CS252493B2 - Method of benzofuranalkyl and benzothiophenalkyl acids' new substituted derivatives production - Google Patents

Description

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

O Ar | H H / O ^x cor ₃ (AND) where ^R 3 represents a group of the formula H..C - CH - CH - CH i Z or H _O C-CH-CH 2 -Z, 1 Z Oh oh f » 0 ^ X

in which R represents the same alkyl group having 1 to 6 carbon atoms, denotes an oxygen atom or a sulfur atom,

Ar 2 represents a phenyl group substituted with methylthio-Hippine and

the dashed line means a single or double bond and the individual (1) - and (d) -isomers of the propionic 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 comprising a compound of formula I are used as analgesics, as anti-inflammatory and anti-inflammatory agents for mammals, wherein an effective amount of a composition comprising a compound of formula I together with a pharmaceutically acceptable excipient or an effective amount of the compound of formula I itself is administered to mammals.

The invention therefore relates to a process for the preparation of compounds of the formula I and their pharmaceutically acceptable salts by esterifying a compound of the formula IV

(IV) wherein Ar, R 1, X 1 and the dashed line are as defined above, and then optionally converting an ester of formula I to a salt, or converting a pharmaceutically acceptable salt to another pharmaceutically acceptable salt or converting an ester of a compound of formula I to another ester of a compound of formula (I), wherein on the produced compounds the individual symbols are as defined above.

An appropriate alcohol is usually used as the esterifying agent. Esterification at room temperature takes up to 4 days.

The compounds of formula (I) fall into two subgroups, depending on whether X 1 is oxygen or sulfur. Within both of these subgroups, suitable compounds are those wherein Ar is a phenyl group substituted with an alkylthio group. The most preferred compounds are: 7-benzoylbenzofuran-5-ylacetic acid, d, 1- 2- (benzoylbenzofuran-5-yl) propionic acid, 7,4-methylthiobenzoyl / benzofuran-5-ylacetic acid, 7- (5-chlorobenzoyl) benzo ^{furan-5-ylacetic} acid, d, 1-2- / 7- (4-methylthiobenzoyl) benzofuran-5-yl / propionic acid and d, 1-2- / 7- (4-chlorobenzoyl) benzofuran-5-yl propionic acid.

The numbering of the benzofuran and benzothiophene structures is this

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 are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, isoamyl, pentyl, isopentyl and hexyl.

The phenyl core may be substituted with a single substituent which is preferably in the 4-position, i.e. in the para position, although alternatively it may be in the ortho or meta position.

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, thin layer column chromatography, thick layer chromatography or a combination of zunsobů. ^R · d - ,: liked Spot illustrations of suitable separation and isolation are shown in NASBA-lowing examples. Of course, however, may include any and eq. J va on ^one coucobů their separation and isolation.

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 amine, 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, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, thoebromine, purines, piperazine, piperidine, n-ethylpiperidine, polyamine resins, polyamine . Particularly carbohydrate organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

The compounds of formula I and their pharmaceutically acceptable non-toxic esters and salts thereof are useful as analgesic agents, as anti-inflammatory agents, as anti-fever agents, as vascular spasm inhibitors, as migraine, as platelet-clotting 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 tests using small animals to determine analgesic efficacy, including an analgesic test in the mouse (two opponents) method, 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 a rat as described by Meier et al., Experientia 6, 469-471, and modifications of these. effects.

In addition, the anti-inflammatory activity in certain cases can be evaluated using the adjuvant arthritis assay described by Pearson, Proc. Soc. Exp. Biol. Med., 91, 95-101 (1956). In vitro assays are also possible, for example using synovial explanations of patients with rheumatoid arthritis described by Dayer et al., J. Exp. Copper. 145, i. ^f ίζ 404 (1977). All 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) 162, 67-68 (1962).

AND

Potential smooth muscle relaxant activity was determined in vitro using the method of Vickery, Prostaglandins Med., 2: 299-315 (1979) or Vickery, Prostaglandins Mec., 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 and the like.

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 dose of 0.02 to 20 mg / kg of 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, sucrose, 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, the compositions comprise from about 3.5% to about 60% by weight of a pharmaceutically acceptable compound, the remainder being a pharmaceutically acceptable excipient.

The active compounds of the formula I may be formulated into a suppository using, for example poly ^U hvlenglykolů (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%) as a carrier. 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; 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 or compounds of formula I in a pharmaceutically acceptable amount depending on the amount. appropriate conditions for the treatment of health problems.

25249?

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, if the pregnancy is to be slightly prolonged, which would be beneficial to the mother and / or the fetus, the active compounds according to 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 in connection with premature labor later in pregnancy when the fetus is viable. In both cases, the compositions are administered prophylactically to with the administration against the beginning of labor. This administration is particularly suitable for women who have already had miscarriages or premature births (i.e. 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 time of pregnancy when contractions started, the severity of the contractions and the duration of contractions influence the results achieved with the compounds of Formula I. For example, the intensity and / or duration of contractions may decrease ( . 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 rendered 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 veterinary 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 pharmaceutical compositions 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, excipients 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 of the like, preferably in unit dosage forms suitable for single administration. 1 precise doses. 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 of the above may be ^; Formulated into suppositories using, for example, polyalkylene glycols, for example polypropylene: cola as carriers.

I β

Liquid pharmaceutical compositions may 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 up to 3 or 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 (IV) 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. (PV 5459-84).

The following examples illustrate the invention but do not limit it in any way. Unless otherwise stated, reactions are carried out at room temperature, where room temperature is 20-30 ° C.

Example 1

Method for the preparation of ethyl β / 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 washed with water, dried over sodium sulfate and evaporated to give ethyl [[7- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-yl] acetate, m.p. 64-66. Deň: 32 ° C.

If the procedure is similar but replaced with the appropriate aroyl chloride 4-methylthiobenzoyl chloride, the corresponding 7-aroylsubstituted 2,3-dihydrobenzofuran and 2,3-dihydrobenzothiophene analogues of ethyl [[7- (4-methylthiobenzoyl) -2,3-] may be prepared. dihydrobenzofuran-5-yl / acetate or alkoxy- or alkyl-6-substituted benzofurans.

At 1 a d 2

Process for the preparation of ethyl 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, this solution was cooled to -78 ° C and added to a solution of 9.0 g of ethyl β- (7- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-yl) acetate in 100 mL of tetrahydrofuran under stirring. 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 was 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

Solution 10.0 g c? 1- [1- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-yl] acetate, 1 ml of methanol, 200 ml of water and 4 g of sodium hydroxide are maintained at reflux 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-dihydrobenzofuran-5-ylacetic acid, m.p. 150 DEG-152 DEG C., is obtained.

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

148-150 ° C, 5-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-yloetic acid, m.p.

163 DEG C., 7- (2-thiophenylcarbonyl) -2,3-dihydrobenzofuran-5-ylacetic acid, m.p.

112 DEG C., 7-benzoyl-2,3-dihydrobenzothiophen-5-ylacetic acid, m.p. 167 DEG-169 DEG C., and 7- (4-chlorobenzoyl) -2,3-dihydrobenzothiophen-5-ylacetic acid, m.p.

138 [deg.] C.

Example 4

A process for the preparation of 4- (4-methylthiobenzoyl) benzofuran-5-yl] acetic acid

(a) 1.0 g of 7- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-ylacetic acid is heated to reflux in 100 ml of carbon tetrachloride containing 0.54 g of n-bromosuccinimide and a catalytic amount of benzoyl peroxide. After about 2 hours, the reaction mixture was cooled and extracted with dilute aqueous sodium carbonate. The aqueous extract was acidified with hydrochloric acid, extracted with ethyl acetate, dried and evaporated to give a residue which was recrystallized from acetone / hexane. There was obtained [7- (4-methylthiobenzoyl) benzofuran-5-yl] acetic acid, m.p. 151-153 ° C.

(b) Dissolve 1,0 g of 7- 7- (4-methylbenzoyl) -2,3-dihydrobenzofuran-5-yl] acetic acid in 20 ml of dioxane, and add 1,2 g of 2,3-dichloro-5 to this solution. 6-dicyano-1,4-benzoquinone (DDQ) and the solution was refluxed for one hour. The reaction mixture was poured into water and extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. The residue was loaded onto a silica gel column eluting with a mixture of ethyl acetate and hexane to give ethyl 4- [7- (4-methylbenzoyl) benzofuran-5-yl] acetate. The acetate was hydrolyzed in the same manner as described in Example 1 to give [7- (4-methylbenzoyl) benzofuran-5-yl] acetic acid of the same melting point. This process is particularly suitable when the 2,3-dihydro starting material contains an alkyl group.

Using both of the above methods, but substituting 7- (4-methylthiobezoyl) benzofuran-5-yl] acetic acid for the compounds of Example 3 or [1- (4-methylbenzoyl) benzofuran-5-yl] acetic acid with suitable 2, With the 3-dihydro compounds of Examples 1 and 2, the following compounds can be prepared:

147-150 ° C, 7- (4-methoxybenzoyl) benzofuran-5-ylacetic acid, m.p. 154-155 ° C, 7- (4-chlorobenzoyl) benzofuran-5, 7-benzoylbenzofuran-5-ylacetic acid 159 DEG-160 DEG C., 7- (2,6-difluorobenzoyl) benzofuran-5-ylacetic acid, m.p. 135 DEG-137 DEG C., 7- (4-methylsulfinylbenzoyl) benzofuran-5-ylacetic acid, m.p. 145-146 ° C; d, 1- 2- (7-benzoylbenzofuran-5-yl) propynoic acid, m.p. 114-116 ° C;

151 DEG C. and 7- (4-chlorobenzoyl) benzothiophen-5-ylacetic acid, m.p. 168 DEG-170 DEG.

Example 5

A process for the preparation of 7- (4-methylthiobenzyl) benzofuran-5-ylacetyl chloride

A solution of 7- (4-methylthiobenzyl) benzofuran-5-ylacetic acid (10 g), dichloromethane (100 ml), thionyl chloride (10.0 ml) and dimethylformamide (0.2 ml) was stirred at room temperature for 6 hours. The solvent was then evaporated to give a residue containing 7- (4-methylthiobenzyl) benzofuran-5-ylacetyl chloride, m.p. 118-123 ° C.

If the same procedure is followed, all the acids of Examples 3, 4 and 5 can be converted to their corresponding chlorides.

Example 6

2-Propen-1-yl-7- (4-methylthiobenzoyl) benzofuran-5-ylacetate

2.0 ml of allyl alcohol were added to a solution of 2.0 g of 7- (4-methylthiobenzoyl) -2,3-dihydrobenzofuran-5-ylacetyl chloride in 100 ml of acetonitrile and 2.0 ml of triethylamine. The solution was stirred at room temperature for 12 hours. The solvent is then evaporated to dryness and the residue is taken up in ethyl acetate / water, washed three times with water, dried and evaporated to dryness and then purified by chromatography.

When using the same method, any of the acid halide of Example 7 is converted to its 2-propan-1-yl ester.

Example 7

Method for the preparation of 2,2-dimethyl-1,3-dioxolan-4-ylmethyl-7 '(4-methylthiobenzoyl) benzofuran-5-

A solution of 8 g of 7- (4-methylthiobenzoyl) benzofuran-5-ylacetyl chloride, 75 ml of tetrahydrofuranif, 8.0 ml of 2,2-dimethyl-1,3-dioxolane-4-methanol and 8.0 ml of pyridine is stirred at room temperature. for 4 days. The reaction mixture was then added to ether and water, extracted with ether and washed six times with water. The ether was dried and evaporated, then the residue was separated on silica gel to give the title compound, mp 88-90 ° C.

All other acetyl chloride or propionyl chloride compounds prepared according to Example 7 can be converted to 2,2-dimethyl-1,3-dioxolan-4-ylmethyl ester. Also, substituting 2,2-dimethyl-1,3-dioxolane-4-methanol with other 2,2-di (lower alkyl) -1,3-dioxolane-4-yl-methanol compounds can also produce other compounds of formula I wherein: R is lower alkyl.

Example 8

Process for the preparation of 2,3-dihydroxypropen-1-yl-H- (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-ylacetate in 30 ml of acetone is added 10 ml of 10% hydrochloric acid and stirred with 2a 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 affords 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 7, additional 2,3-dihydroxyprop-1-yl esters of the invention are prepared.

Example 9

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

A solution of 300 mg of 7- (4-methoxybenzoyl) benzofuran-5-ylacetic acid in 5 ml of isoamyl alcohol was saturated with hydrogen chloride. After 24 hours, excess alcohol was distilled off in vacuo and the residue was purified by silica gel chromatography to give isoamyl-4- (4-methoxybenzoyl) benzofuran-5-yl acetate. Similarly, other esters, such as pentylester, hexyester, octyester, nonyl ester, dodecyl ester and the like, are obtained using other alcohols such as pentylalcohol, hexyl alcohol, octyl alcohol, nonyl alcohol, dodecyl alcohol etc. instead of isoamyl alcohol.

In the same way, the compounds obtained in the free acid form by the method of Examples 3, 4 and 5 are esterified with the appropriate alcohol to the corresponding esters.

Example 10

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.

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

sodium 7- (4-methylthiobenzoyl) benzofuran-5-yl acetate, m.p. 130 ° C (as trihydrate); and potassium 7- (4-methylthiobenzoyl) benzofuran-5-yl acetate, m.p. 148-151 ° C.

Example 11

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 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, 4 and 5 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 12

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

To a solution of 200 mg of 7- (4-methoxybenzoyl) benzofuran-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-yl-acetate is added to a solution of 150 mg of copper (II) nitrate trihydrate in 5 ml of water. The precipitate formed is collected, washed with water and air-dried. There was thus obtained 7- (4-methoxybenzoyl) benzofuran-5-yl acetate copper (II).

In a similar manner, the free acid form compounds of Examples 3 and 4 can be converted to the corresponding copper salts.

Example 13

Process for the preparation of isopropylamine- [7- (4-methylthiobenzoyl) benzofuran-5-ylacetate]

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 can be converted to the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethanine, choline, and caffeine salts by the method of Examples 3 and 4.

Example 1 and cl 14

Process for the preparation of methyl-1,2-(7-benzoylbenzofuran-5-yl) propionate

A solution of 200 ml of d, 1-2- (7-benzoylbenzofuran-5-yl) propionic acid in 5 ml of dichloromethane is treated with excess ether diazomethane and the reaction mixture is maintained at room temperature for 30 minutes. The solvent and excess reagent were removed under reduced pressure, and the residue was recrystallized from ethyl acetate-methanol to give methyl [d] 1-2- (7-benzoylbenzofuran-5-yl) propionate.

Similarly, but using diazoethane, diazopropane and diazobutane instead of diazomethane, the following are obtained:

ethyl [d, 1-2- (7-nemzoylbenzofuran-5-yl) propionate, propyl [d, 1- 2- (7-benzoylbenzofuran-5-yl) propionate, and butyl d-1-2-] 7-Benzoylbenzofuran-5-yl / propionate J.

In a similar manner, the free acids obtained by the methods of Examples 3 and 4 can be converted to the corresponding methyl, ethyl, propyl and butyl esters.

Example 15

Ingredients Quantity, mg / tablet D, 1- 2- (7-benzoylbenzofuran-5-yl) propionic acid 25 corn starch 20 lactose, spray-dried 153 magnesium stearate 2

The above ingredients are thoroughly mixed and compressed to form. individual tablets with a line.

Example 16

Compositions · Quantity, mg / tablet: other substance 100 lactose, spray-dried 148 magnesium stearate 2

The above ingredients are mixed thoroughly and placed in a hard gelatin capsule.

Example 17

Ingredients Quantity, mg / tablet active ingredient 200 maize starch

AND

145 and compressed into individual tablets provided

0.2 g

2.0 ml to pH 7 to 20 ml lactose magnesium stearate

Mix the above ingredients thoroughly with a line.

Example 18

Ingredients Amount of active substance

KH ^ PO ^ buffer (0,4M solution) potassium hydroxide (IN) water (distilled, sterile)

Example 19

An orally administered suspension of the following composition is prepared:

Amount

0.1 g

0/5 g

2,0 g

0.1 g

25,5 g

12.85 g

1/0 g

0.035 ml

0.5 mg to 100 ml

Ingredients Active Substance Fumaric Acid Sodium Chloride Methyl Paraban Granulated Sugar Sorbitol (70% solution)

Veegum K (manufactured by Vanderbilt Co.) flavor additive dye distilled water

Example 20

Local resource

Ingredients active substance

Sleep 60

Quantity, g

0.2 and 2.0

Tween 60 mineral oil 5 Vaseline 10 methylparaban 0.15 propylparaban 0.05 butylated hydroxyanisole (BHA) 0.01 water 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.

Example 21

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

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

New York, N.Y. (USA) to add.

The trademarks in Examples 20 and 21 designate the following substances:

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

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

Sleep 60 is a sorbitol hexane ester which is used as an emulsifier.

Example 22

Anti-inflammatory screening assay. Anti-inflammatory activity was determined using carragenine-induced inflammation in a rat as described by Winter et al., Proc. Soc. Exp. Biol. Med., III, 544- (1962).

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. The rats are killed at hour 4, the two hind paws are separated and their weights are individually determined. The percent increment of the paw size is calculated from:

right paw weight - left paw weight

----- _x 100 right paw weight

The smaller the increase in paw size, the less 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:

(AND)

Phenylbutazone = 1 Anti-inflammatory activity of phenyl phenyl

4-CH ₃ S-phenyl

4-Cl-phenyl

4-CH ₃ S-phenyl

4-Cl-phenyl

4-Cl-phenyl

H

H

H

H

H

H

H

O

O o

o o

with

OHH o ch ₃ II

OHH

OHH o ch ₃ H o ch ₃ H

OHH

1.5

0.5

1.5

Example 23

Analgesic efficacy screening test

Potential oral analgesic efficacy was determined using a mouse analgesized (anti-writhing) assay by papsal Hendershot and Forsaith, 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 indicates the efficacy of the test compound. The compounds of formula I prepared according to the invention exhibit the analgesic activity shown in Table TI.

Table II

Ar

cx ₂ r ₃

O

II

Ar ^R 3 Analgesic activity (Aspirin = 1) (Aspirin = acetylsalicylic acid) phenyl phenyl

4 '

4-Cl-phenyl

4-CH 2 S-phenyl

4-C1-phenyl

4-Cl-phenyl

CH _O

Claims (1)

A process for the preparation of novel substituted benzofuranalkyl and benzothiophenalkyl acids of the general formula I in which R represents the same alkyl group having 1 to 6 carbon atoms, denotes an oxygen atom or a sulfur atom, Ar represents a phenyl group substituted with a methylthio substituent, and the dashed line is not a single or double bond, and pharmaceutically acceptable salts thereof; e) esterifying a compound of formula IV (IV) wherein Ar, R ₂ , and the dashed line are as defined above, and then optionally converting an ester of formula I to a salt, or converting a pharmaceutically acceptable salt to another pharmaceutically acceptable salt or converting an ester of a compound of formula (I) into another ester of a compound of formula (I), wherein in the produced compounds the individual symbols are as defined above.