CS214807B2 - Method of making the derivatives of the auron - Google Patents

Description

(54) Method of producing auron derivatives

The present invention relates to a process for the preparation of novel auron derivatives having significant pharmacological activity.

In recent years, great efforts have been made to find new compounds useful for alleviating allergic diseases; in particular, there is a need for therapeutic agents that are effective in the treatment of immediate hypersensitivity conditions, such as asthma.

The present inventors have found that certain auron derivatives having a structural formula

have such efficiency.

The present invention allows for the production of novel substituted aurons of the formula I in which the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , which may be the same or different, each represent a hydrogen atom, a halogen atom, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, amido, amino, cyano, hydroxyl, carboxyl, 5-tetrazolyl or -CH = CHCOOH, or R ¹ and R ² together represent -CH = CH-CH = CH-, with the proviso that at least one of R ^1, R ^2, R ^3, R ^4, R ^5, and R ⁶ represents a carboxyl group, a 5-tetrazolyl group or a group of the formula - CH = CHCOO'H, and is 214807 of their pharmaceutically acceptable salts or esters.

Compounds of formula I may exist in either the (EJ- or the (ZJ-form), the (ZJ-form being more preferred).

A more preferred class of auron derivatives according to the invention are those compounds of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, but with the proviso that when all three substituents R ¹ R ² and R ³ represent hydrogen atoms, at least one of R ⁴ , R ⁵ and R ⁶ represents a 5-tetrazolyl group or a group of the formula —CH — CHCOOH. It is preferred that in the compounds of the invention the benzofuran ring is substituted, and therefore, those compounds of formula I wherein at least one of R ¹ , R ² and R ³ is other than hydrogen are preferred.

Another preferred class of auron derivatives according to the invention are those compounds of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, but with the proviso that when one of the R substituents ^l, R ² and R ³ represents a carboxyl group, denotes at least one of R ^4, R ^N and R ^c halogen, cycloalkyl having 3 to 8 carbon atoms, halogenoalkyl having 1 to 6 carbon atoms, amido, cyano, carboxyl, 5-tetrazolyl or -CH = CHCOOH. It is often preferred that at least one of substituents to separate the benzene ring is one such substituent, and therefore preferred are those compounds of formula I in which at least one of R ^4, R ^5, and R ^G represents halogen, cycloalkyl having 3 C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyl, amido, cyano, carboxyl, 5-tetrazolyl or the group -CH = CHCOOH.

A particularly preferred group of new derivatives Auron invention are compounds of formula I in which at least one of R ^1, R ² and R ³ is other than hydrogen and at least one of R ^4, R ^5, and R ^f> represents halogen, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, amido, cyano, carboxyl, 5-tetrazolyl or -CH = CHCOOH.

The term "halogen atom" as used herein refers to a chlorine, bromine or fluorine atom. The term "C 1 -C 6 alkyl" includes, for example, methyl, ethyl, popyl, isopropyl, butyl, tertiary butyl, pentyl and hexyl, with methyl, ethyl or tertiary butyl being preferred.

The term "alkoxy". C 1 -C 6 includes, for example, methoxy, ethoxy, propoxy, butoxy, preferably methoxy. The term "C 3 -C 8 cycloalkyl" preferably refers to a cyclohexyl group.

For example, the term "C 1 -C 6 haloalkyl" refers to any of the groups included in the term "C 1 -C 6 alkyl" substituted with one to three halogen atoms such as fluorine or chlorine, and preferably denotes trifluoromethyl. It is preferred that R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 be} selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyclohexyl, trifluoromethyl, N-lsopropylkarboxamidovou group, acetamido, dimethylamino, hydroxy, carboxyl, 5-tetrazolyl and a group of formula -CH = CHCOOH, or when R ¹ and R ² together represent -CH = CH-CH = CH—.

Other preferred auron derivatives included within the scope of Formula I are those having one or more of the following characteristics:

a) R ¹¹ represents a C 1 -C 6 alkyl group such as a methyl group;

b) R ¹ is C 1 -C 4 alkoxy, such as methoxy;

c ¹ R ¹ represents a halogen atom such as a chlorine atom;

d ¹ R ¹ represents a C 3 -C 8 cycloalkyl group such as a cyclohexyl group;

e) R ¹ is amino;

f JR ¹ denotes a carboxyl group;

g) R ¹ denotes a substituent in the 5-position or

6-;

h ¹ R ¹ represents a hydroxyl group;

i) R ² is hydrogen;

j) R ³ represents a hydrogen atom;

k) R ⁴ represents a carboxyl group;

l) R ⁴ represents a 5-tetrazolyl group;

m) R ⁴ represents a group of formula -CH = -CHCOOH;

nj R ⁵ represents a hydrogen atom;

o R ^G represents a hydrogen atom.

A particularly preferred group of auron derivatives according to the invention are those compounds of formula (I) wherein R @ ¹ is C1 -C4 alkyl, carboxyl or halogen, R @ ² and R @ ³ are hydrogen, R ^{@ 4} is carboxyl or of the formula -CH = CHCOOH, and R ⁵ and R ⁶ represent hydrogen atoms. Of this group of most preferred are those compounds of formula I wherein R ¹ is alkyl or karboxylobou group, R ² and R ³ are hydrogen, R ⁴ represents a carboxyl group or

2W4W7 group of formula --CH2 GHGQOH, ^{1a ;} R ⁵ and R ® translate hydrogen atornes:

The compounds of formula (I) may be used in the form of their pharmaceuticals according to the invention. suitable salts or esters. T & Ktová derivatives ¹ can be prepared »example ¹ when they do not take a multi substittientů R ^1, R ^2; R ^{3, R 1} · R ^{5 and} R® idea jfkyseloufunkci, Jaker · karboxylovou- group or 'a group of formula "-CH = CHCGQH. ¹ like- suitable salts are used, e.g., 's- salts with inorganic bases ^1; such as alkali metal hydroxides; in particular potassium or sodium salts or salts with metal hydroxides of alkali metal, especially calcium salts; or salts with organic bases, such as ¹ with amines, as esters, can be - preferably - used for esterified alkali atoms having 1 to 4 carbon atoms; for example ¹ methyl-, ethyl-, propyl-, isopropyl-, butyl-, tert-butyl-, methoxyethyl- or ethoxyethyl- ethers.

The novel auron derivatives of the formula I according to the invention can be prepared by substituting a substituted benzaldehyde of the formula III;

in which R ' ⁴ , R ⁵ and R ⁶ are as defined above, reacts with ω-substituted. acetOphenone. of formula IV,

wherein R ¹ , R ² and R ³ are as defined above and X is a leaving group, and optionally in the compound of formula (I) obtained, at least one of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} converted to another; and the resulting compound of formula (I) is optionally converted to a pharmaceutically acceptable salt or ester.

In the preparation of the compounds of formula (I), the ω-substituted acetophenone of formula (IV) is reacted with the corresponding benzaldehyde of formula (III) as shown in the following reaction ^. sohé »atú ..

In the general formula (IV) in the above scheme, X represents a leaving group such as, for example, a halogen atom, especially a chlorine or bromine atom, or. a tosyl group. The reaction is carried out in an environment of a suitable solvent, for example an ether, such as dioxath. or tetrahydrofuran; or in a liquid alkanol such as ethanol; The reaction may conveniently be catalysed by bases such as sodium hydroxide, potassium hydroxide or sodium carbonate. The reaction proceeds at temperatures ranging from 0 ° C to 150 ° C. The reactants of the general formulas. III and IV are mostly known compounds and can be prepared by known routine; procedures described in the literature.

Compounds of formula (I) in which one of the substituents R is a 5-thrazolyl group can be prepared from the next nitrile by treating preferably non-nucleophilic azides, for example, trimethylsilyl azide, in a high boiling solvent such as dimethylformamide, such as dimethylformamide. C.'

These reactions give the (Z) -isomers which, if desired, can be converted to the corresponding ones. (Eyedimeters of photochemical methods well known to those skilled in the art.

Ahtoors of the invention. found that the aurons of Formula I are effective in the prophylactic treatment of asthma in mammals. The " activity " (London) 17, 251 (1952), and further, in testing on isolated lung strips of guinea pigs described by Mongara Schlld: in the journal Journat of 'Physiology (London)' 3; 207 (1956). or: Brockleburst in Journal of Physiology (London), 52/414 (1960). The compounds of formula I are also effective in the peritoneal anaphylaxis test in rats. which · consists in controlling the allergic reaction, peritoneal cavity, in the rat, and which, described by Orange, Steehschulte and Abstén in the journal. Prou. 28, 1710 (1960).

Hérxheimer's dough-is based on herring? The effect of the test compounds on allergic bronchial spasm (hronchospasms) induced by guinea pigs, which are very likely to be asmatic in humans. Mediates causing hronchospasms are very similar to those that are released when the tissue is sensitized. human lungs is. ignited by an anti-antigen. The compounds of formula (21807) I exhibit efficacy in the Herxheimer assay at doses ranging from 25 d: 0-200 mg / kg.

The Aurones of Formula I may be administered by a variety of routes and may be formulated into a variety of dosage forms for this purpose; however, a special property of the compounds of the invention is that they are effective when administered orally. The compounds of formula I may be administered orally, rectally, locally or parenterally, for example by injection, in the form of, for example, tablets, troches, sublingual tablets, sachets, capsules, elixirs, suspensions, aerosols, ointments, e.g. in the form of soft or hard capsules, suppositories, injectable solutions and suspensions in a physiologically acceptable environment and sterile packed powders adsorbed to a suitable carrier for the preparation of injectable solutions. The nature of the various excipients and additives required to manufacture said compositions is well known to those skilled in the art.

Examples of suitable additives and excipients which can be used in the pharmaceutical compositions of the invention include lactose, glucose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffins, white soft paraffin, kaolin, silica powder, microcrystalline cellulose, calcium silicate, calcium silicate Silica gel, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum arabic, calcium phosphate, cocoa butter, ethoxylated esters, cocoa oil, arachis oil, alginates, traganite, gelatin, syrup BP, methylcellulose, monolaurate, polyoxyethylene sorbitol, polyoxyethylene sorbitol propylhydroxybenzoate, sorbitan trioleate, sorbitam tetraoleate and oleyl alcohol, and suitable propellants include, for example, trichloronofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the preparation of tablets, glidants may be added to the tablet mixture to prevent sticking and adhering of the sprayed components to the punches and punches of the tabletting machines. For example, aluminum, magnesium or calcium stearate, talc or mineral oils may be used.

The invention also includes pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or ester thereof as an active ingredient and a pharmaceutically acceptable carrier. Said pharmaceutical preparations may conveniently be presented in unit dosage form, each unit dosage containing preferably 5 to 500 mg of a compound of formula I (5.0 to 50 mg for parenteral administration, 5.0 to 50 mg for inhalation) and up to .500 mg for oral or rectal administration). The term "unit dosage form" as used in the specification and the subject matter of the invention refers to physically discrete individual doses of the formulation suitable as individual doses for humans and animals, each unit dose containing a predetermined amount of active ingredient determined to produce the desired dosage. A therapeutic effect, together with the required pharmaceutical diluent, carrier or vehicle.

The Aurones of Formula I may be administered at a total dose of 0.5 to 200 mg of active ingredient per kilogram of patient's weight, preferably at a dose of 1 to 20 mg / kg daily. It will be understood, however, that precise dosages of the compounds of Formula I administered on a case-by-case basis will be determined by the physician based on other serious circumstances such as the condition being treated, the type of compound administered and the route of administration chosen. limitations of the invention.

The process according to the invention is explained in more detail in the following examples.

Example 1 (Z) -4‘-Carboxyl-2-benzylidene-5-methylbenzofuran-3 (2H) -one

To a solution of <<) - chloro-2-hydroxy-5-methylacetophenone (8.73 g, 0.05 mol) [Chem. Ber. 41, 4271 (1908)] and 4-carboxybenzaldehyde (7.5 grams, 0.05 mol) in ethanol (100 mL) at 60 ° C, with stirring, are slowly added sodium hydroxide solution (4 g, 0.1 mL). mol) in water (20 mL); the mixture turns dark red. After one hour at 60 ° C, a pale yellow precipitate formed, which was heated at reflux for an additional hour. The resulting suspension was cooled to 0 ° C and acidified with hydrochloric acid (5M). The light yellow colored product obtained is filtered off, washed with water, dried under reduced pressure and recrystallized from dioxane. The title compound is obtained in the form of yellow needle crystals, m.p. 288 DEG-290 DEG C. (dec.). Examples 2 to 5

The following compounds were prepared as described in Example 1, but using the appropriately substituted benzaldehydes and chloroacetophenones:

(Z) -2‘-carboxy-2-benzylidene-5-methylbenzofuran-3 (2H) -one, m.p. 187-189 ° C;

(Z) -2‘-carboxy-2-benzylidene-6-methylbenzofuran-3 (2H) -one, m.p. 196-198 degrees C (dec.);

(Z) -2‘-carboxy-2-benzylidene-naphthalene (2,1-b) furan-3 (2H) -one, m.p. 207 DEG-208 DEG C .;

(Z) -4‘-carboxy-2-benzylidene-5-i-propylbenzofuran-3 (2H) -one, m.p. 252-253 ° C.

Claims (1)

SUBJECT A process for the preparation of auro, nu derivatives of the general formula I according to the invention (I) in which the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , which may be the same or different, each represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an amido group, an amino group, a cyano group, a hydroxyl group, 5-tetrazolyl or a group of formula -CH = CHCOOH, or in which R ¹ and R ² together represent -CH = CH-CH = CH-, with the proviso that at least one of R ^1, R ^2, R ³ , R ⁴ , R ⁵ and R ⁶ represent a carboxyl group, 5-tetrazolyl or a group of formula -CH = CHCOOH, and pharmaceutically acceptable salts or esters, characterized in that a substituted benzaldehyde of the formula III wherein R ^4, R ⁵ and R ⁶ have the above meanings, is reacted with an ω-substituted acetophenone of formula IV, wherein R ¹ , R ² and R ³ are as defined above and X is a leaving group, and optionally at least one of the substituents R ¹ , R ² , R ³ in the compound of formula I obtained R ⁴ , R ⁵ and R ^{6 are} converted to another substituent within the scope of formula I and / or the compound of formula I obtained is optionally converted to a pharmaceutically acceptable salt or ester.