NO742077L - - Google Patents

Description

Compounds with formula:

The invention relates to new compounds, methods for their production and preparations containing them. According to the invention, compounds of formula I are prepared

where R^, R^, Rg, R^, Rg, R^, R-^ q, R-q °S Ri2> which may be the same or different, denote hydrogen, alkyl, alkoxy, halogen, alkenyl, amino, hydroxy, -CF^, -CN, alkylamino, alkoxy alkoxy, hydroxy-alkoxy, -NO^, or Rg and Ry together form a -(CHg)^- or -(CH^^O chain and

E is a carboxylic acid group, a 1H-tetrazol-5-yl group, an N-(1H-tetrazol-5-yl)carboxamide group, a group -CHgCOOH, a group

-C0NH0H or a group -CO-CHRgCO-Rj^

R-]_ denotes alkyl-C--C8, alkoxy-C--C8, phenyl, amino or

mono- or di-alkyl-C 1 -C 8 -amino,

Rg denotes hydrogen or -CORx and

Rx denotes alkyl-C-Cg-Cg, alkoxy-G-Cg-Cg, amino or mono- or di-alkyl-C-pCg-amino or

R-^ and Rg together form a 3- or 4-membered alkylene chain which is optionally interrupted by -NH groups, and where the chain is optionally substituted with one or more alkyl-C^-Cg groups and/or substituted on the carbon atom in a-position to the methine proton with a carbonyl oxygen atom,

and such that (i) when E denotes a -COOH group or a pharmaceutical derivative thereof and R^, Rg, R^, Rjq»°S ^ 2. 2 a^ e Denotes hydrogen, denotes

(A) R^not hydrogen or alkoxy or

(B) Rg is not hydrogen, hydroxy, alkyl or alkoxy or

(C) R 7 not hydrogen or alkoxy,

or (ii) when E denotes a -COOH group or a pharmaceutical derivative thereof, E is not in the 2<*->position,

as well as the pharmaceutical derivatives of these compounds.

According to the invention, a method for the production of the compounds of formula I, or their pharmaceutical derivatives, is also provided, which is characterized by

(a) ring-closes a compound of formula II

where R^, R^, Rg, R^, Rg, R^, R1Q, R-^, R12, E and the additional conditions are as indicated above,

Z denotes a reactive halogen atom or a group -OM and M denotes hydrogen or an alkali metal cation,

(b) forms a compound of formula Ia

where R^, R^, Rg, R^, Rg, R^, R-^q» %i» ^12°S "the additional conditions are as stated above,

by hydrolyzing a compound of formula III

where R^, R^, Rg, R^, Rg, R^, R-^, Rll'R]_2 and "the additional conditions are as previously indicated, and Ry denotes a group which can be hydrolyzed to a -COOH group, ( c) forms a compound of formula Id

where R^, R,-, Rg, R^, Rg, R^, R-|_q, R-q and R^ have meanings as previously stated,

by reacting a compound of formula VI

where R^, R^, Rg, R^, Rg, R^, R-^, rh and R12 have meanings as previously indicated,

with an azide in an inert solvent,

(d) forms a compound of formula le;

where R^, R^, Rg, R^, Rg, R^, R-j_o» Rn°S R]_2 have b meaning as indicated previously,

by reacting an anhydride, ester or acid halide of a compound of formula Ia with hydroxylamine,

(e) forms a compound of formula I where E denotes the group

-CO-CHRgCOR-L,

by (i) reacting an acid halide or mixed anhydride of a compound of formula Ia with a compound of formula CHgRgCOR-^ or its enamine;

and if using an enamine, hydrolyzing the resulting compound, or (ii) hydrolyzing a compound of formula VII

where R^, R^, Rg, Ry, Rg, R^, <R>1Q, R11 and R-^ have meanings as previously indicated and

Ra and Rb, which may be the same or different, denote an alkyl-C-^-Cg group, or together with the nitrogen atom form a 5->6- or 7-membered heterocyclic ring which optionally contains an oxygen atom,

(f) forms a compound of formula Ih

where R^, R^, Rg, Ry, Rg, R^,<R>]_q»%i °S ^12 ^are meaning as previously indicated, by treating a compound of formula VIII wherein R^, R^, Rg, Ry, Rg, R^, R]_q» R-q°&^12^are meaning as previously indicated, with water*(g) forms a compound of formula I where R^ denotes a

halogen atom, by selective halogenation of a corresponding compound of formula I where Ro denotes a hydrogen atom,

(h) forms a compound of formula I where R^ denotes an -OH group by oxidative cyclization of a compound of formula X

where R^, R,-, Rg, Ry, Rg, R^, R<->j_q» %l' R12'e°S m has the meaning as previously indicated, (i) forms a compound of formula I where one or several of the groups R^ to R^^ denote alkoxy or hydroxy-alkoxy, by reacting a corresponding compound of formula I where one or more of the groups R^ to R^^ denote -OH groups, with an alkylating agent, or with a alkylene oxide, respectively,

(j) selectively dehydrogenates a corresponding flavanone of formula

XV

where Ry R^, Rg, Ry, Rg, R^, R1Q, R^, R12, E and the additional terms are as previously stated,

(k) forms a compound of formula I in which at least one of the groups R^ to R-^2 denotes amino, by selective reduction of a corresponding compound of formula I in which at least one of the groups R^ to R-^ denotes a -NOg- group,

(1) forms a compound of formula II

where R^, R^, Rg, R^, Rg, R^, R-j_q, R-q°S Ri2 has the meaning as previously indicated,

by reacting an anhydride, ester or acid halide of a compound of formula Ia

with 5-aroinotetrazole,

or (m) forms a compound of formula I where R^ to R-^ and the additional conditions are as previously stated, except that one of the groups R^ to R-^ denotes an -OH group, by dealkylation of a corresponding compound with formula I where R^ to R-^ have meanings as previously indicated, (but do not fulfill the additional conditions), except that one of the groups R^ to R^ is an alkoxy group,

and, if desired or necessary, converts the compound of formula I into a pharmaceutical derivative thereof, or vice versa.

The cyclization process (a) can be carried out by heating

in basic or neutral environment. When Z denotes the group -OM, it is however better to close the ring in the presence of an acid such as hydrochloric acid and in a solvent which is inert under the reaction conditions. e.g. ethanol. The reaction can also be carried out in a mixture of sulfuric acid and acetic acids. The reaction can be carried out at 20 to 150°C. When Z is a reactive halogen atom such as chlorine, the reaction is advantageously carried out in a basic environment, e.g. at elevated temperature in pyridine and in the presence of potassium hydroxide.

In process (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 can be carried out by usual methods, e.g. in weakly basic conditions, e.g. with sodium carbonate or bicarbonate, or in an acidic environment with e.g. a mixture of aqueous dioxane and hydrochloric acid or hydrogen bromide in acetic acid. The hydrolysis can take place at a temperature of between approx. 25 and 120°C depending on the compounds used.

Suitable inert solvents for method (c) include solvents in which both reagents are soluble, e.g. N,N-dimethylformamide. Other suitable solvents can be dimethyl sulfoxide, tetrahydrofuran, diethyl glycol and ethyl methyl glycol. The reaction is advantageously carried out at a temperature between approx. 20 and 130°C, for a period of 1 to 20 hours. The azide used in the reaction is preferably ammonium or an alkali metal azide, e.g. sodium or lithium azide, but other azides such as aluminum azide or azides of nitrogenous bases such as mono-, di-, tri- and tetra-methylammonium, anilinium, morpholinium and epiperidinium azides may also be used if desired. When azides other than alkali metal azides are used, the former can be produced in the reaction mixture by double decomposition. If desired, the reaction can take place in the presence of an electron acceptor such as aluminum chloride, boron trifluoride, ethylsulfonic acid or benzenesulfonic acid. As an alternative to the above conditions,

can the reaction take place with hydrazonic acid (hydrogen azide) at a temperature of between approx. 20 and 150°C in a suitable solvent, under super-atmospheric pressure. When using azides other than hydrazoic acid, e.g. sodium azide, the reaction product will be the corresponding tetrazole salt. This salt can easily be converted into the free acid by treatment with a strong acid such as hydrochloric acid.

In process (d), the anhydride is preferably a mixed anhydride of such a type that it will be split into the desired flavone-carbohydroxanoic acid as the main product by reaction with hydroxylamine. Examples of suitable acids from which the mixed anhydride can be derived are sulfonic acids such as benzenesulfonic acid, sterically hindered carboxylic acids such as pivalic acid, isovaleric acid, diethylacetic acid or triphenylacetic acid, and alkoxyformic acids such as ethoxy- or isobutoxy-formic acid. The reaction is advantageously carried out in an anhydrous environment in a solvent which will not react either with the hydroxylamine or the mixed anhydride, e.g. pyridine or dimethylformamide. However, when the reaction is carried out in a non-basic solvent such as dimethylformamide, at least two molar equivalents of acid acceptor such as triethylamine should preferably be present. The reaction is preferably carried out at a temperature between -15 and +20°C. When using an acid halide, this can preferably be an acid chloride. Suitable esters of compounds of formula Ia are those derived from alkanols with 1

to 10 and preferably 1 to 6 C atoms. When using an ester, the reaction can preferably be carried out in an inert solvent such as

dimethylformamide and in the presence of a base such as sodium hydroxide, at room temperature, i.e. at approx. 20°C.

Procedure (e)(i) can take place in a water-free environment and preferably'! a suitable non-protic solvent such as chloroform, methylene chloride or 1,2-dichloroethane. The reaction advantageously takes place in the presence of an acid acceptor which, when a basic solvent is used, may be an excess of solvent, or which may

be a tertiary amine such as triethylamine. The reaction can be carried out at between approx. 0 and 100°C.

The acid halide can e.g. be an acid chloride or an acid bromide. The mixed anhydride is preferably of such a type that it preferentially splits into the desired flavone dicarbonyl derivative. • Examples of suitable acids which can give the mixed anhydride are sulfonic acids such as benzenesulfonic acid, sterically hindered carboxylic acids such as pivalic acid, isovaleric acid, diethylacetic acid or triphenylacetic acid and alkoxyformic acids such as ethoxy- or isobutoxy-formic acid.

The hydrolysis in method (e)(i) and (e)(ii) can e.g. carried out at an elevated temperature in an aqueous acid such as aqueous hydrochloric acid.

Process (f) can be carried out in a suitable solvent such as diglyme (ie bi-s(2-methoxyethyl)ether), and in the presence of a suitable catalyst such as e.g. silver oxide. Alternatively, the reaction can be carried out with silver benzoate in triethylamine and t-butanol as solvent. Process (f) is the last step in an Arndt-Eistert reaction.

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

Process (h) can be carried out in the presence of an inorganic peroxide such as hydrogen peroxide and in a basic environment. The reaction can be carried out in a protic medium such as aqueous methanol. The reaction can be carried out at a temperature of between approx. -10 and +10°C.

In process (i), the alkylating agent can be a reactive alkyl halide such as e.g. a bromide or mono- or di-alkyl sulfate such as dimethyl sulfate. The reaction can be carried out in an inert solvent such as acetone or 2-butanone, and at a temperature of approx. 20 to 150°C.

In process (j), the dehydrogenation can be carried out by oxidation with a mild oxidizing agent such as selenium dioxide, palladium black or chloranil, lead tetraacetate or triphenylmethyl perchlorate. Optionally, the dehydrogenation can be carried out indirectly by halogenation followed by dehydrohalogenation, e.g. by treatment with N-bromosuccinimide or pyridine bromide-perbromide to form the 3-bromo derivative which is then dehydrobrominated. The reaction can be carried out in an inert solvent such as e.g. a halogenated hydrocarbon, xylene, n-amyl alcohol or glacial acetic acid. The reaction can be carried out at an elevated temperature, e.g. 20 to 150°C, and in strongly alkaline environments, e.g. in the presence of an alkali metal hydroxide.

Under method (k), the reduction is advantageously carried out from the ester form of the compound when E is a carboxylic acid group. The reduction can be carried out in the usual way according to known methods for the reduction of nitro groups, e.g. reaction with stannous chloride in concentrated HC1 at elevated temperature. It is an advantage that the amino group is not in the R^ position.

In process (1), the anhydride is preferably a mixed anhydride which is preferentially split into the desired flaven-carboxamido-tetrazole as the main product when the compound is reacted with 5-amino'tetra'Zol Examples of suitable acids from which the mixed anhydride can be derived

from are sulfonic acids■such as benzenesulfonic acid, sterically hindered carboxylic acids such as pivalic acid, isovaleric acid, diethylacetic acid or triphenylacetic acid and alkoxyformic acids such as ethoxy- or isobutoxy-formic acid. The reaction is advantageously carried out in an anhydrous environment in a solvent

which does not react either with 5-aminotetrazole or with the mixed anhydride, e.g., pyridine or dimethylformamide. However, when 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 added. When an ester is used, this can preferably be an ester derived from a C-^-C-^q alkanol. When using an acid halide, it may be an acid chloride. The reaction is advantageously carried out at a temperature between approx. -15 and +20°C.

During process (m), the reaction can be carried out according to known techniques, e.g. with an acid such as HC1 in ethanol, aqueous HBr or HBr in glacial acetic acid. Optionally, the reaction can be carried out with other ether-cleaving reagents, e.g. with pyridine hydrochloride, at elevated temp.

The starting materials for methods (g) and (i) are either compounds of formula I or can be prepared from known compounds in ways known per se.

Compounds of formula II wherein Z is an OM group can be prepared by reacting a compound of formula IV wherein R^, R^, Rg, R^, Rg and M have the meanings previously indicated, with a compound of formula V

or an ester thereof, where E, R^, R-j_0' ^11 and ^12^ have meanings as previously indicated and

Rz is a group which can react with hydrogen in the COCHgR^ group in the compound of formula IV, e.g. an alkoxy group, under usual Claisen condensation conditions.

Compounds of formula II where Z represents a group -OM can also be prepared by reacting a compound of formula IV with a compound of formula V where Rz represents a halogen atom, forming a compound of formula IX

where R^, R^, Rg, R^, Rg, R^, R1Q, R-^, R12, E and the additional terms are as stated in the introduction,

which on treatment with an anhydrous base is rearranged to a compound of formula II.

Compounds of formula II where Z is a reactive halogen atom are either known or can be prepared from known substances according to methods known per se.

Compounds of formula X can be prepared by reacting a compound of formula IV where R^ denotes hydrogen, with a compound of formula XI

where R^, R"lo»^H' ^120&^ ^are meaning as previously stated.

Compounds of formula III can be made from known compounds analogously to method (a) above.

Compounds of formula VI can be prepared by converting the corresponding ester to the corresponding amide and dehydrating the amide in known ways.

Compounds of formula IV, V and XV are either known substances or can be made from known substances according to known methods.

Compounds of formula VIII can be prepared by reacting an acid chloride of a compound of formula Ia with diazomethane in a solvent which is inert under the reaction conditions, e.g. diethyl ether. This is the first part of an Arndt-Eistert reaction.

Compounds of formula I and their intermediates can be isolated from the reaction mixture in known ways.

Certain of the groups R^ to R-^ may be affected by the reaction. It may therefore be necessary to protect these groups during one or more of the reaction steps, and in the present description the groups R^ to R-]_2», in the event that this is appropriate or necessary, can be present in the form of their protected derivatives, e.g. . can amino- . the groups are acetylated and hydroxy groups can be esterified.

Pharmaceutical derivatives of compounds of formula I are pharmaceutically usable salts and, when E is a COOH group, esters and amides of the compounds. Suitable salts are water-soluble salts such as ammonium, alkali metal (e.g. sodium and potassium) and alkaline earth metal (e.g. calcium and magnesium) salts and salts with suitable organic bases, for example salts with lower C 1 -C 8 alkylamines, e.g. methylamine or ethylamine, with hydroxy-substituted C-^-Cg alkylamines or with simple monocyclic nitrogen-heterocyclic compounds such as piperidine and morpholine. Suitable esters are C 1 -C 2 -, preferably C 2 -C 3 -alkyl esters and C 4 -C 8 -alkylamino-C 4 -C 8 -alkyl esters such as diethylaminoethyl ester, as well as their acid addition salts.

Pharmaceutical derivatives of compounds of formula I can be prepared and converted into each other in known ways, e.g. by methods described in the examples, e.g. example 7«

Compounds of formula I and their pharmaceutical derivatives have pharmacological activity in mammals, in particular they counteract bronchospasm induced by methacholine and histamine in guinea pigs (see the method of J. Konzett and R. Arch. Rossler, exp. Path. Pharmak. 194°>195 (71) modified by D.T. Burden and M.W. Parkes in Br. J. Pharmac-1971 41 122). The compounds are therefore useful as bronchodilators for humans.

For the above purpose, the dose given will of course vary with the compound used, the route of administration and the desired treatment. In general, however, satisfactory results are obtained when the compounds are given in doses of from 0.5 to 5>0 mgPr» kg body weight for animals. For humans, the stated total daily dose is between approx. 20 and 1000 mg, preferably 20 to 200 mg, which can be given in separate doses from 2 to 3 times a day or as preparations with extended absorption. Dosage units suitable for administration

(by inhalation or orally) thus contains from approx. 10 to 500 mg of the compound in question mixed with solid or liquid pharmaceutical carrier or diluent.

The compounds are also useful because they inhibit the release and/or action of pharmacological intermediates resulting from the in vivo combination of certain types of antibodies and specific antigens, e.g. the combination of reaginic antibody and specific antigen (see Example A below).

In humans, both the subjective and objective changes resulting from the inhalation of specific antigens in the: sensitive persons will be inhibited by prior ingestion of the new ones. substances. Thus...

are the new compounds applicable in the treatment of asthma, for example allergic asthma. The new substances can also be used in the treatment of so-called "intrinsic" asthma (where no sensitivity to an external antigen can be demonstrated). The new substances also have value in the treatment of other conditions where antigen-antibody reactions are the cause of diseases, e.g. high fever, certain eye diseases such as trachoma, urticaria and stomach and intestinal allergies, especially in children, for example milk allergy.

For use in conditions where antigen-antibody reactions are the cause of diseases, the given dose will naturally depend on the compound used, the route of administration and the disease treated. Satisfactory results are generally obtained with doses of 0.1

to 50 mg per kg body weight in animals, in experiments mentioned under example A. For humans, the total daily dose is from approx. 1 to 3500 mg, which can be given in separate doses from 1 to 6 times a day, or as preparations with prolonged action. Suitable dosage units■for inhalation or oesophageally include daff ra approx. 0.17 to 600 mg of compound mixed with solid or liquid carriers.

According to the invention, pharmaceutical preparations are also provided which contain (preferably a smaller amount of) a compound of formula I or a pharmaceutical derivative thereof, in combination with pharmaceutical diluents, drench agents or carriers. Examples of suitable substances of this type are: for tablets and dragees: lactose, starch, talc or stearic acid; for capsules: tartaric acid or lactose; for suppositories: natural or hardened fat, oil or wax; for inhalation: coarse lactose. For use in inhalation preparations, compounds of formula I or their pharmaceutical derivatives preferably have a mean particle diameter of from 0.01 to 10 microns. The preparations can also contain suitable preservatives, stabilizers and wetting agents, solubilizing substances, sweeteners and coloring agents etc. The compounds can optionally be processed into preparations with extended release.

According to the invention, a method for the production of pharmaceutical salts of the compound of formula I is also provided, which consists in treating a compound of formula lx

where R^, R^, Rg, R^, Rg, R^, R10, R-^, R12 and the additional conditions are as previously indicated and G denotes a group E, or another salt of this compound, or when E in connection with formula I denotes a carboxylic acid group G may denote a carboxylic acid ester group, a nitrile group, an acid halide group or an amide group, with a compound containing an available pharmaceutically usable cation and which can convert the group G into a pharmaceutical salt of an E group. Compounds capable of converting group E into a pharmaceutically usable salt include compounds such as bases and ion exchange resins containing pharmaceutical cations, e.g. sodium, potassium, calcium, ammonium and suitable nitrogen-containing organic cations. In general, it is advantageous to form the pharmaceutical salt by treating the derivatized acid of formula I with a suitable base, e.g. with an alkaline earth or alkali metal hydroxide, carbonate or bicarbonate in aqueous solution, or by treating another salt of a compound of formula I with a suitable salt according to an extraction process. When using a strong basic compound, care should be taken, e.g. by keeping the temperature sufficiently low, so that the compound of formula I is not hydrolyzed or otherwise degraded. The pharmaceutically usable salts can be prepared from the reaction mixture, e.g. by solvent precipitation and/or by removing the solvent by evaporation, e.g. by freeze drying.

Preferred compounds of formula I are those where R 1 , R 2 , R 3 , R 3 , R 3 , R 3 , R 10 , R 12 and R 12 each contain less than 7 and preferably less than 6 carbon atoms. It is also an advantage that only one,

two or three of the groups R 1 >R 2 , R 2 , Ry , R 2 , R 2 , R 2 , R 1 and R 12 are different from hydrogen. When one or more of the groups R 1 to R 12 denote halogen, it is an advantage if this is bromine or preferably

chlorine.

Specific groups in the form of R^ to R-^g include hydrogen, chlorine, bromine, methoxy, methyl, hydroxy, amino, allyl, t-butyl, 3-methyl-n-butoxy, 2-ethoxy-ethoxy, 2-hydroxy -propoxy,.ethyl, ethoxy and nitro, or Rg and Ry together form a -(C<H>g)^- or (CHg)^O chain. Preferably, compounds are also prepared where R^ is hydrogen, alkyl such as methyl, halogen such as chlorine or hydroxyl, R^ denotes hydrogen, halogen such as chlorine or bromine, alkoxy such as methoxy or 3_methyl-ii-butoxy, hydroxy, hydroxy- hydroxy such as hydroxy- propoxy, or alkoxy-alkoxy as-ethoxy-ethoxy, Rg denotes hydrogen, halogen as chlorine, amino or alkyl, e.g. t-butyl or ethyl, Ry denotes hydrogen, halogen such as chlorine or bromine, alkyloxy such as methoxy or ethoxy, amino, hydroxy or hydroxy-alkyloxy, e.g. hydroxypropoxy, or Rg and Ry together form a CHgCHgCHgO- or (CHg)^ -chain, Rg denotes hydrogen, halogen, such as chlorine, alkoxy such as methoxy, alkyl such as ethyl or _t-butyl, or alkenyl such as allyl, R^ and R-^q denote hydrogen, alkoxy such as methoxy, halogen such as chlorine, nitro or amino and R-j^ and R-^g both represent hydrogen.

Special versions of R 1 and R 8 that may be mentioned are ethyl, ethoxy, phenyl, amino, methylamino and diethylamino. Special types of the group CO-CHRgCO-R-^er. cyclo.pentanone-2-carbophtyl-, 2-benzoylacetyl-, C*),CO-di-ethoxycarbonyl, a>-acetyl-co-ethoxycarbonyl, oi,u>-diacetyl, 5,5-dimethylcyclohexane-1,3- dione-2-carbonyl and cyclohexanone-2-carbonyl.

It is an advantage if the E group is in the ?4' position, i.e. para to the bond connecting the béhzen nucleus with the benzopyran nucleus.

It is also advantageous if the E group is a COOH group or a CONHOH group.

Preferred compounds of formula I are those wherein a,

two or three of the groups R^ to R-^g denote halogen such as chlorine or bromine, alkoxy such as e.g. methoxy or 3-roethyl-n-butoxy, amino, alkyl, such as methyl, ethyl or _t-butyl, hydroxy or alkenyl such as allyl, and the rest of the R₂ to R₂₂ groups are hydrogen. As a more particular group of the preferred compounds, those are mentioned where one, two or three (preferably one or two) of the groups R^ to R-^g denote chlorine, bromine, methoxy, amino, methyl, ethyl, _t-butyl or hydroxy and the remainder is hydrogen. An even more preferred and special class of compounds are those where one or two of the groups R^, Ry, Rg and R-^q "(in the 2<*-> position) is chlorine or Rg denotes NHg or R,- denotes OH , or Rg and Rg

both denote t-butyl and (in each case) the remainder of the group R₂

to R-^2 represents hydrogen.

The invention is illustrated by the following examples where the temperature is in degrees Celsius, but these examples must not be construed as limiting.

Example 1

4-(8-chloro-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

(a) 2-( 4- Carbomethoxybenzoyloxy)- 3- chloroacetophenone

A solution of 3-chloro-2-hydroxyacetophenone (10.9 g) in dry pyridine (70 ml) was added to a solution of p-carbomethoxybenzoyl chloride (139 g) in dry pyridine (70 ml). The reaction mixture was stirred for 24 hours, poured into water, and the precipitated product was filtered off to give 19.5 g of 2-(.4-carbomethoxybenzoyloxy)-3-chloroacetophenone. After recrystallization from ethanol, the melting point was IO7-IO9<0.>

(b) 1-(3-chloro-2-hydroxyphenyl)-3-(4-carbomethoxyphenyl)propane-113-dione

Powdered potassium hydroxy (3.2 g), 2-(4-carbomethoxy-benzoyloxy)-3-chloroacetophenone (17.3 g) and dry pyridine (250 ml) were heated at 60-80°C for 2 hours with stirring. The reaction mixture was poured into dilute aqueous acetic acid and the precipitated yellow solid filtered off, washed with water and dried. The yield of 1-(3-chloro-2-hydroxyphenyl)-3-(4-carbomethoxyphenyl)propane-1,3-dione (melting point 191-192<0>) was 6.9 g after recrystallization from ethanol.

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

A solution of 1-(3-chloro-2-hydroxyphenyl)-3-(4-carbomethoxyphenyl)propane-1,3-dione (6.9 g) in glacial acetic acid (150 mL) and concentrated sulfuric acid (1.5 mL) hie heated under reflux ill/2 hours. The mixture was poured into water and the precipitate was filtered off, washed with water and dried, yielding 6.1 g of 4-(β-kl°r-4-oxo-4-H-1-benzopyran-2-yl)benzoic acid- methyl ester, melting point 212-214°»

(d) 4-(8-chloro-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

A mixture of 4-(8-chloro-4-oxo-4H-1-benzopyran-2-yl)-benzoic acid methyl ester (6.0 g), ethanol (400 ml) and dioxane (200 ml) was heated under reflux for 3 hours, with sodium carbonate (2.0 g) and water (100 ml). The cooled reaction mixture was added to water, filtered and the filtrate acidified. The precipitated product was collected and washed with water and dried. Recrystallization from tetrahydrofurfuryl alcohol gave 3.5 g of 4-(8-chloro-4-oxo-4H-1-benzopyran-2-yl)benzoic acid, melting point 343°•

(e) 4-(8-chloro-4-oxo-4H-1-benzopyran-2-yl)benzoic acid sodium salt

4-(8-Chloro-4-oxo-4H-1-benzopyran-2-yl)benzoic acid (2.0 g) was suspended in water (50 mL) and titrated with 0.1 N sodium hydroxide solution (66.3 ml). The resulting solution was filtered and freeze-dried to give 2.0 g of (4-(8-chloro-4-oxo-4H-1-benzopyran-2-$±)benzoic acid sodium salt, m.p. above 3OO<0.>

Example 2

2- Chloro- 6- hydroxyacetophenone

2-Amino-6-chloroacetophenone (28.2 g) was heated with dilute sulfuric acid (Jl>7 ml of concentrated sulfuric acid and 83.2 ml of water)

until it was all dissolved. The solution was cooled to 0-5° and stirred. rapidly together with a solution of sodium nitrite (13.5 g) in water N (36.7 ml), so that the temperature did not exceed 5°» Stirring was continued for 15 minutes and the mixture was poured through a cooling apparatus into a mixture of refluxing dilute sulfuric acid (176 ml of concentrated acid in 176 ml of water), in such a way that foaming was minimal. The reaction mixture was refluxed for 10 minutes, cooled and extracted with ether. The ether extract was dried, evaporated and the residue distilled to give 15.6 g of 2-chloro-6-hydroxyacetophenone as a yellow oil, bp 78-800 (0.5 mm)^.

Example 3

In the same way as described in example 1 (a) to (e) above, the following compounds are prepared from known starting materials.

Acylation products:

Diketoesters

Circular products

Hydrolysis products

Sodium salts

Example 4

4-( S- allyl- S-( 3- methylbutoxy)- 4- oxo- 4H- 1- benzopyran-2- yl) benzoic acid (a) 1-( 3- allyl- 6-( 3- methylbutoxy) phenyl)- 3-(4-carbomethoxyphenyl)propane-1,3-dione

Sodium hydride (50% dispersion in oil, 19.2 g) was added in portions to a stirred solution of 3-allyl-2-hydroxy-6-(3-methylbutoxy)acetophenone (26.2 g) and dimethyl terephthalate (20.4 g) in dry dioxane (150 ml). The resulting dark solution was heated on a steam bath for 1 hour and concentrated by evaporating the dioxane under reduced pressure. The solid residue was dissolved in water (600 ml) and the solution acidified. The orange-yellow solid was filtered off, washed with water and dried to give 48.36 ra of 1-(3-allyl-6-(3-methylbutoxy)-phenyl)-3-(4-carbomethoxyphenyl)propane- 1,3-dio'n. This compound was not purified but used directly for the next step. (b) Benzoic acid (melting point 235>5-236.5°)'^en's ester (not isolated) and the sodium salt (melting point >350°) °le made from the product of (a) above in the same manner as described in Example 1( c'), (d) and (e) earlier.

Example v

The procedure from example 4 was repeated with suitable known starting materials, which gave the compounds indicated below

(a)

Example 6

4-(1H-tetrazol-(5-yl)flavone

4-Cyanoflavone = (7.7 g) > sodium azide (2.29 g) °g ammonium chloride (1.67 g) was suspended in dimethylformamide and heated with stirring on a steam bath for 48 hours. The mixture was cooled completely

water and acidified with dilute hydrochloric acid. The precipitated solid was filtered off, washed with water and dried. Recrystallization from tetrahydrofurfuryl alcohol gave " J , 0 g of 4-(1H-tetrazol-5-yl)flavone, mp 286-287<0> (decomp.).

4-(1H-tetrazol-5-yl)flavone sodium salt

4-(1H-tetrazol-5-yl)flavone (6.1 g) suspended in water (100 ml) was treated with sodium bicarbonate (1.7 g) in small portions, with stirring and heating. After each addition, the pH was measured to ensure that most of the sodium bicarbonate had been used up. After adding the entire amount of sodium bicarbonate (about 7 hours), the solution was left to stir overnight. The solution was filtered and freeze-dried to give 6.5 g of 4-(1H-tetrazol-5-yl)flavone sodium salt, melting point greater than 300°.

Example 7

2- Diethylaminoethyl- 4-( 4- oxo- 4H- 1- benzopyran- 2- yl) benzoate (a) 4-( 4- 0xo- 4H- 1- benzopyran- 2- yl) benzoyl chloride

A suspension of 4-(4-°xo-4H-1-benzopyran-2-yl)benzoic acid (10.0 g) in dry dichloroethane (100 ml) was treated with thionyl chloride (3j0 ml) and dry dimethylformamide (2 drops) . The mixture was stirred and heated at reflux for 3 l/2 hours, and allowed to stand for 24 hours. The precipitated solid was filtered off, washed with dry petroleum ether and dried to give 8.3 g of 4-(4-°x°-4-H-1-benzopyran-2-yl)benzoyl chloride, mp 201-202°.

(b) 2- diethylaminoethyl- 4-( 4- oxo- 4H- 1- benzopyran- 2- yl) benzoate hydrochloride

A mixture of 4-(4-°xo-4H-1-benzopyran-2-yl)benzoyl chloride (7.4 g), 2-diethylaminoethanol (6.1 g) and dry pyridine (100 ml) was stirred overnight at room temperature, then added to water. An ethyl acetate extract of the aqueous mixture was washed with sodium carbonate solution, water and dried and evaporated to give 4>4 g of 2-diethylaminoethyl-4-(4-oxo-4H-1-benzopyran-2-yl)benzoate. This was dissolved in a mixture of dry ether (150 ml) and dry ethanol (50 ml) and treated with dry hydrochloric acid gas for 1 hour. The precipitate was filtered off and recrystallized from dry ethanol to give 3.3 g of 2-diethylaminoethyl-4-(4-oxo-4H-1-benzopyran-2-yl)benzoate hydrochloride, melting point 217-220°.

Example 8

3- chloro- 4- ( 4- ox' o- 4H- l- benzopyran- 2- vl) benzoic acid

(a) 2-(2-chloro-4-nitrobenzoyloxy)-acetophenone

2-Hydroxyacetophenone (16.4 g) in dry pyridine (100 mL) was added to 2-chloro-4-nitrobenzoyl chloride (26.6 g) in dry pyridine

(100 ml) and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was poured into dilute HCl to precipitate a . oil which quickly solidified. The product was extracted with ethyl acetate, washed with dilute HCl, aqueous sodium carbonate solution and then with water, and dried. The ethyl acetate was evaporated to a slightly sticky solid mass. This was rubbed out with 40-60° petroleum ether and filtered to give 30.8 g of light brown solid, melting point III-II3<0>.

1.0 g was recrystallized from ethanol to 0.6 g colorless oblong needles, m.p. 113-114°•

(b) 1-(2-hydroxyphenyl)-3-(2-chloro-4-nitrophenylj-propane-1,3-dione

The ester product from step (a) (1.0 g) in dry pyridine

(15 ml) was treated with powdered KOH (0.193 g) and heated and stirred at 80° ill/2 h. The reaction mixture was poured into aqueous acetic acid and the yellow solid was filtered off and dried to 0.8 g of product, melting point 117-124°. Recrystallization of this product from petroleum ether (boiling point 100-120°) with decantation from a black gummy mass gave 0.3 g of product with melting point 133-134°• A new recrystallization from 100-120° petroleum ether gave 0.23 S yellow» crystalline substance with melting point 135-136° (23

(c) 2-(2-chloro-4-nitrophenyl)-4-oxo-4H-1-benzopyran

The diketone product from step (b) (2.0 g) was refluxed in glacial acetic acid (75 mD°g conc. sulfuric acid (0.5 ml)) for 1 hour. The reaction mixture was poured into water and the precipitated pale-colored, the solid filtered off, yielding 1.9 g of material, mp 148-151° Recrystallization from ethanol gave 1.1 g of colorless needles, mp I54-I55<0> (5<8.>3% yield).

(d) 2-(4-amino-2-chlorophenyl)-4-oxo-4H-1-benzopyran

The product compound from step (c) (1.8l g) was refluxed with stannous chloride (10 g) in concentrated hydrochloric acid (100 ml)

for 30 minutes while stirring. An orange-yellow solid precipitated from the reaction mixture after qa. 15 minutes. The entire reaction mixture was cooled at 0° overnight and the insoluble solid filtered off and dried in vacuo over K0H. The solid was dissolved in a minimal amount of boiling ethanol adjusted to pH 7-8 with aqueous ammonia, and evaporated to dryness. The residue was boiled with ethanol (500 ml), filtered hot and the filtrate evaporated to a small volume which was poured into water. The precipitated product was collected and dried

1.4 g of yellow substance with melting point I43-I44<0.>

(e) 2-(2-chloro-4-cyanophenyl)-4-oxo-l-benzopyran

The amine product from step (d). (14 g) in 50 µl sulfuric acid (300 ml) at 0° was treated with sodium nitrite (3*92 g) in water (15 ml) with stirring. After addition, the mixture was kept at 0°

for 1/2 hour and cuprocyanide (18.2 g) and potassium cyanide (27 g) in water (300 ml) were added at .0°. The reaction mixture was stirred further for 1/2 hour at 0° and then allowed to warm to room temperature without cooling. After heating for 2 hours at 60°, the mixture was filtered and the product washed with water and then air-dried. The solid was extracted three times with boiling acetone and insoluble excess cuprocyanide filtered off. The acetone was evaporated and the moist residue used for the next step (f) without purification.

(f) 3-chloro-4-(4-oxo-4H-1-bQnzopyran-2-yl)benzoic acid

The nitrile product from step (e) was heated on an oil bath with glacial acetic acid (150 ml), water (150 ml) and concentrated sulfuric acid (150 ml) for 3 hours at 130°C. The reaction mixture was cooled and brined in water and the precipitated substance was filtered off. This was stirred with hot sodium carbonate solution, filtered to remove insolubles and the filtrate acidified. The precipitated substance was filtered off

and dried to 2.2 g with melting point 285-288°. Recrystallization from tetrahydrofurfuryl alcohol gave 1.4 g with melting point 293-294° (9% calculated on 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

Sodium hydride (80 fo, 6 g) was washed with dry ether and suspended in glyme (50 mL). 3-Chloro-2-hydroxyacetophenone (10.6 g) dissolved in glyme (75 ml) was added dropwise over 10 minutes. After 2 minutes a slurry of 4-carbomethoxy-3-chlorobenzoic acid (13 g) in glyme (100 ml) was added over 5 minutes. The mixture was then stirred under reflux for 13 hours. The reaction was carried out under nitrogen, from the beginning.

The mixture was poured into water, washed with CHCl 2 and acidified. The filtered material was extracted with NaHCO 3 solution. Soluble substance was chloroterephthalic acid (7.44 g)• The insoluble substance, a mdrkeerrcSnt solid riroduct. were washed with CHCl₂ to remove unreacted ketone. This gave 6.11 g of 3-chloro-4-(2-hydroxy-3-chlorobenzoylacetyl)benzoic acid.

(b) 3- chloro- 4-( 8- chloro- 4- oxo- 4H- 1- benzopyran- 2- yl) benzoic acid

A mixture of the acid product from step (a) and acetic acid (70 ml) and concentrated sulfuric acid (7 ml) was heated for 4 hours at 95° • The mixture was filtered, the solid washed with water and dried. Recrystallization from tetrahydrofurfuryl alcohol gave the desired compound as an off-white solid, (2.34 g), mp 292-294°.

Example 10

3-Methoxy-4-r(4-oxo-4H-1-benzopyran-2-yl)benzoic acid

(a) 1-(2-hydroxyphenyl)-3-(4-acetylamino-2-methoxyphenyl)propane-1,3-dione

Sodium hydride (27 g of 80 percent rdj suspension) was suspended in dry pyridine (400 mL). Orthohydroxyacetophenone (29.2 g) was added dropwise, followed by a solution of methyl 2-methoxy-4-acetylaminobenzoate (48 g) in dry pyridine. After 4 hours, part of the pyridine was evaporated under reduced pressure and the reaction mixture was carefully poured into water. The aqueous solution was extracted with ether to remove starting materials, acidified and extracted with chloroform. The organic extract was washed, dried and evaporated and

gave a thick brown oil which crystallized from ethanol. Yield = 36>5g>melting point 122-130°C. The compound was recrystallized again from

• ethanol, yield 32 g, (45.5 %), melting point 131-134°C.

(b) 2-(4-Amino-2-methoxyphenyl)-4-oxo-4H-1-benzopyran

The intermediate diketone (33 g) dissolved in boiling ethanol (200 ml) and concentrated hydrochloric acid (200 ml) was added dropwise through the condenser. The reaction was followed by thin layer chromatography. After 1 hour, the reaction mixture was allowed to cool and poured

in water. The solution was made alkaline with NagCO^ and the product filtered and dried to give 26 g of product which after crystallization from toluene/ethanol gave 6.8 g of product, mp 169-171°. A secondary yield weighed 13 g, mp 168-1700. Total yield = 19.8 g (76 fo).

(c) 3-Methoxy-4-(4-oxo-4H-1-benzopyran-2-yl)benzoic acid

The amine product from step (b) was converted to 2-(4-cyano-2-methoxyphenyl)-4-oxo-4H-1-benzopyran, mp 185-190<0>» in the manner indicated in Example 8(e ). This cyano compound was converted to 3-methoxy-4-(4-°xo-4H-1-benzopyran-2-yl)-benzoic acid, melting point 279-281°, in the same manner as described in Example 8(f). The corresponding sodium salt, melting point >300°, was prepared as indicated in Example 1(e).

Example 11

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

(a) 4-(3-Chloro-4-oxo-4H-l-benzopyran-2-yl)benzoic acid

4-(4-Oxo-4H-1-benzopyran-2-yl)benzoic acid (1 g) was heated under reflux with sulfuryl chloride (20 ml) and dry benzene, for 4 hours. The reaction mixture was poured into water. The precipitated substance was filtered off and crystallized from ethanol, giving 0.5 g of white substance, melting point 288-289°.

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

The acid product from step (a) (0.75 g) was stirred with aqueous sodium bicarbonate (0.2 g) at room temperature for 1/2 hour. The suspension was heated to approx. 40° for 10 minutes. The solution was filtered and the filtrate freeze-dried to a pale yellow solid which was dried under vacuum at 110°C, melting point >300°C.

Example 12

4-(3-Methox-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

(a) 2- Hydroxy- 41carboxychalcone

Sodium hydroxide (32 g) in water (64 ml) was added to a stirred solution of o-hydroxyacetophenone (32 g) and p-carboxybenzaldehyde (32 g) in ethanol (400 ml). The mixture was heated at reflux for two hours and after cooling acidified (diluted HC1). The pale yellow product was filtered off and crystallized from ethanol/dioxane to 28.3 g, melting point 274°.

(b) 4-(3-Hydroxy-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

2-Hydroxy-4<*>carboxychalcone (11.5 g) was dissolved in methanol (115 ml) and 20 percent NaOH (57 ml). Hydrogen peroxide (30 per cent), (23 ml) was slowly added dropwise with stirring at 0° and the solution left overnight at 0°. Excess 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,

melting point >300°.

(c) Methyl-4-(3-methoxy-4-oxo-4H-1-benzopyran-2-yl)benzoate

Dimethyl sulfate (6.5 mL) was added to a suspension of the hydroxy acid product from step (b) (6.6 g), and potassium carbonate (6.6 g) in dry acetone (100 mL). The mixture was stirred for 19 hours at reflux, cooled and filtered. The filtrate was washed with acetone (6 x 100 mL) to remove all product. Total yield of ester 3>$6 g (53 f°) • Recrystallization from methanol gave a product with melting point 154-156<0>..

(d) 4-(3-Methoxy-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

To a solution of the product from step (c) (2.0 g) in methanol (150 ml) and dioxane (100 ml) was added 0.1 N NaOH (70 ml) dropwise over 10 minutes. A yellow color was immediately formed followed by a yellow precipitate immediately after addition of the base. The precipitate was dissolved by adding dioxane (100 mL). The solution was left overnight. The solvents were evaporated by gentle heating

0

under reduced pressure. Filtration of the resulting aqueous solution gave unchanged ester (0.2 g). The filtrate, on acidification, gave the desired acid which required purification by extraction of a CHCl^ solution with aqueous NaHCO^. Yield pure acid 1.5 g, melting point 214.5-217°.

Example 13

2- Bromo- 6- hydroxy- acetophenone

(a) 2- Bromo- 6- nitrobenzoyl chloride

2-Bromo-6-nitrobenzoic acid (42.5 g) was refluxed

in thionyl chloride (100 ml) for 3 hours. The reaction mixture was filtered from some insoluble material and the filtrate evaporated to a residual oil which quickly solidified to 3^.7 g of the desired product with a melting point of 53-54° (84.7*). '

(b) Diethyl-2-bromo-6-nitrobenzoyl malonate

Diethyl malonate (55*6 g) was added to a stirred suspension of magnesium filings (8.3 g) in dry ethanol (80 ml) and carbon tetrachloride (3.0 ml). After the initial reaction had subsided, the mixture was refluxed and stirred until all the magnesium was dissolved. The ethanol was distilled off in vacuo, dry benzene was added (160 ml) and this was also distilled off. A new volume of dry benzene (160 ml) was added and a solution of 2-bromo-6-nitrobenzoyl chloride (3^.7 g) in dry benzene

(100 mL) was added to the stirred solution. The solution was then boiled at reflux for 2 l/2 hours.

The reaction mixture was cooled and diluted with HgSO 4

(300 ml) added while stirring. The benzene layer was separated from, the

aqueous portion washed with benzene and extract and wash water was dried ;--c-and evaporated to a yellow solid which was washed thoroughly with 6O-8O<0>petroleum to remove some diethyl malonate.

Yield: 45.1 g, melting point 114-116° (79.6%).

(c) 2- Bromo- 6- nitroacetophenone

A mixture of diethyl 2-bromo-6-nitrobenzoyl malonate (45.1 g) > glacial acetic acid (40 ml), concentrated sulfuric acid (3.0 ml) and water (25 ml) was heated at reflux in 5 L/2 hour. The mixture was cooled in ice, made alkaline with 20% aqueous NaOH to pH 7-8 and shaken out with ether. The ether extract was washed with water and dried. The solvent was evaporated and the residual oil solidified to give 26.8 g of product with a melting point of 73-74°•

(d) 2- Amino- 6- bromo-acetophenone

To a solution of 2-bromo-6-nitroacetophenone (26.8 g) in glacial acetic acid (120 ml) at 90-95° was added iron powder (31.5 g) in small portions over the course of 1 hour. The mixture was stirred all the time and water was added in 30 ml portions after 0, 20, 40 and 60 minutes during the reaction, the temperature was kept at 90-95°»After 3 hours at this temperature, water (200 ml) was added and the product .was extracted with ether. The ether extract was washed with water, aqueous sodium carbonate. and with water again and dried. The ether was evaporated, which gave 18 g of the desired product with a melting point of 114-116 .

(e) 2- Bromo— 6- hydroxyac etophenone

To 2-amino-6-bromoacetophenone (18 g) was added hot dilute sulfuric acid (15 ml concentrated HgSO, + 42 ml H^O). The clear solution was stirred and cooled to 15 whereupon ice (38 g) was added. The amine sulfate separated. Sodium nitrite (6.8 g) in water (18.5 mL) was added to the reaction mixture at a temperature of less than 5°C. The solution was stirred for a further 5 minutes and then water (60 mL), urea (0. 6 g) and ice (60 g) one after the other. The diazonium salt solution was added portionwise to anhydrous sodium sulfate (31.5 g)>concentrated sulfuric acid (23 ml) and water (20 ml), maintaining the mixture temperature at 130-135°. The product which distilled over solidified immediately. The reaction mixture was then steam distilled. The distillate was extracted with chloroform and the extract dried and evaporated to 9*1 g of a light brown solid with a melting point of 106-108°.

Example 14

4-(6-amino-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

(a) Methyl-2-acetyl-4-acetamidophenyl-terephthalate

5-Acetamido-2-hydroxyacetophenone (9.65 g) in dry pyridine (50 mL) was added to p-carbomethoxybenzoyl chloride (10.9 g) in dry pyridine (50 mL) at room temperature and stirred overnight. The reaction mixture was poured into water and the precipitate extracted with chloroform which was washed with dilute HCl, sodium bicarbonate solution, then water, and dried. Evaporation of the solvent gave 15.6 g of the desired product with a melting point of 179-183°

1.0 g of the product was recrystallized from dioxane to give 0.7 g of pure substance with melting point 187-188<0>.

(b) Methyl- 4- f( 2- hydroxy- 6- acetamidophenyl)- 1, 3- diketopropyl- 3- yl benzoate

The ester product from step (a) (12.4 g) in pyridine (300 ml) was treated with powdered KOH (2.09 g) and heated with stirring at 80° for 1/2 hour. The reaction mixture was poured into aqueous acetic acid and the product extracted with ethyl acetate. The organic extract was washed with dilute HCl, then twice with water and dried. The solvent was evaporated to 7.1 g of product with a melting point of 214-216°. (c) Methyl-4-(6-amino-4-oxo-4H-1-benzopyran-2-yl) benzoate hydrochloride

The diketone product from step (b) (5.3 g) was dissolved in methanol (750 ml) under reflux and concentrated HCl (250 ml) added through the condenser. After approx. For 1/2 hour, a colourless, solid substance separated and reflux was continued for 2 1/2 hours. The reaction mixture was cooled and the product filtered, yielding 4>4g of product with melting point 273-277° (decomp.) (88.9%).

(d) 4-(6-Amino-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

The amine ester hydrochloride product from step (c) (4.4 g) was suspended in ethanol (450 ml) and NaCl (2.81 g) in water (200 ml) was added. J

The reaction mixture was heated and stirred until a clear solution formed. More water (400 ml) was added and the solution was refluxed for 2 hours, filtered and the filtrate adjusted to pH 4 with dilute HCl. The precipitated substance was filtered off, washed with a little water and dried. 3.7 g of substance were obtained, melting point 286° (decomp.). Recrystallization from aqueous ethanol gave 3»! g product with melting point 29O0 (decomp.).

The acid product was transferred to the sodium salt, m.p

>300°C, in the same way as in example l(e).

By means of the above method and starting from_4-acet-amido-2-hydroxyacetophenone, 4-(7-amino-4-oxo-4H-1-benzopyran-2-yl)benzoic acid, melting point >300°, was prepared via methyl-2 -acetyl-5-acetamidophenyl terephthalate (melting point 166-169°), methyl 4-[i2-hydroxy-4-acetamidophenyl)-1,3-diketopropyl-3-yl] benzoate (melting point 243-246°) and methyl -4-(7-amino-4-oxo-4H-1-benzopyran-2-yl)benzoate (melting point 284-286°).

Example 15

4-(5-hydroxy-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

(a) Methyl- 4-( t5- hydroxy- 4- oxo- 4H- 1- benzopyran- 2- yl) benzoate

Methyl 2-acetyl-3-chlorophenyl terephthalate (2.0 g) in pyridine (30 mL) was treated with powdered KOH (0.372 g) and heated on. steam bath for 1 hour at approx. 80-90°, then boiled at reflux for 1 hour. The reaction mixture was poured into dilute aqueous acetic acid. and the precipitated solid collected by filtration, washed with water and dried. Recrystallization from ethanol gave 0.4 g of yellow voluminous needles with melting point 203-206°. Further crystallization from ethanol gave 0.1 g of product with melting point 206-207°.

(b) 4-(5-Hydroxy-4-oxo-4H-1-benzopyran-2-yl)benzoic acid

The 5-hydroxyester product from step (a) (1.7 g) was dissolved in ethanol (200 ml) and dioxane (50 ml). Sodium carbonate (0.609 g) was added to the mixture in portions, followed by water, and refluxed for 2 hours. The reaction mixture was diluted with water, filtered and the filtrate acidified. The precipitated product was filtered off, washed with water and dried to give 1.1 g of product with a melting point of 33°

(decomp.). Recrystallization from tetrahydrofurfuryl alcohol gave 0.74 g of pure substance, melting point 335-337°.

The acid product was converted to the sodium salt, melting point >300°C, as indicated in example 1(e).

Example 16

4-(4-Oxo-4H-1-benzopyran-2-yl)benzohydroxanoic acid

(a) 4-(4-Oxo-4H-1-benzopyran-2-yl)benzohydroxanoic acid

4-(4-Oxo-4H-1-benzopyran-2-yl)benzoyl chloride (10 g) was added to a solution of hydroxylamine hydrochloride (2.57 g) in pyridine (100 ml) at room temperature. After vigorous stirring for 15 minutes, the mixture was heated at 80° for 10 minutes until a clear solution formed. After standing overnight, the mixture was poured into ice/excess hydrochloric acid and the product was collected, washed with water and dried. Crystallization from tetrahydrofurfuryl alcohol gave needles (4.9 g), mp 226-228° (decomp.).

(b) Sodium 4-(4-oxo-4H-1-benzopyran-2-yl)benzohydroxamate

Sodium hydroxide (148.2 ml, 0ℓLN) was added to the hydroxanoic acid product from step (a) (4*265 g) and the suspension was stirred overnight. Ethanol (100 mL) was added and the mixture stirred. for 3 hours at 60°.

Evaporation of the clear solution gave a yellow substance which was dried at 60° in vacuo to give a product (4>-3 g) m.p. >300°.

Example 17

2- f4-( Cyclopentanone- 2- carbonyl) phenyl] - 4- oxo- 4H- l- benzopyran (a) 2-[ 4-( Cyclopentanone- 2- carbonyl) phenyl]- 4- oxo- 4H- l- benzopyran '

N-(1-cyclopenten-1-yl)-morpholine (6.94 g) and triethylamine (4.83 g) were dissolved in chloroform (65 ml) and cooled to 0°. 4-(4-Oxo-4H-1-benzopyran-2-yl)benzoyl chloride (12.9 g) in chloroform (75 ml) was added slowly with stirring over 2 hours keeping the temperature below 10°C. The mixture was allowed to warm to room temperature and stirring was continued for 30 hours. The mixture (dark brown) was heated at reflux for 1 hour before adding concentrated hydrochloric acid (6.5 mL) and water (15 mL). Refluxing was continued for 3 hours. The mixture was cooled, filtered, and the chloroform layer above the filtrate was separated, washed with sodium bicarbonate solution twice, washed twice with water and dried over magnesium sulfate. The solvent was evaporated leaving a tan sticky substance. This was treated with ether and filtered, yielding 5.7 g of yellow-brown material.

Crystallization of this from ethyl acetate/petroleum ether (60-80) gave crystals (2.6 g) which recrystallized from toluene/petroleum ether (twice) (b.p. 6O-8O<0>) formed prisms (1.6 g) with m.p. I78 -I8I<0>. Recrystallization from toluene gave prisms (1.2 g)

with melting point I8I-I83<0>.

(b) 2-[ 4-( Cyclopentanone-2- carbonyl) phenylj 4- oxo- 4H- l- benzopyran sodium salt

Sodium hydroxide (0.1N, 24.9 ml) was added to the β-diketone (825 mg) as the product of step (a), at room temperature, and the resulting suspension was stirred at room temperature for 1 hour and at 60° for 1 hour .

At this point, some unreacted P-diketone remained.

Ethanol (20 ml) was added and the mixture was stirred at room temperature overnight. The clear solution was evaporated and the residue dried by evaporating toluene from the residue three times.

The solid was dried at 100° in vacuo for 4 hours which gave 820 mg of product with a melting point above 250<0>(-decomp.).

Example 18

4-(4-Oxo-4H-1-benzopyran-2-yl)phenylacetic acid

A suspension of 4-(4-oxo-4H-1-benzopyran-2-yl)benzoyl chloride (5% g) in ether (200 ml) was added at 0-10° to a stirred solution of diazomethane ( about 3*0 g) in ether (200 ml). The reaction mixture was stirred until it had reached room temperature and continued at this temperature for 18 hours. The insoluble product was filtered off to give 4.1 g of product with a melting point of 175-177°. The diazoketone (4.1 g) was suspended in diglyme (100 ml) and added slowly to silver oxide (1 g), anhydrous sodium carbonate (2 g) and sodium thiosulphate (1.5 g) in water (200 ml) at 60-70° with stirring. Stirring was continued for 1 hour at this temperature and the reaction mixture was finally heated at 90-100°. The reaction mixture was filtered and the filtrate acidified.

The oily precipitate was extracted with ethyl acetate which was washed with aqueous saturated sodium bicarbonate solution. The washing liquids were acidified and gave 1.5 g of product with melting point I92-I96<0>. Recrystallization from aqueous ethanol gave 0.8 g of the desired substance with a melting point of 195-199°»

The acid was converted to the sodium salt by the same method as in example 1(e). The sodium salt had a melting point > 300°C.

Example 19

Following the same procedure as described in examples 8(a) to (f) earlier, the following compounds were prepared from known starting materials:

Acylation products

Diketones Cyclization products

Aminoflavones

Cyanoflavones Benzo<y>rer Sodium salts

Example 20 _ . 4-[ 7-( 2- Hydroxypropoxy) - 4- oxo- 4H- l- benzopyran- 2- yl) benzoic acid (a) 4-( 7- Hydroxy- 4- oxo- 4H- l- benzopyran- 2- yl) benzoic acid methyl ester

A mixture of 4-(7-methoxy-4-oxo-4H-1-benzopyran-2-yl)-benzoic acid methyl ester (13 g) and pyridine hydrochloride (40 g) was heated at 200° for 2 hours and then cooled. The oil formed was rubbed out with water and a green, solid substance was obtained. This was crystallized from methanol as green needles in the form of 4-(7-hydroxy-4-oxo-4H-1-benzopyran-2-yl)benzoic acid m.p. 33° (decomp.), yield 10 g.

The above hydroxy acid was esterified in methanol-hydrogen chloride solution. and the methyl ester was then obtained as green needles with melting point 3O6-307<0>, yield 6.5 g.

(b) 4-[ 7-(Hydroxypropoxy)~ 4~ ox°- 4- H- l- benzopyran- 2- yl benzoic acid

A mixture of the product from step (a) above (2.5 g)>propylene oxide (2 ml) and Triton B (5 drops) in dioxane (20 ml) was heated in a sealed container for 3 days.

The resulting brown solution was evaporated to dryness leaving a brown oil. This was hydrolysed with sodium bicarbonate, ethanol and water until the thin layer chromatogram showed complete hydrolysis.

The solution was boiled with activated charcoal and acidified with dilute hydrochloric acid which gave a light brown solid. This was crystallized from ethanol as light brown needles m.p. 265-267° (decomp.), yield 0.85 g.

The sodium salt was prepared as described in example 1(e) and had a melting point > 350°C•

Example 21

With the methods described in examples 1(a) to (e) and with the 2-chloro-, 2-nitro- and 3-nitro derivatives of 4-carbomethoxybenzoyl chloride, the following compounds were prepared from known starting materials :

Acylation products

Diketones

Circular products

Hydrolysis products

Example 22

3»4- dichloro- 2- hydroxyacetophenone

(a) 7»8- Dichloro- 4- oxo- 4H- 1- benzopyran- 2- carboxylic acid

Triton B (30 drops) was added to a mixture of 2,3-dichlorophenol (100 g) and dimethyl acetylene dicarboxylate (87 g) in dry dioxane (150 ml).

The mixture was heated on a steam bath for 15 minutes and heated at 95° for 2 hours, and then left overnight at room temperature. A solution of NaOH (60 g) in water (300 mL) was added and the solution heated until hydrolysis was complete (8 hours). The aqueous solution was acidified and the precipitated acid extracted with ether. After evaporation, the dry ether extracts gave a solid which was dissolved in aqueous sodium bicarbonate. The aqueous solution was washed thoroughly with ether to remove impurities. Acidification of the bicarbonate layer gave a solid which was extracted with ether. The ether extracts were dried and evaporated to give 112 g of intermediate product in the form of 2,3-dichlorophenoxyfumaric acid.

This acid was slowly added to concentrated H^SO^

(550 ml) during J, 0 minutes. The solution was stirred at room temperature for 2 l/2 hours and poured into ice water. The separated acid was crystallized from ethanol and gave 74»4g of the desired product with melting point 235-238<0>, yield 47

(b) 3, 4- Dichloro- 2- hydroxyacetophenone

A mixture of NaOH (24.0 g) and the chromonic acid product from step (a) (30 g), in water (750 ml) was heated at 95° for 1/2 hour, left at room temperature for 1 hour and acidified. The ether extract of the acid solution was washed with sodium bicarbonate, dried and evaporated to 9.0 g of substance, melting point 109-110° (38 56).

Example 23

4- Carbomethoxy- 3- nitrobenzoyl chloride

(a) 4- Carbomethoxy- 3- nitrobenzoic acid

Dimethyl nitroterephthalate (83.1 g) was refluxed

in methanol (2.5 L) and treated with KOH (19.5 g) 1 methanol (500 ml) dropwise with stirring over 1 l/2 h. The reaction mixture was refluxed for a further 1 hour, concentrated to half the 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 substance was obtained which was boiled with water (approx. 1 3/4 1)°g and set aside for cooling. The insoluble substance was filtered off and gave 47.4 g with a melting point of 177-178° (60.6 1o).

(b) 4-Carboxymethoxy-3-nitrobenzoyl chloride

The acid product from step (a) (53.2 g) was refluxed in thionyl chloride (150 ml) for 3 l/2 h. After grace period

at room temperature overnight, a colorless, crystalline substance was precipitated. After drying, this gave 34.7g of melting point 174-176<0> (the thin-layer chromatogram showed that this was unchanged acid). Evaporation of the thionyl chloride gave a viscous residue which on distillation yielded 12.0 g of the desired product as a pale yellow oil, which rapidly solidified, boiling point 150°/0.1 mm. The recovered acid was refluxed with thionyl chloride (120 ml) and 2 drops of pyridine for 2 hours. The excess of thionyl chloride was evaporated and the residue distilled, yielding 33>9g of the desired substance, boiling point 156°/0.15 mm.

Total yield: 45.9 g (79.7 5<6>).

Example 24

4- Carbomethoxy- 2- nitrobenzoyl chloride

4-Carbomethoxy-2-nitrobenzoic acid (172.8 g) was refluxed in thionyl chloride (500 ml) containing a few drops of pyridine

for 2 hours, then set aside at room temperature overnight. The excess thionyl chloride was removed in vacuo. On cooling, the residue solidified in the flask, after crystallization from toluene/petroleum ether, 149.1 g of colorless substance with melting point 41-42° (79.8

Example 25

2- Amino- 4-( 4- oxo- 4H- l- benzopyran- 2- yl) benzoic acid

(a) Methyl- 2* amino- 4-( 4- oxo- 4H- 1- benzopyran- 2- yl) benzoate

Methyl 2-nitro-4-(4-oxo-4H-1-benzopyran-2-yl)benzoate

(10.0 g) was refluxed with stannous chloride (50 g) in concentrated hydrochloric acid (500 ml) for 30 minutes with stirring. The reaction mixture was cooled to 0°C within 1 hour and the insoluble substance was filtered off and dried in vacuo over KOH. The hydrochloride was treated in boiling methanol (500 mL) and then adjusted with ammoniacal solution to pH 7-8. The mixture was poured into water and a pale yellow solid filtered off and dried to 8.0 g of crude product. This was extracted with boiling dioxane, filtered, and the filtrate evaporated, yielding 5.5 g of material with melting point 221-223° (60.6%).

Following the same procedure as in example 1(d), the ester was converted to acid, melting point 306-308°, in 77% yield.

3-Amino-4-(4-°xo-4H-1-benzopyran-2-yl)benzoic acid, melting point 285-286°, was prepared directly by the above procedure in 85% yield.

Example 2b~

3, 6- Dichloro- 2- hydroxyacetophenone

(a) 5, 8- Dichloro- 4- oxo- 4H- 1- benzopyran- 2- carboxylic acid

Benzyltrimethylammonium hydroxide solution (30 drops) was added to a solution of 2,5-dichlorophenol (162g) and dimethylacetylene dicarboxylate (142g) in dioxane (250ml). The solution was heated on a steam bath for 1 hour. A solution of sodium hydroxide (80 g) in water (320 ml) was added and the mixture refluxed on a steam bath for 6 hours. About. 100 ml of solvent was distilled off under reduced pressure. Water (200 ml) was added, followed by an excess of concentrated hydrochloric acid. A yellowish-white solid separated, filtered off, washed with water and dried.

This mixture of 2,5-dichlorophenoxy-fumaric acid and -maleic acid was stirred overnight at room temperature with concentrated sulfuric acid

(600ml). Addition of the acid solution to ice water gave a colorless substance which was filtered off and washed with water. The product was purified by hot water extraction (to remove 2,5-dichlorophenoxymaleic acid), then recrystallized from ethanol to give 97.5 g of 5,8-dichloro-4-oxo-4H-1-benzopyran-2 -carboxylic acid, melting point 268-270°.

(b) 3. 6- Dichloro- 2- hydroxyacetophenone

Sodium hydroxide (26.4 g) and the acid product from step (a)

(43»7g) in water (1 liter) was. heated for 1 hour on a steam bath (while stirring). The yellow solution was stirred for 1 hour at room temperature, acidified and extracted with ether. The ether layer was washed with sodium bicarbonate solution, dried and evaporated to 3>6-dichloro-2-hydroxyacetophenone as a yellow oil, which solidified rapidly. Yield 31>7g>melting point 55-56°.

Example 27

3- Chloro- 4-( 5, 8- dichloro- 4- oxo- 4H- 1- benzopyran- 2- yl) benzoic acid

3,6-Dichloro-2-hydroxyacetophenone (5 g), 2-chloro-4-carbomethoxybenzoyl chloride (6.25 g) and potassium carbonate (25 g) were heated at reflux in dry acetone (300 ml) for 10 hours. The acetone was distilled off and the pale yellow residue was acidified with glacial acetic acid (150 ml) and concentrated HgSO 4 (15 ml). The mixture was heated with stirring on a steam bath for 5 hours. The mixture then showed on the thin-layer chromatogram a main spot and a smaller spot which indicated a mixture of ester and acid where the ester was the main component. The reaction mixture was heated at reflux for 5 hours and then showed only one spot on the thin layer chromatogram. After cooling, the reaction mixture was poured into water. The precipitate was filtered off, washed thoroughly with water and dried to 7.5 g of product.

Crystallization from tetrahydrofurfuryl alcohol gave 5.2 g, melting point >300°.

Example 28

(a) 5-^4-(4-Oxo-4H-1-benzopyran-2-yl)-benzamido)-tetrazole

5-Aminotetrazpl (3»3^ g) °g 4-(4-oxo-4H-1-benzopyran-2-yl)benzoyl chloride (8.0 g) in dry pyridine (200 ml) was stirred for 1 hour at room temperature and heated on a steam bath at about »85° for 12 hours. Most of the pyridine was evaporated under vacuum and the mixture completely

out in ice/concentrated hydrochloric acid.. The mixture was made acidic and the cream-coloured substance was filtered off and dried to 11.7 g of substance, melting point > 290°.

Crystallization of the product from tetrahydrofurfuryl alcohol, washing with 50% hydrochloric acid and drying gave 7>3 g of the desired substance.. (b) 5-^4-(4-Oxo-4H-1-benzopyran-2-yl)benzamido] tetrazole- sodium sait ■.

The amidotetrazole product from step (a).(5.0 g) was suspended in water (100 ml). Dilute sodium hydroxide (0.1N) (150 ml)

was added while stirring. The mixture was stirred and heated at approx. 50° for 2 hours and then filtered. On cooling, some sodium salt was precipitated and filtered off. ; The filtrate was freeze-dried and yielded 2.5 g of the desired substance, melting point >300°.

Example 29

The following compounds and their sodium salts can be prepared according to the method described in example 1, with suitable starting materials: (a) 4-(5-(2-Hydroxypropoxy)-4-oxo-4H-1-benzopyran-2- yi) -benzoic acid (b) . 3r-(5-(2-Hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-yl)-benzoic acid. (c) .2-p-(2-Hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-yl)-benzoic acid-(d) 2-.(3-Carboxyphenyl)-6,7,8,9 -tetrahydro-4-oxo-4H-naphthoU2,3TbJpyran (e) 2-(2-Carboxyphenyl)-6,7,8,9-tetrahydro-4-ox6-4H-naphtho(2,3-b)pyran'

The following compounds (and the sodium salt of the hydroxanoic acid) were prepared according to the procedure in Examples 7(a), 16(a) and 1(e), respectively.

3-Chloro-4-(8-chloro-4-oxo-4H-1-benzopyran-2-yl)benzoyl chloride, melting point approx. 190°, and 3-chloro-4-(8-chloro-4-oxo-4H-1-benzopyran-2-yl)benzohydroxanoic acid, melting point 246-247°•

Example 30

Diethyl (4'-[4-oxo-4H-1-benzopyran-2-yl]benzoyl)malonate

Diethyl malonate (8.02 g) was added to a stirred suspension of magnesium filings (1.2 g) in dry ethanol (15 mL) containing carbon tetrachloride (1 mL). After the initial reaction had subsided, it was boiled at reflux until all the magnesium had dissolved (about 10 minutes). The ethanol was distilled off in vacuo and dry benzene added (20 ml). This was distilled off in vacuum and any residue removed

alcohol.

Dry benzene' (20 ml) was added to the magnesium salt and a suspension of 4t<->(4-oxo-4H-1-benzopyran-2-yl)benzoyl chloride (6.0 g)

in dry benzene (70 mL) was added. The mixture was stirred at reflux for 5 1/2 hours and then cooled in ice and treated with ice-cold dilute sulfuric acid. The mixture was filtered and the ethyl acetate added to the filtrate. The ethyl acetate layer was separated, washed with water, dried and evaporated to give 1.2 g of material which was treated with petroleum ether to remove residual diethyl malonate. The filtered material was triturated with dilute sulfuric acid and extracted with ethyl acetate. The ethyl acetate was separated, dried, evaporated and combined with the previous product to give 7.6 g (88.3%) of a beige material. Twice recrystallization from ethyl acetate/petroleum ether gave needles, 4.6 g, mp 130-1330 (53.4

Example A

The procedure below can be used to form

a measure of the compound's effect with respect to inhibiting the release of pharmacological intermediates in anaphylaxis.

In this experiment, the effect of the compounds is measured as inhibition of passive cutaneous anaphylactic reaction in rats. It is believed that this test method provides useful qualitative indications of the test compound's ability to inhibit antibody-antigen reactions in humans.

In these experiments, Charles River France/Fisons rats (male or female) with a body weight of 100 to 150 g are infected subcutaneously every week with N. brasiliensis larvae in doses increasing from approx. 2000 larvae per animal to 12,000 larvae per animals, to create an infection. After 8 weeks, the animals are bled by cardiac puncture and 15-20 ml of blood is collected from each animal. The blood samples are centrifuged at 3500 rpm. for 30 minutes to remove the blood cells from the blood plasma. The serum is collected and used as a serum containing N. brasiliensis antibodies. A sensitivity test is carried out to find the smallest amount of serum that is necessary to produce a skin spot on control animals in the above test, of 2 cm in diameter.

It has been found that optimal sensitivity in rats with a body weight of 100-130 g is achieved with a serum diluted with eight parts of physiological saline. This diluted solution is called antibody serum A. The antigen to react with the antibody in serum A is prepared by removing N. brasiliensis worms from the intestine of infected rats, centrifuging the homogenate and collecting the supernatant liquid. This liquid is diluted with saline to a protein content of 1 mg/ml and is called solution B.

Rats of the strain Charles River France/Fisons, with a body weight range of 100 to 130 g are sericitized by intradermal injection of 0.1 ml of serum'A in the right side. The sensitivity is allowed to develop for 24 hours and the rats are then injected intravenously with 1 mfli per 100 g body weight of a mixture of solution B (0.25 ml), Evans blue solution (0.25 ml) and a solution of the test compound in question (0.5 ml containing varying percentages of active substance). Insoluble substances are given as a separate intraperitoneal injection 5 minutes before the intravenous administration of solution B and Evans blue dye. For each percentage level of active substance in the solution being tested, five rats are injected. Five rats are also used as control animals in each experiment. The doses of the test compounds are chosen so that a spectrum of inhibition values is obtained.

Thirty minutes after injection of solution B, the rats are killed and the skin is peeled off and sniffed. The intensity of the anaphylactic reaction is assessed by comparing the size of the characteristic blue spot that is formed by the spread of Evans boat from the site of sensitization with the size of the spots in control animals. .100 for inhibition) to 4 (no change in spot size, i.e. no inhibition), and percentage inhibition for each dose (dosage level) is calculated as follows: (Control group's number - treated group's number^xlOCfoinhibition = =—— ——

The control group's numbers

Percentage inhibition for the different dosage levels is plotted graphically for each compound. The dose required to achieve 50% inhibition of the anaphylactic reaction (ID^q) is read from these curves.

The compounds are also assessed in the above way by giving the compounds in the stomach and intestines.

Claims (30)

1. Process for the preparation of compounds of formula IN, where R^ , R^ , Rg, R^, Rg, R^ , R]_q» R]_]_ and R^ g» which may be the same or different, each represents hydrogen, alkyl, alkoxy, halogen, alkenyl, amino, hydroxyl,'-CF^ , -CN, alkylamino, alkoxyalkyloxy, hydroxyalkyloxy, -NO^ , or Rg and Ry together.form a -(CHg)^ -or -(CHg)^ O chain and E denotes a carboxylic acid group, a 1H-tetrazol-5-yl group, a N-(1H-tetrazol-5!-yl)carboxamide group, a gH^ COOH group, a CONHOH group or a -CO-CHRgCO-R-L group, R-^ denotes alkyl(C-^-Cg), alkoxy (C-^-Cg), phenyl, amino, or mono- or di-alkyl(C-j_-Cg)-amino, R^ represents hydrogen or -CORx and Rx denotes alkylKC-^ -Cg), alkyloxyC-^-Cg), amino or mono- or di-alkylC-j^-Cg)-amino or R-^ and Rg together form a 3- or 4-membered alkylene chain as ■ • is optionally interrupted by an NH group and which is optionally substituted with one or more alkyl (C-^-Cg) groups and/or on the carbon atom a to the methine proton is substituted with a carbonyl oxygen atom, with the additional proviso that (i) when E is a COOH group or a pharmaceutical derivative thereof and- R^, Rg, R^ , R-j _q, R-q and R-^ all denote hydrogen, denote (a) R^ not hydrogen or alkoxy or (B) Rg does not represent hydrogen, hydroxy, alkyl or alkoxy or (C) R 7 does not represent hydrogen or alkoxy, or (ii) when E is a COOH group or a pharmaceutical derivative thereof, E is not in the 2 <*-> position, as well as their pharmaceutically usable derivatives, which consist in (a) ring-closing a compound of formula II, where Ry R^ , Rg, R^ , Rg, R^ , R10 , R^ ; R12 , E and the additional conditions are as previously stated, Z. denotes a reactive halogen atom or a group -OM and M denotes hydrogen or an alkali metal cation, (b) prepares a compound of formula Ia where R^ , R^ , Rg, R^ , Rg, R^ , R-^q, R^i» R12 and the additional conditions are as previously indicated, ■ by hydrolyzing a compound of formula III where R^, R^ , Rg, R^ , Rg, R^ , R1Q , R-^ , R12 and the additional conditions are as previously indicated, and Ry denotes a group that can be hydrolyzed to a COOH groupf. where R^ , R,_, Rg, R^ , Rg, R^ , R1Q> r.^0 g R^ has meaning as previously stated, by reacting a compound of formula VI where R^ , R^ , Rg, R^ , Rg, R^ , R-j_q, R-q and R-^ have meanings as previously indicated, with an azide in an inert solvent, (d) produces a compound of formula le where R^ , R^ , Rg, Rrj, Rg, R^ , R-j_q, R-q° g Ri2 ^are meanings as previously indicated, by reacting an anhydride, ester or acid halide of a compound of formula Ia with hydroxylamine, (e) prepares a compound of formula I wherein E represents a group -CO-CHRgCO <R> -p by (i) reacting an acid halide or mixed anhydride of a compound of formula Ia with a compound of formula CHgRgCO <R->^ or its enamine; and, if an enamine is used, hydrolysis of the compound formed, or (ii) hydrolysis of a compound of formula VII where R^ , R^ , Rg, R^ , Rg, R^ , R-j_q, R-q° S Ri2 have betvcining as previously stated, and Ra and Rb, which may be the same or different, each represents alkyl (C-L-Cg) or, together with the nitrogen atom, forms a 5-, 6- or 7-membered heterocyclic ring which optionally contains et. oxygen atom, (f) produces a compound of formula Ih where R^, R^, Rg, R^ , Rg, R^ , R-|_q, R-^ p and R-^ have the meaning as before, by treating a compound of formula VIII J where R^ , R^, Rg, R^ , Rg, R^ , R1Q , R-q and R-^ have meanings as previously indicated, with water, (g) prepares a compound of formula I where R 1 denotes a halogen atom, by selective halogenation of a corresponding compound • with formula I where R^ denotes a hydrogen atom, (h) manufactures a. compound of formula I where R^ denotes a OH group, by oxidative ring closure of a compound of formula X where Ry Ry Rg, R^ , Rg, R^ , R1Q , R-^ , R12 , E and M have meanings as previously stated, (i) prepares a compound of formula I in which one or more of the groups R^ to R-^ denotes alkoxy or hydroxy-alkoxy, by reacting a corresponding compound of formula I in which one or more of the groups R^ to R-^ denotes -OH, with an alkylating agent, or with an alkylene oxide, respectively, (j) selectively dehydrogenates a corresponding flavanone of formula XV where Rg, R5 , Rg, Ry, Rg, Rg, R1 0, R1P <R> 12, E and the additional conditions are as previously stated, (k) prepares a compound of formula I in which at least one of the groups Rg to: R^2 denotes an amino group, by selective reduction of a corresponding compound of formula I in which at least one of the groups R^ to R12 is a NOg group, 5 (1) produces a compound of formula II where Rg, R^, Rg, R^ , Rg, R^ , R-j_q, Rq and R-^ have meanings as previously stated, by reacting an anhydride, ester or acid halide of a compound of formula Ia, with 5-aminotetrazole, or (m) prepares a compound of formula I wherein Rg to R, and the additional conditions are as previously stated, except that one of the groups Rg to R-^ denotes an OH group, by dealkylation of a corresponding compound of formula I wherein Rg to R-^ have the meaning as previously indicated (but where the additional conditions do not apply), except that one of the groups Rg to R-^ denotes alkoxy, and if necessary or desired, converts a compound of formula I into a pharmaceutical derivative thereof or vice versa. 2. Method according to part (a) of claim 1, characterized in that, when Z denotes the group -OM, the ring filtration is carried out in the presence of an acid and in a solvent which is inert under the reaction conditions. 3. Method as stated in part (a) of claim 1, characterized in that when Z is a reactive halogen atom, the reaction is carried out in a basic environment. 4. Method as stated in part (b) of claim 1, characterized in that the group Ry is an amide, nitrile or w RTF' ester group. 5. Method as stated in part (b) of claim 1 or claim 4, characterized by the hydrolysis being carried out in a weakly basic environment or in an acidic environment. 6. Method as stated in part (c) of claim 1, characterized in that the reaction takes place in the presence of a solvent in which both reagents are soluble, and with ammonium or alkali metal azide. 7. Method as indicated in part (d) of claim 1, characterized in that an acid halide of a compound of formula Ia is reacted with hydroxylamine. 8. Method as stated in part (e) (i) of claim 1, characterized in that an acid halide of a compound of formula Ia is used and that the reaction is carried out in an aprotic solvent and in the presence of an acid acceptor. 9. Method as stated in part (e) (i) of claim 1, characterized in that the hydrolysis is carried out with aqueous acid. 10. Method as stated in part (f) of claim 1, characterized in that the reaction takes place in the presence of silver oxide or silver benzoate. 11. Procedure as stated in part (g) of claim 1, k a r a k- .terized that the selective halogenating agent used is sulphuryl chloride and that the reaction takes place at 20 to 150oC. 12. Method as specified in part (h) of claim 1, characterized in that the ring closure is carried out in a basic environment and in the presence of an inorganic peroxide. 13» Method as stated in part (i) of claim 1, characterized in that the alkylating agent is a reactive alkyl halide or a mono- or di-alkyl sulfate, and the reaction is carried out in an inert solvent. 14" - F reaction method as indicated in part (j) of claim 1, characterized in that the dehydrogenation takes place by oxidation with a mild oxidizing agent, or by halogenation followed by dehydrohalogenation. 15. Method as specified in part (k) of claim 1, characterized in that the reduction is carried out with stannous chloride. 16. Method as stated in part (1) of claim 1, characterized in that an acid halide of a compound of formula Ia is reacted with 5-aminotetrazole. 17" Method as specified in part (m) of claim 1, characterized in that the reaction takes place with an acid in a suitable solvent or with pyridine hydrochloride at an elevated temperature. l8. Process for the preparation of pharmaceutical salts of compounds of formula I according to claim 1, characterized in that a compound of formula lx is treated 1 where Rg, R^ , Rg, Ry, Rg, R^ , Rjq, rh» Ri2 and the additional conditions are as previously stated, and G denotes a group E, or another salt thereof, or where, when E in the compound of formula I is a carboxylic acid group, G may be a carboxyl ester group, a nitrile group, an acid halide group or an amide group, with a compound containing an available pharmaceutically usable cation which can convert the group G into a pharmaceutical salt of the group E. 19. Method as stated in claim 18, characterized in that one treats a free acid of formula I according to claim 1, with a suitable base or treats another salt of a compound of formula I with a suitable salt according to a recovery process. 20. Method as stated in claim 18 or 19, characterized in that the pharmaceutical salt is the sodium salt. 21. Process as stated in one or more of the above claims, characterized in that Rg, R^, Rg, Ry, Rg, Rg, R-^ qj R-Q and R-^2 contain less than 7 C atoms. 22. Method as stated in one or more of the above claims, characterized in that only one, two or three of the groups R^ , R^ , Rg, Ry, Rg, R^j R-^q, R-q and R-^ is different from hydrogen. 23" Method as specified in one or more of the above claims, characterized in that R^ to R-^ is selected from hydrogen, chlorine, bromine, methoxy, methyl, hydroxy, amino, allyl, t-butyl, 3-methyl- H-" butoxy, 2-ethoxy-ethoxy,' 2-hydroxy-propoxy ethyl, ethoxy and nitro, or Rg and Ry together form a (CHg)^ -or (CHg)^ O chain. 24. Method as set forth in one or more of claims 1 to 22, characterized in that R^<1> denotes hydrogen, alkyl, halogen, or hydroxyl, R^ denotes hydrogen, halogen, alkoxy, hydroxy-alkoxy, alkoxy-alkoxy or hydroxy, Rg denotes hydrogen, halogen, amino or alkyl, Ry denotes hydrogen, halogen, alkoxy, amino, hydroxy or hydroxy-alkoxy, or Rg and Ry together form a CHgCHgGHgO or (CH2 )^ chain, Rg denotes hydrogen . 25. Method as specified in one or more of the above claims, characterized in that the group E is in the ?4f position. 26. Method as stated in one or more of the above claims, characterized in that E is a COOH group or a CONHOH group. 27" Method as stated in one or more of the above claims, characterized in that one, two or three of the groups R^ to R-^ denote halogen, alkoxy, amino,"alkyl, hydroxy or alkenyl and that the rest of the groups RQ to R denotes , , , and at3 •12 hydrogen. 28. Method as stated in one or more of the above claims, characterized in that one, two or three of the groups R^ to R-^ denote chlorine, bromine, methoxy, amino, methyl, ethyl, t-butyl or hydroxyl and that the remainder represents hydrogen. 29. Method as stated in one or more of the above claims, characterized in that one or two of the groups R^, Ry, Rg and R-^q (in the 2' position) is chlorine, or Rg denotes NH2, or R ^ denotes OH, or Rg and Rg both denote t_-butyl and ■ 0 . ! (in all cases) the rest of the groups R 1 to R 2 represent hydrogen. 30. Method as stated in claim 1, essentially as described in one or more of examples 1, 3 t^ 1 12 inclusive, 14 to 21 inclusive, 25, 27, 28 or 29.