IT8224817A1 - Process for preparing 2 (3H) -benzofuranones, some new 2 (3H) -benzofuranones and pharmaceutical compositions containing them - Google Patents

Description

DESCRIPTION

of the industrial invention entitled:

"Process for preparing 2 (3H) -benzofuranones, some 2- (3H) -benzofuranones and other pharmaceutical compositions containing them".

SUMMARY

New process for preparing 2 (3H) -benzofuranones by simultaneous hydrogenolysis of benzyl hydroxyl and condensation of new (o-hydroxyaryl) -methanols.

Some of the 2 (3H) -benzofuranones so? obtained are new and are equipped with activities? anti-inflammatory, anti-pyretic, analgesic and antiplatelet agent.

Pharmaceutical compositions containing the new 2 (3H) -benzofuranones.

DESCRIPTION

The present invention relates to a new process for preparing 2 (3H) -benzofuranones, the new 2 (3H) -benzofuranones so? obtained and the pharmaceutical compositions containing them.

The German patent application 2,608,697, the European patent application 33 * 614, the English patent 1 * 494 * 773 describe some 2 (3H) -benzofuranones endowed with activity? anti-inflammatory, antipathic, analgesic and antiplatelet agent.

U.S. Pat. 4 * 120,871 discloses other physiologically active 2- (3H) -benzofuranones.

Specific 2 (3H) -benzofuranones can be obtained by particular procedures such as the oxidation of the corresponding 2-hydroxy, 2-alkoxy, 2-dialkylamino, or 2-alkanoyloxy-benzofurans but, to date, the only method that has a certain applicability? general consists in the condensation of o-hydroxy-arylalkanoic acids in an acid environment, A. Mustaf ?, The Chemistry of heterocyclic compounds (Weissberger Ed.) - Vol. XXIX - Pubi, by Wiley & Son 1974 pag. 251-79 *

But the difficulties? inherent in the synthesis of o-hydroxy-a relalkanoic acids do not make available many types of 2 (3H) -benzofu ranones or make them available at very high costs and such as to discourage possible practical applications.

Now ? It has been surprisingly found that the 2 (3H) -benzofuranones can be easily prepared by treatment of new (o-hydroxyaryl) -methanols whose preparation? has been described in the Italian patent application No. 22076 A / 82 of 28.6.1982.

Pi? precisely the procedure essentially consists in the simultaneous hydrogenolysis and condensation of compounds of formula (I)

where n? 1, 2 or 3;

R? hydrogen, alkyl with 1-3 carbon atoms, phenyl optionally substituted by one or more? halogens, alkyls with 1-4 carbon atoms or alkoxy with 1-3 carbon atoms; each R ', equal or different from the others,? alkyl with 1-6 carbon atoms, cycloalkyl with 3- 8 carbon atoms, phenyl optionally substituted by one or more? halogens, alkyls with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, benzyl optionally substituted by one or more? halogens, alkyls with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, possibly substituted heterocycle? from one or pythialogens, alkyls with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, halogen, -0-A, -S-A, OCO-A where A? hydrogen, alkyl with 1-6 carbon atoms, phenyl optionally substituted by halogen, alkyl with 1-4 carbon atoms, so-called alkoxy with 1-3 carbon atoms or, finally,? two adjacent R 'groups, taken together, can represent the groups necessary to complete an alicyclic ring with 5-6 C atoms, phenyl or heterocyclic; And

R "is 1-4 carbon hydrogen or alkyl;

to give the 2 (3H) -benzofuranones of the formula:

(II)

Specific examples of substituted phenyl are 2-chlorophenyl, 4-bromophenyl, 2,4-difluorophenyl, 2,4,6-trichlorophenyl, 4-hydroxyL phenyl, 3-methoxyphenyl, 2-chloro-4-methoxyphenyl, 2,4-dimethoxyphenyl , 3, 4, 5-trimethoxyphenyl, 2-bromo-4-propoxyphenyl, 2-fluoro-4-ethoxyphenyl.

Specific examples of heterocycles are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-pyrimidyl, 2-pyrazyl, 3-pyridazyl, 3-quinolyl, 1-isoquinolyl, 3,6-methyl-pi ridyl, 3- (5,6-dimethyl) -pyridyl, 3- (6-methoxy) -pyridyl, 2? (5? Chloro) -furyl, 2- (3-bromine) -N -benzyl-pyrrole.

Examples of the meanings assumed by the two radicals R 'when taken together are: 1,3-propanediyl (-CH2-CH2-C-H2), 1,4-bii tandiyl (-CH2-CH2-CH2-CH2-), methoxy-methyl (-CH20CH2-), etJ_ tndioxy (-O-CH2-CH2-O-), 1,3-butadienylidene (-CH = CH-CH = CH-). Preferably two radicals R 'complete a benzene ring; specific and preferred examples of these products have formula

(Ila ') (II a ")

where R has 1 meanings seen more? above n = 1 or 2 and each L equal or different from the other,? hydrogen, hydroxyl, alkoxy with 1-3 carbon atoms or alkyl with 1-4 carbon atoms.

The simultaneous hydrogenolysis and condensation of compounds (I) is carried out in the presence of a mineral or organic protic acid and a reducing agent known to the skilled in the art such as, for example, (a) acid / metal, (b) hydrogen / catalyst in an acid medium or (c) hydrogen iodide or its precursors.

Typical examples of metals are zinc, tin and iron in the form of powders, shavings or wires used in quantity? pi? than stoichiometric. When is a mineral acid used? it is preferable to carry out the reaction in the presence of an organic solvent at a temperature higher than 60 ° C. Metal salts with reducing power such as tin, chromium and ranadium salts can be used in the place of the metals; they are used in quantity? at least stoichiometric at a temperature between room temperature and 150? C.

Typical examples of catalysts which can be used in the presence of hydrogen are palladium, platinum, rhodium, iridium, nickel and ruthenium supported on silica carbon or in the form of soluble complexes with suitable ligands. Similar mind can? copper chromite must be used, always in the presence of hydrogen. In these cases, the hydrogenolysis is carried out at temperatures between 25? and 100? C, under hydrogen pressures ranging from 1 to 50 atmospheres.

Compounds (I) are subjected to hydrogenolysis and condensation preferably in the raw state, that is? Certain obtained according to the Italian patent application No. 22076 A / 82 of 28.

6.1982.

Many compounds (II) are new, they therefore constitute a further object of the present invention.

Pi? precisely they are new compounds of formula

(The B)

where R has the meanings seen more? above, and R1, R, R and R. the same or different from each other, have the same meanings seen more? above for R 'provided that

(a) at least one of the groups R1, R, R and R? other than i (b) R, R or R are not halogen, alkyl, hydroxy, thio ether, alkoxy or alkanoyloxy when R? 1-6 carbon alkyl, 3-8 carbon cycloalkyl or unsubstituted phenyl and R? hydrogen or alkyl with 1-3 carbon atoms; or (c) R1, R, R and R are not hydrogen, alkyl, halogen or alkoxy when R? unsubstituted phenyl; or (d) R not? unsubstituted alkyl, cycloalkyl or phenyl when R, R and R are hydrogen and R? hydrogen or alkyl with 1 - 3 carbon atoms; or

(e) R and R not? -O-phenyl or -S-phenyl optionally substituted by alkyl, hydroxy, alkoxy or halogen when R and R are hydrogen and R? hydrogen or alkyl.

The compounds (Ilb) are endowed with activity? anti-inflammatory, antipyretic and analgesic as well as? of activity? anti-platelet aggregation.

Specific compounds (IIb $ are those in which (a) R = R = H, R R4 are the necessary atoms

to complete a methoxy-naphthalene ring, R = CH3

Therefore, the present invention also relates to the pharmaceutical compositions which contain the compounds (IIb).

These compositions may contain the active ingredient together with pharmaceutical, organic or inorganic, solid or liquid excipients and may be suitable for oral, parenteral or rectal administration.

The finished pharmaceutical forms can be solid, such as for example tablets, sugared almonds, capsules, powders, granules, suppositories, candles, or liquid such as for example solutions, suspensions, emulsions.

They can also be prepared in such a way that the release of the drug after administration is prolonged over time.

In addition to the excipients, they may contain preservative agents, stabilizers, humectants, emulsifiers, salts for regulating the osmotic pressure, buffers, dyes, flavorings, etc.

They can be prepared according to known methods and can contain other therapeutic principles.

The following examples are used to illustrate the invention without, however, limiting it.

EXAMPLE 1

6-roethoxy-3-methyl- (3H) -benzofuran-2-one

1- (2'-hydroxy-4'-methoxyphenes1) -1-methyl-1-ethyloxycarbonyl-methylnol (0.89 g .; 3.7 mnoles) was heated in acetic acid (40 ml) for 4 hours at 80 ? C in the presence of powdered zinc (0.49 g .; 7.5 mmoles). The mixture was then hydrolyzed with water and extracted with methylene chloride. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was purified by chromatography on silica 60 gel column (Merk 70-230 mesh) eluting with 9: 1 n-hexane / ethyl acetate.

The chromatographic fraction was evaporated in vacuum; was obtained co s? a viscous oil (0.4 g.); yield, $ 60.

Working in a similar way they were prepared

EXAMPLE 2

3-methyl- (3H) -benzofuran-2-one

1 g. of Pd / C at 10% was introduced into a Teflon autoclave and 1- (2'-hydroxyphenyl) -1-methyl-1-ethyloxycarbonyl-methanol (10.5 g .; 0.05 mmol), acetic acid was added (150 ml) and paratoluenesulfonic acid (0.5 g?). The autoclave was charged with hydrogen at a pressure of 10 atmospheres and stirred at 50? C.

The hydrogenation was followed by withdrawing at successive times aliquots of solution (0.5 ml.) Until the reagent disappeared (12 h). In the end it cooled down? the autoclave, you discharged? the content by filtering the catalyst and washing it with 10 ml of acetic acid. The filtrate was distilled by reducing the volume to about 50 ml. The remaining solution was cold treated with water and ethyl ether; the organic phase separated and the aqueous phase was re-extracted with ethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with n-hexane / tile acetate (8: 2). After evaporation were obtained cos? 6.5 g. of pure 3-methyl- (3H) -benzofuran-2-one. Yield, $ 88.

Claims (1)

1. process for preparing the compounds of formula (II) where ne l, 2 or 3} R? hydrogen, alkyl with 1-3 carbon atoms, phenyl optionally substituted by an opi? halogens, alkyls with 1-4 carbon atoms or alkoxy with 1-3 carbon atoms; each R ', equal or different from the others,? alkyl with 1-6 carbon atoms, c? chloalkyl with 3-8 carbon atoms, phenyl optionally substituted by one or more? halogens, alkyl 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, benzyl possibly substituted by one or more? halogens, alkyls with 1-4 carbon atoms, alkyls with 1-3 carbon atoms, heterocycle possibly replaced by one or more? halogens, alkyls with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, halogen, -O-A, -S-A, OCO-A where A? hydrogen, alkyl? to 1-6 carbon atoms, phenyl optionally substituted by halogen, alkyl to 1-4 carbon atoms and alkyl to 1-3 carbon atoms or, finally, two adjacent R? groups, taken together, can represent the necessary groups to complete a 5-6 C, phenyl or heterocyclic alicyclic ring; characterized in that the compounds of formula undergo hydrogenolysis and condensation (THE) where R "is hydrogen or alkyl with 1-4 carbon atoms and n, R and R1 have the meanings seen above; in the presence of a prptic acid and a reducing agent. 2. Process according to claim 1, characterized in that the reducing agent? a metal, a metal salt, hydrogen iodide or a precursor thereof, hydrogen and a suitable catalyst. 3 Process according to claim 2, characterized in that the metal? zinc, tin and iron. 4 Process according to claim 2, characterized in that the metal salt? a salt of tin, chromium or vain god. * Compounds of formula where R? hydrogen, alkyl with 1-3 carbon atoms, phenyl optionally substituted by one or more? halogens, alkyls with 1-4 carbon atoms or alkoxy with 1-3 carbon atoms; R1, R, R and R, equal or different from each other, are alkyl with 1-6 carbon atoms, cycloalkl with 3-8 carbon atoms, phenyl possibly substituted by one or more? halogens, alkyls with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, benzyl optionally substituted by one or more? halogens, alkyls with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, heterocycle possibly replaced by one or more? halogens, alkyls with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, halogen, -0-A, -S-A, OCO-A where A? hydrogen, alkyl with 1-6 carbon atoms, phenyl optionally substituted by halogen, alkyl with 1-4 carbon atoms and alkoxy with 1-3 carbon atoms or, finally, two adjacent R 'groups taken together, can represent the groups necessary to complete a 5-6 C atom ring, phenyl or heterocyclic; provided that (a) at least one of the groups R1, R, R and R? other than hydrogen; And (b) R, R or R are not halogen, alkyl, hydroxy thio ether, alkoxy or alkanoyloxy when R? 1-6 carbon alkyl, 3-8 carbon cycloalkyl or unsubstituted phenyl and R? hydrogen or alkyl with 1-3 carbon atoms; or (c) R1, R, R or R are not hydrogen, alkyl, halogen or alkoxy when R? unsubstituted phenyl; or (d) R not? unsubstituted alkyl, cycloalkyl or phenyl when R, R or R are hydrogen and R? hydrogen or alkyl with 1-3 carbon atoms; or (e) R or R not? -O-phenyl or -S-phenyl optionally X replaced by alkyl, hydroxy, alkoxy or halogen when R and R are hydrogen and R? hydrogen or alkyl. 6. Pharmaceutical compositions containing a quantity? pharmacologically active of a compound according to the preceding claim 5 and pharmaceutically acceptable excipients.