DE2427597A1 - BENZOPYRANE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE - Google Patents

Description

Dipl.-ing. P. WSRTH Dr. V. SCHMIED-KOWARZiK DipL-ing. G. DAN N ENBERG ■ Dr. P. WEiNHOLD Dr. D. GUDEL

2S1134 6 FRAMKFURT AM MAIN

PHONE! (0611)

287014 GR. IiSCKEWKUSMEH! 3TRAGKE

tfo / Eh

Eh

FiROiI Hoi '<. ^: .-C

9 Groi? Venor Street London

—Derivate VeriCaiiren for their production . and pharmaceutical preparations containing them

The present invention "relates to new Yer" bonds, a process for their manufacture and for preparations containing them Connections included.

509818/1206

Through the process according to the invention, compounds of the following formula I and their pharmaceutically useful derivatives are obtained: %

in this formula have B · *?

R / -, R ₇ , Rp, Rq, R

-J q

U2ld

R-, ο identical or different meanings and stand for hydrogen j alkyl, alkoxy, halogen, alkenyl, amino, hydroxy-CF ₇ .-, -CH-, alky! Amino, alkoxyalkoxy, hydroxyalkoxy- or ₂ Cr groups, or R ^ and R ^ form susa.inin.en. a chain - (CHp) / - or

B stands for a carboxyl group, a 1H-tetrazol-5-yl group, an N- (iH-! Detrazol ~ 5 ~ yl) -carboxaniid group, a group -CONHOH or a G group -CO-CHR ₂ CO -R ₁ ;

R ^ stands for a C 1-6 alkyl, C 1-6 alkoxy, phenyl, amino or mono- or di-C 1-4 alkylamino group; R ₂ stands for hydrogen or -CORx, where Rx is a C 1-6 alkyl, C 1-6 alkoxy, amino or mono- or di-C, g-alkylamino group

istj or

R 1 and R ₂ together form a three- or four-membered alkylene chain, which is optionally interrupted by an -NH- group and optionally by one or more C 1-6 alkyl groups

509818/1206

and / or, on the carbon atom irxaL position to the methine protonj dureh. a carbonyl oxygen atom may be substituted, 'where, however, (i) when E is a group --GOOH or a pharmaceutical

R ₁₁ and

useful., derivative thereof and R ^, Hg) Rq, S IU ₀ all stand for hydrogen, (A) R ₁ - not for hydrogen or an alkoxy group or (B) Rg not for hydrogen or a hydroxy Alkyl or alkoxy group or (G) R ^ not for hydrogen or an alkoxy group must $ or $ (ii) - "'when E is a group -COOH or a pharmaceutically acceptable derivative thereof, E is not in the 2'-position allowed.

The inventive method for producing a compound of the formula I or a pharmaceutically usable derivative thereof is characterized in that: (a) a compound of formula II cyclizes:

Ii h

in the

R ₅ ,

R ₆ , R ₇ , Eg, R ₉ , R ₁₀ , R ₁₁ , R ₁

and E the

₅ , R ₆ , R ₇ , Eg, R ₉ , R ₁₀ , R ₁₁ , R _{12 have the} above meanings and are also subject to the above requirements, Z stands for a reactive halogen atom or a group -OM and M is hydrogen or an alkaline cation;

5098 18/1 206

(b) a compound of .Formula Ia produces;

coqb

in which R- ₅ R ₅ , Hg.R ₇₅ R ₈ , R ₉₅ H ₁₀ , R ₁₁ , R ₁₂ have the narrowest meanings, η 2>, and the above requirements of tin-

subject by hydrolyzing a compound of the formula III siert s

in the R ^, R ^, Rg, Ry, Rg, Rg, RJ ₀ ? Rj -j, RJ ₂ "have the meanings given above, and are subject to the above requirements and Ry stands for a group which can be hydrolyzed to a group -COOK; (c) a compound of the formula Id produces:

509818/1206

in the S, R ₁ -.

called meanings "by connecting the

Pormel? I; .

Rr

R /

VI

R,

1.0

^v ll

in the IU, K ^. _} R-, R ^, R _g , Rg, K ₁₀ , IL ,, and Ii _{12 have} the abovementioned requirements, with a ^r aid in a solvent that is inert under the hedge:
(d) produces a compound of the formula Ie:

Ie

R.

CONHOH

in which R ^, R ^, Rg, R ^, R _Q , R «, have the meanings mentioned, by reacting an anhydride, an ester or an acid halide of a compound of the formula Ia with hydroxylamine;

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(e) a compound of the formula I in which E represents a group -CO-CHRpCOR-j 'by (i) an acid halide or ei: -' mixed anhydride of a compound of the formula Ia with a: ¹ compound of the Formula CHgR ^ COH., Or an enamine thereof and, if an enainine is used, hydrolyzes the compound thus obtained, or (ii) hydrolyzes a compound of the formula VII:

Ra

CO - C = C -

VII

in the

^{ol3e: 11} ""

, Ec, Rg ₅ , R ₇ , Rg> Rq? ^r -] a> S-] -j j2 have the meanings mentioned and Ra and Rb ^ can have the same or different meanings, each stand for a C ^ g-alkyl group or together with the nitrogen atom a five-, six- or seven- form a membered heterocyclic ring, which optionally contains an oxygen atom;
(f) produces a compound of the formula Ih:

Rr

R.

Qi ₂ COOH

509818/1206

and

the above

in which R ^, R ^, Rg, R ^, R ₈ , Rg, R ₁₀ , R

Have the meanings mentioned by making a connection

the Fon.el VIII:

VIII

~ 0

COCHM.

₁₁

in the R _7. , R _KS Rg, R

Have the meanings mentioned, reacts with water;

R ₈ , Rq,

the above

(g) a compound of formula I produces in which R ^ for a Halogen atom stands by making a corresponding compound of formula I, in which R ^ is hydrogen, selectively halogenated;

(h) a compound of formula I produces in which R * is a Group -OH is oxidative by eyelidizing a compound of the formula X:

Rr

in which R ₃ , R ₅ , Rg, R ₇ , R ₈ , R _g , R ₁₀ have the abovementioned meanings;

, E and M die

509818/1206

(I) a compound of the formula I produces in which one or several of the radicals R ^ to R., ρ for an alkoxy or one

- · Hydroxyalkoxy group by reacting a corresponding compound of the formula I, in which one or more of the radicals R ^ to R _{] 2 are} the group -OH, with an alkylating agent, especially an alkylene oxide;

(j) a corresponding flavanone compound of the formula XV selek tively dehydratedί

^R S

^R 3

in the R ^, R ₅ , Rg, R ~ _i Rg, Rq, S ^ q, "R ^ ₁ , R ^ p ^ ¹ Ki E the

G,

have the above meanings and are also subject to the same requirements;

(k) a compound of the formula I in which at least one of the radicals R ^ to R ^ is an amino group by adding a corresponding compound of the formula I in which at least one of the radicals R ₅ to R ^ _2. ^ Ie . Group is, selectively reduced;

(1) produces a compound of the formula II:

509818/1 206

11

R,

CX) NH - C - N

N; θ · ν

in the IU, R, -, Rg? R.? " Rg * Rg>

1 and ^l "^ 12

have the meanings mentioned- by adding an anhydride, an ester or an acid halide of a compound of Formula Ia reacts with 5-aminotetrazöl j or

(M) a compound of the formula I produces -in which R ^ to R-, ρ have the meanings given above and are subject to the same requirements, but one of the radicals R ^ to R.J2 is the group -OH by having a corresponding compound of the formula I dealkylated, in which R 1 to R _{12 have} the meanings given above (without the abovementioned requirements), but one of the radicals R 1 to R ^ _{2 is} an alkoxy group,

and, if desired or necessary, the compound of the formula I converts to one of its pharmaceutically acceptable derivatives or the other way around.

The cyclization of process (a) can be changed by heating can be carried out under basic or neutral conditions. If Z stands for a group -OM, the cyclization is preferred in the presence of an acid such as hydrochloric acid, and

5Ö9818 / 120 6

- ίο -

carried out a solvent which is inert under the reaction conditions, such as ethanol. The reaction can also be carried out in a mixture of sulfuric and acetic acid * It is carried out at a temperature between 20 ° and 150 ° , B. at elevated temperature in pyridine and in the presence of potassium hydroxide «

In the method (b), the group Ry can be an amide or nitrile group or, preferably, an ester group such as a lower alkyl ester group. The hydrolysis takes place by means of known Process, e.g. under slightly basic conditions, such as using sodium carbonate or bicarbonate, or under acidic conditions, such as using a mixture of aqueous dioxane and hydrochloric acid or hydrogen bromide in acetic acid. The hydrolysis can take place at a temperature between

ο - η

about 25 and -120 are performed, with the. Temperature from

the connections used. .

Suitable solvents, which under the reaction conditions of the Process (c) are inert, are those in which both reactants are soluble, such as Jf, N-dimethy! Formamide. Other suitable solvents are e.g. dimethyl sulfoxide, tetrahydrofuran, Diethylene glycol and ethyl methyl glycol. The reaction is preferably carried out at a temperature of about 20 ° to 130 ° and takes about 1 to 20 hours. The preferred azide is

509818/1206 "

- π · ■

ammonium azide or an alkali azide such as sodium or lithium azide, used; However, it can also be used with other azides, such as -. Aluminum azide or the azides of nitrogenous bases, such as mono-, di-, tri- or tetramethyl-ammonium-, -anilinium-, -morpholiniura- or -piperidiniumaziden, are worked. Will If an azide other than an alkali azide is used, it can be prepared by double conversion in the reaction mixture, The reaction can optionally be carried out in the presence of an electron acceptor, such as aluminum chloride, boron trifluoride, ethylsulfonic acid or benzenesulfonic acid. Its alternative the reaction is under the conditions described above using hydrazoic acid → nitric acid → at a temperature of about -20 ° to 150 ° in a suitable solvent and. .untar.more.than atmospheric pressure.will be different Aciz used as hydrazoic acid, e.g. sodium azide, so will obtained as the reaction product, the corresponding tetrazole salt. This salt can easily be converted to the free acid by reaction with a strong acid such as hydrochloric acid will.

In the method (d), the anhydride is preferably a mixed one Anhydride is used, the desired by splitting it. Flavonearbohydroxamic acid as the main product in the reaction with Hydroxylamine supplies. Examples of suitable acids from which the mixed anhydride can be obtained are sulfonic acids, such as benzenesulfonic acid; hindered carboxylic acids, such as Pivalic, isovaleric, diethyl acetic or triphenyl acetic acid; and Alkoxy formic acids, such as ethoxy or isobutoxy formic acid. the

509818/1206

Heating takes place preferably under anhydrous conditions in a solvent that neither interacts with the hydroxylamine nor with deya mixed anhydride reacts, e.g. ir-pyridine or dimethylformamide. If the reaction is carried out in a non-basic solvent, as s.B, Diinethylfornamid, carried out, should preferably ausεerden at least two molar equivalents of one

such as Triäthylaiain, be present. Thieves-

vorsiujte Reaktionsteciperatur is between about -15 ° and + 20 ° "is esters of compounds of formula Ia are obtained such ₅ consisting Allcanolen with 1 ms 10 carbon atoms and vorsugsweise 1 to 6 carbon atoms, for example, as Säurfchalogonid zweckraässigerweise a SäurechloriöL Suitable used. If an ester is used, the reaction is carried out in a solvent which is inert under the reaction conditions, such as, for example, methyl formamide, and it is carried out in the presence of a base, such as, for example, sodium hydroxide, and at room temperature, for example about 20 ° .

The method (e) (i) can be carried out under waterfmenu conditions and conveniently in a suitable, non-protic solvent, v / ie e.g. chloroform, methylene chloride or 1,2-dichloroethane, be performed. It is preferable to work in the presence of an acid acceptor which - if a basic one Solvent is used - may consist of an excess of the solvent or a tertiary amine such as e.g. Triethylamine, can be. The reaction takes place at one temperature from about 0 ° to 100 °.

509818/1206

The acid halide. can, for example, be an acid chloride or an acid bromide A mixed anhydride is preferred, which splits preferentially to the desired fla ^ ondiearbonyl derivative » Examples of suitable acids from which the mixed anhydride can be obtained are stilfonic acids such as benzene sulf onic acid, sterically hindered carboxylic acids, such as pivalic, isoiralerian ~, "- J) läthylessig- or triphenylacetic acid, and alkoxyformic acids, such as ethoxy or isobutoxy acid.

The hydrolysis of processes (e) (i) and (e) (ii) can be carried out, for example, in elevated temperature in an aqueous acid, such as aqueous hydrochloric acid.

Process (f) is carried out in a suitable solvent, v; ie e.g. diglyme, i.e. bis (2-methoxyethyl) ether, and in the presence of a suitable catalyst such as silver oxide. The reaction can also be carried out using silver benzoate in triethylamine and tert-butanol as solvents carry out. Process (f) is the final stage of an Arndt-Eistert reaction.

Process (g) can be carried out in a solvent which is inert under the reaction conditions, for example in benzene. Suitable selective halogenating agents are, for example, sulfuryl chloride. The reaction can take place at a temperature of about 20 ° to 150 °.

509818/1206

-H-

Process (h) can be carried out in the presence of an inorganic peroxide, such as hydrogen peroxide, and can be carried out under "basic conditions" Medium such as aqueous methanol. The reaction temperature lies between approximately -10 ° and + 10 °.

In the method (: L), the alkylating agent may be a reactive one Alky! Halide, like a bromide, or a mono- or di * - alkyl sulfate, e.g., dimethyl sulfate. The reaction can be in be carried out a solvent under the Eeaktions- "be conditions en is inert, e.g. in acetone or 2-butanone. The heak tion temperature is between about 20 and 150 °.

In the process (j), the dehydration by oxidation " with a mild oxidizing agent such as selenium dioxide, palladium black or chloranil, lead tetraacetate or iriphenyl methyl perchlorate. Dehydration can also be done indirectly by halogenation and subsequent dehydrohalogenation, e.g. by treatment with K-bromosuccinimide or pyridinium bromide perbromide, thereby obtaining the 3-bromo derivative which is then dehydrobrominated. The reaction can take place in a solvent which is inert under the reaction conditions, e.g. in a halogenated hydrocarbon, Xylene, n-amyl alcohol or glacial acetic acid, which may increase The reaction temperature is, for example, about 20 and 150. The process can be carried out under strongly basic conditions, for example in the presence of an alkali hydroxide.

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In method (k), the reduction is preferably carried out below Use of the ester form of the compound when E is a Carboxylic acid group. It is done using known procedures carried out to reduce nitro groups, e.g. through implementation Rait tin-II-chloride in concentrated HGl with increased -Temperature, preferably the amino group should not be in order stand"

In process (1), the anhydride used is preferably a frozen anhydride used that when reacting with 5-aminotetrazole predominantly to the desired IPlavoncarboxamidotetrazole splits, examples of suitable acids from which the mixed anhydrides can be derived are sulfonic acids, such as Benzenesulfonic acid; sterically hindered carboxylic acids, such as pivalic, isovalerian- ^ diethyl acetic acid or triphenylacetic acid, and alkoxyformic acids, such as ethoxy- or isobutoxyformic acid. The reaction is preferably carried out under anhydrous conditions in a solvent that does not interact with the 5-aminotetrazole still reacts with the mixed anhydride, e.g. in pyridine or dimethylformamide. However, if the reaction is carried out in a non-basic solvent such as dimethylformamide, a sufficient amount of acid acceptor, such as triethylamine, should preferably also be present. As an ester can e.g., an ester of a C 1-4 alkanol can be used. Wirä If an acid halide is used, this can be an acid chloride. The reaction is preferably carried out at one temperature between about -15 ° and + 20 °.

509818/1206

The reaction of the procedure on (m) can be any of the usual procedures performed v / earth, ζ..15, using an acid such as HCl in ethanol, v / äeiisrig & r KBr or HPr in Disesoig, It can also other ether - palhm ^ ßinmittel used v / ground, ζ.Ιϊ. Pyridine hydrochloride at elevated temperature "

The off {-, fingßmateri _t /.lie;-i are for the process (g) and (i) either Yerbindiin ^ ÜR! the Fonael I or can also be established connections by means of] iß] -: uiinter Verfahreti "

Compounds of Pornel II, in which Z stands for a group -OM, can be obtained by adding a compound of the formula IV

IV

COQi ₇ R ₃

in the E ^, R, -, Rg, Ry, Rg and M the abovementioned meanings with a compound of formula V or its ester:

in the E, Rg,

and

y <

I hl

^ie above meanings

509818/1206

own and Rs stands for a group which can react with a hydrogen in the group -COCHgR · * of the compound according to formula IV _? e.g. an alkoxy group, under the usual clasene condensation conditions uras et at,

The compounds of the formula II in which Z represents a group -OM can also be obtained .; indora one a compound of the formula IV with a compound of the formula V in which Re represents a halogen atom; converts and produces a compound of the formula IX:

IX ^R 5

s, A oco -.--

in which R ^, R ^, Rg, Ry, R _Q , R ^, R ^ ₀ , R ₁₁ , R ₁₂ , E have the meanings given above and are subject to the above prerequisites; treatment with an anhydrous base rearranges this compound to a compound of formula II.

The compounds of the formula II in which Z represents a reactive halogen atom are either known or can be prepared from known compounds by known processes.

509818/1206

Compounds of the formula X are prepared, for example, by adding a Compound of the formula IY in which R ^ is hydrogen with a compound of the formula XI:

XI R ₁₀

in dor Rg, R-jq * ¹ ^ II ' ^R 12 ^and · ^{E ciie} ^ have unnamed meanings ".

The compounds of the formula III are prepared according to process (a) made from known compounds *

Compounds of formula VI can be obtained by converting the corresponding ester to the corresponding amide and the Amide dehydrated in a known manner.

The compounds of the formulas IV, V and XV are either known or can be prepared from known compounds by known processes getting produced.

The compounds of the formula VIII can be obtained by reacting an acid chloride of a compound of the formula Ia with diazomethane reacts in a solvent, which under the reaction

509818/1 2ÖS

■ conditions is inert, ζ, .B. in diet ether, this procedure is the first part of an Arndt-Eistert reaction.

The compounds of Iforiuöl I and the corresponding intermediates can be isolated from the reaction mixtures using established procedures.

Some of the groups R- "to R * ρ can be influenced by the reaction * -?" Conditions. It may therefore be necessary to protect these claws during one or more reaction stages; if necessary, the groups R ₇ to R ^ p can also be present in the form of their protected derivatives, EB ₄ amino groups can be acetylated and hydroxyl groups can be esterified.

The pharmaceutically acceptable derivatives of the compounds according to Formula I encompass the pharmaceutically usable salts and - when E stands for a group -COOH- - their esters and amides. Suitable salts are the water-soluble salts, such as ammonium salts, alkali salts such as sodium and potassium salts, and alkaline earth salts, such as calcium and magnesium salts, as well as salts with suitable organic bases, e.g. salts with lower (Cj_g) Alkylamines, such as methylamine or ethylamine, with hydroxy-substituted ones C ^ __g-alkylamines or with simple ionocyclic Nitrogen containing heterocyclic compounds such as piperidine and morpholine. Suitable esters are the C-i-iq- and preferably Cj_g-alkyl esters, the C ^ _g-alkylamino-C ^ _g-alkyl esters, such as the diethylaminoethyl ester, as well as their acid addition salts.

509818/1206

The pharmazeui; iecli acceptable derivatives of compounds of formula I may, in a known V / else prepared and uir into other derivatives: i ^ -.- be 7ar.delt _5, for example, in the examples, "as Example V, by the methods described.

The compounds of Forrael I and their pharmaceutically "usable derivatives have good ο pharmacological activity in animals; they are particularly suitable for preventing bronchospasm caused by lhacholine and histamine in guinea pigs (see the method of Konsett and Rossler ir." Rath, Pharinak. 1940 ", 195, page '/ 1, modified by Burden and Parkes in" J. Pharmao. 1971 ", 41» page 122). They can therefore be used as bronchodilators for iJensohen *

The dosage for the above use depends of course on the compound used, the route of administration and the treatment desired. In the above test In general, satisfactory results have been obtained when the compounds are used in an amount of from 0.5 mg to 5.0 mg per kilogram Body weight of the animal were given. In humans, a total daily dose of about 20 mg to 1000 mg is preferred 20 mg to 200 mg, indicated, given in two to three aliquots per day or as a long-term drug can be. A unit dose suitable for administration (by inhalation or swallowing) contains approximately 10 mg up to 500 mg of the compound in admixture with a solid or

509813/1206

liquid pharmaceutically "acceptable diluent, ^r frager or adjuvant.

The compounds are also useful for inhibiting the release and / or action of pharmakologisehen mediators λνerden caused by certain in vivo combination of types of antibodies and specific Antigene-, eg _t combining re & ginischer antibody EIIT specific antigen (see Böispiel A, below) .

In humans, both subjective and objective changes can occur, caused by inhalation of a specific antigen by sensitized persons, by prior administration " the "new compounds are inhibited. Therefore, the new compounds for the treatment of asthma, z # B, allergic asthma. However, you can also do the so-called with them Treat "intrinsic" asthma in which there is no sensitivity to external antigen. Besides that The new compounds are valuable agents for treating other disorders caused by antibody-antigen reactions caused such as hay fever, certain eye diseases such as trachoma; Urticaria; and allergies of the Gastrointestinal tract, especially in children, such as milk allergy.

Also in diseases caused by antibody-antigen reactions caused, the dose administered depends on the

509818/1206

used compound, mode of administration and desired Treatment. In the test described in Example A, good results were obtained with a dosage of 0.1 mg to 50 mg per kg body weight of the animal achieved, "for humans is the daily G-eeamtdose about 1 mg to 3500 mg, and it can be in one to six portions per day or as a long-term drug administered v / ground. One for administration (diir Inhale or squeeze) a suitable dosage unit et /; a 0.17 kg to 600 mg of the compound mixed with a solid or liquid, pharmaceutically acceptable diluents or carriers.

The present invention thus also provides a pharmaceutical preparation which consists of a preferably smaller amount of a compound of the formula I or a pharmaceutically usable derivative of this compound in combination with a pharmaceutically usable auxiliary, diluent or carrier. Examples of suitable auxiliaries, diluents or carriers are: for tablets and dragees - lactose, starch, talc or stearic acid; for capsules - tartaric acid or lactose; for suppositories - natural or hydrogenated oils and waxes; for inhalation preparations - coarse lactose. After inhalation preparations, the compound has the formula I or its pharmaceutically usable derivative preferably has a mean mass diameter of 0.01 μ until 1Ou ,. The preparations can also contain suitable preservatives, stabilizers and irritants, solubilizing agents, sweeteners, coloring agents and

509818/1208

Contain flavorings. A preparation can be used for Tails can be produced with long-term effects.

The present invention also provides a method sur Preparation of a pharmaceutically acceptable salt of a compound of the formula I, which is characterized if; t that one a connection of the Poriael'Ixi

Ix Rc 0. R ₉

/ ^ T , R _{1 (} R ₇ R ₆ i » R ₉ V ^R 8

R, 11

12 R,

in which R ^, Rn, Rg, Ry, Rq, Rg, R-] q> ^ i ι 'RJ ₂ ^ ^{6 have the} above meanings and are subject to the above requirements and G stands for a group E or another salt thereof, or, if E in the compound of formula I is a carboxyl group /

for a carboxylic ester group, a methyl group, an acid halide group or an amide group; reacted with a compound containing a pharmaceutically acceptable cation and converting the G group into a pharmaceutically acceptable group E salt.

For converting group E into a pharmaceutically useful one Salts of the same are compounds such as bases and ion exchange resins which contain pharmaceutically acceptable cations, e.g. sodium, potassium, calcium, ammonium and suitable

509818/1206

Nete nitrogen-containing organic cations, the pharmaceutically "usable salt is preferably prepared by reacting the free acid of the formula T. with a suitable base, for example with an alkaline earth or alkali hydroxide, carbonate or bicarbonate in aqueous solution, or some other Treat the salt of a compound according to formula I to carry out a double reaction with a suitable salt. If a strongly basic compound is used, precaution should be taken, e.g. by maintaining

Maintaining a low temperature that the connection the por ine1 I is not hydrolyzed or otherwise broken down " The pharmaceutically usable salts can be obtained from the reaction mi. · -; urge can be gained, e.g. by using a solvent * Carries out precipitation and / or the solvent by evaporation removed, e.g. by freeze-drying.

Preferred compounds of the formula I are those in which E ^, E ₁ -, Rg, Εγ, Eg, Eq, E.JQ, EJJ and E ^ each contain fewer than 7 carbon atoms and preferably fewer than 6 carbon atoms. It is also preferred that only one, two or three Eeste Ε · *, E, -, Eg, B ~, Bg, Eq, B.jq, E-., Or E-ρ stand for groups other than hydrogen. If one of the groups B- * to E ^ _{2 is} a halogen, this can be, for example, bromine or, preferably, chlorine.

Examples of Eeste E ^ to E ^ are hydrogen, chlorine, bromine, methoxy, methyl, hydroxy, amino, allyl, tert-butyl, 3-methyl-n-butoxy, 2-ethoxyethoxy, 2-hydroxypropoxy, ethyl, ethoxy and nitro groups, or Eg and E ₇ together form one

509818/1206

Chain - (CH ₂ ), - or - (CHp), 0-. Furthermore, compounds are preferred in which R ^ is hydrogen, an alkyl group, for example a methyl group, halogen, z <.B. Chlorine, or a hydroxyl group5 Rc represents hydrogen, halogen, zH. Chlorine or bromine, an: alkoxy group, for example a methoxy or 3-methyl-n-butoxy group, a hydroxy group, a hydroxyalkoxy group, for example a hydroxyprbpoxy group, or an alkoxyalkoxy group, for example an ethoxyethoxy group; Rg represents hydrogen, halogen, for example chlorine, an amino or alkyl group, for example a tert "butyl" or ethyl group; Rj represents hydrogen, halogen, for example chlorine or bromine, an alkoxy group, for example a Methoxy ™ or ethoxy group, an amino group, a hydroxy group or a hydroxyalkoxy group, for example a hydroxypropoxy group, or Rg and R ^ together form a chain -CII ₂ CH _{2 form} CHpO- or - (CH ₂ ) , - ; R _{ß represents} hydrogen, halogen, for example chlorine, an alkoxy group, for example a methoxy group, an alkyl group, for example an ethyl or tert-butyl group, or an alkenyl group, for example an allyl group; Rq and R ^ q stand for hydrogen, alkoxy groups, for example methoxy groups, halogen, for example chlorine, nitro or amino groups, and Rjj and R ^ ₂ each stand for hydrogen.

Examples of radicals R ^ and R ₂ are ethyl, ethoxy, phenyl, amino, methylamino and diethylamino groups. Examples of the group -CO-CHR ₂ CO-R ^ are cyclopentanone-2-carbonyl-, 2-benzoylacetyl-, Q, (J -diethoxycarbonyl-, CJ -acetyl- CU-ethoxycarbonyl-, 0} , (j -diacetyl -, 5, 5-dimethylcyclohexane-1,3-dione-2-carbonyl and cyclohexanone-2-carbonyl groups. '.

509818/120 6

Torsugly, the group E is in the 4'-position, i.e. in the p-position to the bond that connects the benzene nucleus to the benzopyrane grain. Group E is preferably one out of order Group -COOE or -GOKHOH.

■ Preferred compounds are distant 1 I in which one, κν.ei or three of the radicals 1L · to iL ₂ ^ ¹ ' ^e ^ ⁿ halogen, such as chlorine or bromine, an Alko ^ y group, such as a methoxy or 3-methyln-butoxy groups, an allyl group, an alkyl group such as a ethyl, ethyl or tert-butoxy group, a hydroxyl group or an allcenyl group such as an allyl group, and the remaining radicals K ~ to R «P for hydrogen. Particularly preferred are compounds in which one, two or three (preferably one or two) of the radicals R ^ to R- «i for chlorine, bromine, a methoxy, amino, methyl, ethyl, tert. Butyl or hydroxy. stand group and the remaining radicals are hydrogen. Compounds in which one or two of the radicals R ₅ , R ^, R _g and R _{1 Q} (in the 2'-position) are chlorine, or Rg is KH ₂ , or R _{5 is} -OH are very particularly preferred or Rg and Rg each represent a tert-butyl group, the remaining radicals R ^ to RJ _{2 being} hydrogen in all cases.

The following examples illustrate the present invention.

509818/1206

Example 1; ^ - (e-chlorine ^ -o ^^

( ^a ) fL ~ (4-Car b ome tfrpxy b eiiK o ^ yloxy;) -3-chl or ac et ο phen on A solution of 10.5 g of 3-chloro-2-hydroxyacetophonone in 70 ccra of dry pyridine was added to added to a solution of 139 g of p-carbomethxybenzoylechloride in 70 ecm of dry pyridine. The reaction;; the mixture was stirred for 24 hours, poured into water and the precipitated product was collected; 19.5 g of 2- (4- Oarbomethoxy'benaoyloxy) -3-chloroacetoplienone were obtained, P = 107-109 "after recrystallization from ethanol,

propane-1,5 -dione

There were 3 »2 g of powdered potassium hydroxide, 17 * 3 g of 2- ~ (4 ~ carbomethpxy" benzoyloxy) -3-chloroacetophenone and 250 ecm of dry pyridine heated to 60 ° to 80 ° for 2 hours with stirring. The reaction mixture was then poured into dilute aqueous acetic acid and the precipitated yellow pesticide was filtered off, washed with water and dried. The yield of 1- (3-chloro-2-hydroxyph.enyl) ~ 5- (4-carbomethoxyphenyl) propane ~ 1,3-dione (P = 19I-192 ⁰ ) "was 6.9 g after recrystallization Ethanol.

(c) 4- (8-Chloro-4-oxo-4H-1-'benzopyran-2-yl) -benzoic acid methyl ester

A solution of 6.9 g of 1- (3-chloro-2-hydroxyphenyl) -3- (4-carboiaethoxyphenyl) -propane-1,3-dione in 150 ecm of glacial acetic acid and 1.5 ecm of concentrated sulfuric acid was refluxed for 1 1/2 hours heated. Then the mixture was poured into water, and the

50 98 18/120 6

The precipitated solid was filtered off, washed with water and dried. 6.1 g of 4- (8-chloro-4-02: o ~ 4H ~ 1 ~ benzopyra.i} ~ 2 ~ yl) -benzoic acid ethyl ester obtained; F = 212-214 °.

(d) 4- (_ 8 ~ Chl or ~ 4-ο; £ ο. ", 4Ji"'' T * ft. ^enz . ° PJ ^r an-2 ~ yl) -b enz- oes aur e a hybrid off 6.0 g of 4 ~ (8-chloro-4-o>: o-4H-1-ben.2opyran-2-yl) -benzoic acid methyl ester, 400 ecm ethanol and 200 ecm dioxane MVT (Le 3 hours under reflux with 2, 0 g of potassium carbonate and 100 ecm of water. The cooled reaction mixture was poured into water and filtered, and the filtrate was acidified. The precipitated product was collected, washed with water and dried. Recrystallization from tetrahydrofurfuryl alcohol gave 3.5 g of 4- (8 ~ Chloro-4-o3co-4H ~ 1-benzopyran-2-yl) benzoic acid; I? - 343.

(e) 4 ~ ζ 8-chloro-4 - οχο ··· 4Η ~ 1 -b enz opyr an-2-yl) ~ b enso e acid sodium salt

There were 2.0 g of 4 ~ (8-chloro-4-oxo-4H-1-bensopyran-2-yl) -benzoic acid suspended in 50 ecm water and with 66.3 ecm 0.1- ¥ -Iiatriumhydroxydlösung titrated. The resulting solution was filtered and freeze-dried to yield 2.0 g of 4- (8-chloro-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid sodium salt; F = ^ 300.

Example 2t 2-chloro-6-hydroxyacetophenone

There were 28.2 g of 2-amino-6-chloroacetophenone with dilute sulfuric acid (31.7 ecm concentrated sulfuric acid in 83.2 ecm water) heated until dissolved. The solution was at 0 ° bis

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Cooled to 5 ° and quickly stirred, while a solution of 13.5 g of sodium nitrite in 36.7 ecm of water was added so that the. ! Temperature did not rise above 5 °. The reaction solution was stirred for a further 15 minutes and then poured through a condenser into refluxing dilute sulfuric acid (176 ecm concentrated acid in 176 ecm water), the foaming being kept as low as possible. The reaction mixture was then refluxed for 10 meows, cooled and extracted with ether. The iithex'extrakt was evaporated and the residue distilled getroclaiet ixnä. There were 15 _? β g ^f 2-0hlor-6 »- hydr oxy acetophenon keep in the form of a yellow oil ea ^; > Kp- ^ ~? 8r-80 °. - ^; .- ■■ .- ι ■ · ■ - .- ■ -. · ... '

Example 3

According to the procedure of the example: 1_ (a) .bis. (e) - v / are the following Terbindungen made from known starting materialsί

Acylation product e;

CG ₂ CII ₃

4-bromine.
6-bromine
6-chlorine
5-chlorine

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Melting point 119-121 °

"109-110 ° 105-106 ° 112-115 °

4-chloro 3-methoxy-methyl. 3,6 -D inie th oxy 3,4,6 - ir imexhory 4 j 5-dihydropyran.

6- (4-C ar ¹ O ο me t iioxy-

■ bensoyloxy) -3,5-diethyl

3 »5 ~ 3) ichlor, 3,6-dichloro 124-127 °

152-134 °

79-81 °

125-129 °

168-169 °

153-155 ° ο

90-91

172-173
116-119
.139-140

Diketoesterj

-COCH ₂ CO

6-0hlor 5-Chloro 4-chloro 3-methoxy 6-bromo-4 Broia 2-methyl melting point 147-149 ° 153 °

178-181 ° 138-142 ° 138-142 ° 179-181 ° not isolated

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-.31

3,4, -6-Trimethoxy 4,5: -I> ihydrop 3, .4 - dichloro ^; 3,5 ~ Μ chlorine 3,6-dichloro

Schme 1 ζ punlct

.146-148 ° .... 132-135 ° not determined 212-213 ° 199-201 ° 167-169 °

Cyclization modules:

5-bromine
7-bromine
5-chloro 6-chloro 7-chloro 8-methoxy 3-methyl 5,8-dimethoxy 5,7,8-trimethoxy 6,7 ~ dihydropyran melting point 185-187 °> 300 °
229-230 ° 182-186 ° 257-260 ° 204 °

not isolated 191-193 ° 205-208 ° not isolated

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- 32 - JL 2427597 7,8-Mclilor Melting point 6,8-I) ethyl-5-hydroxy 247-249 ° 6.8 Mchlor 169-170 ° 5.8 ~ 3) ieiilor 250-254 ° > 300 °

Hydro -l.ye ο prpduk tej_

5-bromine
7 ~ bromine
5-chloro 6-chloro 7-chloro 8-methoxy 3-methyl 5 j8-dimethoxy 5,7,8-trimethoxy 6,7-dihydropyrano 7,8-dichloro 6,8-diethyl-5-hydroxy 6,8- Dichloro 5,8-dichloro

Melting point

346-348 °> 340 °> 350 °> 35O °> 35O ° 343-345 ° (decomposition) 219-220 ° 314-316 ° 316-318 °

337-339 °> 360 ° about 300 ° (decomposition)

>300> 300 ^c

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ITatrurrjsalze;

JL.

5-chlorine 6-chlorine 7-chlorine:, 8-methoxy 3-methyl

Sohriiel · ζ punk t

5, Ö

$ 5.7

6,7-I) iliydropyran 5-bromine

7-bromine

7 5 8-Diilor 6 j 8-Dietliyl-5-hydroxy 6,8-Dicilor 5,8-dichloro

> 300

> 300

> 300

> 300 ⁽

> 3OO ^l >300> 320 ^c > 300

> 300 ^υ > 36O °>300>300> 300

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Example 4: 4- / 8- Al lj ± -5. ~ {3 - me thy! "But ox y) -4- oxo -4H-1 ~ b enz q - pyr qn- 2 ~ y l7-T3 enz ο es aur e

"^", (Λ "· ¹ " · ¹⁰ "ffi-ff l'b utoxy ) - ph --- nyl7-5- _i (4-car bometIioxy ·"

There are 19.2 g Iiatriumhydrid (50 ^ ige oil dispersion) in portions to a solution of 26.2 g of 3-allyl-2-hydroxy ~ 6- (3-methy3.-butoxy) acetophenone and 20.4 g of dimethyl terephthalate in 150 ecm The dark solution obtained in this way is introduced Heated on a steam bath for 1 hour and then concentrated, by removing the Dloxan under reduced pressure. The solid residue was then dissolved in 600 ecm of water and the Acidified solution. The precipitated yellow-orange solid was filtered off, washed with water and dried, and yielded 48.3 g of crude 1- ^ 3-AlIyI-O- (3-methylbutoxy) -phenyl / -3- (4-carbomethoxyphenyl) -propane-1,3-dione. This material was not purified, but used immediately in the next step.

(b) Following the procedure of example i (c), (d) and (e)

compound converted the product of step (a) above into the benzoic acid / (F = 235.5 236.5 °), its ester (not isolated) and the sodium salt (F = ^ 350 °).

Example 5

The procedure of Example 4 was repeated using known starting materials and those listed below Connections were obtained:

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COCH ₂ CO

R-

4,5-Cyclohexane 3,5 - Di-tert-butyl 6- (2 ~ ethoxyethoxy) Sohrne1 z punlrt

122-125 ° not isolated not isolated

"7 L

6,8-di ~ tert-butyl 5- (2-Äthoxyätlioxy) 6,7-Cycloliexan S chme1ζ point not isolated

146-147.5 ° not isolated

5098-18 / 1206

JR

6 j 8- ~ di - tert. -butyl 5- (2-ltho: vyätiiox.y) 6 j 7-0ycloliexan

S chrae Iz pun kt 309-312 ° 223-225 ° 263-264 °

—CO ₂ Ka

, R

6,8-di-ter t * - "butyl 3- (2-ethoxyethoxy)

^ 300 °
> 35O °

Example 6

f lavon

7.7 g of 4-cyanflavone and 2.29 g of hatriuniazide were obtained. and 1.67 g of ammonium chloride suspended in dimethylformamide and heated with stirring on a steam bath for 48 hours. The mixture was cooled, poured into water and acidified with dilute hydrochloric acid. The precipitated solid was collected, washed with water and dried. Recrystallization from tetrahydrofurfuryl alcohol gave 7.0 g of 4- (1H-tetrazol-5-yl) flavone; Έ = 286-287 ° (with decomposition).

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- "57 -

.4. "(I ΙΙ ~ Ά ^ί '.5 ^τ . ^Β - ^ζ - ^ο1 - ~' 5 ~} ^τ 1) -flavone sodium salt With stirring and warming, 6.1 g of 4- (1H - tetrazole-5- yl) - · flavonj, which were suspended in 100 ecm of water, treated with 1.76 g of N = trium bicarbonate in small portions. The pH value was examined after each addition to ensure that most of the jiatrium bicarbonate was consumed. ITacL - to which all of the sodium bicarbonate had been added (about 7 hours). the solution was stirred overnight. i'lavonnatriuinG§: lz received; ϊ ¹ => 500.

2 £ i ££ iSl_Ji. 2-diethylaminoethyl-4- (4- "OXo-4H-1-benzop, yran" 2-yl) " bjsjizojrt

(a) 4- (4- 0ΣΟ-4Η-1-benzopyran-2-yl) -benzoylchloride_

A suspension of 10.0 g of 4- (4-0xo-4H-1-benzopyran-2-yl) benzoic acid in 100 ecm of dry dichloroethane was treated with 3.0 ecm of thionyl chloride and 2 drops of dry dimethylformamide. The mixture was stirred and refluxed for 3 1/2 hours and then allowed to stand for 24 hours. The precipitated solid was filtered off, washed with dry petroleum ether and dried. 8.3 g of 4- (4-0xo-4H-1-benzopyran-2-yl) benzoyl chloride were obtained; Ϊ ¹ = 201-202 °.

(b) 2- diethylaminoethyl-4- (4-oxo-4H-1-benzop7 / ran-2-yl) benzoate hydrochloride

A mixture of 7.4 g 4- (4-0xo-4H-1-benzopyran-2-yl) -benzoyl chloride, 6.1 g of 2-diethylaminoethanol and 100 ecm of dry pyrine

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din was stirred overnight at room temperature and then in Poured water. An ethyl acetate extract of the aqueous mixture was washed with iiatrium carbonate solution and with water / water, dried and evaporated; 4.4 g of 2-ethylaminoethyl 4- (4-O2: o-4H-1-benzopyr & n-2-yl) benzoate were obtained obtained in a mixture of 150 ecm dry ether and 50 ecm dry ethanol dissolved and treated with dry hydrogen chloride gas for 1 hour The precipitate was filtered off and recrystallized from dry ethanol and yielded 3.3 g of 2-diethylaminoethyl-4- (4-oxo ~ 4H ~ 1-benzopyran ~ 2-yl) benzoate hydrochloride; F = 217-220 °.

Example 8? 5-0 "chloro-4- (4-oxo-4H-1-benzo pyran-2-yl) benzoic acid

(a) 2- (2 ~ 0h lor-4 ~ nit robenzoyloxy) -acetophenone 16.4 g of 2-hydroxyaeetophenone in 100 ecm of dry pyridine were converted to 26.6 g of 2-chloro-4-nitrobenzoylechloride in 100 ecm of dry pyridine added, whereupon the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was then poured into dilute HCl and an oil precipitated which quickly solidified. The product was extracted with ethyl acetate, washed with dilute HCl, aqueous lithium carbonate solution and then with water / water and dried. The ethyl acetate was evaporated and a slightly sticky solid remained. This was triturated with 40-60 ° petroleum ether and filtered and yielded 30.8 g of a light brown solid; i ¹ = 111-113 °.

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By. Recrystallization of 1.0 g of the product from ethanol was carried out 0.6 g colorless; Obtain elongated needles; F = 113-114 °.

(b) 1 - (2-lydrox ν phenyl) -3 ~ ■ (2-chloro-4 ~ nitrophenyl) propane-1,3- dione

1.0 g of the product from step (a) in 15 cc of dry pyridine was treated with 0.193 g of powdered KOH, heated and stirred at 80 for 11/2 hours. The reaction mixture was poured into aqueous acetic acid and the yellow solid collected by filtration and dried; the product weighed 0.8 g; 1? = 117-124 °. By recrystallizing this product from petroleum ether (bp = 100-120) while decanting a black one, 0.3 g of product was obtained; F = 133-134 °. The renewed recrystallization from 100-120 ° petroleum ether yielded 0.23 g of a yellow crystalline product; Mp = 135-136 ° (23% yield).

(C-) 2- (2-chloro-4-nitrophenyl) -4-OXO-4H-1 -benzopyran The diketone product of step (b) (2.0 g) was 1 hour in 75 ecm glacial acetic acid and 0, 5 ecm of concentrated sulfuric acid heated to reflux. The reaction mixture was poured into water and the cream-colored solid which had precipitated out was filtered off and dried; 1.9 g of product were obtained; mp = 148-151 °. Recrystallization from ethanol yielded 1.1 g of colorless needles; M.p. 154-155 ° (58.3% yield).

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(d) 2- (4-Amino -2-chlorophenyl) -4 -OX Q-4H-1 - "ben ζ ο pyran

1.81 g of the product from stage (c) were heated to reflux for 30 minutes with stirring and 1 ^ g of tin (II) chloride in 100 ecm of concentrated hydrochloric acid. A crange-colored solid separated from the reaction mixture for about 15 minutes each time. The entire reaction mixture was cooled to 0 ° overnight. the insoluble solid collected and dried in vacuo over KOH. Then the solid was dissolved in a minimum of boiling methanol, which had been brought to a pH of 7 to 8 with aqueous ammonia, and evaporated to dryness * The residue was heated to reflux with 500 ecm of ethanol and filtered hot, whereupon the filtrate reduced to a small volume and poured into water. The precipitated product was collected and dried to give 1.4 g of a yellow solid; F = 143-144 °.

(e) 2- (2-chloro-4-cyanophenyl) -4-OXO-1-benzopyran

There were 14 g of the amine product from stage (d) in 300 ecm 50 igp Sulfuric acid with stirring at 0 ° with 3.92 g of sodium nitrate in Treated 15 ecm of water. After the addition, the reaction mixture was held at 0 ° for 1/2 hour and then at 0 ° to give 18.2 g Copper-ll yanide and 27 g of potassium cyanide in 300 ecm of water. The reaction mixture was stirred for an additional 1/2 hour at 0 and then slowly warmed to room temperature. After you Was heated to 60 ° for 2 hours, the mixture was filtered and the product washed with water and allowed to air

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dries. The pest was exposed three times with boiling acetone ex extracted and the insoluble excess of copper-_I'-cyanide filtered. The acetone was evaporated and the moist residue applied without further purification in step (f).

- ~ y - * ·) "^ ^{enzoe s} ^ - ^ure

The nitrile product of step (e) was left in an oil bath for 3 hours with 150 ecm glacial acetic acid, 150 ecm Y-barrel and 150 ecm more concentrated Sulfuric acid heated to 130 °. The reaction mixture was cooled and poured into water, and the precipitated product became collected by filtration. This material was made with a to warm. Liatric carbonate solution treated to remove the insoluble Filtered material and acidified the piltrate. The precipitate was filtered off and dried to yield 2.2 g Product; F = 285-288 °. By crystallization from tetrahydrofurfuryl alcohol 1.4 g of product were obtained; F = 293-294 ° (9 ^ of the amine).

Example 9: 3-Chloro-4- (8-chloro-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid

(a) 3-chloro-4- (2-hydroxy-3-chlorobenzoylacetyl) -benzoic acid 6 g of sodium hydride (80%) were washed with dry ether and then suspended in 50% of glyme. 10.6 g of 3-chloro-2-hydroxyacetophenone, dissolved in 75 ecm of glyme, were added dropwise within 10 minutes. After 2 minutes, a slurry of 13 g of 4-carbomethoxy-3-chlorobenzoic acid in 100 ecm

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G-lyme added within 5 minutes. The mix was Heated to reflux with stirring for 13 hours. Pie overall reaction was carried out under nitrogen.

The mixture was never poured into water, _{washed with CIiOl 7} and acidified. The filtered solid was extracted with HOHO ^ solution. As soluble material 7 _S were obtained 44 g Chlorterepiithalsäure. The insoluble material, a dark green solid, was washed several times with CHCl 4 to remove the unreacted ketone. 6.11 g of 3-chloro-4- (2-hydroxy-3-chlorobenzoylacetyl) benzoic acid were obtained.

(b) 3-chloro -4- (e- chloro-4-o3co-4H-1-benzopyrari "2-yl) -benzoic acid A mixture of the acid product of step (a), 70 ecm acetic acid and 7 ecm concentrated sulfuric acid was made The mixture was heated to 95 ° for 4 hours, the mixture was filtered and the solid was washed with a tap and dried. Recrystallization from tetrahydrofurfuryl alcohol gave 2.34 g of the desired product in the form of a whitish solid; melting point 292-294 °.

Example 10: 3-Methoxy-4- (4-oxo-4H-1-benzop.yran ~ 2-yl) -benzoic acid

(a) 1- (2-Hydroxypheny1) -3- (4-acylamino-2-methoxyphenyl) propane-1,3-dione

There were 27 g of an 80 ^ igen sodium hydride dispersion in 400 ecm suspended in dry pyridine. Then 29.2 g of o-hydroxy

609818/1206

acetophenone was added dropwise and then a solution of 48 g Methyl ~ 2 ~ methoxy-4-acetylaminobenzoate in dry pyridine. laugh Part of the pyridine was reduced under reduced pressure for 4 hours removed and the reaction mixture carefully poured into water. The aqueous solution was extracted with ether in order to remove remaining starting material and acidified with Chloroform extracted. The organic extract was washed, dried and evaporated to give a thick brown oil, which crystallized from ethanol. The yield was 36.5 gj 1 = 122-130 °. The compound was recrystallized from ethanol, and the yield was 32 g (45.5 #); F = 131-134 °.

(b) 2 ;-( 4- Amino- ⁱ -2 - methoxyphenyl) - 4-oxo - 4H - 1 - benzopyran 33 g of the diketone obtained as an intermediate were dissolved in refluxing 200 ecm of ethanol , and then 200 ecm of concentrated hydrochloric acid were added in portions through the condenser * The reaction was followed by thin-layer chromatography. After 1 hour, the reaction mixture was allowed to cool and poured into water / water. The solution was basified with NapCO ^ and the product filtered and dried. There were 26 g of one. Product obtained which after recrystallization from toluene / ethanol gave 6.8 g of product; I ¹ = 169-171 °. Its second crop weighed 13 g; F = 168-170 °. The overall yield was 19.8 g (76 #). ■

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(c) 5-Methoxy-4 - (4 -QXQ-4H-1 -be nzopyran ~ 2- yl) -benzoic acid. The amine product of step (b) was converted into 2- ( 4-cyano-2-methoxyphenyl) ~ 4-oxo-4H-1-benzopyran converted; P = 185-190 °. The cyano compound was converted to 5-methoxy-4- (4-oxo-4H-1-benzopyraii-2-yl) -benzoic acid according to the procedures of Example 8 (f); 3? = 279-281 ° «The corresponding Ή atrium salt (P = i> 300} was prepared according to the method of example i (e).

Example 11: 4- (3- chloro-4-oxo -4H-1 -b

(a) 4 - (3-Chloro-4- oxo- -4H- 1 -benzop ^ yran ^ -yl ) -benzoic acid

It became 1 g of 4- (4-0xo-4H-1-benzopyran-2-yl) -benzoic acid for 4 hours under reflux with 20 ecm sulfuryl chloride and dry benzene heated. Then the reaction mixture was poured into water. The precipitated product was filtered off and crystallized from ethanol and yielded 0.5 g of a white pesticide; P = 288-289 °.

(b) 4- (3-Chloro-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid sodium salt

0.75 g of the acid product from step (a) were stirred with 0.2 g of aqueous sodium bicarbonate for 1/2 hour at room temperature. The suspension was then heated to about 40 ° for 10 minutes. The solution was filtered and the piltrate freeze-dried. It a pale yellow plague was obtained, which was dried in vacuo at 110 °; P = ^ 300.

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Example 12: 4 ~ (3-Methoxy-4-oxo-4H-1- benzoopyran-2-yl) ~ benzoic acid

32 g of sodium hydroxide in 64 ecm V / water were added with stirring to a solution of 32 g of o-hydroxyacetophenone and 2 g. p-öarboxj '- benaaldehyde given in 400 ecm of ethanol. The mixture was refluxed for 2 hours and, after cooling, acidified (dilute HCl). The bright yellow product was filtered off and crystallized from ethanol / dioxane. 28.3 g of product were obtained; Έ = 274 °.

( ^"D) - 4 ~ (3-hydroxy-4-oxo-4H-1-b enzopyran-2-- _i) yl) - beiizoe acid were 11.5 g of 2-hydroxy-4'-carboxychalcon in 115 ecm methanol and 57 cc of 20 conclude IJaOH dissolved. at 0 ° WLirden added dropwise 23 cc hydrogen peroxide (30 "£ strength) are added and the solution thus obtained was kept overnight at 0 °. Then an excess of dilute acetic acid was slowly added dropwise. The pale yellow precipitate was filtered off, washed with water and dried. The yield was 6.6 g; F => 300 °.

(c) Meth yl 4- (3-methoxy-4-oxo-4H-1 -benzppyran-2-yl) benzoate 6.5 ecm of dimethyl sulfate were added to a suspension of 6.6 g of the hydroxy acid product of Stage (b) and 6.6 g of potassium carbonate in 100 ecm of dry acetone. The mixture was stirred under reflux for 19 hours, cooled and filtered. The filtered solid was washed 6 times with, ie 100 ecm acetone,

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iim to remove all of the product «the total yield at Ester was 3.86 g ($ 53). The unicrystallization from methanol provided a product with a melting point of 154-156 °,

(ä-) 4- ( 3 ~ Hethoxy -4 _i ~ pxp- "4 H-1 ~ benzopyran-2 ~ yl ) --benzoesäui'e To a solution of 2.0 g of the product from step (c) in 150 1 cm of methanol and 100 ccn of dioxane were added dropwise to 70 ccra of 0.1n ITaOH over a period of 10 minutes. A yellow color was immediately evident, and after the addition of the base a yellow precipitate formed. This precipitate was dissolved by adding 100 ml of dioxane The solvents were evaporated by heating slightly under reduced pressure. By filtering the aqueous solution thus obtained, 0.2 g of unchanged ester was obtained. Acidification, the piltrate provided the desired acid aqueous NaHCO ^. The yield of pure acid was 1.5 g; P = 214.5-217 °.

Example 13: 2-Bromo-6-hydroxyacetophenone

(a) 2-Bromo-6-nitrobenzoyl chloride

There were 42.5 g of 2-bromo-6-nitrobenzoic acid in 100 ecm thionyl chloride Heated to reflux for 3 hours. The reaction mixture was filtered off from the soluble material and the filtrate evaporated, leaving an oil that quickly solidified and provided 38.7 g ($ 84.7) of the desired product; = 53-54 °.

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(b) Diethyl - ^ - bromo-O-nitrobenzoylmalonate

55/6 g of diethyl malonate became a suspension with stirring of 8.3 g of magnesium shavings in 80 ecm of dry ethanol and 3.0 ecm carbon tetrachloride given. So: soon the initial reaction When finished, the mongrel was heated to reflux and stirred until all of the magnesium was dissolved. The ethanol was distilled off in vacuo, and there were 160 ecm dry Benaol added and also distilled off. Then another 160 com dry benzene was added, and a solution of 38.7 g 2-Bromo-6-nitrobenzoyl chloride in 100 ecm dry benzene was stirred into the solution. Then the solution was 2 Ί / 2 hours sum Heated to reflux.

The reaction mixture was cooled and diluted with 300 ecm HgSO. stirred. The benzene layer was separated and the aqueous portion was washed with benzene; the extract and washings were dried and evaporated to give a yellow Peststoff, the collected and washed carefully with ether 60-80 ° petroleum -was, remove traces of diethyl malonate to. The yield was 45.1 g ($ 79.6); P = 114-116 °.

(c) 2-bromo-6-nitroacetophenone

A mixture of 45.1 g of diethyl ^ -bromo-o-nitrobenzoylmalonate, 40 ecm glacial acetic acid, 3.0 ecm concentrated sulfuric acid and 25 ecm Water was refluxed for 5 1/2 hours. The mixture was then chilled in ice, diluted with 20% aqueous UaOH

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Brought pH from 7 "to 8 and extracted with ether. The ether extract was washed with water and dried. The solvent was evaporated and the remaining oil solidified, whereby 26.8 g of the desired product were obtained; F-73 -74 ⁰ .

(d) 2-A mino-6-bromac etophenone

To a solution of 26.8 g of 2-bromo-6-nitroacetophenone in 120 ccni Glacial acetic acid became 31.5 g within 1 hour at 90 ° to 95 ° Iron powder given in small portions. The mixture was stirred continuously, and after 0, 20, 40 and 60 minutes respectively were 30 ecm of water were added while the temperature was maintained at 90 ° to 95 °. After 3 hours at this temperature were 200 com of water was added and the product was extracted with ether. The ether extract was washed with water, aqueous sodium carbonate and again with water and dried. Hach distance of the ether, 18 g of the desired product were obtained; P = 114-116 °.

(e) 2-bromo-6-hydroxyacetophenone

Hot dilute sulfuric acid became 18 g of 2-amino-6-bromoacetophenone (15 ecm concentrated HpSD, + 42 ecm HpO) given. the clear solution was stirred and cooled to 15 °, whereupon 38 g Ice was added. Then the amine sulfate was separated. at a temperature of> 5 ° were 6.8 g of sodium nitrite in 18.5 ecm Added water to the reaction mixture. The solution was

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Stirred for 5 minutes, after which 60 ecm of water, 0.6 g of urea and 60 g of bis were added one after the other. The mazonium salt solution was added in portions to 31.5 g of anhydrous sodium sulfate, 23 ecm of concentrated sulfuric acid and 20 cc in water, the internal temperature being kept at 130 ° to 135 °. The product that formed solidified immediately. Finally, the reaction mixture was subjected to steam distillation. The distillate was extracted with chlorine form and the extract dried and evaporated, whereby 9.1 g of a light brown pesticide were obtained; S ¹ = 106-108 °.

Example 14- '4- (6 ~ Amineq- _: 4-oxq ~ 4H-1-boron, Hopyran -2- y1) -benzoic acid

(a) Methyl-2-ac.e; by l-4-acetamidophenylterep htha _i lat 9.65 g of 5-acetamido-2-hydroxyacetophenone in 50 ecm of dry pyridine at room temperature to 10 ₅ 9 g of p-carbomethoxybenzoyl chloride in 50 ecm dry pyridine and stirred overnight. The reaction mixture was poured into water, the precipitate was extracted with chloroform and the extract was washed with dilute HCl, sodium bicarbonate solution and water and dried. Evaporation of the solvent gave 15.6 g of the desired product; I ¹ = 179-183 °.

Then 1.0 g of the product was recrystallized from dioxane and provided 0.7 g of pure product; P = 187-188 °.

BATH ORIGINAL 5098 18/1206

** " J \ J -

(b)] uethyl-4- / r2-hydroxy-6-acetamidophenyl ) -1 _} 3-diketopro p--

12.4 g of the ester product from stage (a) were treated in 300 ecm PyridiK with 0.9 g of powdered KOE and heated and stirred 1/2 η do dt- at 80. The reaction mixture was poured into aqueous acetic acid and ds, The product was extracted with ethyl acetate, the organic extract was washed with dilute HGl and then with water and dried. 7.1 g of product were obtained by evaporation of the solvent; ¹ = 214-216 °.

(ο) IJe thy 1-4- (6 " aiaino-4-oxo ~ 4 H-1 -benzop yran -2-yl) -evenat-

id

5.3 g of the diketone product from step (b) were refluxed dissolved in 750 ecm of methanol, and 250 ecm of concentrated HGl were added through the cooler. After about 1/2 hour it was a colorless solid precipitated, and it v / urde a further 2 1/2 Heated to reflux for hours. The reaction mixture was cooled and the product filtered. The yield was 4.4 g (88.9 #); F = 273-277 ° with decomposition.

(d) 4- (6-Anri.no-4 ~ oxo-4H-1-benzopyran-2-yl) benzoic acid 4.4 g of the amine ester hydrochloride product from stage (c) were suspended in 450 ecm of ethanol and mixed with 2.81 g of FapCO-z are added to 200 ecm of water.

The reaction mixture was heated and stirred until a clear solution formed »Then a further 400 ecm of water was added.

BATH

509818/1206

ben, and the solution was heated to reflux and filtered for a further 2 hours and the filtrate was diluted with dilute HCl pH- '. vert brought from 4. The precipitated product was filtered off collected, washed with a little water and dried. 3j'7 g of product were obtained; F = 286 ° (decomposition), Avg Recrystallization from aqueous ethanol gave 3.1 g of product; F.- 290 ° (decomposition).

The acid was added to the according to the procedure of Example 1 (e) corresponding iiatrium salt converted; F = ^ 300 °.

The procedure described above was performed using 4-acetamido-2-hydroxyacetophenone repeated as starting material; it became 4- (7-amino-4-oxy-4H-1-benzopyran-2-yl) benzoic acid (F => 300 °), and the intermediates were: Methyl ~ 2-acetyl-5-acetamidophenyl terephthalate (F = 166-169 °), Methyl 4- / T2-hydroxy-4-acetamidophenyl) -1,3-diketoprop-3-yl7-benzoate (F = 243-246 °) and methyl 4- (7-amino-4-oxo-4H-1-benzopyran-2-yl) benzoate (F = 284-286 °).

Example 15: 4- (5-Hydroxy-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid

(a) Methyl 4- (5-hydroxy-4-oxo-4H-1-benzopyran-2-yl) benzoate There were 2.0 g of methyl 2-acetyl-3-chlorophenyl terephthalate in 30 ecm of pyridine with 0.372 g treated with powdered KOH, heated for 1 hour on a steam bath to about 80 ° to 90 ° and then

509818/1206

~ 52 ~

1 hour away. Heated to reflux. The reaction mixture was poured into dilute aqueous acetic acid and the precipitated yellow pesticide was collected by filtration, washed with water and dried. Recrystallization from ethanol gave 0.4 g of yellow, fluffy needles; Έ = 203-206 °. Further recrystallization from ethanol yielded 0.1 g of product; 1 = 206-207 °.

(b) 4- (5-Hydroxy-4-oxo-4H-1-benzopyran-2-yl ) -benzoic acid 1.7 g of the 5-hydroxyester product from stage (a) were dissolved in 200 ecm of ethanol and 50 ecm of dioxane solved. Then 0.609 g of sodium carbonate and then water were added in portions, whereupon the mixture was refluxed for a further 2 hours. The reaction mixture was diluted with water and filtered and the filtrate was acidified. The precipitate was collected, washed with water and dried to give 1.1 g of product; 3? = 330 ° (decomposition). Recrystallization from letrahydrofurfuryl alcohol gave 0.74 g of pure product; ϊ ¹ = 335-337 °.

The acid was added to it according to the procedure of Example 1 (e) ITsodium salt converted; 1 => 300 °.

Example 16: 4- (4-0xo-4H-1-benzopyran-2-yl) -benzohydroxamic acid.

(a) 4- (4-0XO-4H-1-benzopyran-2-yl) -benzohydroxane-acid. 10 g of 4- (4-oxo-4H-1-benzopyran-2-yl) benzoyl chloride were added at room temperature to a solution of 2.57 g of hydroxylamine hydrochloride in 100 ecm of pyridine. After 15 minutes of violent

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had been stirred, the mixture was heated to 80 ° for 10 minutes, until a clear solution was formed. The mix was Left idle overnight and then in sis and a surplus Poured in hydrochloric acid, whereupon the product is collected, washed with water and dried.

Recrystallization from tetrahydrofurfuryl alcohol provided 4.9 g needles; F = 226-228 ° (decomposition).

("b)" Ha trium-4 -J 4-oxo ~ 4H-1 -b enz ο pyran- 2 -y 1) -b eng ohy dr oxamajb 148.2 ccra 0 _s 1n-sodium hydroxide was 4.265 g of the hydroxamic • acid product of step (a) was added, and the suspension was stirred overnight. 100 ecm of ethanol were then added and the mixture was stirred at 60 ° for a further 3 hours.

Evaporation of the clear solution gave a yellow solid which was dried at 60 ° in vacuo to give 4.3 g of product; ¥ => 300 °.

Example 17: 2- / 4 - (Cyclopentanone ~ 2-carbonyl) -pheny l7 -4-px p -4H-1-benzopyran

(a) 2- / 4 - (Cyclopentanone-2-carbonyl) -pheny l / ^ - oxo ^ Hi -benzopyran

There were 6.94 g of H-Ci-Cyclopenten-i-ylJ-morpholine and. 4.83 g Triethylamine dissolved in 65 ecm chloroform and cooled to 0 °. Within 2 hours, 12.9 g of 4- / 4 "-0xo-4H-1 -benzo-

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Pyran-2-yl7-benzoyl chloride in 75 ecm chloroform slowly stirred in, keeping the temperature below 10 * The mixture I was then allowed to slowly warm to room temperature and stirring continued for 30 hours. The dark brown · ■ The mixture was refluxed for 1 hour, and then 6.5 ecm of concentrated hydrochloric acid and 15 ecm of water were added. The mixture was then refluxed for a further 3 hours. The mixture was cooled and filtered, and the chloroform layer the filtrate separated, twice with sodium bicarbonate solution and washed twice with water and dried over magnesium sulfate. After removing the solvent, a yellow-brown, sticky pesticide remained, which was treated with ether and was filtered and gave 5.7 g of yellow-brown product.

By crystallizing this solid from ethyl acetate / petroleum ether (60-80 °) 2.6 g of crystals were obtained, which were recrystallized twice from toluene / petroleum ether (bp = 60-80 °) and Gave 1.6 g prisms; F = 178-181 °. Recrystallization from toluene yielded 1.2 g of prisms; F = 181-183 °.

(* 0 2- / 4- (Cyclopentanone-2-carbonyl) -pheny l 7-4- "OXQ-4H-1-benzopyran sodium salt

At room temperature, 24.9 ecm 0.1N sodium hydroxide increased 825 mg of the β-diketone product of step (a) were added, and the suspension thus obtained was 1 hour at room temperature and then Stirred at 60 for 1 hour. At this point in time, there was still some ß-diketone that had not been converted.

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20 ecm of ethanol was added and the mixture was over Stirred overnight at room temperature. Then it became the clear solution evaporated and the residue dried by evaporating toluene three times. The pesticide was at 100 ° in a vacuum of 4 stalls dried to provide 820 mg of product; F => 250 ° (decomposition). ,

Example 18; 4- (4-0xo-4H-1 -benzppyran-2-yl) -phenylacetic acid sine suspension of 5.0 g of 4- (4-oxo-4H-1-benzopyran-2-yl) -benzoyl chloride in 200 ecm Ether was added at 0 ° to 10 ° with stirring to a solution of about 3.0 g of diazomethane in 200 ecm of ether. The reaction mixture was allowed to warm to room temperature and was stirred at this temperature for 18 hours. The insoluble product was collected by filtration and the yield was 4.1 gj P - 175-177 °. 4.1 g of diazoketone were then suspended in 100 ecm diglyme and slowly added at 60 ° to 70 ° with stirring to 1 g of silver oxide, 2 g of anhydrous sodium carbonate and 1.5 g of sodium thiosulfate in 200 ecm of water. The mixture was stirred for a further hour at this temperature, after which the reaction mixture was heated to 90 ° to 100 °. The reaction mixture was then filtered and the filtrate acidified. The oily precipitate was extracted with ethyl acetate and the extract was washed with aqueous, saturated sodium bicarbonate solution. The wash liquors were acidified and yielded 1.5 g of a product; 3? = 192-196 °. By! ^ Crystallization from aqueous ethanol 0.8 g of the desired product were obtained; 1 = 195-199 °.

5Q9818 / 1206

The acid was converted into its catriuins according to the item procedure of Example 1 (e): P -> 300 ^o .

Dao Y '.- 3?; Tahi'en of the} -3 example S (a) to (f) was repeated, and it v / urd'm following Yorbinduii ^ eij au α "beicierten .mü ^ angsKiateriali manufactured:

R.
3-chlorine

Melting point

89-91

Diketones

, R
3-Cfclor

COCH ₂ CO

Melting point 162-164 °

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BATH ORIGINAL

CjreJL is ± eTxm £ βρϊ _ ο ftukt β

236-233

Amino ti avone

R.
3-chlorine

Melting point 185-186 °

Cyanf la \ ^r one

- CN

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Sodium salts

JL

3-chloro 2-J-J.ithoxy not isolated 185-190 °

B e η s ο e s air en

JL

2 ~ Mc-thoxy 2-Clilor melting point 245-246 ° 301-102 °

CO ₂ Na

2-methoxy 2-chloro

Melting point

286 °> 300 °

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4- / 7 - (2 -H y ^ yopcypr opopryj - J ~ οχο ^ - · _4-Η "1 ~ b enz ο pyran-2-y l7 -" benzo es aure e

A mixture of 13 g of 4- (7 "iiethoxy-4 ~ o3co-4H-1-be2izopyraji" 2 ~ yl) ~ beii ζ oo acid era et hy le st er and 40 g pyridine hydrochloride v / .urde 2 hours heated to 200 ° and then cooled »The oil thus obtained was triturated with y / ater to give a green solid. This solid was crystallized from methanol and gave 10 g of green blemishes of 4- (7-hydroxy-4-oxo ~ 4H-1 ~ benzopyran ~ 2 ~ yl) benzoic acid; F = 336 ° (decomposition).

This hydroxy acid was dissolved in a kethanol-chlorohydrate solution esterified and provided 6.5 g of methyl ester in Porm greener Needles; F = 306-307 °.

(b) 4- / 7 - (Hydroxypropoxy) -4-OXO-4H-1 -benzopyTan ~ 2-yl 7; -benzoic acid

A mixture of 2.5 g of the product of step (a), 2 ecm of propylene oxide and 5 drops of Triton B in 20 ecm of dioxane were heated in a sealed vessel for 3 days.

The brown solution thus obtained was evaporated to dryness, and a brown oil remained. This oil was made with sodium bicarbonate, Ethanol and water hydrolyzed until the thin-layer chromatogram showed complete hydrolysis.

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The solution was treated with "charcoal" and with dilute hydrochloric acid acidified to give a beige colored solid. This solid was crystallized from Etha .- :. ol and provided 0.85 g of beige needles; F == 265-267 ° (decomposition).

Following the procedure of Example 1 (e) ', the sodium salt was obtained manufactured; F = 350 °.

Example 21

According to the method of Example 1 (a) to (e) and using of the 2-chloro, 2-uritro and 3-nitro derivatives of 4-carbomethoxybenzoyl chloride the following connections were made:

Acylation products

COOCH,

4-ethoxy

5-acetamido

6-chlorine

2-nitro 3-mtro 2-chloro 2-chloro 2-chloro

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Melting point

95-97 °
115-117 ° 162-164 ° 129-134 °

Diketones

2 3

CO ₂ CH ₃

SI R " H 2-nitro H 3-ETitro 4-ethoxy 2-chlorine 5-acetamide. 2-Gblor 6-chlorine . 2-chlorine

mp oint

137-140 "133-136 °

120-122 ¹ 191-194

Cyclization products

CO ₂ CH ₃

7-ethoxy

6-amino

5-chlorine

2-mtro 3-liitro 2-chloro 2-chloro 2-chloro

M chme1ζpunkt

201-202 ° 169-172 ° 239-241 ° not isolated

09813/120

Hydrolysis products

-si

7-ethoxy

6-amino

5-chlorine

3 ~ iTitro 2-Nitro 3-chloro 3-chloro 3-chloro

S chm e1 ζ point 3H-31-5

273-275

317-318 ° (dec) 298-299 °

Example 22: 3 »4-J) iGhlor-2-hydroxyacetoph.enon

(a) 7τ 8-dichloro-4-oxo-4H-1-benzopyran-2-carboxylic acid Bs, 30 drops of Triton B were added to a mixture of 100 g of 2,3-dichlorophenol and 87 g of dimethyl acetylenedicarboxylate in 150 ecm of dry dioxane.

The mixture was heated on a steam bath for 15 minutes and heated to 95 ° for 2 hours and left to stand overnight at room temperature. A solution of 60 g ITaOH in 300 ecm \ 7asser was added and the Löoung heated for 8 hours until hydrolysis ended v / ar. The aqueous solution is acidified and the precipitated acid is extracted into ether. The dried ones

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Ether extracts provided "on evaporation a pesticide which was dissolved in aqueous sodium bicarbonate. The aqueous solution was carefully washed with ether in order to remove the impurities. Acidification of the bicarbonate of soda gave a solid which was extracted into ether. On evaporation, the dried ether extracts yielded 112 g of 2,3-dichlorophenyl oxyfumaric acid as an intermediate product.

This acid was slowly added to 550 ecm of concentrated HgSO 2 within 30 minutes. The solution was stirred at room temperature for 2 1/2 hours and then poured into ice water. Crystallization from ethanol gave 74.4 g of the desired acid ; P = 235-238 °. The yield was $ 47 . -

3,4-dichloro-2-hydroxyaeetophenone A mixture of 24.0 g of liaOH and 30 g of the chromonic acid product of stage (a) in 750 ecm of water was heated to 95 ° for 1/2 hour, left to stand at room temperature for 1 hour and then acidified. The ether extract of the acid solution was washed with sodium bicarbonate, dried and evaporated and gave 9 »0 g (38 $) of the desired product; P = 109-110 °.

Example 23: 4 ~ carbomethoxy-3-nitrobenzoyl chloride

(a) 4-carbomethoxy-3-nitrobenzoic acid

There were 83.1 g of dimethyl nitroterephthalate in 2.5 1 of methanol

heated to reflux and within 1 1/2 hours under Hüh Ren treated dropwise with 19.5 g of KOH in 500 ecm of methanol.

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The reaction mixture was refluxed for an additional hour, concentrated to half volume, and poured into water. The precipitated diester was extracted with ethyl acetate and the aqueous layer acidified and extracted with ethyl acetate,

The ethyl acetate was evaporated, and the desired product was obtained, which was boiled with about 1 3/4 l of water and then allowed to cool. Filtration collected 47.4 g (60.6 %) of the insoluble product; F = 177-178 °.

(b) 4 -Garboxymethoxy ~ 3- nit roben2: oyl chloride 53.2 g of the acid product from stage (a) were refluxed for 3 1/2 hours in 150 ecm thionyl chloride. After the solution had stood more than once at room temperature, a colorless crystalline solid was precipitated which, after drying, weighed 34.7 g; F = 174-176 ° (thin-layer chromatogram showed that the acid was modified in practice). Evaporation of the thionyl chloride gave a viscous residue which, after distillation, gave 12.0 g of the desired product in the form of a yellow oil which rapidly solidified;

Kp _{n Λ} = 150. The recovered acid became 2 hours with ^u * 'mm

120 ecm thionyl chloride and 2 drops of pyridine heated to reflux. The excess thionyl chloride was evaporated and the residue was distilled to give 33.9 g of the desired product; Kp _{n 1C} = 156 °. The overall yield was 45.9 g

^υ »'--mm

(79.7 Ji).

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Example 24; ft-carbomethox y ^ -nJLt: ^^

172.8 g of 4-C "arbomethoxy-2-nitrobenzoic acid in 500 .ecm thionyl chloride, which contained a few drops of pyridine, were heated to reflux for 2 hours and then left to stand at room temperature over K. The excess thionyl chloride was removed in vacuo The residue in the flask solidified on cooling, liacli dej ¹ recrystallization from toluene / petroleum ether gave 149.1 g (79.8 fo) of colorless product; - F = 41-42 °.

Example 25: 2-Amino-4- (4-QXQ-4H-1 ~ benzopyran - 2- yl) -benzoic acid

( ^a ) Meth yl 2-amino-4- (4-QXQ-4H-1- benzopyran-2-yl) benzoate 10.0 g of methyl 2-nitro-4- (4-oxo-4H- 1-benzor> yran-2-yl) benzoate heated to reflux for 30 minutes with stirring with 50 g of tin (II) chloride in 500 ecm of concentrated hydrochloric acid. The reaction mixture was cooled to 0 ° within 1 hour and the insoluble solid was collected by filtration and dried in vacuo over KOH. The hydrochloride was treated with 500 ecm boiling methanol and with ammonia solution on one. pH from 7 to 8 brought. The mixture was poured into water and the pale yellow solid filtered off and dried to give 8.0 g of crude product. This product was extracted with boiling dioxane and filtered and the filtrate was evaporated; 5.5 g (60.6 fo) of product were obtained; F = 221-223 °.

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Following the procedure of Example 1 (d) the ester was converted to the acid; i ¹ = 506-308. The yield was $ 77.

Using the procedure described above, 3-amino-4- (4-oxo-4H «1-benzopyrsin-2-yl) -benzoic acid (3? = 285-286 °) immediately produced in 85% yield.

Example 26 ^ 3_ ₁ 6-Mcnlor-3 -h _[ Ydroxyaceto _r ph e non

( ^a ) 5 _i? 30 drops of a benzyltrimethylammonium hydroxide solution were added to a solution of 162 g of 2,5-dichlorophenol and 142 g of diinethylacetylenedicarboxylate in 250 ecm of dioxane . The solution was heated on a steam bath for 1 hour. A solution of 80 g of sodium hydroxide in 320 ecm of water was then added and the mixture was heated on the steam bath for 6 hours. About 100 ecm of the solvents were distilled off under reduced pressure. Then 200 ecm of water and then an excess of concentrated hydrochloric acid were added. A whitish pest was precipitated, filtered off, washed with water and dried.

This mixture of 2,5-dichlorophenoxyfumaric and maleic acids became more concentrated overnight at room temperature with 600 ecm Sulfuric acid stirred. Pouring the acidic solution into ice water gave a colorless solid which was filtered off and washed with water. The product was through

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Extraction with hot water (to remove 2,5-diclilorphe'noxymaleic acid) and then purified by recrystallization from ethanol and yielded 97.5 g of 5,8-dichloro-4-oxo-4H-1-benzopyran-2-carboxylic acid; F = 268-270.

(b) ^ fi-dichloro - ^ - hyd rozyacetophenone

26.4 g of sodium hydroxide and 43.7 g of the acid product are obtained of stage (a) for 1 hour with stirring on a water vapor bath heated in 1 1 Y barrel. The yellow solution was at Zim-

Mertemperature stirred, acidified and extracted with ether. The ether layer was washed with sodium bicarbonate solution and dried and evaporated. There were 31> 7 g of 3 »6-dichloro-2-hydroxyacetophenone obtained in the form of a yellow oil which quickly solidified; F = 55-56 °.

Example 27 ,: 3-chloro-4- (5,8-dichloro-4-oxo-4H ~ 1 -benzopyran-2- .

yl) -benzoic acid '

There were 5 g of 3,6-dichloro-2-hydroxyacetophenone, 6.25 g of 2-chloro-4-carbomethoxybenzoyl chloride and 25 g of potassium carbonate were heated to reflux in dry .300 ecm acetone for 10 hours. The acetone was distilled off and the bright yellow residue with 150 ecm of glacial acetic acid and 15 cm concentrated HgSO. acidified. The mixture was heated on a steam bath with stirring for 5 hours. The thin-light chromatogram showed a large spot and a minor stain that indicated it was a Mixture of ester and acid acted and the ester was the main

609818/1206

component was. The reaction mixture was then allowed to cool for 5 hours Heated to reflux and then showed only one spot the thin sheet chromatogramin. After cooling, the Poured the reaction mixture into water. The precipitate was collected, carefully washed with water and dried and yielded 7.5 g of the desired product «

By recrystallization from tetrahydrofurfuryl alcohol were 5.2 g of product obtained; P => 300 °.

Example 28

(a) 5- / 4 - (4-0xo-4H-1 -l> enzopyran-2-yl ·) - "benzamid o / -tetrazole 3.36 g of 5-aminotetrazole and 8.0 g of 4- ( 4-0xo-4H-1-benzopyran-2-yl) benzoyl chloride was stirred in 200 ecm of dry pyridine for 1 hour at room temperature and then heated for 12 hours on a steam bath to about 85 ° Most of the pyridine was removed in vacuo and the mixture was poured into ice and concentrated hydrochloric acid. The mixture was acidified and the cream-colored solid was filtered off and dried. 11.7 g of product were obtained; P = ^ 290 °.

By crystallization of the product from tetrahydrofurfuryl alcohol, Washing with 50% hydrochloric acid and drying gave 7.3 g of the desired product.

509818/1206

(b) 5 ~ / 4 - (4-0xo ~ 4H-1-benzopyran-2 ~ yl) - 'i3engainla o 7 - tetra2iol ~

sodium salt '"' · ■

5.0 g of the amidotetrazole product from stage (a) were suspended in 100 ecm of water. 150 ecm of diluted 0.1N capricum hydroxide were added with stirring. The mixture was stirred for 2 hours and heated to about 50 and then filtered. On cooling, part of the sodium salt was precipitated and filtered off. The filtrate was freeze-dried and yielded 2.5 g of the desired product; ί =,> 300 ^o . '. *.

Example 29

Following the procedure of Example 1 were made from suitable starting materials the following compounds and their sodium salts manufactured:

(a) 4- / 5- (2 ~ hydroxypropoxy) -4-O2CO-4H-1 -benzopyran-2-yl / -benzoic acid «

(b) 3- ^ 5- (2-Hydroxypropoxy) -4-OXO-4H-1-benzopyran-2-yl7-benzoic acid.

(c) 2- / 5- (2-Hydroxypropoxy) -4-oxo-4H-1-benzopyran-2-yl7- benzoic acid.

(d) 2- (3-carboxyphenyl) -6,7,8,9-tetrahydro-4-oxo-4H-naphtho-

(e) 2- (2-carboxyphenyl) -6,7,8,9-tetrahydro-4-oxo-4H-naphtho-

The following compounds and the sodium salt of hydroxamic acid were according to the procedures of Examples 7 (a), 16 (a) respectively. 1 (e) produced:

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3-chloro-4- (8 ~ chlor-4-oxo-4H-1-benzopyran ~ 2-yl) benzoyl chloride, F = about 190 °; and 3-chloro-4- (8-ehJLor-4-oxo-4H-1-benzopyran-2-ylj-benzohydroxamic acid F = 246-247 °.

Example 30: Mäthyl- (4 '- / 4 -oxo-4H-1 -benzopyran - ^ - yl J-benzoyl ·) ~

malonat

8.02 g of diethyl malonate became a suspension with stirring of 1.2 g of magnesium shavings in 15 ecm of dry ethanol containing 1 ecm of carbon tetrachloride. Once the initial The reaction subsided, the mixture was heated to reflux until all of the magnesium had reacted (about 10 minutes). The ethanol was distilled off in vacuo and 20 ecm of dry benzene were added. This was distilled off in vacuo, whereby the remaining alcohol was removed.

Fun was added 20 ecm of dry benzene to the magnesium salt and then a suspension of 6.0 g of 4 '- / 4-0xo-4H-1-benzopyran-2-yl7-benzoyl chloride in 70 ecm dry benzene. The mixture was stirred and refluxed for 5 1/2 hours, cooled in ice and treated with ice-cold, dilute sulfuric acid. Then the mixture was filtered and ethyl acetate was added to the filtrate. The ethyl acetate layer was separated, washed with water, dried and evaporated; after being treated with petroleum ether to remove anything that was left behind Remove diethyl malonate. 1.2 g of solid were obtained. The filtered solid was decomposed with dilute sulfuric acid.

509818/1208

grind and extracted with ethyl acetate. The ethyl acetate was separated off, dried and evaporated and combined with the previous product, v / o by 7.6 g ($ 88.3) of a beige-f work Solid were obtained. By two TJ recrystallization 4.6 g of needles were obtained from ethyl acetate / petroleum ether; F = 130-133 °. The yield was 53.4%. .

Example A.

The following procedure can be used to see the effectiveness of a compound in inhibiting the release of pharmacological Mediators of anaphylaxis ie * are determined.

In this approach, the effectiveness of the compounds in inhibiting the passive cutaneous anaphylactic response of Rats identified. It has been shown that this experiment provides reliable qualitative inferences about the capability of the test compound allowed to inhibit antibody-antigen reactions in humans.

Charles River France rats (Fisons breed; male or female) with a body weight of 100 g to 150 g at weekly intervals subcutaneously with larvae of the U. brasiliensis infected, the dose being about 2000 larvae was increased to 12,000 larvae per animal. After 8 weeks, blood was drawn from the rats by heart puncture, and 15 ecm to 20 ecm of blood collected from each animal. These blood samples were

509818/1206

now 30 minutes "centrifuged at 3500 rpm to get the blood cells to separate from the blood plasma. The serum was collected and used to prepare a serum, i.e. H. brasiliensis antibody contained. A sensitivity test was carried out in order to determine the smallest amount of serum, which is called the In the experiment below, we found a skin swelling with a diameter of less than 2 cm. Ss was found that optimal sensitivity of hats with a body weight between 100 g and 130 g is achieved if one a serum diluted with 8 parts of physiological saline is used. This diluted solution is called the antibody serum A denotes.

The one needed to react with Serum A antibodies Antigen was made by getting the U.brasiliensis worms removed from the intestines of the infected hats, centrifuged the homogenate and collected the supernatant fluid. This liquid was diluted with saline solution to a protein content of 1 mg / ccm and designated as solution B.

Charles River Franee rats (Fisons breed) having a body weight between 100 g and 130 g have now been sensitized by they were injected intradermally into the right plank with 0.1 ecm of serum A. The sensitivity developed within of 24 hours, and the rats were then given 1 cc / 100 g intravenously Body weight of a mixture of 0.25 ecm solution B, 0.25 ecm

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Evans Blue dye solution and 0.5 ecm (with different Percentage of active ingredient) of the test compound solution. Insoluble compounds were given as separate intraperitone ale injection 5 minutes before the intravenous injection Solution B and Evans Blue dye administered. There were 5 rats for each percentage of the active ingredient in the Test solution was used, and 5 rats were used as controls in each experiment. The dosages of the test compounds were so chosen that a range of inhibition values was obtained.

30 minutes after the injection of solution B, the rats were killed and their fur peeled off and turned over. The intensity of the anaphylactic reaction was determined by measuring the Size of the characteristic blue swelling caused by spreading of the Evan Blue dye from the sensitized The size of the swelling in the control animals compared. The size of the swelling was Ό (no noticeable swelling, i.e. 100% inhibition) to 4 (no difference in the size of the swelling, i.e. no inhibition) and the percent inhibition of each dose calculated as follows: -

ττ, η ^ πω,. ,, ^ (value of control - value of treated animals) χ 100 inhibition = A- '

For each compound, the percent inhibitions for the various dosages were plotted. From the-

50 981871206

The dosages can be read from these graphical representations, required to achieve 50% inhibition of the anaphylactic reaction (ID ™) ".

The same procedure was also used for effectiveness to determine the compounds when administered intestinally or gastricly.

- patent claims -

509818/1206

Claims (92)

Patent claims: ' ^R 10' 7> 8 ^} 9 '10 can have different meanings and for water Substance, alkyl, alkoxy, halogen, alkenyl, amino, hydroxy, -CN, alkylamino, alkoxyalkoxy, hydroxyalkoxy or groups, or Rg and R "together form a chain - (CH ₂ ) ₄ - or - (CH ₂ > ₅ p- form; E for a carboxyl group, ·. a 1H-tetrazol-5-yl - {? group, an N- (1H-tetrazol-5-yl) -carboxamide group, a group -CH ₂ COOH, -CONHOH or -CO-CHR ₂ CO-R ₁ , where R _{1 is} a C 1-6 alkyl, C 1-6 alkoxy, phenyl, amino or mono- or di-C 1-6 alkylamino group; R _{2 is} hydrogen or -CORx and Rx is a C ₁ , - alkyl, C, g-alkoxy, amino or mono- or di-C _1e g-alkylamino group or R ₁ and R ₂ together represent a three- or four-membered alkyl S09818 / 1206 Form a chain, possibly interrupted by a group -KH- and optionally by one or more Cj_g-alkyl groups and / or on the carbon atom in the ^ -position may be substituted for the methine proton by a carbonyl oxygen atom; provided that, (i) when E is a group -COOH or a pharmaceutically acceptable derivative thereof and R ^, Rg, Rq, R-jo * - ^ 11 ' ^Cüa ^ ^ 12 ^a ^ - ^e ^^ are hydrogen, " (A) Rj- does not represent hydrogen or an alkoxy group, or (B) Rg not for Y / ass he substance, a hydroxy, alkyl or Alkoxy group, or. (C) En does not represent hydrogen or an alkoxy group, or, (ii) when E is the group -COOH or a pharmaceutically acceptable derivative thereof, E is not in the 2 'position stands; characterized by: (a) a compound of formula II cyclizes: II COCHR ₇ O in which R ₅ , R ₅ , Rg, R ^, Rg, R _g , R ₁₀ , R ₁₁ , R ₁₂ , E have the meaning given above and are subject to the above requirements; Z for a reactive halogen atom or 509818/1206 a group -OM and M is hydrogen or an alkaline cation;
(b) produces a compound of the formula Ia: R ₃ ^R 1Q >> / = 4 = COOH ^R ll in which R-, R ₅ , Rg, R ₇ , R ₈ , R _g , R ₁₀ , R ₁₁ , R _{12 have} the abovementioned meaning and are subject to the above requirements by having -a * compound of. formula III hydrolyzed: III R, in which Rz, Rc »Rg, R7» Rg, Rq »R-iq» S-ii> R ₁ ρ di © have the above meaning and the above requirements Group and Ry stands for a group that belongs to a / -COOH can be hydrolyzed; creates a compound of the formula Id: 509818/1206 Id in which R ₅ , R ₅ , R _g , R ₇ , Rg ,. R _g , R ₁₀ , R ₁₁ and R _{12 have} the abovementioned meanings by adding a compound of the formula YI: YI in which R ₅ , R ₅ , Rg, R ₇ , Rg, R _g , R ₁₀ , R ₁₁ and R _{12 have} the abovementioned meanings, is reacted with an azide in a solvent which is inert under the reaction conditions;
(d) produces a compound of the formula Ie: Ie CONHOH 509818/1206 in the E ₃ , R ₅ , L ₅ , R ₆ , R ₇ , R ₈ , S _g , R ₁₀ , R ₁₁ and R _{12 have} the abovementioned meanings by reacting an anhydride, an ester or an acid halide of a compound of the formula Ia with hydroxylamine; (e) a compound of the formula I in which E stands for a group -CO-CHRpCOR ₁ by (i) an acid halide or a mixed anhydride of a compound of the formula Ia with a compound of the formula CHpRpCOR ₁ or their Enamine converts and, if an enamine is used, hydrolyzed the compound thus obtained, or
(ii) hydrolyzes a compound of formula VII: Ra Rb VII CO-C = C- and the in which R ₃ , R _5. , R _ß , R ₇ , R ₈ , R ₉ , R ₁₀ , R _{11 12} have the meanings mentioned above and Ra and Rb _{stand for identical or different C 1} ^ -alkyl groups or together with the nitrogen atom one Form 5-, 6- or 7-membered heterocyclic ring, optionally containing an oxygen atom; 509818/1206 (f) a compound of the formula Ih produces: CH ₇ COOH in which E ,, E, -, E ₆ , Εγ, Eg, Eg j R- \ q> R -] - j and S _{12 have} the abovementioned meanings by adding a compound of the formula VIII: VIII ' in the , R ₅ , R ₆ , R ₇ , R ₈ , E ₉ , E ₁₀ , E ₁₁ and the Have the above meanings, treated with water; (g) a compound of formula I prepares in which E, for represents a halogen by adding a corresponding compound of the formula I in which R, represents hydrogen, selectively halogenated; (h) a compound of the formula I produces in which E * stands for the group -OH is obtained by oxidatively cyclizing a compound of the formula X: 509818 / 12ÖS in the R ^, R _R , Rr-, R ₇ , Ro ».Rq, Hint Eid - ^ ₉ , R ₁₀ , R _{11 12} , E and M have the above meanings "; (I) a compound of the formula I in which one or more of the radicals R ₁ "to R 1 ρ are an alkoxy or hydroxyalkoxy group by adding a corresponding compound of the formula I in which one or several of the remains to R .. ρ the group -OH are BEZW with an alkylating agent. with an alkylene. oxide converts; (J) a corresponding flavanone compound of the formula XV is selectively dehydrated: Rr R, in which R ₃ , R ₅ , R ₆ , R ₇ , R _Q , R _g , R ₁₀ , R ₁₁ , R ₁₂ , E and the requirements have the meanings given above; 509818/1206 (k) a compound .der formula I, in which at least one of the radicals R * to R-J2 for an amino group ste / .t by connecting the Formol I, in which at least one of the radicals R ~ to R- for a group -ITOp is selectively reduced; (1) a compound of the formula II 'produces: ρ R. 3. &% CON N
N N
/ η ^R 12 R ₇ J A. τ
^R 8 ^R ll in which R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R _g , R ₁₀ , R ₁₁ and R _{12 have} the abovementioned meanings by adding an anhydride, an ester or an acid halide of a compound of the formula Ia with 5 -Aminotetrazol converts; or
(m) prepares a compound of the formula I in which R 1 to R _{12 have} the meanings given above and are subject to the above requirements, but one of the radicals R ₃ to R ^ _{2 is} the group -OH by using a corresponding compound of the formula I, in which R ₃ to R «(but without the requirements) have the meanings given above and one of the radicals R ₃ to R _{12 is} an alkoxy group, dealkylated, 509818 / $ 120 and. optionally converting the compound of formula I into a pharmaceutical converts usable derivative or vice versa. 2. The method according to claim 1, part (a), characterized in that that, when Z stands for a group -OM, the cyclization is carried out in the presence of an acid and a solvent which is inert under the reaction conditions. 3. The method according to claim 1, part (a), characterized in that when Z is a reactive halogen atom, the Reaction is carried out under basic conditions. 4 «Method according to claim 1, part (b), characterized in that that the group Ry stands for an amide, ITitrile or ester group stands. 5 «The method according to claim 4, characterized in that the hydrolysis under mild basic conditions or under acidic conditions. 6. The method according to claim 1, part (c), characterized in that that the reaction is carried out in the presence of a solvent in which both reactants are soluble and using an ammonium or alkali azide is carried out. 609818/1206 7. The method according to claim 1, part (d), characterized in that that an acid halide of a compound of the formula Ia is reacted with hydroxylamine. 8. The method according to claim 1, part (e) (i), characterized in that that an acid halide. a compound of formula Ia is used and the reaction in a non-protic Solvent and is carried out in the presence of an acid acceptor. 9. The method according to claim 1, part (e), characterized in, that the hydrolysis is carried out using aqueous acid. 10. The method according to claim 1, part (f), characterized in that the reaction in the presence of silver oxide or Silver benzoate is carried out. 11. The method of claim 1, part (g), characterized in that used as the selective halogenating agent sulfuryl chloride and the reaction is carried out at ²⁰ to 150 °. 12. The method according to claim 1, part (h), characterized gekennzeiöhnet, that the cyclization is carried out under basic conditions and in the presence of an inorganic peroxide will. 509818/1206 13. The method of claim 1, part (i), characterized in that used as the alkylating agent a reactive Älkylhalogenid or a mono- or dialkyl sulfate and the reaction is carried out in a solvent which is inert under reaction conditions ö.en. 14. Procedure according to. Claim 1,! Part (j), characterized in that • net that the dehydrogenation by oxidizing using: a mild oxidizing agent or by halogenation and subsequent splitting off of hydrogen halide is carried out. 15. The method according to claim 1, part (k), characterized in that the reduction using tin-II ~ chloride is carried out. 16. The method according to claim 1, part (1), characterized in that that an acid halide of a compound of the formula Ia is reacted with 5-aminotetrazole. 17. Procedure according to. Claim 1, part (m), characterized in that that the reaction using acid in a suitable solvent or using pyridine hydrochloride is carried out at an elevated temperature. S098 18/1206 18, Process for the preparation of a pharmaceutically useful Salt of a compound of the formula I according to claim 1, characterized in that a compound of the formula Ix: Ix in which R ^, R, -, Rg, Ηγ, Rg, Rg, R- | q, RJ ₁ * R ^ ° lie have the meanings mentioned above and are subject to the above requirements and G for a group E or another salt the same or, if E in the compound of the formula I is a carboxyl group, it can also stand for a carboxylic acid ester group, a nitrile group, an acid halide group or an amide group; treated with a compound which contains a pharmaceutically acceptable cation and which can convert the group G to a pharmaceutically acceptable group E salt. 19. The method according to claim 18, characterized in that the free acid of the formula I is treated with a suitable base or another salt of a compound of the formula I treated in a double reaction with a suitable salt. 5098 18/120 20. The method according to claims 18 and 19> characterized in that the pharmaceutically "acceptable salt" is the sodium salt is. 21. The method according to claim 1 "to 20, characterized in that the radicals R ^, Rc, Hg, R ^, Rg, Rg, R ₁ g> ^ 11 ^and ^ ^ 12 each contain at least 7 carbon atoms. 22. The method according to claim 1 to 21, characterized in that only one, two or three of the radicals R ~, R ₁ -, Rg, Ry, Rg, Rq, R ^ Q, R ₁₁ and R ₁₂ for groups other than hydrogen stand. 23. The method according to claim 1 to 22, characterized in that the radicals R ~ to R ₁ O represent hydrogen, chlorine, bromine, methoxy, methyl, hydroxy, amino, allyl, tert-butyl, 3 -Methyl-n-butoxy, 2-ethoxyethoxy, 2-hydroxypropoxy, ethyl, ethoxy or nitro groups or Rg and Ry together form a chain - (CELp) 4- or - (C ^) * 0- form. 24; Process according to Claims 1 to 22, characterized in that R ^ stands for hydrogen, an alkyl, halogen or hydroxy group; R, - for hydrogen, a halogen, alkoxy, hydroxyalkoxy, alkoxyalkoxy or hydroxyl group; Rg for hydrogen, a halogen, amino or alkyl group; Rrj for hydrogen, halogen, alkoxy, imino, hydroxy 509818/1206 or hydroxyaikoxy group; or IL- and S ^ together form a chain -CH ₂ CH ₂ CH ₂ O- or - (CH ₂ ), - "; Rg stands for hydrogen, a halogen, alkoxy, alkyl or alkenyl group; Eq and R * q each represent hydrogen, an alkoxy, halogen, nitro or amino group; R ^ and R., ρ are each hydrogen and all radicals are subject to the requirements specified in claim 1. 25. The method according to claim 1 Ms 24, characterized in that the group E is in the 4 'position. 26. The method according to claim 1 to 25, characterized in that the group E is a group -COOH or -COIHOH, 27. The method according to claim 1 "to 26, characterized in that one, two or three of the radicals R ^ to R * ₂ stand for a halogen, alkoxy, amino, alkyl, hydroxyl or alkenyl group and the remaining radicals R * to R ^ _{2 represent} hydrogen. 28. The method according to claim 1 to 27, characterized in that one, two or three of the radicals R, to R- | ₂ stand for chlorine, bromine, a methoxy, amino, methyl, ethyl, tert-butyl or hydroxyl group and the remaining radicals stand for hydrogen. 509818/1206 29. The method according to claim 1 to 26, characterized in that one or two of the radicals R ₁ -, H «, Rg and R -, -, (in the 2 'position) stand for chlorine, o -:" er Rg stands for ITH _2, or is Rr is -OH, or Rg and Rg oeide for a tert-butyl group and the remaining radicals R to R ^ ₁ ⁿ ρ i all cases hydrogen. 30. Compounds of the formula I or their pharmaceutically useful ones Derivatives: in which R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R _g , R _1Q , R ₁₁ , and R ₁₂ , can have the same or different meanings and represent hydrogen, alkyl, alkoxy, halogen, alkenyl -, Amino, hydroxy, -CF ,,, -CN, alkylamino, alkoxyalkoxy, hydroxyalkoxy or -NOp groups or Rg and Ry together form a chain - (CHp) λ- or - (CHp) ^ O - form; E for a carboxyl group, an IH-tetrazol-5-yl group, an N- (iH-tetrazol-5-yl) -carboxamide group, a group -CH ₂ COOH, -CONHOH or -CO-CHR ₂ CO- R _1, wherein R ₁ g-alkyl, C, a C ^ / - alkoxy, phenyl, amino or mono- or di-C ₁ _g is alkylamino. Rp is hydrogen or -CORx, and Rx is a Cjc-alkyl, C ₁ -C -alkoxy, amino or mono- or di-C ₁ -C -alkylamino group, or R ₁ and Rp together are three- or four-membered Form alkylene chain, optionally through a group 509818/1206 -NH- interrupted and possibly by a «? or several CL r alkyl groups and / or can be substituted on the carbon atom in -position to the methine proton by a carbonyl oxygen atom; provided that, (i) when E <j is a group -COOH or a pharmaceutically acceptable derivative thereof and R ,, Ro, Rg, R ^ ₀ , R ₁₁ and R _{12 are} all hydrogen, (A) Rf- does not represent hydrogen or an alkoxy group, or (B) Rg does not represent hydrogen, a hydroxy, alkyl or Alkoxy group, or (C) R ₇ does not represent hydrogen or an alkoxy group, JDder, (ii) when E is the group -COOH or a pharmaceutical useful derivative thereof, E is not in the 2'-position stands. 31. A compound according to claim 30, characterized in that IU, Rc, Rg, Rrjt, Rg, Rq, R-jq, R-ji and R ₁₂ each contain fewer than 7 carbon atoms. 32. Compound according to claim 30 and 31, characterized in that only one, two or three of the radicals R ₅ , R ₅ , Rg, R ₇ , Rg, Rg, R ₁₀ , R ₁₁ and R _{12 represent} groups other than hydrogen . 33. Compound according to claim 30 to 32, characterized in that R ^ to R ₁₂ for V / hydrogen, chlorine, bromine, methoxy, methyl, hydroxy, amino, alkyl, tert-butyl, 3- IIethyln-butoxy, 2-ethoxyethoxy, 2-hydroxypropoxy, ityl, ethoxy or nitro groups or Rg and Ry together 509818/1206 form a chain - (CHg) ₄ , - or - (CH ₂ ) ₅ 0- ". 34. Compound according to claim 30 "to 33 *, characterized in that Rz stands for hydrogen, an AlLyI, halogen or hydroxyl group; Ec for hydrogen, a halogen, alkoxy, hydroxyalkoxy, alkoxyalkoxy or hydroxyl group; Eg for 'Represents hydrogen, a halogen, amino or alkyl group; E7 represents hydrogen, a halogen, alkoxy, amino, hydroxy, or hydroxyalkoxy group, or Eg and E «together form a chain -CH ₂ CH ₂ CH ₂ O- or - (CH ₂ ). form; Eo represents hydrogen, a halogen, alkoxy, alkyl or alkenyl group; Eg and E ^ q each represent hydrogen, an alkoxy, halogen, nitro or amino group; E ^ and E ₁₂ both stand for hydrogen and all Eeste are subject to the requirements mentioned in claim 1. 35 «Connection according to claim 30 to 34, characterized in that that group 1 is in the 4 'position. 36. Compound according to claim 30 to 35, characterized in that . that E is a group -COOH or -COlTHOH. 37. A compound according to claim 30 to 36, characterized in that one, two or three of the groups E, to E- _{2 are} a halogen, alkoxy, amino, alkyl, hydroxyl or alkenyl group and the remaining E groups are E until E ^ _{2 are} hydrogen. 5 0 3 8 18/1206 38. Link to. Claim 30 to 37, characterized in that one, two or three of the radicals IU to R ^ ^ u ^{37 are} chlorine, bromine, methoxy, amino, Llethyl, ethyl, tert-butyl or hydroxyl groups and the remaining radicals 7 / are hydrogen. 39 · Compound according to claim 30 to 38, characterized in that one or two of the radicals R, -, R «, R _g and Rq (in the 2'-position) stand for chlorine, or Rg stands for IiH ₂ , or R, - stands for -OH, or R, - and Rr ₇ both stand for a tert-butyl group and in all Palls the other radicals R-? to R ^ 2 are hydrogen. 40th. 4- (8-0hlor-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 41. 4- (5-Bromo-4- oxo-4H-1-benzopyran-2-yl) -benzoic acid. 42. 4- (7-Bromo-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 43. 4- (5-chloro-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 44. 4- (6-Chloro-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 45 x 4- (7-chloro-4-oxo-4H-1-benzopyran-2-yl) benzoic acid. 46. 4- (8-I, ethoxy-4-oxo-4K-1-benzopyran-2-yl) -benzoic acid. 509818/1206 47. 4 »(3-Methyl-4-oxo-4H-1-ben2opyran-2-yl) -benoic acid. 48. 4- (5 »8 ~ T1-dimethoxy-4-oxo-4H« 1-benzopyran-2-yl) »benzoic acid. 49. 4- (5,7,8-TriBie "feho2y-4-o3co-4H-1 ~ benzopyran-2-yl) -" benzoic acid. 50. 4- (6,7-Dihydropyrano-4-oxo-4H ~ 1- "benzopyran-2-yl) -benzoic acid. 51. 4- (7,8-DiGh.lor-4-oxo-4H'-1-benzopyran-2-j ^r l) -benzoic acid. 52. 4- (6,8-Dietlayl-5-hydro:> cy-4-oxo-4H-1-beiizopyran-2-yl) -benzoic acid. 53. 4- (6f 8-Dich.-lor-4-oxo-4H-1-'ben3op3'Tan-2 ~ yl) '- TDGnzoic acid. 54. 4- (5,8-Bichlor-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 55. 4- (8-Allyl-5- (3-methylbutoxy) -4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 56. A- (6,8-Di-tert-butyl-4-oxo-4H-1-ben3opyran-2-yl) -benzoic acid. 57. 5- / 5- (2-I.-t;] ioxyethoxy) -4-oxo-4H-1-benzopyran-2-yl7-benzoic acid. 509818/1206 58. 4- (6, T-Cyclohexane ^ -oxo ^ H-i-benzopyran- ^ - yl) -benzoic acid. 59. 4- (1H-2etrasol-5-yl) -flavone. 60. 2-Dietliylarainoät] iyl-4- (4-oxo-4H-1-l3enzopyran-2-yl) - 'benzoate. 61. 3-chloro-4- (4-o: co-4H "1-benzopyran-2-yl) -13enzoic acid. 62. 3-Ciilor-4- (8-chloro-4-oxo-4H-1 ~ l-benzopyro, n-2-yl) -benzoic acid, 63. 3-Ket3aoxy-4- (4-oxo-4H-1-benzopyran-2-yl) -benzoic acid, 64. 4- (3-chloro-4-oxo-4H-1-beiisopyran-2-yl) -benzoic acid. 65. 4- (3-Iietiioxy-4-oxo-eH-1-benzop3Tan-2-yl) -benzoic acid. 66. 4- (3-Hydroxy-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 67,4- (6-Amino-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 68. 4- (5-Hydroxy-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 69. 4- (4-0xo-4H-1-benzopyran-2-yl) -benzohydroxam 70. 2- / 3- (Cyclopentanoii-2-carbonyl) -phenyl7-4-oxo-4H-1 -benzo- pjrran. 509818/1 206 71. 4- (4-0xo-4H-1-benzop _i Yran-2-yl) phenylacetic acid. 72. 2-Me-fcho: vy-4- (4-oxo-4H-1 -benzopyran-2-yl) -benzoic acid. 73. 2-Chloro-4- (4-oxo-4H-1 -benzopyran-2-yl) -benzoic acid. 74. 4- ^ / 7- (2-Hydroxypropoxy) -4-OXO-4H-1 - ~ T3enzopyrran-2-yl7-benzoic acid. 75. 4- (7-Hydroxy-4-oxo-4H-1 -Tdenz-opyran-2-yl) -benzoic acid. 76. 3-ITitro-4 - (. 4-oxo-4K-1-'benzopyran-2-yl) -benzoic acid. 77. 2-H "itro-4- (4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 78. 3-C-Or-4- (7-ethoxy-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 79. 3-Chloro-4- (6-amino-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 80. 3-chloro-4- (5-chloro-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 81. 2 ~ Amino-4- (4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 82. 3-Amino-4- (4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 83. 3-Glilor-4- (5,8-dichloro-4-oxo-4H-1-benzopyran-2-yl) -benzoic acid. 509818/1206 84. 5 - /? - (4-0xo-4H-1-benzopyran-2-yl) -benzamido-7-tetrazole. 85 x 4- / 5- (2 "hydroxypropoxy) -4-oxo-4H ~ 1-acid. 86. 3- / 5- (2-Hydroxypropoxy) -4-oxo-4K-1-benzopyran-2-yl7-'benzoic acid. 87. 2- / 5-C 2-hydroxypropoxy) -4-OXO-4H-1 - ■ benzopyran-2-yl7-'benzoic acid. 88. 2- (3-GarT3oxyph.er.yl) -6,7,8,9-tetrahydro-4-oxo-4H-naphtho- 89. 2- (2-Carboxyplienyl) ~ 6,7,8,9-tetrahydro-4-oxo-4H-naplitiio- 90. 3-chloro-4- (8-clilor-4-oxo-4H-1-benzopyran-2-yl) - 'benzo hydroxaic acid. 91 x 4- (7-Amino-4-oxo-4H-1 -benzopyran-2-yl) - "benzoic acid. 509818/1206 92. Compound according to claim 30 to 91} .n the form of a pharmaceutical useful salt of this compound. ... Terbindv.üg according to claim 92 in the form of a sodium salt. 94, compound according to claim 30 to 93, characterized in that it has an average mass diameter of 0.01 to 10 μ / . A pharmaceutical preparation consisting of a compound according to claim 3Ό to 94 as an active ingredient in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. A preparation according to claim 95 _f characterized in that it mg 0.17 to 600 mg per dosage unit contains the Yfirkstoffes. Preparation according to claim 95, characterized in that 10 mg to 500 mg of the active ingredient per dosage unit contains. ORIGINAL INSPECTED 5098 18/1206