DD146046A5 - PROCESS FOR THE PREPARATION OF AURON DERIVATIVES - Google Patents

Abstract

The invention relates to the preparation and use of substituted aurones of general formula I, in which: R & exp1 !, R & exp2 !, R & exp3 !, R & exp4 !, R & exp5! and R &agr6; which are the same or different from each other are each hydrogen, halogen, C & ind 1-6 alkyl, C & ind1-6! alkoxy, C & sub3-8! cycloalkyl, optionally substituted phenyl, C & ind 1-6! -haloalkyl, amido, Amino, cyano, hydroxy, nitro, C & ind2-4! Alkenyl, carboxyl, tetrazol-5-yl and -CH = CHCOOH, or R & exp1! and R & exp2! together form a group of the formula -CH = CH-CH = CH-, with the specification that at least one of the radicals R & exp1 !, R & exp2 !, R & exp3 !, R & exp4 !, R & exp5! and R & exp6! Carboxyl, tetrazol-5-yl or -CH = CHCOOH, and their salts or esters, in particular their pharmaceutically acceptable salts or esters, which are useful for the prophylactic chemotherapy of allergy, in particular bronchial asthma.

Description

Applicant: Lilly Industries Limited

Henrietta House, Henrietta Place London W. 1 ,, England

Title de r Fiction invention:

Process for the preparation of auron derivatives, pharmaceutical compositions containing them and process for their preparation.

Field of application of the invention:

The invention relates to processes for the preparation of novel aurone derivatives which have a valuable pharmacological activity? pharmaceutical compositions containing them and process for their preparation.

Target of the jj-rf induηg:

Extensive efforts have been made in recent years to find new compounds which are useful in alleviating allergic diseases because there is a particular need for therapeutic agents useful in the treatment of acute hypersensitivity conditions, particularly asthma ,

Presentation of the WeSeHS _{1 of} the invention;

It has now been found that certain aurone derivatives having the following basic structure such a valuable activity

have: 4 11

= CH

The substituted aurones forming an object of the invention may be represented by the following general formula:

, 4

in which mean:

R, R, R, R, R and R, which are the same or different, are each hydrogen, halogen, C ₁ , -alkyl, C ₁ , -alkoxy, C-C-cycloalkyl, optionally substituted phenyl, C- ₁ . Haloalkyl, amido, amino, cyano, hydroxy, nitro, C ^, - Alkenyl, carboxyl, tetrazol-5-yl or -CH = CHCOOH, or wherein R and R "together form a group of the formula -CH = CH-CH = CH - represent,

12 3

with the proviso that at least one of the radicals R, R, R,

4 5 6

R, R and R are carboxyl, tetrazol-5-yl or -CH = CHCOOH,

and their salts and esters, especially their pharmaceutically acceptable salts and esters.

The compounds of the formula (i) may be in the (E) or (Z) form, the (Z) form being preferred *

A particularly preferred group of compounds is one

T O * ϊ Λ ί \ Α

those of the formula (I) in which R, R, R, R, R "and R have the meanings given above, with the proviso that

12 3 when R, R and R are all hydrogen, at least one

4-5 6 of the radicals R, R and R represents tetrazol-5-yl or -CH = CHCOOH. It is further preferred that the benzofuran ring is substituted and a preferred group of compounds are therefore those of formula (i) wherein at least one of R, R and R is other than hydrogen (i.e., not hydrogen).

A particularly preferred group of compounds are those of the formula (I) in which R, R, R, R, R and R have the meanings given above, with the proviso that if one

12 3 of the radicals R, R and R represents carboxyl, at least one of

4 5 6 radicals R, R and R are halogen, C 1 -C 10 -cycloalkyl, optionally substituted phenyl, C 1 -haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl or -CH = CHCOOH. Frequently. it is preferred that at least one of the substituents on the free benzene ring is such a substituent and a preferred group of compounds are therefore those of formula (I) wherein at least one of R, R and R is halogen, cycloalkyl, optionally substituted phenyl , C ₁

Ί-6

HalogensIky1, amido, cyano, nitro, carboxyl, tetrazol-5-yl or -CH = CHCOOH means.

A particularly preferred group of compounds are those of the formula (I) in which at least one of the radicals R, R and R does not denote hydrogen (other than hydrogen)

4 5 6

and at least one of the radicals R, R and R, halogen, C "" "cycloalkyl, optionally substituted phenyl, C, -Haiogen- alkyl, amido. Cyano, nitro, carboxyl, tetrazol-5-yl or

-CH = CHCOOH.

Among the! As used herein, "Hdogen" means, in particular, chlorine, bromine and fluorine. The term "C 1-6 -alkyl" as used herein includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, with methyl, ethyl and tert-butyl being preferred. As used herein, the term "C, alkoxy" includes, for example, methoxy, ethoxy, propoxy, butoxy, with hethoxy being preferred. As used herein, the term "C-" cycloalkyl "preferably means cyclohexyl" -3-o

The term "optionally substituted phenyl" includes, for example, phenyl which is optionally substituted by 1 to 3 substituents selected from the group consisting of methyl, methoxy, halogen and nitro. As used herein, "C., haloalkyl" is, for example any of those detailed above for "C ₁ alkyl" groups substituted by 1 to 3 Halogenatonie, such as fluorine or Qhlor, preferably trifluoromethyl. Dsr used herein, the term "C-, alkenyl" is preferably allyl "R, R, R, R, R and R are preferably selected from hydrogen, halogen, C. _{1-alkyl, C1,} alkoxy, cyclohexyl, Triflüormethyl , M-isopropylcarboxamido, acetamido, dimethylamine, hydroxy, carboxyl, tetrazol-5-yl and -CH = CHCOOH

12 or R and R preferably represent together -CH = CH-CH = CH-.

Other preferred compounds falling within the scope of

Aurones according to the invention of the formula (I) are such

Compounds having one or more of the following characteristics:

a) R is C ₁ -alkyl, preferably methyl

O) R ¹ h) R ¹ i) R ² j) R ³ k) R ⁴ I) R ⁴ ) R ⁴

C _{1 represents} alkoxy, preferably methoxy I -4

is halogen, preferably chlorine is C- "-cycloalkyl, preferably cyclohexyl means amino, carboxyl means a 5- or 6 ~ substituent means hydroxyl means hydrogen means hydrogen is carboxyl means tetrazol-5-yl means -CH = CHCOOH means hydrogen means hydrogen ,

A particularly preferred group of compounds are those of formula (I) in which R C.. Alkyl, carboxyl or halogen, R ² and R ³ is hydrogen ,. R ^{4 is} carboxyl or -CH = CHCOOH and R ⁵ and R are hydrogen. Among these compounds are the

1 2

in which R is alkyl or carboxyl, R and R is hydrogen,

4 5

R is carboxyl or -CH = CHCOOH and R and R are hydrogen, with very particular preference.

According to a preferred embodiment, the invention relates to substituted aurones of the general formula.

, 4

or in which R and R together are a group of the formula -CH = CH-CH = CH-

in which mean:

12 3 4 5 6

R, R, R, R, R and R, which are identical or different, are each hydrogen, halogen, C. alkyl, C., alkoxy, C_ "cycloalkyl, optionally substituted phenyl, C., - halogenoalkyl , Amido, amino, cyano, hydroxy, nitro, C 1-6 alkenyl, carboxyl, tetrazol-5-yl and -CH = CHCOOH, or in which I represents

1 O * ϊ Α

with the proviso that at least one of the radicals R, R, R, R,

5 6

R and R are carboxyl, tetrazol-5-yl or -CH = CHCOOH, and the salts and esters, especially the pharmaceutically acceptable salts and esters thereof,

which can be used for the prophylactic chemotherapy of allergy states, especially bronchial asthma «

The compounds of the formula (i) may also be present in the form of their salts or esters, in particular their pharmaceutically acceptable salts or esters. Such derivatives are obtained, for example, when one or more of the substituents. R, R, R, R, R and R represent the acid function, carboxyl or -CH = CHCOOH. For example, suitable salts include those. Mine Albasen such as alkali metal hydroxides, especially the potassium and sodium salts, alkaline earth metal hydroxides, especially the calcium salts thereof, and those of organic bases such as amines "Preferred esters are those which, alkanols derived yon C. as _ζ β Β. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxyethyl and ethoxy

21

ethyl ester.

The invention further provides a process for the preparation of the aurones of the general formula (i) given above which consists of reacting a benzaldehyde of the general formula

R ⁴

OHC

implemented with

a) a Benzofurcmon of the general formula

R '

• r3

^ U '

III

b) a to-substituted acetophenone of the general formula

»1 0

IV

OH

in which R, R, R, R, R and R have the meanings given above and X denotes an leaving group,

-δ

2

then, if one or more of R, R is R, R, R and R is cyano, optionally followed by reaction with an azide to prepare the corresponding tetrazol-5-yl compound.

As indicated above, the aurones of formula (i) can be prepared by condensing a suitably substituted benzaldehyde (II) with a benzofuranone derivative (HI) as schematically represented by the following reaction equation:

(in)

4 OHC

(H)

(D

Suitable solvents for this reaction include ethereal solvents, such as dioxane and tetrahydrofuran, and liquid alkenols, such as ethanol. The temperature is generally not critical and it only determines the reaction rate. The reaction generally proceeds at all temperatures between the ambient temperature and the reflux temperature of the reaction mixture, for example between 25 and 150 ° C. The reaction is preferably carried out by a

Acid or a base catalyzes. Suitable acid catalysts include mineral acid, such as hydrochloric acid, and strong organic acids, such as p-toluenesulfonic acids, while suitable inorganic or organic catalysts include alkalis, such as sodium hydroxide, potassium hydroxide, sodium carbonate, and triethylamine. This type of condensation reaction is known per se and those skilled in the art will readily appreciate the reaction conditions and reagents required to prepare a particular aurone of formula (i).

An alternative method of preparing compounds of formula (i) comprises reacting a 60-substituted aceto-phenone (IV) with a suitable benzaldehyde (II) as schematically represented by the following reaction scheme:

-f

OHC

  (D

where X is an exiting group, e.g. Halogen, in particular chlorine or bromine, or the Tosyigruppe means.

Suitable solvents include essential solvents such as dioxane and tetrahydrofuran, and liquid alkanols such as ethanol. In this case, the reaction is preferably carried out by

a base catalyzes using a catalyst such as sodium hydroxide, potassium hydroxide or sodium carbonate. Temperaturoh from 0 to 150 C can be used to carry out the reaction. The reactants of formulas (II), (HI) and (IV) are generally known compounds and can be prepared by known methods as described in the literature.

In addition, compounds of formula (i) in which one of the R groups is tetrazol-5-yl can be prepared by preparing the corresponding nitrile and forming the tetrazole therefrom using a preferably non-nucleophilic azide, e.g. Trimethylsilylazide, in a high boiling solvent such as dimethylformamide, at temperatures above

These reactions yield the (Z) isomer, which can be converted into the corresponding (E) isomer, if desired, using methods known in the art.

The aurones of the formula (.1). have been found to be useful in the prophylactic treatment of asthma in mammals. This activity was demonstrated in guinea pigs using the "Herxheimer" test as described in "Journal of Physiology (London)", 1J7, 251 (1952) or using the "chopped guinea pig lung test". as described by Mongar and Schild in the Journal of Physiology (London), TJ3T, 207 (1956), or by Brocklehurst in the Journal of Physiology (London), JJ52, 414 (1960).

The compounds are also active in the "Rat Peritoneal Anaphylaxis Test" based on an allergy reaction in the rat peritoneal cavity as described by Orange, Stechschulte and Austen in "Fed Proc", 28, 1710 (1969) *

The "Herxheimer" test is based on guinea pig-induced allergy bronchospasm, which is very similar to an asthma attack in humans. The mediators that cause the bronchospasm are very similar to those released when a sensitized human lung tissue is challenged with an antigen. The compounds of the invention were active (effective) in the "Herxheimer" test at doses within the range of 25 to 200 mg / kg.

The compounds of formula (I) may be administered by a variety of routes and may be for this purpose in a variety of pharmaceutical agents, although it is a specific feature of the compounds of the invention that they are effective when administered orally. The compounds of the invention can therefore be administered orally and rectally, topically, parenterally, for example by injection, for example in the form of tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, suspensions, aerosols, ointments containing, for example, up to 10 % of Gevj. % of active compound contained (the active ingredient) in a suitable base, in the form of soft and hard gelatin capsules, suppositories, injection solutions and suspensions in physiologically acceptable media _unc J i _n the form of sterile packaged

Powders adsorbed to a carrier material for the preparation of injection solutions. The nature of the various excipients and additives required for the preparation of such drugs or preparations is known per se to those skilled in the art.

However, some examples of excipients that can be used in pharmaceutical compositions or preparations according to the invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silica, microcrystalline cellulose, calciurosilicate, silica, Polyvinyl pyrrolidone, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, theobromene oil, acrchis oil, alginates, tragacanth, gelatin, B * P. syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, Sorbitan sesquioleate and oleyl alcohol, and propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent the sticking and sticking of the powdered components in the molds and punch of the tabletting apparatus. For example, aluminum, magnesium and calcium stearates, talc and mineral oil can be used for this purpose.

The invention furthermore relates to a pharmaceutical agent which contains or comprises at least one compound of the formula (i) and / or at least one pharmaceutically acceptable one

Salt and / or at least one pharmaceutically acceptable ester thereof as an activating ingredient (active ingredient), optionally in combination with at least one pharmaceutically acceptable carrier suitable therefor.

The pharmaceutical agents may be in unit dosage form, each dosage unit preferably containing 5 to 500 mg (5.0 to 50 mg in the case of parenteral administration, 5.0 to 50 mg in the case of inhalation and 25 to 500 mg in the case of oral or rectal administration) of a compound of formula (i). The term "unit dosage form" as used herein refers to physically discrete units suitable as unit doses for humans and animals, each unit containing a predetermined amount of the active ingredient calculated to be used in combination with the required dose pharmaceutical diluent, carrier or excipient gives the desired therapeutic effect.

Doses of from 0.5 to 200, preferably from 1 to 20 mg / kg of the active ingredient per day may be administered, although of course the actual amount of aurone of formula (I) actually administered will be determined by a physician, taking into account the relevant Circumstances including the disease state to be treated, the particular compound administered and the route of administration chosen so that the invention is by no means limited to the above-mentioned dosage range.

The invention is further illustrated by the following examples, but is not limited thereto.

- Ϊ4 -

From f U hruncjsjjei spie le: Example 1

(Z) -4'-Carboxyl-2-benzylidene- 5-methylbenzofuran-3 (2H) -one

8.73 g (O _f O 5 mol) of w-chloro-2-hydroxy-5-ethylacetophenone [Chem. Ber. 4L 4271 (1908)] and 7.5 g (0.05 mol) of 4-carboxybenzaldehyde were dissolved in 100 ml of ethanol and the mixture was heated to 60G. Then, slowly, 4 g (0.1 mol) of sodium hydroxide in 20 ml of water were added to the stirred mixture, which turned deep red. After 1 hour at 60 C, a pale yellow precipitate formed, which was then heated under reflux for an additional hour. The resulting suspension was then cooled to 0 C and acidified with 5 N hydrochloric acid. The pale yellow solid which was obtained was filtered off with Water, dried under reduced pressure and recrystallized from dioxane to give the title compound as pale yellow needles, mp 288-290 ° C (dec.).

The following compounds were prepared in a similar manner using the appropriate benzaldehyde and chloroacetophenone.

(Z) -2'-Carbo-yl _X ^ 2 enzyIiden-.5-methylben _Z ofuran-3 (2H) -one F. ' 187-1

(Z) -2'-Carbo _X yl-2-benzylidene »6-methylbeji _Z ofuran -. 3 (2H) -one, mp 19 <H98 ° C _{(dec #)} _

(Z) -2 '<: a _r bo _X yl-2-ben _Z yHd _e nnopilho (2, lb) furan-3 (2H) -one, F, 2Q7-208 ° C.

-5-isopropyibenzofuran-3 (2H) -one, mp 262-263 ⁰ C.

Example 6 (Z) ~ 3 ⁱ ° Ca rboxy l- "2 ~ benz ylicien-5" niethoxybenz ofuran-3 (2H) - one

6.0 g (0.036 mol) of 5-methoxybenzofuran-3 (2H) -one [Annalen. 405, 281 (19H)] and 5.4 g (0.036 mol) of 3-carboxybenzaldehyde [J. Chem. Soc. 4778 (1952)] were dissolved in 50 ml of dioxane and 10 ml of concentrated hydrochloric acid were added. The resulting yellow solution was then refluxed for 2 hours. After cooling and after the addition of 20 ml of water, a yellow precipitate formed. Upon recrystallization from acetic acid, this material gave the title compound as yellow needles, mp 252-254C.

Examples 7 - 36

The compounds listed below were prepared using a, .ähnliche '' ¹ procedure as in Example 6, wherein the Berizofuran used and the benzaldehyde used were varied in a suitable manner.

(Z) -2'-Carboxyl-2H-benzylidene-6-methoxybenzofuran-3 (2H) -one , m.p. 217-220 ° C (dec.) (Z) -3 ^f -carboxyl-2-benzylidene-6-methoxybenzofuran "3 (2H) -cn,

• F .. 258-260 ° C (dec.). '.

(Z) -4 ^T -Carboxyl-2-benzylidene - 6-meihoxybenzofuran-3 (2H) -one ,

F. 273-275 ° C (Zers.).

(Zj-SM ^ arboxyM-benzylidene-5-methylbenzofuran-i; (2H) -one,

F. 264-265 ⁰ C.

:. (Zj, -Carboyl) -baicylidene-6-methylbenzofuran-3 (2H) -one, m.F. 263-264 ° C

(Z) -4- ^f -arboxyl-2-benzylidene-6-methylbenzofuran-3 (2H) -one,

F. 288-289 ⁰ C

, (Z) -3 ^{f-carboxyl-4'-hydroxy-2-benzylidene} -6-methylbenzofuran-3 (2H) -one F, 290-291 ⁰ C.

(Z) -3 ^{f "f} Carboxyyl-4-hydroxy-2 - ^) enzyliden-benzofuran - 3i2H) -one, F; 268-27O ⁰ C

(Z) ^{-4-carboxyl-2-t} ^ b izyliden-benzofuran-3 (2H) -one,

F. 2'4-275 ° C (Z) ~ 3'-carboxyl-2-aryl-6-chloro-benzofuran-3 (2H) -one,

F. 278-280 ⁰ C

 (Z) -2'-carboxyl-2-benzylidene-5-chlorobenzofuran-3C2H) -one,

F. 205-206 ⁰ C. '

(Z) -3 ^f -carboxyl-2-bizycylidene-5-chlorobenzofuraii-3C2H) -one,, p. 286-288 ° C.

(Z) -4'-arboxyl-2-bQizylidene-6-chloro-zero-furan-3 (2E) -one , ^ F ^ 3

^ W i - 17 -

(Z) -3 ^T -Carboxyl-2-benzylidene. -5-ethylbenzofuran-3 (2H) -one, m.p., 252 ° C.

(Z) -3'-carboxyl-2-benzylidene-berizofuran-3 (2H) -one,

f. 259-26O ⁰ C.

(Z) -4'-i (E) -Carboxyvinyl] -2-benzyiiden-5-methylbenzofuran-3 (2H) -one · F .. 275-276 ⁰ C.

(Z) -3 ^f -Carbosyl-2-bicyclidene-5-cyclohexylbenzofuran-3 (2H) -one, m.p. 252-253 ° C.

(Z) -4 ^T -Carboxyl-2-benzylidene-6-chlorobenzofuran-3 (2H) -one, F ² O 30.

(Z) -2-carboxyl ^f "2-benzyiiden-o-chlorobenzofuran ~ 3 (2H) -one, f. 184 ° C.

, _F. ) F300 ^o C (.

, ·. (ZJ-S'-Carbosyl ^ -benzylidene-6-hydroxybenzofuran "3 (2H)" on,,: '.Fs 320 ° C (Zers.) (Z) -2 ^f -Carbo: cyl ~ 2-benzyiiden- 6-hydroxybensofuran-3 (2H) -one, mp 282-283 ⁰ C.

: (Z) -4 '- [(E) -2-carboxyvinyl] -2-benzyl] iden-5-yl-dichlorobenzofuran-3 (2H) -one, ο F.%, 300 ° C. ΐ

) - "2-carboxyvinyl" ~ 2-benzylidene-5,7-dichlorobenzofuran-3- (2H) -one; -f. 300 ⁰ C "'(Z) -3 ^T - {(E) -2- Carboxyvinyl] -2-benzenediiden-6-hydroxybenzofuran-3- (2H) -one,

(Z) ~ 3 ^r, -C (E) -2-CFFL * boxyAanyl] -2-b ^ n liden - 5-methcxybenzofuran-3- (2H) -one

F .. · 242 ° C. ί

(Z) 3 ~ ⁵ '~ Cai'boxyl 2-benzy3idennaphiho (l, 2-b'> fur-an-3 (2H) -one, F, 276-278 ⁰ C.

F. 28O ⁰ C.

(Z) -3'-Carboxyl-2-ben _2- yndene-4-hydroxybenz _Z ofuran-3 (2H) -on _I , F, 285-287 ⁰ C.

F. 2S8-260 ° C

 Example 37

(Z) -4 ^t - (5-Tetra-2-olyl) -2 "benzylidene-5-chlorobenzofuran" -3- (2H) -one

13.1 g (0.1 mol) of 4-cyanobenzaldehyde, 6.2 g (0.1 mol) of ethylene glycol and 19.0 mg (0.1 mmol) of toluene-4-sulfonic acid were prepared using a Dean-Stark apparatus Refluxed in 100 ml of benzene for 8 hours. The benzene was then evaporated to dryness to give 4-cyano- (2-1.3-dioxalane) benzene as a waxy colorless solid (m.p. 44-45 C) which was used without further purification.

17.1 g (θ, 1 mole) of the above-mentioned dioxalane, 6.5 g (0.1 mole) of sodium azide and 6.5 g (0.15 mole) of lithium chloride were refluxed in 100 ml of 2-methoxytfthanol for 8 hours heated. The suspension was then poured into a mixture of ice and 5N hydrochloric acid. After standing, white crystals of 4- (5-tetrazolyl) benzaldehyde separated from this solution, mp 200 ° C.

This benzaldehyde and 5-chlorobenzofuran-3 (2H) -one [Annalen 2924, 40J5, 346] were reacted together using the procedure of Example to give the title compound, which was recrystallized from dimethylformamide, m.p. 260C (dec. ).

Examples .38 _- 41

The following compounds were prepared in a similar manner using the appropriate cyanobenzaldehydes and the appropriate benzofuranone.

(Z) r-3 '- (5-Tetrazolyl) -2H3enylidene-5-methoxybenzofuran-3 (2H) -one, m.p. 278-280 ° C (dec.)

(Z) -4 ^f - {5-TetrazolyI) -2-benzylidene €.-Hydroxybenzofuran-3 (2H) -one, F. -Soo ⁰ C (ZeM).

(Z) -4 '- (5-Tetrazolyl) -2-benzylidene-5-methoxybenzofuran-3 (2H) -one , m. 268-270 ° C (dec.)

(Z) -3 ^f - <5-tetrazoyl) "2-benzylidene-5,7-dichlorobenzofuran-3 (2H) -ori, m. 283-2S5 ° CCZers.)

_ (Z) "3 ^" ~ (5 "tetra-2-olyl) -2-benzylidene" 5-ethylben2ofuran-3 (2H) -one,

3.4 g (0.02 M _{t o} l) of 5-Äthylbenzofuran-3 (2H) -one [J. Indian Chem. Soc. 42, 20 (1905)] and 2.62 g (0.02 mole) of 3-cyanobenzaldehyde were dissolved in 100 ml of dioxane and 5 ml of concentrated hydrochloric acid was added. The resulting yellow solution was refluxed for 2 hours. Upon cooling, yellow needles of (Z) -3'-cyano-2-benzylidenebenzofuran-3 (2H) -one, F * 162 C, were obtained, which were removed by filtration. 0.5 g (0.0018 mol) of the aurone (0.86 mol) of trimethylsilyl azide was refluxed with dimethylformamide for 6 hours, and the cooled solution was added to a mixture

poured from ice and hydrochloric acid. The suspension was then heated at 70 ° C for 30 minutes and the precipitate formed upon cooling was filtered off. This yellow oily solid gave, after chromatography, the title compound, mp 242-243 ° C.

Example 43

(Z) -2'-carboxy-1-benzylidene-S'-carbomethoxy-o-aminobenzofuran- 3 (2H) -one

8.0 g (0.038 mol) of methyl 3-ocetyl-4-hydroxy-o-2-thiobenzoate in 2Sql ml of dichloromethane was added to 16 g (0.076 mol) of trifluoroacetic anhydride and the solution was stirred for 15 minutes at room temperature. Evaporation gave a pale yellow solution which gave methyl 3-acetyl-4-acetoxy-6-trifluoroacetamidobenzoate, m.p.

17.0 g (0.076 mol) of copper (II) bromide were suspended in 300 ml of ethyl acetate with rapid stirring. To this suspension was added Π 5'g (0.038 mol) of the benzoate obtained above in the form of a solution in 200 ml of ethyl acetate, and the resulting mixture was stirred and refluxed for 3 hours. The pale green copper (I) bromide formed upon cooling was removed by filtration and the solution was evaporated to give a pale yellow solid, which was recrystallized from ether / tetrahydric ether (40-60 C), yielding methylene chloride. bromoacetyl-4-acetoxy-6-trifluoroacetamidobenzoate in the form of white crystals, mp 260 to 261C.

SS f. -21 -

1.9 g (0.005 mol) of this compound and 0.75 g (0.005 mol) of 2-carboxybenzaldehyde in 100 ml of methanol were then heated to 60 ° C. To the stirred solution was added slowly 0.6 g (0.015 mol) of sodium hydroxide in 20 ml of water. The resulting red solution was refluxed for 3 hours and then poured onto a mixture of ice and 5N hydrochloric acid. The resulting yellow solid was filtered off and dissolved in a 10% aqueous sodium bicarbonate solution at 50 ° C. The pH of this solution was adjusted to 7 and Amberlite Resin IRA-401 in the hydroxy form was added. The resin was then filtered off and washed, first with water and then with glacial acetic acid. Concentration of the acetic acid washings gave the title compound as shiny yellow prisms, mp 280C (dec.).

Example 44

(Z) -3'-Carboxy1-2-benzyIiden-5,7-dibromo-4-hydroxybenzofuran-3-

88 g (0.4 mol) of finely ground copper (II) bromide were suspended in 200 ml of a 50:50 mixture of ethyl acetate and chloroform. To the above suspension was added 10 g (0.0ό57 mol) of 2,6-dihydroxy · acetophenone in 20 ml of chloroform, followed by stirring at reflux for 8 hours, whereby hydrogen bromide was evolved The above reaction formed copper (l) bromide filtered off and the di-e solution was evaporated to dryness to give 3, 5-dibromo-2,6-dihydroxy-io-bromo

^! acetophenone, mp 1 50 ° C. 8.2 g (0.21 mol) of this ί ^ -bromoacetophenone and 20 g of sodium acetate were refluxed for 15 minutes in 100 ml of 90 t ethanol. After cooling and after the addition of 100 ml of water, the greenish solid precipitated from the yellow solution was recrystallized from ethanol / water, giving .5,7-dibromo-4-hydroxybenzofuran-3 (2H) -one, m.p. ° C (Zers.) _E

The benzofuran-3 (2H) -or "was then reacted with 3-carboxylbenzaldehyde using the procedure described in Example 6 to give the title compound, R 2 F 2 C (dec.).

- Example e 45 ond 46

/. ' The following compounds were prepared using V similar procedure to Example 44 and using the appropriate benzaldehyde:

300 ° C. (Dec.)

(Z) -2 ^f -carboxyl-2'-benzylid3n-5,7-dibromo-4-hydroxybenzofiiran-3f 2 H) -one

F. 258-260 ⁰ C

Example 47

(Z) -4 '- [(E) ^ - GJR boxyvinyl] -2-ben zy the Ii -6 ~ a mi no-5-c ya no ben' zo fura.n-3 (2H) -one

4 ~ amino ~ 5-cyano-2-hydroxyacetophenoh _i [JCS Perkin I 1979, 3, 6771 was performed using the United described in Example 43

This acetophenone was then brominated using copper (II) bromide according to the procedure described in Example 44 to give 4-trifluoroacetamido-5-cyano = 2-hydroxy-bromoacetophenone, mp 202C.

3.8 g (0.011 mol) of the Cu bromoacetophenone were dissolved in 50 ml of aqa, nol, and excess sodium acetate (10 g) was added along with 10 ml of water. The mixture then became 20 ^; Refluxed for minutes and after cooling -. .- fancy orange solid was made from ethanol / water

recrystallized to give orange platelets of 6-amino. 5-Feyanobenzofuran-3 (2H) -one, mp 270C (dec.).

This benzofuran was then reacted with (E) -4-formylcinnamic acid using the procedure described in Example 6 '"to give the title compound as orange crystals, 100 ° C.

Example 48

88 g (0.5 mol) of 4-cyclohexylphenol and 39 g (0.5 mol) of acetyl chloride were heated together to 170 C for 3 hours. The resulting clear liquid was then cooled to 100 ° C. and long-scrm Γ33 g (1.0 ^- MoJT) of aluminum chloride was added The brown sticky oil was then heated at 130 ° C. for 5 hours After cooling, ice and chlorine water became -

added and the phenol was extracted with chloroform. This extract was then evaporated to dryness and the residue was subjected to steam distillation to give 2-acetyl-4-cyclohexylphenol as a clear oil. This phenol was then reacted with copper (II) bromide using the procedure described in Example 43. This reaction gave 2-bromoacety1-4-cyclohexylphenol as a yellow oil. This oil was dissolved in 100 ml of ethanol and 44 g of sodium acetate and 20 ml of water were added. This solution was then refluxed for 10 minutes, cooled, and after the addition of water, a brown oil which was extruded with chloroform separated out. Evaporation of the chloroform extract to dryness afforded the 5-cyclohexylbenzofuran-3 (2H) -one, which was then reacted with 3-carboxybenzaldehyde using the procedure of Example 6 to give the title compound as yellow crystals, m.p. 253 C.

Example 4 9

(Z) -3 ^f , 4 ', 5'-trimethoxy- "2-benzylidene-5" -carboxy-bonofuran ~ 3- (2H) -one _ _ ' _ __

a) 126 g (0.65 mol) of methyl ~ 4-acetoxybenzoate and 220 g (1.63 mol) of aluminum chloride were intimately mixed with each other, stirred and reacted at 160 C by the method of G .. Dora et al, Eur J. Med. Chenu 1978, 13, 33. The crude solid product obtained after the acid treatment was stirred with a saturated sodium bicarbonate solution and the mixture

was filtered. The filtrate was carefully acidified to give the 3-acetyl-4-hydroxybenzoic acid, which was filtered off, washed with water and dried, m.F.

The insoluble solid from the above bicarbonate extraction was dissolved in a dilute 2N sodium hydroxide solution and cautiously acidified with a dilute 5N hydrochloric acid solution to give methyl 3-acetyl-4-hydroxybenzoate, which was filtered, washed with water, and after the drying had a F. of 90 to 92 C.

b) 24.0 g (0.133 mol) of 3-acetyl-4-hydroxybenzoic acid were dissolved at 40 C in 400 ml of dioxane and 10.2 ml (0.14 mol) of bromine were added dropwise with stirring. The color soon faded and after 45 minutes the clear supernatant liquid was decanted off some insoluble material and evaporated to dryness to give a light straw-yellow solid, 3H-bromoacetyl-4-hydroxybenzoic acid, F 22 C.

c) The product of step (b) was dissolved in ethanol / water (350 ml / 70 ml), 30 g of sodium acetate added and the solution was stirred at 60 ° C. for 10 minutes »The resulting deep orange solution became The resulting pale yellow solution was diluted with an equal volume of water and placed in a refrigerator overnight. The yellow crystalline solid was filtered off, washed with cold water and dried, yielding 10 g 5-Carboxybenzofuran "-3 - * (2H) -one was obtained, F ₅ 204 C (Zers").

d) 3.5 g (0.02 mol) of 5-coco-carboxy-benzofuran-3- (2H) -one and 3.92 g (0.02 mol) of 3,4,5-trimethoxybenzaldehyde were dissolved in 50 ml of warm dioxane 10 ml of concentrated hydrochloric acid were added and the mixture was stirred and gently heated in a steam bath for 15 minutes. After cooling and after adding an equal volume of water, the yellow crystalline solid was filtered off, washed with water and dried. After recrystallization from glacial acetic acid gave the title compound, mp 290 C.

The following compounds were prepared using a similar procedure to Example 49:

(Z) -2-Benzylidene "-5-carbycosbenzofuran" 3- (2H) on. ·, F, 28O ⁰ C.

F.> 300 ° C.

(Z) -2'-chloro-4-dimethylamino-2-benzylidene-5-carboxybenzofuran-3 (2H) on: m. 275 ° C (dec.) -

(Z) -4 ~ ^T-butyl 2-benzynden "-3-carboxybenzofuran-3- {2H) -one, F., 252 ⁰ C.

(Z) ^{-4-dimethylamino-2-t} ben2yUden "" 5 ~ ~ carboxybeczofuraji 3- (2H) -one, mp 295 ⁰ C.

(Z) -4-methoxy-2 ^f - öenzyliden - 5-carboxybenzofuran-3- (2H5on <, F. 300 ° C.

(Z) -4 '- [(E) -2-carboxyvinyl] -2-benzylidene- ⁱ -5-carboxybenzofuran3- (2H) on, F. > 300 ° C.

(Z) -3 ^f arboxyM ^T Hhydroxy-2-benzylidene-5-carboxyben-25-furan-3- (2H) one , m.p.> 300 ° C.

(Z) -Acetamido-2-bisylisidene-5- <2arboxybenzofuran-3- (2H) one, m.p> SOO ⁰ C

(Z) -3 ^r -Trifluoromethyl-2-benzybutene-5-carboxybenzofuran-3- (2H) on,. F.284 ° C.

(Z) -3MN-Isopropylcarboxamido) -2-benzyIiden - 5 - carboxy-benzofuran-3- {2H) -one 300 ⁰ F. G.

Example 6)

5-Ca rbpxy1-6-hydroxybenzofo τα η-3- (2H) -one

α) 21.1 g (0.094 mol) of o-acetyl ^^ - dimethoxybenzoic acid [iBer. 41 , 1607, 1908] were stirred in 200 ml of dioxane at room temperature and 5 ml (about 0.1 mol) of Brora were added dropwise * The bromine color gradually disappeared over a period of 30 minutes and the mixture was then placed in a steam bath 30 Weakly warmed for minutes, cooled and the dioxane was removed in vacuo. The solid product was treated with boiling ethyl acetate, filtered hot, and the filtrate was evaporated to give 5'-bromoacetyl-2,4-dimethoxybenzoic acid, m.p. 236 ° C. '

b) 21.6 g (0.071 mol) of the product obtained in step (a) were stirred in 250 ml of dichloromethane, cooled in an ice bath

and 25 ml of bread ribromide were added dropwise. The solution was then refluxed for 4 hours in a water bath. The mixture was carbonized and poured onto 1 kg of ice. After removal of the dichloroisethane, the resulting pink solid was filtered off, washed with water, sucked dry and dissolved in ethanol / water (200 ml / 80 ml). 25 g of sodium acetate were added and the solution was warmed to 60 C for 30 minutes. After cooling and after removal of the ethanol in vacuo, a further 150 ml of water were added. The solution was cooled in an ice-bath and a 5N hydrochloric acid solution was added dropwise with stirring until reaching pH 2. After overnight storage in a refrigerator, the resulting pale yellow crystalline solid was filtered off, washed with water and dried to give the title compound , F. 216C.

Example 62

(Z ^ S ^ ^ Cbrboxyl benzylidene-S-carboxyl-o-hydroxybenzofuran-S- _r C2H) _- ._ _ on .......

5.82 g (0.03 mol) of 5 "carboxy-6-hydroxybenzofuran-3- (2H ^ on were dissolved in 75 ml of dioxane, to which was added 4.50 g (0.03 mol) of 3-carboxybenzaldehyde, and thereafter The solution was heated slowly on a steam bath for 30 minutes with occasional stirring and the solid mixture was cooled, diluted with an equal volume of water and kept in a refrigerator for 1 hour. "The product was filtered off, with water

«29 -

washed and dried. After recrystallization from dimethylformamide, the desired compound was obtained, mp 335 C (dec.).

Examples 63 and 64

The following compounds were prepared using a similar procedure to Example 62:

(Z) -3K-arboxyl-4-hydroxy-2-benzylidene - 5-carboxy-6-hydroxybenzofuran-3- (2H) one,

F. 332 ° C (decomp.) '·

(Z) -4 '- -2-benzylidene (5-tetrazol yl ~). i-5-carbosyl-6-hydroxy-benzofuran-3- <2H) -one F. 327 ^ -28 ⁰ C (dec.) '

Example 65

(Z) -3'-carboxyl-1-benzylidene-S-methoxycarboxybenzofuran-S- (2H) -one- _si . _ _ _Mi '_ ..

5.39 g (0.028 mol) of methyl 3-acetyl-4-hydroxybenzoate were stirred at 40 ° C. in 200 ml of dioxane and 1.5 ml of bromine were added dropwise. After 45 minutes, the colorless solution was evaporated to give a straw-colored oil which was dissolved in ethanol / water (75 ml / 15 ml). 6.0 g of sodium acetate was added and the solution was stirred for 5 minutes at room temperature. The red solution was poured onto 100 g of ice and extracted into chloroform. After evaporation of the chloroform extract gave 5 ~ ~ methoxycarbonylbenzofuran-3 (2H) -one

50 ι - 30 -

in the form of an orange-red oil (purity 65 % according to NMR).

This product was immediately dissolved in 50 ml of dioxane, 4/5 g (0.03 mol) of 3-carboxybenzaldehyde was added, then 10 ml of concentrated hydrochloric acid was added and the solution was heated on a steam bath for 15 minutes. After working up as in Example 19 with recrystallization from dimethylformamide to give the desired aurone, mp 280 C.

For example, 66 (Z) -3 ^< -carbox yl-2 -benzylidene-6-oceta- midobenzofura n-3 ~ (2H) -one

a) 64.5 g (0.5 mol) of 3-aminophenol and 200 ml of acetic anhydride were stirred and heated for 2 hours on a steam bath. The straw-colored liquid was evaporated in vacuo to give a viscous oil which was heated to 110 to 120 ° C, with stirring while slowly adding 170 g (1.27 moles) of aluminum chloride. After 30 minutes, the solid product was cooled slightly and cautiously with about 500 g of ice / water, and then 200 ml of concentrated hydrochloric acid was decomposed, then it was stirred well and slightly heated on a steam bath. After cooling, the crystalline solid was filtered off, washed with water and dried to give the desired compound 2-hydroxy-4-acetamidoacetophenone, m.p.

b) 14.0 g (0.072 mol) of the product from step (a) were dissolved in 300 ml of ethyl acetate and added to a stirred suspension of

Add 32 g (0/143 mol) of copper (II) bromide in 100 ml of ethyl acetate. The mixture was refluxed for 4 hours, then filtered while hot, and the filtrate was evaporated in vacuo to give an oil which crystallized. This solid was converted to benzofuran and reacted with 3-carboxybenzaldehyde as in Example 65. During this reaction, however, the product was partially deacetylated and reacted further with 20 ml of acetic anhydride at reflux to convert it to the fully acetylated compound. This reaction mixture was poured onto 100 g of ice and the excess acetic anhydride was hydrolyzed. The resulting solid was filtered off and recrystallised from glacial acetic acid / water (50 v / v 1/0) to give (Z) -3'-carboxyl-2-benzylidene-6-acetamidobenzofuran ~ 3 ~ (2H). -on, F. 305 C (Zers.), received.

(Z) - '4' -chloro-2-benzyl-the -5-n-butoxycarbonyl 1-benzofuran -3- (2H) -

3.0 g (0.01 'mol) of (Z) -4 ^L ~ chloro-2'-benzylidene-5-earboxybenzofuran-3- (2H) -one were suspended in 50 ml of n-butanol, 1.5 g ml of concentrated sulfuric acid was added dropwise with stirring and the mixture was heated under reflux for 5 hours. From the resulting yellow solution precipitated on cooling yellow flaky needle-shaped crystals of the desired n-butyl ester. The crystals were filtered off, washed with cold n-butanol, then with diethyl ether and dried, mp 154 C *

Ex iel 68 ^ E) ^-4> chloro-2-ben-2-ylidene-5 ~ n -butoxycarbonylbenzofuran - 3 - (2H) '- on

1.0 g of (Z) -4 ^l -chloro-2-benzylidene-5-n-butoxycarbonylbenzofuran-3- (2H) -one was dissolved in 800 ml of benzene and irradiated for 15 hours in a 1 l Hanovia photochemical reaction vessel , The solution was evaporated in vacuo to give 1.0 g of solid, mp about 130 g, with an E / Z isomer ratio of 75/25 (based on NMR and HPLC).

500 mg of this solid was chromatographed on a Sorbsil-Si.licagel powder (200 g) using benzene as a developing solvent and the faster moving (E) -isomers containing fractions were collected. These fractions were combined and evaporated to give a yellow crystalline solid, yield 350 mg, mp. H2 ° C, E / Z isomer ratio 88/12.

200 mg of this solid were recrystallized from dichloromethane / petroleum ether 40 to 60 C (1/3 by volume) to give 130 mg of a crystalline solid, F "142 C, E / Z isomer ratio 92.5 / 7.5.

The following preparations were prepared by using the compound (Z) -3'-carboxyl-2-benzylidene-5-chlorobenzofuran ¹ -3- (2H) -one as the active ingredient (active ingredient) and other compounds of the present invention similar preparations or preparations are produced.

CfI f - 33 -

Example 69

Using the components listed below, hard gelatin capsules were prepared:

Quantity (mg / capsule) active compound (active ingredient) 250 dried starch 200 magnesium stearate 10

The above components were mixed together and filled into hard gelatin capsules.

Example 70

Using the following components, a tablet preparation was prepared.

active compound (active ingredient) 250 * microcrystalline cellulose 400 fumed silica 10 stearic acid 5

The components were mixed together and pressed into tablets.

Example 71

An aerosol solution was prepared containing the following components:

Active ingredient (active ingredient) 0.25 Ethanol 29.75

Propellant 22

(Chlorodifluoromethane) 70

The active compound (the active ingredient) was mixed with ethanol and the mixture was added to the Propellant 22, cooled to -30 C and transferred to a filling device. The required amount was then introduced into a stainless steel container and further diluted with a metered amount of Propellant 22. The valve units were then placed on the container.

Example 72

A suppositories preparation was prepared containing 200 mg of the active compound using the following components:

active compound (active ingredient) 200 mg Polyethylene glycol 1000 750 mg

Polyethylene glycol 4000 250 mg

The active compound (the active ingredient) were melted with the

Glycol bases and then the mixture was poured into suitable suppository molds which gave the active fill weight.

Example 73

An ointment having the following composition was prepared: '

active compound (active ingredient) 1 wt -.% white soft Ραχ-affine ad - 100%

The active compound was added to the molten paraffin and then the mixture was allowed to cool.

Claims (9)

T 51 973 invention claim 1. A process for the preparation of a Auronderivats of the general formula (D in which mean: 12 3 4 5 6 R, R, R, R, R and R, which are the same or different from each other each are hydrogen, halogen, C ₁ , - »alkyl, C, -, alkoxy, C ₀ " cycloalkyl, optionally substituted phenyl, ο-o C ₁ , haloalkyl, amido, amino, cyano, hydroxy, nitro, C ₀ .- alkenyl, carboxyl, tetrazol-5-yl or -CH = CHCOOH, 12 ..
or in which R and R together form a group of the formula -CH = CH-CH = CH-, 12 3 with the proviso that at least one of R, R, R, R, R and R represents carboxyl, tetrazol-5-yl or -CH = CHCOOH, and the salts and esters, in particular the pharmaceutically acceptable salts and esters thereof in that a benzaldehyde of the general formula OHC (IR) implemented with α) a benzofuran of the general formula (Πι) b) a tO ^ substituted acetophenone of the general formula , 1 0 (IV) OH wherein R , R, R, R, R and R have the meanings given above and X represents an leaving group, 1 2 then what if one or more of the radicals R, R , 3 4 5 0 R, R f R and R cyano, optionally followed by a reaction with an arid to prepare the corresponding tetrazolo! 5-yl compound. 2 «method according to item 1, characterized in that ^ a compound of formula (I) is prepared in which at least 12 3 one of the radicals R, R rad R is not hydrogen. 3 · Method according to item 1 or 2, characterized in that a compound of formula (I) is prepared in which 4 5 6 at least one of R, R and R is halogen, C. _Q ~ -cycloalkyl alkyl, optionally substituted phenyl, C, haloalkyl, amido, cyano, nitro, carboxyl, Teti ^- azol-5 ~ yl or -CffcCHCOOH means. 4 · A method according to any one of items 1 to 3, characterized in that oaß a compound of formula (I) is produced,  j 2 3 in the at least one of the radicals R, R and R is not water- 4 5 6 s-tovefef and at least one of the radicals R / R and R is halogen, C- »cycloalkyl, optionally substituted phenyl, C, N, -halogens: alkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl or -CH = CHCOOH. 5. Process according to one of the items 1 to 4, characterized in that a compound of the formula (i) is prepared / 1 2 3 in the R C,. alkyl, carboxyl or halogen, R and R water 4 5 6 substance, R is carboxyl or -CH = CHCOOH and R and R are hydrogen. 6. The method according to item 5, characterized in that a compound of formula (I) is prepared, in the R C. 2 3 4 Alkyl or carboxyl, R and R are hydrogen, R is carboxyl or 5 6 -CK-CHCOOH and R and R are hydrogen. 7. The method according to any one of items 1 to 6, characterized in that a compound of the formula (I) is prepared, in which R is C, -alkyl, < 1-4 ' 8 «method according to one of the items 1 to 6, characterized in that a compound of formula (i) is prepared, in which R is C.-alkoxy. 9. Process according to one of the items 1 to 6, characterized in that a compound of the formula (i) is prepared in which R represents carboxyl. « 10 «method according to one of the points 1 to 9, characterized in that a compound of formula (I) is prepared, .2 3 in which R and R are hydrogen. Method according to one of the items 1 to 10, characterized in that a compound of the formula (I) is prepared, 4
in which R represents carboxyl. 12. The method according to any one of items 1 to 10, characterized in that a compound of formula (I) is prepared, 4
in which R is tetrazol-5-yl. 13. The method according to any one of items 1 to 1Ο _# characterized in that a compound of formula (I) is prepared, in which R ^{4 is} -CH = CHCOOH. 1.4 »Process according to one of the items 1 to 13, characterized in that a compound of the formula (I) is prepared, In def E ' ^? and R ^ö mean hydrogen »