-carboxy-2 '- (3-hydroxy-propoxy) -flavone 6- Carboxy-2 '- (2,3-dihydroxy-propoxy) -flavone 6-carboxy-2' - (2-hydroxy-butoxy) -flavone 6-carboxy-2 '- (2-hydroxy-2-methyl-propoxy) -flavon e-carboxy ^ ¹ - (2-hydroxy-2-methyl-butoxy) -f lavon 6-carboxy-ii · - <e-fcy <ix.o ~ y.-3-methyl-butoxy) -f lavon G-carboxy - ^ '- (2-hydroxy-propoxy) -flavone

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~ 9 -

7-carboxy-2'-isopropoxy-flavone '

7-carboxy-2 ^l - (2-methyl-propoxy) -flavone 7-carboxy-2 ^f - (i-methyl-propoxy) -flavone 7-carboxy-2 ^l - (2-hydroxy-propoxy) -flavone 6 -Carboxy-2'-amino-flavone. ·.

6-carboxy-2'-dimethylamino-flavone "

6-carboxy-2 '- (IT-methyl-H ~ isopropylamino) -flavone 6-carboxy-2'-isopropylamino-flavone 6-carboxy-2-j [2'-pyridyl) chromone "·

6-Carboxy-2- (3'-pyridyl) -chromone 6-Garboxy-2- (2'-pyridyl-IT-oxide) -ch] pOmon 6-Carboxy-2- (3'-pyridyl-N-oxide) -chromon 6-carboxy-2- (2 '-f iiryl) -chromon
6-carboxy-2- (2'-imidazoIyI) chromone

6-carboxy-2- (5 ^l -iniidazolyl) -chromone ■ ·

6-carboxy-2- (2'-pyrazinyl) -chromone '·'

6-carboxy-2- (4'-isopropoxy-3'-pyridyl) -chromone 6-carboxy-2- [4- · - (2-methyl-propoxy) -3'-pyridyl] chromone 6-carboxy-2- [4 '- (1-methyl-propoxy) -3'-pyridyl] chromone 6-carboxy-2- [ ^/ l · ¹ - (3-methyl-butoxy) -3 ^I -pyridyl] chromone' - '· 6- carboxy-2- (3'-isopropoxy-2 ¹ -pyridyl) -chromone · * 'of 6-carboxy-2-C 3' ■ - (2-methyl-propoxy) -2 * pyridyl] chromdn 6-carboxy-2 - [3 '- (I-methyl-propoxy) -2 ^f -pyridyl] chromone 6-carboxy-2-C3' - (5-methyl-butoxy) -2'-pyridyl] chromone. 6-Carboxy-2- [3 '- (2-hydroxy-propoxy) -2'-pyridyl] chromoti 6-Garboxy-8-allyl-2- (2' -pyrasinyD-chröiabn 6-Carboxy-8-allyl-2 - (3 ^r -P

6-carboxy-8-propyl-2- (2'-pyrazinyl) -cbromone 6-carboxy ~ 8-propyl-2- (3'-pyridyl) chromone ^ 6-carboxy-2- (β-phenyl-vinyl) chromone _; , 6-0arboxy-2- (a-methyl-ß-phenyl-vinyl) chromone 6-carboxy-2-Cß-2 '- (2-ethoxy-ethoxy) phenyl-vihyl] chromone 6-carboxy-2-Eß- 2 '- (2-hydroxy-ethoxy) -phenyl-vinyl] chromone 6-carboxy-2- [β-2 · - (2-hydroxy-propoxy) -phenyl-vinyl] chromone 6-carboxy-2- [ ß-2 '- (5-hydroxy-propoxy) phenyl-vinyl] chromone 6-carboxy-2- [ß- (2'-pyridyl) vinyl] -chromone, 6-carboxy-2- [ß- (3'- pyridyl) vinyl] chromone '6-carboxy-2-Cß- (4'-pyridyl) vinyl] chromone 7-carboxy-2- (ß-phenyl-vinyl) chromone 6-carboxy-2- [ß- (2' -pyrazinyl) -vinyl] chromone 6-carboxy-flavone

6-carboxy-3'-hydroxy-flavone 6-carboxy-3'-chloro-flavone, and the salts, preferably the pharmaceutically acceptable salts thereof, in particular the sodium salts and the hydrochlorides of the esters with diethylaminoethanol and morpholinoethanol and the glycolic acid and pivaloxymethyl esters . . ^{

The 5J6-benzo-W-pyrone derivatives of the invention can according to one, another subject of the invention are prepared forming method, which is characterized in that

(a) a compound of the general formula

509828 / IQSt

II

where η, n ^, R,

, R ,, R ₂ ^, R ^, R ^, Rr ;, R _g and X the above

have given meanings, cyclized to produce a Compound of the general formula I in which W denotes -C-;

(b) a compound of the general formula

III

wherein n, R, R ^, R ^ and R, - the meanings given above have reacted with an aldehyde of the general formula

IV

in which Rg, Rr ₇ , Rg and X have the meanings given above, for the preparation of compounds of the formula I in which H ₁ = 1, H, and

Hydrogen and W are -C-;

S

(c) a compound of the general formula

509828/1051

/ where η, n ^, R, R ₁ , R ₂ *

c »

»Rr ₇ , Rq and X die

have the meanings given above , dehydrated for the preparation of compounds of the general formula I in which W is -C-;

(d) a compound of the general formula

VI

wherein one of the radicals M is hydrogen and the other is halogen and n, R, R ^, R ₂ , R, _t \ i Er, Rg, Rm Rg and X have the meanings given above , dehydrohalogenated for the preparation of compounds of the general formula I. , in which

W -C- and a. mean the number zero;

O ■ -,

and, if desired, a compound of the general formula

I ₁ in which W is -C-, into a compound of the general . it

Formula I converted, in which W is -C-, by treatment

S with a sulphurizing agent or, if desired, a

500828/1051

bond of the general formula I, in which W is -C-,

converted into a compound of the general formula I, wherein

S.
W. y ν means where n _{z is} the number 2 or 3

> (CIUL ·. »3

means by reaction with a compound of the formula HS- (CH ₀ ) -SH and / or, if desired, a compound of

/ ^{d n} 3
general formula I is converted into another compound of general formula I in a manner known per se and / or, if desired, a compound of general formula I is converted into a salt, preferably a pharmaceutically acceptable salt thereof, and / or, if desired, a mixture of separates optical isomers into the various isomers.

The cyclization of the compound of formula II is preferably carried out in the presence of acid catalysts, for example in the presence of hydrochloric acid, hydriodic acid, sulfuric acid, formic acid, at a temperature which is preferably within the range between 20 and 120 ° C, and in an inert solvent, for example from the group of methanol, ethanol, dioxane, tetrahydrofuran, benzene, toluene, acetic acid and mixtures thereof. j.

Jm

The reaction of a compound of the formula III with an aldehyde of the formula IV is carried out in the presence of basic condensing agents, 3δ.B. in the presence of sodium ethylate, sodium methylate,

Vo ** 2 * / 1OS1

Sodium hydride, sodium amide, sodium or potassium hydroxide, at a temperature which is preferably within the range from 0 to 10O ⁰ C, and in a solvent which is preferably selected from the group consisting of methanol, ethanol, dioxane, water and mixtures thereof is carried out.

The dehydrogenation of the compound of formula V is preferably carried out with SeOp in organic solvents such as toluene, Xylene or η-amyl alcohol, and carried out at the reflux temperature The dehydrohalogenation of the compound of formula VI is preferably carried out by treatment with a base, which is preferably from the group NaOH, KOH, K ^ CO ,, potassium tert-butoxide, Pyridine, triethylamine is selected in an organic solvent, for example from the group ethanol, Acetone, dimethylformamide and dimethyl sulfoxide is selected, performed at a temperature that is within the range from room temperature to reflux temperature.

The conversion, if carried out, of a compound of the general formula I, in which W is j-G-, into a

δ ... j

Compound of the general formula I, in which W denotes -C-!

S can be obtained by treating a solution of the compound of the general formula Z. in which W is -C-, with P ₀ Sj- at the reflux temperature = peratjur "£ ä an inert organic solvent such as benzene, jM.oxon, tetrahydrofuran and Mixtures thereof can be carried out.

The conversion, if any, of a compound of

SO9028 / 1O51

general formula I, in which W is -C-, in a ver

Il

"bond of the general formula I, in which W

", by reacting with a compound of formula HS- (CH ₀₎ -SH is preferably carried out in the presence of a Säurekata -. 'lysators, for example in the presence of p-toluenesulfonic acid, I ^ yridinhydrochlorid, ZnCl _2, BF, etherate, in an inert solvent, for example benzene or toluene, or in the absence of solvents at temperatures which vary between 20 and 120 C. A compound of the general formula I, as stated above, can be converted into another compound of the general formula I. For example, a compound of general formula I in which E is a cyano group can be converted by acid hydrolysis, for example with hydrochloric acid or sulfuric acid, into a compound of general formula I in which R ^ is a carboxy group a compound of the general formula I in which E is a carboxy group can be obtained by esterification, for example by reaction of the alkali metal zes of the acid can be converted with the desired alkyl halide into a compound of the general formula I in which R is a carbalkoxy group. Free hydroxyl groups can also be etherified by treatment, for example with alkyl halides, or etherified hydroxyl groups can be converted into free hydroxyl groups, for example by treatment with a pyridine salt, preferably the hydrochloride, or with a strong acid or a Lewis acid.

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In a compound of the formula I in which X is a nitrogen-containing heteromonoeyelic radical, a nitrogen atom by oxidation, for example with peracids such as peracetic acid, permaleic acid and perbenzoic acid, into the ent speaking N-oxide. A connection of the Formula I, in which R is a carboxy group, can be prepared according to known Process can be converted into a compound of the formula I in which R is the tetrazolyl radical of the formula

for example by converting the carboxy group into the corresponding halide, preferably the chloride, for example by reacting with thionyl chloride in benzene at the reflux temperature, then reacting the halide, for example with ammonia, to form the corresponding amide, dehydrating the amide to the nitrile, for example using p-toluenesulfonyl chloride in pyridine and reacting of the nitrile with sodium azide and ammonium chloride in dimethylformamide at a temperature varying between room temperature and 10O ⁰ C. The saponification of the compounds of the formula I, which may be carried out, can also be carried out by known processes.

The compounds of the formula II can be prepared by reacting a compound of the formula II

VII OH

509828/1051

wherein η, R, E ^, E £, ^ c have the meanings given above have with a compound of the formula

? y

-R,

VIII

where n ^, E ,, E ^, Eg, E ₁ - ,, Eg and X have the meanings given above, and E /, g is aryl, preferably phenyl, or alkyl.

The reaction between the compound of the formula VII and the compound of the formula VIII v / ird preferably in an organic solvent such as methanol, ethanol, dioxane and pyridine, in the presence of a strong base, for example in the presence of sodium methylate, sodium ethylate, sodium hydride, and with at a temperature within the range of room temperature to reflux temperature.

An alternative process for the preparation of the compound of the formula II consists in reacting a compound of the formula VII with a compound of the formula IX in a known manner

MOC- (C- C) _

JX

50 9828/1051 '

wherein ti * signifies halogen or hydroxy and zl, -, - R ,, R ^, RgY R ", Β" and X have the meanings given above, for the preparation of a compound of the formula

X the

wherein n _t iLp R, R ^, R ₂ »R ^ ♦ R ^, Rc» Rg »' have the meanings given above , and then subjects the compounds of the formula X to a rearrangement which takes place in an inert solvent, for example in pyridine, toluene , Methyl ethyl ketone, is carried out in the presence of a strong base, for example in the presence of sodium, sodium amide, potassium hydroxide, potassium carbonate, at a temperature which varies between room temperature and the reflux temperature.

The compounds of the formula III can be prepared, for example, by acidic cyclization of β-diketones of the general formula

XI

SO 18 287 t CrSt

where η, R ₁ R ^, Rö » ^R 5 ^" ^{β ol> en} have the meanings given, which in turn can be prepared by basic condensation of an acetic acid ester, for example of methyl acetate, ethyl acetate, phenyl acetate, with a sub- ¹ o-hydroxyacetophenone of the general formula VII, wherein the reaction is preferably carried out at a temperature within the range from 20 to 100 ° C. in the absence of solvents or in a solvent which is preferably selected from the group consisting of benzene, toluene, dioxane and mixtures thereof using for example sodium hydride is used as a condensing agent.

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The compounds of formula VII can be prepared by starting, for example, from the suitable substituted phenols, by means of a Friedel-Crafts condensation

or by a frieze rearrangement.
/

The compounds of the formula V can be prepared starting from compounds of the formula

XII

where η, n ^, R, R ^, R ₂ , R * »R ^, Rr, R ^, Rr ₇ , R ₈ and X have the meanings given above, by reaction with basic condensing agents such as sodium or potassium hydroxide, Sodium oxide, sodium hydride, sodium or potassium carbonate, potassium acetate, or acids, such as hydrogen halide, sulfur, phosphorus, p-toluene sulfonic acids, in a solvent which is preferably selected from the group consisting of methanol, ethanol, dioxane, tetrahydrofuran, Benzene, toluene, dimethyl sulfoxide, at a temperature varying between room temperature and reflux temperature.

The compounds of the formula XII can in turn be prepared are made by condensing a compound of formula VII with a substituted aldehyde of formula

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XIII

OHC - (C = C) ₁ ^ ^R 3 ^R 4 ¹

where n ^, R ,, R ^, R ^, Rr ₇ , Rg "and X have the meanings given above.

The condensation can take place in a solvent, for example is selected from the group consisting of methanol, ethanol, dioxane, water and mixtures thereof, and in the presence of a basic one Catalyst, e.g. in the presence of piperidine, ITatriunhydroxid, Sodium hydride, sodium alkoxide, and at a temperature within the range from room temperature to reflux temperature be performed.

The compounds of the formula VI can be prepared by halogenation of compounds of the formula V, for example with IT-bromosuceinimide or pyridine perbromide (NB Lorette ^e "t ⁸ ^ * » "J .. Org, Chem.", 16, 930 (1951) , S. Hishide et al., "J. Chein. Soc. Japan", 2i ».697 O953)) -

The compounds according to the invention have an antiallergic activity which manifests itself, for example, in the fact that they are active in the passive cutaneous anaphylaxis test (FCA) in rats according to Y. Goose and AMYIT. Blair, "Immunology", 1969, 16 , 74-9 · They can therefore be used to prevent and treat

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Bronchial asthma, allergic rhinitis ,. Hay fever, urticaria and dermatosis can be used. An important feature ^ dr mim compounds is that they exhibit an antiallergic activity even when administered orally.

The following table shows the protective effect achieved with the compounds according to the invention when administered orally in the PCA test on rats in comparison to the known antiallergic drugs, ie disodium chromoglycate (DSCG) and AH 7725, ie 2-carboxy-7-hydroxyethoxjo: anthon (J. . Fullarton,. LB Martin and G, Vardey, "Int. 'Arch. All. ¹¹ , 1973, ± £, 84).

Tabel
Inhibition in / j compared to the

Connect Bosie-

tion
(/

rug

(mg / kg / 15 min. 30 min. 60 min. 120 min.

ρ. ο. )

DSCG 50 6.0 5.5 3.2 2.5

AH 7725 50 42.6 14, A 13.3 3 »8

6-carboxy-2'-iso-

propo> ^ - flavone 50 82.9 39.5 27.6; 24.4

6-carboxy-2 ~ (ß-

phenyl-vinyl) - ■

chromone 50 69.9 4-5.8 1-9 »6 16.6.

In addition to an antiallergic activity, those according to the invention have Compounds are effective in relieving airway obstruction and increasing lung capacity filling and can therefore be used for the treatment of vofi

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respiratory insufficiencies, for example for the acute pulmonary insufficiency, such as those with rats using the method described by F. Palecek, M. PaIecekova and D.M. Aviado in "Arch. Environ. Health", 1967, 1 ^>, 332-342, method described demonstrate. In these experiments, the compounds according to the invention, in particular 6-carboxy-2'-isopropoxyflavone, lower the obstruction of the airways and increase the lung filling even with a dosage of only 3 mg / kg / i.v .; at the same dose they act antagonistically (50%) to that bronchial constrictive effect of 5-HT (= 5-hydroxytriptamine, i.e. serotonin) and the compound 4-8 / 80 (a histamine releasing agent Drug).

The compounds of the invention also have anti-ulcer activity, as evidenced by the fact that they have been shown to be active in inhibiting stress-induced ulcers in rats, which according to a modification of the method described by K. Takagi and S. Okabe in, "Jap. J. of Pharmac", 1968, 1j3, 9, have been locked in a Y / water bath at 25 ° C. for 40 minutes. In this experiment, the compounds of the invention exhibited, lnsbeöv ^ ^ -aopg _as sodium salt of 6-carboxy-2'-isopropoxyflavon ^ a 45% Inhttitrw ^ the in rats induced by stress ulcers if in a dose of 50 mg / kg it / iv were administered.

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The compounds according to the invention can in the usual way, "For example orally and parenterally, in a daily dose of preferably 0.5 to 15 mg / kg, or by inhalation, preferably in a daily dose of 0.5 to 100 mg, in particular from 0.5 to 25 mg, or by topical application

be enough.

The nature of the compounds according to the invention in connection pharmaceutical preparations containing pharmaceutically acceptable carriers or diluents depends, of course, on the desired mode of administration. The preparations can be formulated in the usual way with the usual additives. For example, the compounds according to the invention in In the form of aqueous or oily solutions or suspensions, in the form of aerosols as well as powders, tablets, pills, gelatin capsules, Syrups or creams or 'lotions for topical use can be administered.

The pharmaceutical preparations containing the compounds according to the invention are preferably for oral administration in the form of tablets, pills or gelatin capsules, which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; Lubricants, e.g. silicon dioxide, talc, stearic acid, Magnesium or calcium stearate and / or polyethylene glycols, contain, or they can also contain binders, such as starches, Gelatine, methyl cellulose, carboxymethyl cellulose, GuTiuaiara-

509828/1051

bicum, tragacanth, polyvinylpyrrolidone, disintegrant, such as starches, alginic acid, alginates, sodium starch glycolate, Effervescent mixes, dyes, sweeteners, wetting agents such as lecithin, polysorbates, lauryl sulfates, and in general non-toxic and pharmacologically inactive substances such as they are used in pharmaceutical preparations. The pharmaceutical preparations can be based on known ones Be produced, for example by mixing, granulating, Tableting, sugar coating or film coating processes.

For the treatment of allergic asthma, the invention Compounds are administered by inhalation. For this use, suitable preparations can be in the form a suspension or solution of the active ingredient, preferably in the form of a salt, such as the sodium salt, in Water, for administration by means of a conventional nebulizer. Alternatively, the preparations can be in the form a suspension or solution of the active ingredient in a common liquefied propellant such as dichlorodifluoromethane or dichlorotetrafluorathane, which can be obtained using a pressure vessel, i.e. an aerosol atomizer, administered. If the drug is not soluble in the propellant, it may be necessary to use the Preparation of a cosolvent, e.g. ethanol, dipropylene glycol, isopropyl myristate and / or a surface-active one To add agents to the drug in the propellant medium to suspend and these surfactants

509828/1061

can be such as are usually used for such as nonionic surfactants such as lecithin. The inventors Compounds can also be in the form of powders using a //

suitable injection device and in In this case, the finely divided powders of the active ingredient can be mixed with a diluent such as lactose will.

In addition, the connections can according to the invention by intradermal or intravenous injection in the usual way. be enough.

In addition to internal administration, the inventive Compounds are also used in preparations for topical application, such as in creams, lotions or Pastes for use in dermatological treatments. In these preparations the active ingredient can be mixed with usual oily (oil-containing) or emulsifying carrier materials be mixed.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

50 9828 / 1OS1

Example 1 · ■

A solution consisting of 60 g of methyl 3-acetyl-4-hydroxy-likewiseate and 120 g of methyl 2-isopropoxybenzoate in -4-00 ml of dioxane was slowly transformed into a suspension of 4-5 g of 50% sodium hydride in 200 ml at room temperature with stirring ml of dioxane were added. The mixture was kept 4 hours at 80 ⁰ C, cooled, then diluted with 600 ml of petroleum ether and then filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with 5% potassium carbonate and water, then evaporated to dryness and crystallized in ethanol, whereby 70 g (2 ~ hydroxy-5-carbomethoxybenzoyl) - (2-isopropoxybenzoyl) methane, mp 105 to 107 ° C., which were then refluxed for 15 minutes with 280 ml of 99% formic acid. After cooling and diluting with 1 l of water and filtering, the collected precipitate was crystallized in acetone and 60 g of 6-carbomethoxy-2'-isopropoxyflavone, mp 154-155 ° C., were then obtained with 1.020 l of a 1% strength Potassium hydroxide solution was hydrolyzed in 95% ethanol for 3 ° minutes at reflux temperature. The mixture was cooled, acidified with acetic acid, concentrated in vacuo and a precipitate was obtained which was filtered off, washed with 95% ethanol and water and, after crystallization in ethanol, 45 g of 6-carboxy-2'-isopropoxyflavone, F 209 to 211 ° C. The following compounds were made in an analogous manner:

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6-carboxy-2'-propoxyflavone, m.p. 201 to 2O3 ° C 6-carboxy-2 '- (2-methylpropoxy) flavone, m.p. 193 to 195 ° C 6-carboxy-2'-butoxyflavone, m.p. 204 to 206 ⁰ C 6-carboxy-2'-ethoxyflavone, m.p. 225 to 22 ° C 6-carboxy-2'-methxyflavone, m.p. 265 to 267 ° C 6-carboxy-2 ' _} 6'-dimethoxyflavone, m.p. > 300 ⁰ C 6-carboxy-2 '- (1-methylpropoxy) flavone
6-carboxyflavone, m.p. 301 to 303 ^° C
6-carboxy-3 '~ clilorflavone, m.p. 281-283 ° C.

Example 2

A solution of 54 g of methyl 3-acetyl-4-hydroxybenzoate and 135 6 of methyl 2-benzoyloxybenzoate in 400 ml of dioxane was slowly added with stirring at room temperature to a suspension of 40 g of 50% sodium hydride in 150 ml of dioxane. The mixture was held 5 hours at 70 ⁰ C, then cooled and diluted with petroleum ether, then filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with 5% potassium carbonate and water, then evaporated to dryness. After crystallization in methanol gave 74 g (2-hydroxy-5-carbomethoxybenzoyl) - (2-benzoyloxybenzoyl) methane ₁ F. 95 to 97 ° C, then the 24 stun long with 500 ml of 99% formic acid under reflux ge was boiling. After cooling and diluting with 500 ml

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. -29 -

Ethanol, the resulting precipitate was filtered off and 'washed with ethanol, 31 g of 6-carbomethoxy-2'-hydroxyflavone, mp 290 to 291 ⁰ C, obtained, which then in 150 ml of dimethylformamide with 26 g of i-chloro-2- benzoyloxypropane and 18 g of potassium carbonate was reacted for 16 hours at 70 ° C. The mixture was cooled, diluted with 600 ml of water,
filtered, then washed with water to give 4-5 g of 6-carbomethoxy-2 '- (2-benzoyloxypropoxy) flavone which was hydrolyzed with 1,250 of a 1% potassium hydroxide solution in 95% ethanol for 1 hour at reflux temperature. After cooling, acidification with acetic acid, concentration to a small volume in vacuo and after dilution with water, the resulting precipitate was filtered off, then washed with water and, after crystallization from methylene chloride / ethyl acetate, 18.5 g of 6-carboxy-2 were obtained '- (2-hydroxypropoxy) flavone, m.p. 211-213 ° C. The following compounds were prepared in an analogous manner:

6-carboxy-2 '- (2-hydroxyethoxy) flavone, m.p. 238 to 2A-O ⁰ C
6-carboxy-2 '- (3-hydroxypropoxy) flavone
6-carboxy-2 '- (2-hydroxy-3-methylbutoxy) flavone
6-carboxy-3'-hydroxyflavone, m.p. 3.21 to 323 ° C

Example 3

5 g of the 6-carbomethoxy-2'-hydroxyflavone obtained by the method described in Example 2 were in 30 ml

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Dimethylformamide with 3.5 S β -Äthoxyäthylbromid and 3.2 g potassium carbonate for 16 hours at 80 ⁰ C. The mixture was cooled, diluted with water / water, filtered, washed with water. After crystallization in methanol, 4 _{tons of} 5 S 6-carbomethoxy-2 '- (2-ethoxyethoxy) flavone were obtained, which was hydrolyzed for 45 minutes at reflux temperature with 90 ml of a 1% strength potassium hydroxide solution in 95% strength ethanol. After cooling, the mixture was acidified with acetic acid, concentrated, diluted with water, filtered and, after crystallization in ethanol, 3.1 S 6-carboxy-2 ^f - (2-ethoxyethoxy) flavone, P. 198 to 200 C. Using of the appropriate alkyl halides, the following compounds were made:

6-carboxy-2'-isopropoxyflavon, F. 208-210 ⁰ C 6-carboxy-2 '- (2-methylpropoxy) flavon, F. 192-1 "C 94- ⁰ 6-carboxy-2 ^l - (2- hydroxypropoxy) flavone, m.p. 210 to 212 ° C 6-carboxy-2 '- (- i-methylpropoxy) flavone 6-carboxy-2' - (2-hydroxy-2-methylpropoxy) flavone 6-carboxy-2'- (2-hydroxy-2-methylbutoxy) flavone 6-carboxy-2 ^l - (2,3- <iihydroxypropoxy) flavone.

Example 4

A mixture consisting of 10 g of 6-carbomethoxy-2'-hydroxyflavone, prepared according to the method described in Example 2, and 6 g of 1,2-epoxybutane and 0.5 ml of benzyltrimethylamnionium hydroxide in 40 ml of dioxane was treated for 48 hours at the

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-2461870

Maintained reflux temperature. After, cooling, diluting with water and extraction with ethyl acetate became the organic Phase washed with 5% potassium carbonate and water. The solution was evaporated to dryness and that was obtained Product was with the stoichiometric amount of a 1% Potassium hydroxide solution in 95% ethanol treated for 1 hour at reflux temperature. After acidification with acetic acid, concentration in vacuo, dilution with water and filtration were performed after two crystallizations from ethanol 4.7 g of 6-carboxy-2 '- (2-hydroxybutoxy) flavone were obtained.

Example 5

46.2 g of methyl ^ -acetyl - ^ - cinnamoyloxybenzoate, mp 97 to 99 ° C, were dissolved in 350 ml of methyl ethyl ketone. 37 p. Anhydrous potassium carbonate was added and the mixture was refluxed for 6 hours. After cooling, diluting with 500 ml of petroleum ether and filtering, the collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with 5% potassium carbonate and water, then evaporated to dryness. After crystallization in methanol gave 5 ^, 2 g (2-hydroxy-5-carbomethoxybenzoyl) cinnamoylmethan _i F. 138 to 140 ⁰ C, which was boiled for 15 minutes with 140 ml of 99 # formic acid under reflux, after cooling, Dilute with 1 liter of water and filter the collected

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Precipitate crystallized in acetone and 27.8 g of 6-carbomethoxy-2- (yβ-phenylvinyl) chromone, P. 175 to 177 ° C, were obtained with 600 ml of a 1% potassium hydroxide solution in 95% ethanol for 4-5 minutes was hydrolyzed for a long time at reflux temperature. After cooling, acidification with acetic acid, concentration under vacuum and dilution with water, the precipitate was collected and washed with water, 16.1 g of 6-carboxy-2- ( _/ , S- phenylvinyl) chromone, mp 273-275 ° C. Using the appropriate esters of methyl 3-acetyl-4-hydroxybenzoate, the following compounds were prepared:

6-carboxy-2- (oL-methyl- β- phenyl-vinyl) chromone, m.p. 220 to 222 ° C

6-Carboxy-2 ~ (/ 3 -2'-methoxyphenylvinyl) chromone, m.p. 270 ° C (dec.) 6-Carboxy-2- £ β - (2'-pyridyl) vinyl] chromone 6-carboxy-2 - £ ß - (3'-pyridyl) vinyl] chromone 6-carboxy-2- [ρ- (4'-pyridyl) vinyl] chromone. 6-carboxy-2- £ ß- (2'-furyl) vinyl] chromone.

Example 6

The process described in Example 5 gave, starting from methyl ^ -acetyl ^ - Cortho-benzoyloxy-cinnamoyl- oxy) benzoate and after hydrolyzing the bericyl ether group by heating for 24 hours at reflux temperature with an excess of 99% formic acid Crystallization in

809828 / 10S1

Acetone 6-carbomethoxy-2 - (/ 3 -2'-hydroxyphenylvinyl) chromone, - F. 252 to 254 ⁰ C. 7 g of this product, dissolved in 35 ml of dimethylformamide, were mixed with 4.2 g of β- ethoxyethyl bromide and 4 g ■ anhydrous potassium carbonate ^{reacted at 7O 0} C for 24 hours. After cooling, diluting with water and filtering, the collected precipitate was hydrolyzed with the stoichiometric amount of a 1% potassium hydroxide solution in 95% ethanol for 1 hour at the reflux temperature. After cooling, 'dilute' with water, acidify with Citric acid, the precipitate was collected and crystallized in methanol / benzene, 3.6 g of 6-carboxy-2-f / 3-2 ^l - (2-ethoxyethoxy) ■ phenylvinyl] chromone, mp 218 ° C. (Ze'rs .) Using appropriate alkyl halides, the following compounds were prepared:

6-carboxy-2-f β -2 '- (2-hydroxypropoxy) phenylvinyl] chromone 6-carboxy-2- fß -2' - (3-hydroxypropoxy) phenylvinyl} chromone 6-carboxy-2- [β -2 ' - (2-hydroxyethoxy) pheny! Vinyl} chromone.

Example 7

A solution consisting of 16 g of methyl 3-acetyl-4-hydroxybenzoate and 23 g of methyl nicotinate in 100 ml of dioxane was slowly added at room temperature with stirring to a suspension of 12 g of 50% sodium hydride in 60 ml of dioxane. The solution was gehalten- for 6 hours at 80 ⁰ C, then cooled, diluted with 200 ml of petroleum ether and filtered. The received

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Product was dissolved in water and treated with acetic acid; the resulting precipitate was washed with water and / crystallized methanol in methylene chloride, to which 17.2 g * (2-hydroxy-5-carbomethoxyberizoyl) nicotinoylmethan, F. 200-202 ⁰ C, -erhielt which then 300 ml with ethanol, containing 1% concentrated hydrochloric acid was treated at reflux temperature for 2 hours. After concentration in vacuo, dilution with water and neutralization with sodium acetate, the precipitate was filtered off. The crude 6-carbomethoxy-2- (3'-pyridyl) chromone (15 »1 s) was hydrolyzed with s.töchiometrischen amount of 1% in 95% Kaiiumhydroxid is ^em ethanol for 1 hour at reflux temperature. After cooling, diluting with 600 ml of water and neutralizing with acetic acid, the precipitate was collected and after crystallization in dimethylformamide, 9.8 g of 6-carboxy-2- (3'-pyridyl) chromone, melting point> 35O were obtained ⁰ C; IR (KBr): V _C _ _Q - (carboxy) 1680 cm, y _G _ ₀ (chromon) 1630 cm ", 1610 cm", v Q "(ia-substituted pyridine) 770 cm", 696 cm " The following compounds were prepared in an analogous manner:

6-Carboxy-2- (2'-pyridyl) chromone, m.p.> 300 ⁰ C; IR (KBr): V _{c = i! 0} (carboxy) 1710 cm " ¹ , v _{C: r0} (chromone) 1650 cm" ¹ ,) f _C _ _H (b-substituted pyridine) 768 cm "

6-carboxy-2- (4'-pyridyl) chromone, m.p.> 350 ° C; IR (KBr): V _{c = 0} (carboxy) 1690 cm " ¹ , V _c _ ₀ (chromon) 1630 cm" ¹ , Y _C _ _H (p-substituted pyridine) 825 cm "

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6-carboxy-2- (2'-tliienyl) chromone _t · Τ. 301 to. 304 ⁰ C
6-carboxy-2- (2 ^! -Furyl) chromone, m.p. 330 to 332 ° C
6-Carboxy-2- (2'-pyrazinyl) chromone, m.p.> ^ 5O ⁰ C; IR (KBR):

V _{c = 0} (carboxy) 1695 cm " ¹ , V _{c = 0} (chromone) 1645 cm" ¹
6-Carbo.xy-2- (2'-imidazolyl) chroinone
6-carboxy-2- (5'-iniidazolyl) ciirOmon /

6-carboxy-2- [2 '- (2-methylpropoxy) -3'-pyridyl) chromone 6-carboxy-2- £ 2' -. (1-methylpropoxy) -3 '-pyridyl} chromone 6-carboxy-2 - (2'-Isopropoxy-3'-pyridyl) chromone
6-carboxy-2- (2'-but oxy-3'-pyridyl) Ehromon
6 <-Carboxy-2 ~ f2 '- (3-methylbutoxy) -3 ^I -pyridyl] chromone
6-carboxy-2- (2'-pentyloxy-3'-pyridyl) chromone
6-carboxy-2-f3 '- (2-methylpropoxy) -2'-pyridyl} chromone 6-carboxy-2- (3' - (1-methylpropoxy) -2'-pyridyl} chromone 6-carboxy-2- ( 3'-isopropoxy-2'-pyridyl) chromone
6-carboxy-2- (3'-pentyloxy-2'-pyridyl) chromone
6-carboxy-2-f3 '- (3-methylbutoxy) -2'-pyridyl] chromone
6-Carboxy-2-f3 '- (2-hydroxypropoxy) -2'-pyridyl] chromone 6-Carboxy-2- (4' -isopropoxy-3 '-pyridyl) chromone
6-carboxy-2-f4 '- (2-methylpropoxy) -3' -pyridyl] chromone 6-carboxy-2- [* 4 '- (1-methylpropoxy) -3' -pyridyl] chromone 6-carboxy-2 ~ r4 '- (1-methylbutoxy) -3'-pyridyl} chromone.

Example 8

Following the procedure described in Example 7,

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- 56 -.

starting from methyl 3-hydroxy-4-acetylbenzoate, the following Connections made:

7-carboxy-2- (2'-pyridyl) chromone
7-carboxy-2- (3'-pyridyl) chromone
7-carboxy-2- (2'-furyl) chromone
7-carboxy-2- (2'-pyrazinyl) chromone 7-carboxy-2- [2 '- (2-diethylpropoxy) -3' -pyridyl] chromone 7 ~ carboxy ~ 2- [2 '- (1-methylpropoxy) -3 '-pyridyl] chromone 7 ~ carboxy-2- (2'-isopropoxy-3'-pyridyl) chromone 7-carboxy-2- (2'-butoxy-3'-pyridyl) chromone 7 ~ carboxy-2- [ 2 '- (3-methylbutoxy) -3'-pyridylj chromone 7-carboxy-2- [3' - (2-methylpropoxy) -2'-pyridyl] chromone 7-carboxy-2-f3 '- (1-methylpropoxy) -2'-pyridyl] chromone 7-carboxy-2- (3'-isopropoxy-2 ¹ -pyridyl) chromone 7-carboxy-2- (3'-pentyloxy-2 ¹ -pyridyl) chromone 7-carboxy-2-J3 '- (3-methylbutoxy) -2'-pyridylj chromone.

Example 9

Following the procedure given in Example 1, starting of methyl 3-acetyl ~ 4-hydroxybenzoate and the correct methyl-N-alkyl and -N, N-dialkylantranilate, made the following connections:

6-carboxy-2'-methylaminoflavone
6-carboxy-2'-isopropylaminofl

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■ ~ 37 ~

6-carboxy-2'-dimethylaminoflavone

6-carboxy-2 '- (N-methyl-N-isopropylamino) flavone 6-carboxy-2 '- (N-methyl-N-ethylamino) flavone.

Example 10 .

Following the procedure described in Examples 2 and 3 were, starting from the intermediates methyl 3-acetyl-4-hydroxy-5-allylbenzoate (M.p. 106 to 108 ° C) and methyl 3-acetyl-4-hydroxy-5-propylbenzoate (F. 89 to 91 ° C), the after. that in "J. Pharm. Soc. Japan", 2i> ^ 7 095W-), described Procedures had been established that made the following compounds:

6-carboxy-8-propyl-2'-isopropoxyflavone, T. 205 to 207 ° C 6-carboxy-8-allyl-2 '- (2-hydroxypropoxy) flavone 6-carboxy-8-propyl-2 ^l - (2 -hydroxypropoxy) flavone.

Example 11

Following the procedure described in Example 7, starting from the same intermediates as in Example 1O _{1, the} following compounds were prepared:

6-Carboxy-8-allyl-2- (3'-pyridyl) chromone, m.p. 318-323 ° G 6-carboxy-8-propyl-2- (3'-pyridyl) chromone

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6-carboxy-8-allyl-2- (2'-pyrazinyl) ciromone 6 ~ carboxy-8-propyl-2- (2'-pyrazinyl) chroinone,

Example 12

\ ■

To a solution consisting of 5 S 2-methyl-6-carbethoxy-chromone and 5 »5 S 3-eyridyl-carboxyaldehyde in 100 ml of absolute ethanol, a solution of 0.5 g of sodium in 50 ml ^{was slowly added while stirring at 0 ° C.} Ethanol added. The mixture was kept at room temperature for 2 hours, then acidified with acetic acid, concentrated in vacuo, diluted with water and finally the precipitate was collected, yielding 5.8 g of 6-carbomethoxy-2- ( _/ 3 -3 ^l -pyridylvinyl) chromone, F. I70 to 180 ⁰ C, received the strength with the stoichiometric amount of a 1% potassium hydroxide solution was hydrolyzed in 95 # strength ethanol for 1 hour at reflux temperature. After cooling and dilution with 1C% aqueous monobasic sodium phosphate, a precipitate was obtained which was collected by filtration and crystallized from N, N-dimethylforjaamide / methanol, giving 1.8 g of 6-carboxy-2 »(y5 -3 ' pyridylvinyl) chromone, m.p.> 35O ⁰ C; IR (KBr): V _n ,. (Carboxy) 1710 cm "* ¹ , V (Chromon) 1655 cm" ¹ ,

1640 cm ~ ¹ , rCtrans- ^ C »cf) 970 cm" ^1. 'H ^p

The following compounds were prepared in an analogous manner:

50982Θ / 1061

6-carboxy-2- (y3 -2'-pyridylvinyl) chroinone 6-carboxy-2- (y3 -4 ^l -pyridylvinyl) chromone 6-carboxy-2- (A -2'-furylvinyl) chromone.

Example 13
■ J

200 ml of piperidine were added to a solution consisting of 15 S methyl 3-hydroxy-4-acetylbenzoate and 15 S-licylaldehyde in A-00 ml of absolute ethanol, and the mixture was kept at reflux temperature for 40 hours. After cooling, acidification with hydrochloric acid and extraction with ethyl acetate, the organic phase was washed with 5% KpCO * and with water, then evaporated to dryness. The residue thus obtained (11 g) was _{dissolved in 200 ml of n-amyl alcohol with the addition of 11 g of SeO P} , and the solution was kept at reflux temperature for 18 hours. After cooling, the residue was filtered off and the amyl alcohol was distilled in a stream of steam; the distillation residue was obtained by extraction with chloroform and, after crystallization in ethanol, 6.3 g of 7-carbomethoxy-2'-hydroxyflavone were obtained, which was dissolved in 30 ml of dimethylformamide with 3-5 g of 2-bromopropane and 4 g of anhydrous potassium carbonate for 18 hours was reacted at 70 ° C. After cooling, the mixture was diluted with 200 ml of water and then filtered to give 7.9 g of 7-carbocethoxy-2'-isopropoxyflavone, which was then obtained by treatment with the stoichiometric amount of a 1% strength

50 9 82 8/1051

Potassium hydroxide solution in 95% ethanol for 30 minutes Reflux temperature hydrolyzes v / urde. After cooling, acidify with acetic acid, dilute with 7 / water, filter and subsequent crystallization in ethanol gave 5> 7 S 7-carboxy-2'-isopropoxyflavone. In an analogous way were under Using the appropriate alkyl halides, the following compounds are made:

7-carboxy-2 '- (2-methylpropoxy) flavone
7-carboxy-2 '- (1-methylpropoxy) flavone
7-Carboxy-2 '- (2-hydroxypro "poxy) flavone 7-Carboxy-2' ~ (2-ethoxyethoxy) flavone.

Example 14

A mixture consisting of 6 g of ethyl 3-acetyl-4-hydroxybenzoate and 5 S 2-nitrobenzaldehyde dissolved in 100 ml of ethanol and 100 ml of piperidine was kept for 24 hours at reflux temperature. j) ± _e mixture was then cooled, diluted with 800 ml of water, acidified with hydroiodic acid, extracted with ethyl acetate, washed with water and evaporated to dryness, the crude product 6-carbomethoxy-2'-nitro- flavanone being obtained. This product (6.8 g) was dissolved in 40 ml of chloroform and treated with a solution of 0.15 g of benzoyl peroxide and 3.8 g of N-bromosuccinimide dissolved in 60 ml of chloroform. The mixture was held at reflux temperature for 4 hours, then under vacuum to dryness at lower

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The temperature was evaporated, then the residue, dissolved in 150 ml of 95% ethanol, was treated with 25 ml of 4N sodium hydroxide for one night at room temperature. Acidification with hydrochloric acid and filtration gave 3.7 g of 6-carboxy-2'-nitroflavone which was then treated with 20 g of tin dichloride in 15 ml of concentrated hydrochloric acid and 15 ml of glacial acetic acid for 4 hours at dex reflux temperature. After cooling, dilution with water, neutralization with ammonium hydroxide of 28 ° Be, the precipitate was filtered off to give 1.8 g of 6-carboxy-2'-aminoflavon after crystallization in dimethylformamide, F. ^, 300 ⁰ C.

Example 15

10 g of 6-carboxy-2- (3'-pyridyl) chromone suspended in 500 ml of acetic acid were treated with 100 ml of 35% hydrogen peroxide for 24 hours at the reflux temperature. After cooling, dilution with water and after filtering, the collected precipitate was crystallized in dimethylformamide and 5.7 g of 6-oxyoxy-2- (3'-pyridyl-N-oxide) chromium were obtained. > 320 ° C; IR (KBr): v _{c = 0} (carboxy) 17OO ορΓ ^Λ , V _{c = 0} (Chr.omon) 1650 ei " ¹ , V ^ ₀ 1280 cm" ¹ . ...

The following compounds were prepared in an analogous manner:

6-carboxy-2- (2'-pyridyl-N-oxide) chromone 6-carboxy-2- (4'-pyridyl-N-oxide) chromone.

509828/1 OS 1

Example 16

21 g of 6-carboxy-2'-isopropoxyflavone suspended in 75 ml of 1,2-. Dichloroethane, were treated with 6 ml of thionyl chloride for 1 hour at the reflux temperature. The solution was then cooled and with vigorous stirring, 15 ml of ammonium hydroxide were added ^v 28 ⁰ Be ". One hour later, there was obtained, after dilution with 300 ml ethyl ether and filtration, 21 g of 6-carboxamido-2'-isopropoxyflavon, F. 267-270 ° C, which was treated with 37 "5 g of p-toluenesulfonyl chloride in 33 ^m l of pyridine and 160 ml of dimethylformamide was treated at 90 ⁰ C for 8 hours. After cooling, dilution with 1.5 1 water and filtration, the collected precipitate is dried and washed with 300 ml of hot isopropyl ether, 15.6 g of 6-cyano-2'-isopropoxyflavone, mp 172-175 ° C., being obtained, which is then mixed with 33 g of sodium azide and 27 g of ammonium chloride in 120 ml of dimethylformamide 4 hours at 100 ^° C. After cooling, diluting with 600 ml of water, acidifying with concentrated hydrochloric acid and filtering, 11 g of 6- (5-tetrazolyl) -2 were obtained after crystallization in chloroform / ethanol '-isopropoxyflavone, m.p. 293-295 ° C. Na Using the same procedure, the following compounds were made:

6- (5-tetrazolyl) -2 · - (2-methylpropoxy) flayon 6- (5-tetrazolyl) -2 '- (1-methylpropoxy) flavone

6- (5-tetrazolyl) -2'-propoxyflavone '*

6- (5-tetrazolyl) -2'-but oxyflavone

509828/1 OS 1

6- (5-tetrazolyl) -2 '- (2-ethoxyethoxy) flavone 7- (5-tetrazolyl) -2'-isopropoxyflavone
7- (5-tetrazblyl) -2 '- (2-methylpropoxy) flavoL

Example 17

The process described in Example 16 gave, starting from 6-carboxamido-2- (5'-pyridyl) chromone, prepared from the corresponding ethyl ester with gaseous ammonia in. Ethanol for a period of 6 hours at O C, the 6- (5-tetrazolyl) -2- (3'-pyridyl) chromone in a yield of 85%. Following the same procedure, the following compounds were made manufactured:

6- (5-tetrazolyl) -2- (2'-pyridyl) chromone 6- (5-tetrazolyl) -2- ( ⁱ i- ^l -pyridyl) chromone 6- (5-tetrazolyl) -2- (2'- furyl) chromone
6- (5-tetrazolyl) -2- (2'-pyrazinyl) chromone ..

Example 18

⁶ »3 S 6-carboxy-2" -isopropoxyflavone suspended in 25% benzene were treated with 1.8 ml of thionyl chloride for 1 hour at reflux temperature. The solution was evaporated to dryness in vacuo and the residue was in 4-5 ml 1,2-dichloroethane dissolved and with 2 g of 5-aminotetrazole and 2.7 g

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Sodium bicarbonate for 3 hours at room temperature with stirring. The precipitate thus obtained v / urde filtered, washed with water and crystallized from dimethylformamide to give 4- g of 6- (5-l ¹ etrazolylcarboxamido) ~ 2'-isopropoxyflavon, F. 275-278 ⁰ C, obtained. The following compounds were prepared in an analogous manner:

6- (5-tetrazolylcarboxamido) -2 '- (2-ynethylpropoxy) flavone 6- (5-tetrazolylcarboxamido) -2 '- (i-methylpropoxy) flavone 6- (5-tetrazolylcarboxamido) -2 '- (2-hydroxypropoxy) flavone 6- (5-tetrazolylcarboxamido) -2 '- (3-hydroxypropoxy) flavone 6- (5-tetrazolylcarboxamido) -2 '- (2-hydroxy-2-methylpropoxy) flavone

6- (5-tetrazolylcarboxaido) -2 '- (2-hydroxy-2-methylbu "toxy) -

flavone
6- (5-tetrazolylcarboxamido) -2 ^L - (2-hydroxy-5-methylbutoxy) flavone.

Example 19

3.2 g of 6-carboxy-2'-isopropoxyflavone was treated with a hot aqueous solution containing 800 mg of sodium bicarbonate. The small amount of undissolved acid was filtered off and the clear solution was concentrated almost to dryness in vacuo. After treatment with 200 ml of acetone, the sodium salt of 6-carboxy-2'-isopropoxyflavone crystallized out (3.1 g, P.> 300 ° C.). In an analogous manner, the sodium alloys were the

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■ - 45 -

the following connections established:

6-carboxy-2 '- (2-methylpropoxy) flavone
6-carboxy-2 '- (i-methylpropoxy) flavone
6-carboxy-2 '- (2-hydroxypropoxy) flavone 6-carboxy-2' - (3-hydroxypropoxy) flavone 6-carboxy-2 '- (2-hydroxy-2-methylpropoxy) flavone 6-carboxy-2'- (2-hydroxy-2-methylbutoxy) flavone 6-carboxy-2 '- (2-hydroxy-3-diethylbutoxy) flavone 6-carboxy-2- (2'-pyrazinyl) chromone.

Example 20 '^.

5 g of the sodium salt of 6-carboxy-2'-isopropoxyflavon prepared according to Example 19 and suspended in 50 ^m l ^ i ~ methylformamide, were mixed with 5 Jnl chloromethyl pivalate and 1.5 of triethylamine-treated at 70 ° C for 16 hours. The mixture was then cooled, diluted with 500 ml of water, extracted with ethyl acetate and the organic phase was washed with 5% sodium bicarbonate, then with water and finally evaporated to dryness *. The residue was crystallized in isopropyl ether and 3.9 g of the pivaloxymethyl ester of 6-carboxy-2'-isopropoxyflavone, F. 102 to 1CXl- ⁰ G, were obtained. The pivaloxymethyl esters of the following compounds were prepared in the same way:

6-carboxy-2 '- (2-methylpropoxy) flavone

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6-carboxy-2 '- (i-methylpropoxy) flavone
6-carboxy-2 ^f - (2-hydroxypropoxy) flavone
6-carboxy-2 '- (3 ~ hydroxypropoxy) flavone 6-carboxy-2' - (2-hydroxy-2- ~ methylpropoxy) flavone 6-carboxy-2 '- (2 ~ hydroxy-2-methylbutoxy) flavone 6- Carboxy-2 '- (2-hydroxy-3-methy1b ut oxy) f1avoh' 6-Carboxy-2- (2'-pyrazinyl) chromone.

Example 21

4 g of the sodium salt of 6-carboxy-2'-isopropoxyflavone, prepared according to Example 19 and suspended in 40 ml of dimethylformamide, were treated with 1.25 g of chloroacetamide and a few drops of ethylamine for 24 hours at 75 ° C., after cooling , diluting with water and acidifying with acetic acid and filtering gave 4.2 g of the 6-glycolamide ester of 6-carboxy-2'-isopropoxyflavone, mp 230-232 ° C., which was dissolved in 30 ml acetic acid and 20 ml 23 % hydrochloric acid Hach was hydrolyzed for 1 hour at 75 ° C. dilution with water, filtration and crystallization from ethanol to give 3.1 g of the Glykolesters of 6-carboxy-2'-isopropoxyflavon, F. 210 to 212 ⁰ C. The glycol esters of the 6-carboxyflavones given at the end of Example 20 were prepared in an analogous manner.

5.0 9 8 2 8/1 0 B 1

Example 22

5.6 g of 2 ^l -Isopropoxyflavone-6-carbonylchlori., Prepared according to Example 18 and dissolved in 50 ml of anhydrous benzene, were
treated with 4.2 ml of diethylaminoethanol and 1 ml of triethylamine for 4 hours at room temperature. The benzene solution was washed with 5% sodium bicarbonate and water, then to dryness
evaporated. The residue was dissolved in 100 ml of acetone and
after the addition of the stoichiometric amount of concentrated hydrochloric acid, the hydrochloride of the diethylaminoethyl ester of 6-carboxy-2'-isopropoxyflavone precipitated out. After this
Filtration and thorough washing with acetone gave 5 ^ 4 g

Compound, m.p. 215-217 ° C. According to the same ver

drive were the diethylaminoethyl esters at the end of the example 20 indicated 6-carboxyflavones obtained.

Example 23

4.3 g of 2'-isopropoxyflavone-6-carbonyl chloride, prepared according to Example 18 and dissolved in 40 ml of anhydrous benzene, were
5.2 g of E-Hydroxyäthylmorpholin and 1 ml of pyridine for 24 hours b treated & x room temperature. The benzene solution was washed with ^ a ^ aqueous citric acid, sodium bicarbonate and _w ith
Washed water, then evaporated to dryness. The residue crystallized in acetone gave 3.6 g of the morpholinoethyl ester of 6-carboxy-2'-isopropoxyflavone, mp 133.degree. To 135.degree.

509828/1051

the same procedure, the Morpholinoäthylester he were hm. 6-Carboxyflavones indicated at the end of Example 20

• £ li £ {piel 24

■ -ES .. «were tablets with a weight of 300 mg each, which contained 100 mg of the active substance, as follows :

.-H2 ^ ™ 5GÜetzung_ (for_10 _-1 OOO _- tablet s)

rG-carboxyflavone 1,000 g

lactose. 1.4-20 κ

Corn starch 475 _g

oil powder - 75 g

Mon ^ nosiuin stearate $ 0 g

, fe-ünrboxyflavon, the lactose and half of the corn starch _{mixed itolnander) the mixture was passed} through a sieve

Openings of 0.5 mm printed. 35 S corn starch was suspended in warm water. The paste obtained in this way . " F " is used to granulate the powder mixture. The Körn- * »JHlon dried on a sieve having a sieve opening · ^n; ■ ' ^mm crushed, then the remaining amount of V -;' ■ '» ^{> Vll} lb and magnesium stearate added, thoroughly through -5 Vf% and using punches with a

509828/1051

The mixture was processed into tablets with a diameter of 8 mm *

Example 25

There were tablets, each weighing 300 mg, the each containing 100 mg of the active substance, prepared as follows:.

6-carboxy-2'-isopropoxyflavone ^ 1,000 g

Lactose 1,420 g

Corn starch 475 g

Talc powder 75 g

Magnesium stearate $ 0 g

The tablets were prepared as described in Example 24.

Example 26

e-carboxy-J'-chlorflavone 2 %

Ethanol 10%

Lecithin 0.2 %

Mixture of propellants 12

and 114 (70/30 -:>! ischung) ad100 %

509828/1051

Propellant 12 ″. Dichlorodifluoromethane Propellant 114- «dichlorotetrafluoromethane.

Patent claims:

509828/1051

Claims (1)

Claims 1. 5,6-Benzo- ^ - pyrone derivatives, characterized by the general formula (D where mean: η is the number O or 1; n * the number O or 1; R a) cyano, carboxy or the rest b) -CORq, in which Rg can be -NHOH or an -N radical, wherein and 11 each hydrogen or Alkyl, or, if R ^ = hydrogen, R,. ,, also den Radical -C "1] or the group -CH-COOH, in which B. ^ hydrogen or C ^ -Cg-alkyl, or R ^ ₀ and R ^ ₁ together with the nitrogen atom can denote an N-pyrrolidinyl, piperidino or morpholino radical; B 01 9 8 2 8 /. "1 ■ 0 B 1 c) -COOR ,, - ,, where R _{15 is} a C ₁ -C ₁₂ -AIkJl- or -alkenyl group which is unsubstituted or substituted by one or more of the substituents from the group consisting of halogen, carboxy, hydroxy, -OR ₁ ^ and - OCOR ₁ ^ may be substituted, where R ₁ ^ C ^ -C ^ -alkyl, substituted or unsubstitu- > R ated phenyl, -R ^ IO, in which R ^ ₀ and R _{11 have} the meanings given above, or one of the radicals can mean in which R ₁ ^ has the meanings given above; R ,, and Rp, which are identical to or different from one another, are hydrogen or methyl; _{R 1} and R 2, which are identical to or different from one another, water or Cj-Cg-alkyl; R ₁ -, Rg, En and Ro, which are the same as or different from each other, each .R _1n a ^f ) hydrogen, halogen, hydroxy, nitro, -W , in which and R _{11 have} the meanings given above, b ¹ ) the radical - (O) _m - ^R -j3> where m = O or 1 and R ^ has the meanings given above, c ¹ ) the radical -0-CO-R ₁ ^, wherein R ₁ ^ the above for can have given meanings, or the group -N ^ E09828 / 1 0 (> 1 can mean in which R ^ ₀ and R ^ have the meanings given above, d ') the radical -S-R ^ ,, in which R ^ has the meanings given above; or R ₇ and Rq, if they are located on adjacent carbon atoms, together represent a methylenedioxy, ethylenedioxy or propylenedioxy group; X is phenyl or a heteromonocyclic radical with 5 or 6 atoms which has at least one double bond and 1 or Contains 2 heteroatoms from the group consisting of nitrogen, sulfur and oxygen, 'where if X is nitrogen containing radical, a nitrogen atom may be bonded to an oxygen atom to form the N-oxide; W Νϊ «0, ■ ^ C» S or N £ ^ (CH ₂ ) _Q , where n * = 2 or 3, ■ ο S 3 wherein the radical R - (C) - is in the 6- or 7-posi- i η R ₂ tion of the benzopyrone ring, as well as their salts, preferably their pharmaceutically acceptable salts, with the exception of the compounds in which - if '• at the same time X is phenyl, W is the group -CO- and η and n ^. the number 0, R _5, Rg, R ₁ -, and R is hydrogen, if it is in the 6-position _s, signify carboxy -. R _{Q is} hydrogen or, if R _Q is in the 3 ¹ - or 4 'position of the phenyl, * are hydroxy, methoxy, chlorine, bromine, iodine, and 509828/1051 with the exception of the following compounds: 6-carboxy-3'j4'-methylenedioxyflavone, 6-carboxy-7-hydroxyflavone, 6-carboxy-5-ethoxy- ^z i- '-raethoxyflavone, 7-carboxyflavone,
6- (7 »4'-dimethoxy) flavonylacetic acid. 2. 6-carboxy-2'-isopropoxyflavone. 3. 6-carboxy-2'-propoxyflavone. 4. 6-carboxy-2'-butoxyflavone. ^x 5- 6-carboxy-2 '- (2-methylpropoxy) flavone. 6. 6-Carbox "y-2 '- (1-methylpropoxy) flavone. 7. 6-carboxy-2 '- (2-ethoxyethoxy) flavone. 8. e-Carboxy-1 x ¹ - (2-ethioxyethoxy) flavone. 9. 6-carboxy-2 '- (2-hydroxypropoxy) flavone. 10. 6-carboxy-2 '- (3-hydroxypropoxy) flavone. 11. 6-carboxy-2 '- (2,3-dihydroxypropoxy) flavone. 12. 6-Carboxy-2 '- (2-hydroxybutoxy) flavone. 15. 6-carboxy-2 ^l - (2-hydroxy-2-methylpropoxy) flavone. 14. 6-Carboxy-2 '- (2-hydroxy-2-methylbutoxy) flavone. 15. 6-carboxy-2 ^l - (2-hydroxy-3-methylbutoxy) flavone. 509828/1051 16. 6-Carboxy - ^ '- (2 ~ hydroxypropoxy) flavone. 17. 7-carboxy-2'-isopropoxyflavone. 18. 7-Carboxy-2 '- (2-methylpropoxy) flavone. 19. 7-Carboxy-2 '- (1-niethylpropoxy) flavone. ·; 20. 7-Carboxy-2 '- (2-hydroxypropoxy) flavone. · 21. 6-carboxy-2'-aminoflavone. 22. 6-carboxy-2'-dimethylaminoflavone. 2Y. 6-carboxy-2 '- (K -niethyl-N-isopropylamino) flavone. 24. 6-carboxy-2'-isopropylaminoflavone. 25. 6-Carboxy-2- (2'-pyridyl) chromone. 26. 6-Carboxy-2- (3'-pyridyl) chromone. 27. 6-Carboxy-2- (2'-pyridyl-N-oxide) -cliroiaon. 28. 6-Carboxy-2- (3'-pyridyl-N-oxide) ciromon. 29. 6-Carboxy-2- (2'-furyl) chromone. 30. 6-carboxy-2- (2'-imidazolyl) chromone. 31. 6-Carboxy-2- (5'-imidazolyl) chromone. 32. 6-carboxy-2- (2'-pyrazinyl) ghromone. 33. 6-carboxy-2- (4 -'-isopropoxy-3'-pyridyl) chromone. 509828/1051 34. ' 6-carboxy-2- [4 '- (2-methylpropoxy) -3'-pyridyl] chromone. 35. 6-Carboxy-2-f4 ^l - (1-methylpropoxy) -3 ^I -pyridyl] chromone. 36. 6-Carboxy-2-fv- (3-methylbutoxy) -3'-pyridyl] chromone. 37. 6-carboxy-2- (3'-isopropoxy-2 ¹ -pyridyl) chromone. 38. 6-Carboxy-2- [3 '- (2-ynethylpropoxy) -2' -pyridylj chromone. 39. 6-Carboxy-2- [3 '- (I-methylpropoxy) -2'-pyridyl] chromone. 40. 6-Carboxy-2 ~ r3 '- (3-methylbutoxy) -2'-pyridyl] chromone. 41. 6-Carboxy-2- {3 '- (2-hydroxypropoxy) -2'-pyridylj chromone. 42. 6-Carboxy-8-allyl-2- (2 ^L -pyrazinyl) chromone. 43. 6-Carboxy-8-allyl-2- (3 ^I -pyi "idyl) chromone. 44. 6-Carboxy-8-propyl-2- (2 ^L -pyrazinyl) chromone. 45. 6-carboxy-8-propyl-2- (3'-pyridyl) chromone. 46. 6-carboxy-2 - (/ 3-phenylvinyl) chromone. 47. 6-Carboxy-2- (oL-methyl - / ^ - phenylvinyl) chromone. 48. 6-Carboxy-2- [ β -2 '- (2-ethoxyethoxy) phenylvinylchromone. 49. 6-Carboxy-2- [β> ~ 2 ^% - (2-hydroxyethoxy) phenylvinyl] chromone. 50. 6-Carboxy-2 - // ^ - 2 ^l - (2-hydroxypropoxy) phenylvinylJ chromone. 51. 6-Carboxy-2 - / "/ 3-2 ^l - (3-hydroxypropoxy>'phenylvinyij chromon. BO9828 / 105 1 52. 6-Carboxy-2- [A - (2'-pyridyl) vinyIJ chromone. 53. 6-carboxy-2-fy? - (3'-pyridyl) vinyl] chromone. 54. 6-carboxy-2-f /> - ("4 -'-pyridyl) vinyl] chromone. 55. 7-carboxy-2- [ P -phenylvinyl) chromone. 56. 6-Carboxy-2 - [^ - (2'-pyrazinyl) vinyl] chromone. 57. Process for the preparation of the compounds according to at least one of the preceding claims, characterized in that * (a) a compound of the general formula (II) in which n, n ^, R, E ^ j R2 » ^R x» ^R / p ^ 5 » ^R 6 '^ 7' ^R 8 ^{and x have} the meanings given in claim 1, cyclized for the preparation of compounds Äer general formula (I ), wherein -W is -C-; Il (b) a compound of the general formula 50 9 8 287 1051 246167O (III) wherein η, E, R ^, R ^ ^unc * ^ c; ^ ^e ^ ⁿ claim. 1 have given meanings, reacted with an aldehyde of the general formula OHC (IV) wherein E ^, Er ₇ , Rg and X have the meanings given in claim 1, for the preparation of compounds of the formula (I) in which n ^ = 1, H, and R ^ are hydrogen and W -C-; (c) a compound of the general formula 509 828/10 51 where π, Ia ₁ , R, R ₁ , R ₂ , R ^, R ₄ , R ^, R ₆ , R _? , R ₈ and X have the meanings given in claim 1, dehydrated to prepare compounds of the general formula (I) in which W is -C-; ti O (d) a compound of the general formula (VI) wherein one of the radicals M is hydrogen and the other is halogen and n, R, R ₁ , R ₂ , R ^, R ^, Rc »Eg» Rn, Ro and X have the meanings given in claim 1, dehydrohalogenated for the preparation of Compounds of the general formula (i) in which W is -C- and η is the number O; and, if desired, a combination of the general for- mel (I), in which W is -C-, in a compound of the all- Il O
common formula (I), in which W denotes -C-, converted by Il Treatment with a sulphurizing agent or if desired a compound of the general formula (I), in which W denotes -C-, into a compound of the general formula S S " (I), where V / ^ c "^ Η ₂ ) _η means, where n, = 2 or 3, 509828/1051 converted by reaction with a compound of the formula HS- (CH-) -SH and / or, if desired, a compound of the general formula (I) is converted into another compound of the general formula (I) in a manner known per se and / or, if desired, a compound of the general formula (I) is converted into a salt, preferably a pharmaceutically acceptable salt ₁ thereof, and / or, if desired, a mixture of optical isomers obtained in this way is split into the various isomers. 58. Pharmaceutical preparation, characterized in that they together with a suitable carrier and / or diluent as the active ingredient at least one compound the general formula (D where mean: η the number 0 or 1; Ji _{1 is} the number 0 or 1; R a) Cyano, Carboxy or the Best b). -COEq, where R _{Q can be} -NHOH, an -N 'radical, 509828/1051 wherein R ^ ₀ and R ^. Each hydrogen or C ^ -Cg -Alkyl, or, if R ^ ₀ = hydrogen, R ^ also den Radical -O] {'or the group -CH-COOH, ^: -wherein R ^ 2 is hydrogen or C ^ -G ^ -alkyl, or andR ^ ₁ 'together with the nitrogen atom can denote an N-' i ^ yrrolidihyl, fiperidino or morpholino radical · ■; - - '- c) -COOR ^ .v, - where R ^ j, a Cv-C _-1 ^ -Alky] .- or -alkenyl group which is unsubstituted or substituted by one or more of the substituents from the group halogen, carboxy, hydroxy, - OR ^ and -OCOR ^ ₂ , may be substituted, where R _-1 ^, C ₁ -C, - alkyl, substituted or unsubstituted phenyl, -N, in which Ί Ί R ^ j ₀ and R _x , ^ have the meanings given above, or one of the: radicals - »ι -N \, -H p or -N K -R \ _y can mean in which R ^ the meanings given above Has; Ζ ,, and Rp, which are identical or different from one another _t hydrogen or methyl; _: . ■ ■ ^- \;,. and R ^, which are the same or different from one another, are hydrogen or C ₁ -C ^ -alkyl: 603820/051 ..-. :. :. '2A61670 c »Rg» R ₁ -, and Ro, which are the same - pd er are different from each other, respectively a ¹ ) hydrogen, halogen, hydroxy, nitro, -N, where R ^ ₀ and R ^ _x . have the meanings given above, b ¹ ) the remainder · "(Q) _n J-RvIz * where m = 0 or, 1 and -Β ^, .. has the meanings given above _f ■ - -, ..., -. ■■, . c ') the radical -0-CO-Rx ₁ , -, in which R ^, - aie' above 'for "R ^,""can have the meanings given, or the group S ι O -H can mean where R ^ _1n and R ^ x. have the meanings given above, d ¹ ) the radical -SR, * ^, in which R,., has the meanings given above; or Rr ₇ and R _D , if they are on adjacent carbon atoms , together a methylenedioxy, ethylenedioxy or propylenedioxy group; Phenyl or a heteromonocyclic radical containing 5 or 6 atoms containing at least one double bond and 1 or 2 hetero atoms from the group nitrogen, sulfur and Saue XCF _O £ f, wherein when X is a nitrogen-containing group; L _a t, a nitrogen atom can be bonded to an oxygen atom to form the N-oxide; 09828/1051 s ■ W ^ C »'σ, ^ C * ■ S or ^ G ^) (CE ₀ ) , where η, = 2 or 3, . ^ S ^ ^η 3 ^p wherein the radical R - (C) - is in the 6- or 7-IOsi- ■ '■■ "' ■ ^l - ^έ 2 tion of the benzopyron ring can be, or a contains physiologically acceptable salt thereof. 59 · Pharmaceutical preparation according to claim 58 * characterized in that that they are in one for oral, parenteral, or topical administration or in one for inhalation suitable form. 5 0 9 8 2 8 / .1 0 5 -1