CS252495B2 - Method of benzofuranalkyl and benzothiophenylalkyl acids' new substituted derivatives production - Google Patents

Description

The invention relates to a process for the preparation of certain novel substituted derivatives of benzofuranalkyl and benzothiophenkyl acids. In particular, the invention relates to benzofuran-5-ylacetic acid and benzofuran-5-ylpropionic acid derivatives as well as benzothiophen-5-ylacetic acid and benzothiophen-5-ylpropionic acid, optionally substituted in the 6-position and containing an aroyl substituent in the 7-position. it also relates to 2,3-dihydro analogs of the above compounds or pharmaceutically acceptable salts thereof, all of which have the general formula I

(i) where

R @ 1 represents a hydrogen atom or a group of the formula

H _O C - CH - CH - CH _O ² I t ²

OH OH or

H _n C ² I

CH

AND

O

R

CH in which R represents the same alkyl group having 1 to 6 carbon atoms,

X ^ denotes an oxygen atom or a sulfur atom,

Ar represents an unsubstituted phenyl group or a phenyl group independently substituted with at least one substituent selected from the group consisting of methoxy, chlorine or fluorine, methylsulfinyl, methylsulfonyl or methylthio, and the dashed line represents a single or double bond, and (1) - and (d) - isomers of propynoic acid derivatives or propionates.

The compounds of formula (I) are suitable for the preparation of pharmaceutical compositions in admixture with pharmaceutically acceptable excipients. These pharmaceutical compositions containing a compound of formula I are used as analgesics, as anti-inflammatory and anti-inflammatory agents for mammals by administering effective amounts of the compositions comprising a compound of formula I together with a pharmaceutically acceptable excipient or an effective amount of the compound of formula I alone.

The invention thus relates to a process for the preparation of compounds of the formula I and their pharmaceutically acceptable salts, which comprises reacting a compound of the formula II

wherein the aforementioned meaning is an alkyl group with an aroyl acid halide and then optionally converting the ester of formula I to the free acid, or converting the ester of formula I to a salt, or converting a pharmaceutically acceptable salt to another pharmaceutically acceptable salt or converting an ester of formula (I) to another ester of formula (I), wherein in the produced compounds the individual symbols have the meanings given above.

The reaction with the aroyl acid halide is preferably carried out in an organic solvent at reflux temperature.

The compounds of formula (I) fall into two subgroups, depending on whether X ^ is oxygen or sulfur. Within both of these subgroups, preferred compounds are those wherein Ar is phenyl, wherein the phenyl is unsubstituted or is independently substituted with at least one of methoxy, chloro or fluoro, methylthio, methylsulfinyl or methylsulfonyl.

The most preferred compounds are: 7-benzoylbenzofuran-5-ylacetic acid, d, 1- 2- (7-benzoylbenzofuran-5-yl) propionic acid, 7- (4-methylthiobenzoyl) benzofuran-5-ylacetic acid, 7- (4 -chlorobenzoyl) benzofuran-5-ylacetic acid, d, 1-2- [7- (4-methylthiobenzoyl) benzofuran-5-yl] propionic acid ad, 1-2- [7- (4-chlorobenzoyl) benzofuran- 5-yl] propionic acid.

the numbering of the benzofuran and benzothiophene structures is as follows:

Individual terms used have the following meanings:

By alkyl is meant a group containing only carbon and hydrogen atoms with fully saturated bonds and containing 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isoamyl, pentyl, isopentyl and hexyl.

the term halogen atom refers to a fluorine or chlorine atom.

The term methylthio refers to a methyl group attached to an aryl group via a sulfur atom.

The term methylsulfinyl means a methyl group that is attached to the aryl group via the -SO- group as a bridging member.

By methylsulfonyl is again meant an aryl-linked methyl group through the group -SO ₂ '.

The phenyl core may be substituted only by a hydrogen atom, or it may be independently substituted by one or more of the groups defined in the definition of Ar. By independently substituted, it is meant that the core has more than one substituent, the substituents being the same or different. The combination of substituents is not particularly limited.

The phenyl core may be substituted with a single substituent selected from the group consisting of methoxy, chloro, fluoro, methylsulfinyl, methylsulfonyl, and methylthio. If the phenyl core contains only one substituent, the substituent is preferably in the 4-position, i.e. in the para-position, although it may alternatively be in the ortho or meta position. If the phenyl core has several substituents, it is most preferred that they are of the same type, although they may also be different. The position of several substituents is due in part to the chemistry of their preparation. There are no particular requirements for their location, especially for the various substituents. However, in the case of the trisubstituted phenyl ring, the substituents are most often in the 2, 4 and 6 position. The present invention also includes a process for preparing compounds of formula I with a pentasubstituted phenyl ring, where all 2, 3, 4, 5 and 6 positions are substituted. or methyl.

Since the aromatic ring is substituted by a methyl group and / or when Ar is a phenyl group substituted by a methylsulfinyl group, the compounds of formula I can be prepared either in optically active form or in the form of racemic mixtures. Unless otherwise indicated, all of the disclosed compounds are in racemic form. However, it is not intended that the invention be limited to this racemic form; it is to be understood which individual optical isomers of the compounds of formula (I) are meant.

The compounds of the formula I can optionally be resolved into their optical antipodes by methods known per se, for example, by separation (e.g., fractional crystallization) of diastereomeric salts prepared by reacting these compounds with optically active acids. Any other suitable method may be used to achieve such separation.

The isolation and purification of the compounds of formula (I) prepared by the process of the invention and intermediates thereof may be carried out by any suitable method, for example by filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography or a combination thereof. Specific explanations of suitable separation and isolation methods are provided in the following examples. Of course, any equivalent separation and isolation methods may be used.

The pharmaceutically acceptable salt may be any salt derived from an inorganic or organic base that does not interfere with the efficacy of the parent compound and is non-toxic to the subject.

Salts can be derived from inorganic ions such as sodium, potassium, lithium, ammonium, calcium, magnesium, divalent iron, zinc, sword, divalent manganese, aluminum, trivalent iron and trivalent manganese. Particularly preferred salts are the ammonium, potassium, sodium, calcium and magnesium salts. Pharmaceutically acceptable salts derived from organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexyamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, thoebromine, purines, piparazine, piperidine, n-ethylpiperidine, polyamine, n-ethylpiperidine, polyamine . Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

The compounds of the formula I and their pharmaceutically acceptable non-toxic esters and their salts are suitable as analgesic agents, as anti-inflammatory agents, as anti-fever agents, as vascular spasm inhibitors, as migraine, as platelet coagulation inhibitors, as fibrinolytic agents, as smooth relaxants muscles (for example, to treat painful marigolds). The compounds of formula (I) prepared by the process of the invention can be used for both prophylactic and therapeutic purposes.

The compositions containing the compounds of formula (I) prepared according to the invention are thus suitable for the treatment of pain and for the treatment and elimination of inflammation. The compositions are also suitable for relieving pain that is not necessarily associated with inflammation, such as migraine and postoperative pain. In addition, these compositions may be used to treat other conditions such as pyrexia, platelet clotting, smooth muscle relaxation, vasospasm and the like.

Screening assays using small animals to determine analgesic efficacy include an analgesic test in the mouse (anti-wicking) as described by Hendershot and Forsaith, J. Pharmacol. Exp. Ther., 125, 237-240 (1959).

Screening assays to determine anti-inflammatory activity include carragenine-induced rat paw inflammation as described by Winter et al., Proc. Soc. Exp. Biol. Copper. 111,

544-547 (1962) and a granuloma test using a cotton pellet in rats as described by Meier et al., Experientia 469-471 and modifications thereto.

In addition, the anti-inflammatory activity in certain cases can be evaluated using the adjuvant arthritis assay described by Pearson, Proc. Soč. Exp. Biol. Med., 91, 95-101 (1956). In vitro assays are also possible, for example using the synovial explants of patients with rheumatoid arthritis described by Dayer et al., J. Exp. Copper. 145, 1399-1405 (1977). All of these tests are suitable for assessing whether the compounds of formula I have anti-inflammatory activity.

In general, the potential anti-magnesium effect is judged by the anti-inflammatory activity determined in the above tests.

Inhibition of platelet clotting is assessed by the turbidimetric method described by Born, J. Physiol., (London) 1962, pp. 67-68 (1962).

Potential smooth muscle relaxant activity is determined in vitro using the method of Vickery, Prostaglandins, Med., 1979, 2, 299-315, or Vickery, Prostaglandins Med., 2, 225-235 (1979).

Administration of the active compounds of the formula I in the form of suitable pharmaceutical compositions is possible by any suitable conventional means for the administration of compositions for the treatment or prevention of pain, inflammation or fever. For example, administration can be oral, parenteral or topical in the form of solid, semisolid, or liquid dosage forms such as tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, aerosols, ointments and the like. preferably in the form of unit doses suitable for single administration of precise doses. The pharmaceutical compositions may contain conventional pharmaceutical carriers or excipients and the active ingredient of formula (I) and may additionally contain other medicinal agents, pharmaceutical compositions, carriers, adjuvants or similar substances.

A preferred route of administration from the above methods is oral administration with a conventional daily dosage regimen adjusted for the degree of disease. In general, a dosage of 0.02 to 0 mg / kg body weight of active compound of the formula I per day is administered. Most often, a daily dose of 0.05 to 2 mg / kg body weight is administered. For example, when treating a 70 kg person, the daily dose will be 1.4 to 1400 mg, preferably 3.5 to 140 mg.

For such oral administration, pharmaceutically acceptable non-toxic compositions are prepared by incorporating any normally used excipients such as mannitol pharmaceutically pure, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. Such compositions are formulated as solutions, suspensions, tablets, pills, capsules, powders, and the like.

Preferably, the pharmaceutical compositions are in the form of pills or tablets, and therefore the compositions contain, in addition to the active compound of the formula I, a diluent such as lactose, sucrose, dicalcium hydrogen phosphate, a disintegrant such as starch or derivatives thereof, a lubricant such as magnesium stearate; similarly, and a binder such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof, and the like.

Generally, pharmaceutically acceptable compositions comprise from about 1% to about 90% by weight of a pharmaceutically active compound of the invention and from about 99% to about 10% by weight of a suitable pharmaceutical excipient. Preferably, they comprise 3.5 to 60% by weight of a pharmaceutically acceptable compound, the remainder being a pharmaceutically acceptable excipient.

The active compounds of the formula I can be formulated as suppositories using, for example, polyethylene glycols (PEG), for example polyethylene glycol 1000 (96%) and polyethylene glycol 4000 (4%) as carriers. Pharmaceutical compositions administered in liquid form may be prepared, for example, by dissolving, dispersing and the like methods of the active compound described above and optionally excipients in a carrier such as water, saline, aqueous dextrose, glycerin, ethanol and the like to form a solution or suspension. . Optionally, the pharmaceutical compositions may also contain minor amounts of non-toxic excipients such as wetting and emulsifying agents, pH buffering agents and the like. Examples of such non-toxic substances are sodium acetate, sorbitan monolaurate and triethanolamine oleate and the like.

Actual methods of preparing such dosage forms are known or deductible to those skilled in the art. They are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 16th edition, 1980. In any case, the pharmaceutical compositions should contain the active compound (s) of formula I in a pharmaceutically acceptable amount depending on the particular conditions of treatment.

The compounds of formula (I) are also uterine smooth muscle relaxants and are therefore also useful as means for maintaining pregnancy in pregnant mammals that are beneficial to the mother and / or fetus until such time as is considered to be medically terminated. However, in cases where, for example, labor has already begun, i.e. contraction of the mother's uterus, especially during the period of expected labor, administration of the compounds described herein cannot prolong pregnancy. However, in cases where pregnancy is intended to be slightly prolonged, which prolongation would be beneficial to the mother and / or the fetus, the active compounds of the invention are useful.

However, the compounds of formula I are useful as a means of delaying or postponing the onset of labor. By delaying the onset of labor is meant delaying the onset of labor by administering the active compound of formula I at any time prior to the onset of uterine muscle contractions. This means avoiding abortion by premature labor before the fetus is viable and delaying premature labor, which is sometimes used to refer to premature labor later in pregnancy when the fetus is viable. In both cases, the compositions are administered prophylactically to counteract the onset of labor. This administration is particularly suitable for women who have already had spontaneous abortions or premature births (that is births before the calculated date). Such administration is also useful where there are clinical indications that pregnancy could end before such a term and would be considered beneficial to the mother and / or fetus.

With respect to animals, such treatment can also be used to synchronize births in a group of pregnant animals so that births occur approximately at the same time or at a desired time and / or at a desired location where labor can be more easily managed.

By postponing delivery is meant postponement of labor due to the administration of the compounds of formula I when the uterine muscle contractions have already begun. The condition of the woman, including the period of pregnancy when contractions have begun, the severity of the contractions and the duration of contractions influence the results obtained with the compounds of Formula I. For example, the intensity and / or duration of contractions may be reduced. Depending on the condition of the woman, in both cases the delivery may be prolonged and the effect may be weak or stronger in certain circumstances. Such administration may prevent spontaneous abortion, labor may be facilitated and less painful to the mother, or may be advanced to a more appropriate time and / or place.

In all cases, administration of the compounds of Formula I as uterine smooth muscle relaxants as set forth herein would be consistent with best and / or acceptable medical or supine medicine practices, as well as having the most beneficial effect on the mother and fetus. However, administration is not continued if the fetus dies in the uterus.

In the treatment, a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition thereof, is administered to pregnant mammals by any suitable method known in the art. The compound may be administered either alone or in admixture with another compound or compounds as mentioned above, or in admixture with pharmaceutical compositions, carriers, and the like. Such a compound or compounds of formula I or such compositions may be administered orally, parenterally, either in the form of solid, semi-solid, or liquid dosage forms. As a rule, pharmaceutical compositions comprising a pharmaceutically active agent and one or more pharmaceutical carriers or excipients are administered.

The administrable pharmaceutical compositions may take the form of oral tablets, vaginal or uterine tablets or suppositories, pills, capsules of liquid solutions, suspensions or the like, preferably in unit dosage forms suitable for single administration of precise dosages. Common non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.

The active compound mentioned above can be formulated into suppositories using, for example, polyalkylene glycols, for example polypropylene glycol as carrier. Liquid pharmaceutical compositions can be prepared, for example, by dissolving, dispersing and the like of the above active compound and suitable pharmaceutical excipients in a carrier such as water, saline, aqueous dextrose, glycerin, ethanol and the like to form a solution or suspension. Optionally, pharmaceutical compositions containing minor amounts of nontoxic excipients such as wetting or emulsifying agents, buffers and the like, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and the like can also be administered. Appropriate methods of preparing such dosage forms are known to those skilled in the art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 16th Edition, 1980. The composition to be administered in each case contains the active compound or compounds in the active compound. amounts to postpone the onset of labor, or to prolong labor if contractions of the uterus have already occurred. The general daily dose of the active compound is 0.5 to 25 mg / kg body weight, with a single daily dose or from 3 to 4 smaller doses per day. The amount of active compound administered depends on its relative potency.

The starting materials for the preparation of the compound of formula (II) are either known from the literature and in part also commercially available or can be prepared by the sequence of reactions described in our related Czechoslovak patent No. 252-76.

The following examples illustrate the invention without restricting it in any way. Unless otherwise stated, reactions are carried out at room temperature, where room temperature is 20-30 ° C.

Example 1

Process for the preparation of ethyl N - (7- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-yl) acetate]

To a solution of 10.0 g of ethyl [2,3-dihydrobenzofuran-5-yl acetate] in 120 ml of dichloromethane and 9.0 g of 4-methylthiobenzoyl chloride was added 12 ml of tin (II) chloride. The mixture is maintained at reflux for about 3 hours, cooled and added to water. The aqueous solution was extracted with dichloromethane, the combined extracts were washed with water, dried over sodium sulfate, and evaporated to give ethyl ([6- (4-methylthiovenzoyl) -2,3-dihydrobenzofuran-5-yl) acetate, m.p. 66 ° C.

If the procedure is similar, 1-replaced with the appropriate aroyl chloride, 4-methylthiobezoyl chloride, may be prepared by the corresponding .alpha.-arylsubstituted 2,3-dihydrobenzofuran and 2,3-dihydrobenzothiophene salts of ethyl-.alpha. 5-yl / acetate or alkoxy or alkyl-6-substituted benzofurans.

Example 2

A process for the preparation of ethyl β-1,1-2- (7-4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-yl propionate

To a solution of 4.15 ml of isopropylcyclohexylamine in dry tetrahydrofuran at 0 ° C was added 16.6 ml of a 1.6 M n-butyllithium solution. After 30 minutes, the solution was cooled to -78 ° C and added to a solution of 9.0 g of ethyl Q (7- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-yl) acetate in 100 mL of tetrahydrofuran at temperature -78 ° C. After 30 minutes, 4.0 mL of iodomethane was added to this solution while maintaining the temperature at -78 ° C. The solution is allowed to warm to room temperature over the next 30 minutes. After a further two hours at room temperature, the solution was poured into ice / ethyl acetate and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulphate and evaporated after chromatography to give the title compound as an oil.

Using this method, all other acetate compounds prepared by the method of Example 1 can be converted to the corresponding propionates.

Example 3

Process for the preparation of 7- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-ylacetic acid

A solution of 10.0 g ethyl- [7- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-yl] acetate 50 ml of methanol, 200 ml of water and 1 g of sodium hydroxide is maintained at reflux temperature.

4 9 5 for approximately 2 hours. The reaction mixture was then cooled and washed with ether. The ether-washed aqueous residue was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The combined organic extracts were washed with water and evaporated to give a residue which was recrystallized from acetone / hexane. 7- (4-Methylthiobenzoyl) -2,3-dihydro-benzofuran-5-ylacetic acid, m.p. 150 DEG-152 DEG C., is obtained.

If the procedure is similar, but the ethyl 1- (7- (4-methylthiobenzoyl) - [2,3-dihydrobenzofuran-5-ylacetate] is replaced by any of the 2,3-dihydro compounds prepared according to Examples 1 and 2, the free acids can be obtained, as illustrated on the following compounds:

148-150 ° C, 2-benzoyl-2,3-dihydrobenzofuran-5-ylacetic acid, m.p. 170-171 ° C, 7- (4-chlorobenzoyl) -2,3-dihydrobenzofuran-5-ylacetic acid, 7- (2,6-difluorobenzoyl) -2,3-dihydrobenzofuran-5-ylacetic acid, m.p. 161-163 ° C; 7- (2-thiophenylcarbonyl) -2,3-dihydrobenzofuran-5-ylacetic acid, m.p. 111-112 ° C, 7-benzoyl-2,3-dihydrobenzothiophen-5-ylacetic acid, m.p. 167-169 ° C, and 7- (4-chlorobenzoyl) -2,3-dihydrobenzothiophen-5-ylacetic acid, m.p. Mp 137-138 ° C.

Example 4

Process for the preparation of 2,3-dihydroxyprop-1-yl-β- (4-methylthiobenzoyl) benzofuran-5-yl acetate

To a solution of 1.5 g of 2,2-dimethyl-1,3-dioxolan-4-ylmethyl-7- (4-methylthiobenzoyl) benzofuran-5-yl acetate in 30 ml of acetone is added 10 ml of 10% hydrochloric acid and stirred under stirring. of room temperature for 12 hours. This solution was then added to an ether / water system, extracted with ether, washed six times with water, dried and evaporated. Chromatography on silica gel yields the prepared 2,3-dihydroxypropan-1-yl-7- (4-methylthiobenzoyl) benzofuran-5-yl acetate, m.p. 88-90 ° C. If the procedure is similar but using the appropriate 2,2-dialkyl-1,3-dioxolane-4-methyl compound of Example 1, additional 2,3-dihydroxyprop-1-yl esters of the invention are prepared.

Example 5

A process for the preparation of sodium 7- (4-chlorobenzoyl) benzofuran-5-yl acetate

To a solution of 250 mg of 7- (4-chlorobenzoyl) benzofuran-5-ylacetic acid in 5 mL of methanol was added 1 molar equivalent of sodium hydroxide as a 0.1 N solution. The solvent is evaporated to dryness and the residue is taken up in 2 ml of methanol and then precipitated with ether to give sodium 7- (4-chlorobenzoyl) benzofuran-5-yl acetate.

Similarly, other salts, such as ammonium and potassium salts of 7- (4-chlorobenzoyl) benzofuran-5-ylacetic acid, are prepared using ammonium hydroxide or potassium hydroxide instead of sodium hydroxide.

Similarly, other acetic acid and propionic acid derivatives prepared by the method of Examples 3 and 4 can be converted to the corresponding sodium, potassium and ammonium salts, as exemplified by the following compounds:

sodium 7- (4-methylthiobenzoyl) benzofuran-5-ylacetate, m.p. 130 DEG C. (as trihydrate) and potassium 7-4-methylthiobenzoyl / benzofuran-5-ylacetate, m.p. 148-151 DEG.

Example 6

Process for preparing calcium 7-benzoylbenzofuran-5-yl acetate

To a solution of 200 mg of 7-benzoylbenzofuran-5-ylacetic acid in 5 mL of methanol was added 1 molar equivalent of potassium hydroxide as a 0.1N solution to give a solution containing 7-benzoylbenzofuran-5-ylacetate. A solution of 60 mg of calcium carbonate in the minimum amount of 1N hydrochloric acid required to dissolve the calcium carbonate is buffered with 150 mg of solid ammonium chloride, followed by the addition of 5 ml of water. The thus obtained buffered calcium solution is then added to a potassium 7-benzoylbenzofuran-5-yl acetate solution and the precipitate formed is collected by filtration, washed with water and air-dried to obtain calcium 7-benzoylbenzofuran-5-yl acetate.

Similarly, magnesium 7-benzoylbenzofuran-5-yl acetate was prepared using magnesium carbonate instead of calcium carbonate.

Similarly, using other carboxylic acids of Examples 3 and 4 instead of 7-benzoylbenzofuran-5-ylacetic acid, the corresponding magnesium and calcium salts are obtained, as exemplified by the following salt:

Calcium 7- (4-methylthiobenzoyl) benzofuran-5-yl acetate, m.p. 148 DEG C. (decomposition).

Example 7

A process for the preparation of cupric 7- (4-methoxybenzoyl) benzofuran-5-yl acetate

To a solution of 200 mg of 7- (4-methoxybenzoylbenzofura-5-ylacetic acid) in 5 ml of methanol was added 1 molar equivalent of potassium hydroxide as a 0.1N solution. Strip the solvent and dissolve the residue in 5 mL of water. The thus obtained aqueous solution of potassium 7- (4-methoxybenzoyl) benzofuran-5-ylacetate is added to a solution of 150 mg of copper nitrate trihydrate in 5 ml of water. The precipitate formed is collected, washed with water and air-dried. There was thus obtained cupric 7- (4-methoxybenzoyl) benzofuran-5-yl acetate.

In a similar manner, the free acid form compounds of Example 3 can be converted to the corresponding copper salts.

Example 8

Process for the preparation of isopropylamine-4- (4-methylthiobenzoyl) benzofuran-5-yl acetate

A solution of 200 mg of 7- (4-methylthiobenzoyl) benzofuran-5-ylacetic acid in 15 ml of hot benzene was treated with 60 mg of isopropylamine. The solution was allowed to cool to room temperature and the product was filtered off, washed with ether and dried to give 7- (4-methylthiobenzoyl) benzofuran-5-ylacetic acid isopropylamine salt.

Similarly, other amine salts are obtained, for example, diethylamine salt, ethanolamine salt, piperidine salt, tromethamine salt, choline salt, and 7- (4-methylthiobenzoyl) benzofuran-5-ylacetic acid caffeine salt, using the corresponding amines instead of isopropylamine.

In the same manner, the compounds obtained in the free acid form by the method of Example 3 can be converted to the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethanine, choline and caffeine salts.

Example 9

Folders Amount, mg / tablet

d, 1- 2- (7-benzoylbenzofuran-5-yl) propionic acid 25 cornstarch 20 May lactose, spray dried 153 magnesium stearate 2 The above ingredients are mixed thoroughly and compressed into individual tablets with a line

Example 10

Folders Amount, mg / tablet active substance 100 ALIGN! lactose, spray dried 148 magnesium stearate 2 The above ingredients are mixed thoroughly and introduced into a hard gelatin capsule.

Example 11

Folders Amount, mg / tablet active substance 200 cornstarch 50 lactose 145 magnesium stearate 5 Mix the above ingredients thoroughly with a line. and compressed into individual tablets provided

Example 12 Folders Amount active substance 0.2 g KH ₂ PO ₄ buffer (0,4M solution) 2.0 ml potassium hydroxide (IN) to pH 7

water (distilled, sterile) up to 20 ml

Example 13

An orally administered suspension of this composition is prepared

Folders Amount active substance 0.1 g fumaric acid 0.5 g sodium chloride 2,0 g methylparaban 0.1 g granulated sugar 25,5 g sorbitol (70% solution) 12.85 g Veegum K (manufactured by Vanderbilt Co.) 1.0 g flavor additive 0.035 ml dye 0.5 mg Distilled water to 100 ml

Example 14

Local resource Folders Quantity, g active substance 0.2 to 2.0 Sleep 60 2 Tween 60 2 mineral oil 5 vaselina 10 methylparaban 0.15 propylparaban 0.05 butylated hydroxyanisole (BHA) 0.01 water up to 100 g

All the above ingredients, except water, are mixed and kept at 60 ° C with stirring. Sufficient water is then added at 60 ° C with vigorous stirring to emulsify the ingredients and the water is then made up to 100 g.

The trademarks in Examples 13 and 14 designate the following substances:

Veegum K is a colloidal clay based on magnesium aluminum silicate, which is used as an inorganic emulsion, a suspending agent or a gelling agent.

Tween 60 is a polyoxyethylene sorbitol derivative that is used as a surfactant.

Sleep 60 is sorbitol hexatane ester which is used as an emulsifier.

Example 15

Suppositories with a total weight of 2.5 g are prepared from the following mixture:

7- (methylthiobenzoyl) benzofuran-5-yloxic acid 25 mg, witepsol H-15 (saturated fatty acid triglycerides of vegetable oils), product of Riches-Nelson, Inc.,

New York, N.Y. (USA) to be added.

Example 16

Anti-inflammatory screening test

Oral anti-inflammatory activity was determined using carragenine-induced paw inflammation in a manner described by Winter et al., Proc. Soc. Exp. Biol. Med., III, 544-547 (19621.

Female rats weighing 80 to 90 g are used. The test substance is administered orally in 1 ml of an aqueous vehicle at 0 hour. At hour 1, 0.05 ml of a 1% (in 0.9% sodium chloride) solution of carragenine is injected into the right front paw, causing injection of the paw. Rats are sacrificed at hour 4, the two hind paws are separated and their weights are individually determined. The percentage increment of the paw size is calculated from:

right paw weight - left paw weight _χ right paw weight

The smaller the size of the paw is, the lower the degree of inflammation and the greater the anti-inflammatory activity.

The compounds of formula I prepared according to the invention exhibit the anti-inflammatory activity shown in Table I:

Table 1

Ar R 2 X _χ X ₂ R ₂ R ₃ Phenylbutazone% 1

Anti-inflammatory activity of phenyl phenyl

4-CH ₃ S-phenyl

1.5

Table 1 continued

Ar R ^ Χ _χ X ₂

Phenylbutazone% 1 Anti-inflammatory activity

4-Cl-phenyl

4-CH ₃ S-phenyl

4-Cl-phenyl

4-Cl-phenyl

CH,

0.5

1.5

Example 17

Analgesic efficacy screening test

Potential oral analgesic efficacy was established using a mouse analgesized (anti-writhing) assay described by Hendershot and Forsieth, J. Pharmacol. Exp. Ther.,

125, 237-240 (1959).

The test substance is administered orally in an aqueous vehicle at hour 0 to a 18-20 g Swiss-Webster male mouse. 0.5 ml of a 0.02% phenylquinone solution is injected intraperitoneally over 20 minutes. This solution induces writhing. The total number of mice writhing and the mean number of convulsions per mouse indicate the efficacy of the test compound, less writhing means greater efficacy of the composition. The compounds of formula I prepared according to the invention exhibit the analgesic activity shown in Table II.

Table II

Analgesic activity (Aspirin = 1) (Aspirin = acetylsalicylic acid) phenyl phenyl

4-CH2-phenyl

4-Cl-phenyl

4-CH2-phenyl

4-Cl-phenyl

4-Cl-phenyl

CH,

CH,

Claims (1)

A process for the preparation of novel substituted benzofuranalkyl and benzothiophene derivatives wherein R @ 1 (1) represents a hydrogen atom or a group of the formula H, C - CH ² f CH I OH OH CH _n or H _O C ² I CH - CH. I ² v R · ^N R Ar in which R represents the same alkyl group having 1 to 6 carbon atoms, denotes an oxygen atom or a sulfur atom, represents an unsubstituted phenyl group or a phenyl group independently substituted by at least one substituent selected from the group consisting of methoxy, chlorine or fluorine, methylsulfinyl, methylsulfonyl or a methylthio group and a dashed line means a single or double bond, and pharmaceutically acceptable salts thereof, characterized in that a compound of formula II is reacted Η H (II) wherein X ^ is as defined above and R 'is an alkyl group, with an aroyl halothienide, and then optionally converting an ester of formula I to a free acid, or converting an ester of formula I into a salt, or converting a pharmaceutically acceptable a salt to another pharmaceutically acceptable salt or to converting an ester of formula I to another ester of formula I, wherein in the produced compounds the individual symbols are as defined above.