HU195179B - Process for producing benzoic acid derivatives and pharmaceutical preparations comprising these compounds as active substance - Google Patents

Abstract

Cpds. of formula (I) and salts are new where R1 = lower alkyl; R2 = opt. protected carboxyl; and X = halogen. Pref. R1 = Me, R2 = carboxyl; X = Br; and R2 = a gp. of formula (II) -COO(CH2)nNR3R4 (II) where n = 2,3 or 4; and R3 and R4 each = H, or 1-3C alkyl, or NR3R4 may form a 5- or 6-membered heterocycle.

Description

The present invention relates to novel benzoic acid derivatives and their salts, and to pharmaceutical compositions containing them as active ingredients. The compounds of the present invention possess an antagonistic action of a class of chemical mediators of bronchial and other smooth muscle contraction, the slow-reacting substance of anaphylaxis (allergic shock) (SRS-A).

Examples of compounds having a SRS-A antagonistic action as a class of chemical mediators of bronchial smooth muscle contraction are known from British Patent Specification No. 1,384,530 and European Patent Specification Nos. 28,063 and 80,371.

However, the SRS-A antagonizing activity of the compounds disclosed in the examples of British Patent Specification No. 1,384,530 and of European Patent Specification No. 28,063 is unsatisfactory, and it would be desirable to improve this activity. For compounds described in European Patent Publication No. 80,371, it would be desirable to improve oral absorption and increase the duration of action.

Thus, compounds having an adequate SRS-A antagonizing activity were sought. In our experience, a certain class of benzoic acid derivatives meets the above requirements.

The process of the present invention provides novel compounds of formula I wherein R ¹ is C 1 -C 4 alkyl, R ² is carboxyl, C 1 -C 6 alkoxycarbonyl, tetrahydropyranyloxycarbonyl, or a di (C 1-4) alkylamino (C 1-6) alkoxycarbonyl group, and

X refers to the preparation of halogen atoms and their salts.

According to the process of the invention, a compound of formula II, wherein R ² and X are as defined above, or a salt thereof, is acylated with a compound of formula V, wherein R ¹ is as defined above and Y is a leaving group. .

According to the process of the present invention, a compound of formula II, wherein R ¹ and X are as defined above, and R ² 'is (C 1-6) alkoxycarbonyl, tetrahydropyranyloxy, carbonyl or di (Ci-C4) alkylamino (C1-6) alkoxy-carbonyl group - and their salts can also be prepared by reacting a compound (IV): - wherein ^R1 and X is the above - or one of its salts is selected from the group consisting of (C 1 -C 6) alkoxycarbonyl, tetrahydropyranyloxycarbonyl or di (C 1 -C 4) alkylamino (C 1 -C 6) alkoxycarbonyl-; with a reactant suitable for introducing a group.

Compounds of formula (IV), which is a narrower group of compounds of formula (I), i.e. compounds of formula (I) wherein R ² is a free carboxyl group, and their salts may also be prepared from a compound of formula (I) wherein R 'and X are as defined above, and R ^2' R ⁵ 'protecting group COOH - R ^5' protecting group is removed by either a (II) compound of the formula: - wherein X is as defined above -, or a salt of R ⁵ 'is reacted with a reactant suitable for the introduction of a carboxyl protecting group, the resulting compound of formula II', wherein R ² 'is as defined above, is acylated with a compound of formula V, and the resulting compound of formula I' wherein R 'and R ² ' and X are as defined above - R ⁵ 'is deprotected.

In the above formulas, C 1-4 alkyl, preferably as defined for R ', is preferred

It contains from 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl or isopropyl.

Especially preferred are methyl and ethyl

R ² is a protected carboxyl group or R ² 'is a protected carboxyl group R ⁵

May be represented by the symbol 3Q and represents a group of general formula (VI) wherein n is 2-4 and

R ³ and R ⁴ are each independently

C 1-3 alkyl, tetrahydropyranyl, or tert-butyl.

Of the above groups R ⁵ is preferably a group of general formula (VI).

The protected carboxyl group represented by R ² 'has a R ⁵ ' protecting group other than the protecting group represented by the general formula VI in which n, R ³ and R ⁴ are as defined above, for example tetrahydropyranyl, tert-butyl, trityl, benzyl, benzyloxymethyl, phenacyl.

The C 1-3 alkyl group represented by R ³ and R ^{J in} formula (VI) may be, for example, methyl, ethyl, π-propyl or isopropyl.

In the above formulas, X is halogen, bromine, chlorine, fluorine or iodine. The leaving group Y in the acylating agent (V) is, for example, an acyloxy group such as acetoxy, propionyloxy, s b., Or a halogen atom such as chlorine, bromine and the like. may.

In the above formulas, the "X" substituent is preferably in the ortho position, while the carboxyl group or the substituents R ² , R ² 'and R ² "are preferably in the para position.

If the compounds of the formula I or their salts are the compounds of the formula II or their salts and the ac

The reaction is preferably carried out in the presence of a base such as pyridine, 4-dimethylaminopyridine, triethylamine, and about 2 to 30 equivalents of an acylating agent of formula (V). , etc. in its presence.

Examples of the solvent include chloroform, dichloromethane, dimethylformamide, tetrahydrofuran, dioxane, and the like. and, in general, an excess of pyridine as solvent.

The reaction time may be from 1 to 48 hours. The reaction temperature may range from the temperature of the ice bath to the boiling point of the solvent and reactants.

When the compounds of formula (III) are prepared by protecting the carboxyl group of the compounds of formula (IV), the compounds of formula (IV) or salts thereof may first be reacted with a halogenating agent and the resulting halide of the acid of formula IV obtained.

The acid halide of compound (IV) may be prepared by reacting compound (IV) with a halogenating agent such as thionyl chloride, phosphoryl chloride, thionyl bromide, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, phosphorus. -tribromide, etc. - respond. Examples of the solvent include chloroform, dichloromethane, dimethylformamide, tetrahydrofuran, dioxane, and the like. can be used in the above reaction. The reaction temperature may range from 80 ° C to 120 ° C. The reaction time is 0.5 to 4 hours.

As an alcohol derivative of the protecting group in the above reaction, for example, a compound of formula VII wherein R ⁵ is as described above can be used. In the reaction of the above alcohol derivative (VII) with the acid halide, 1 to 4 equivalents of the alcohol derivative are used per equivalent acid halide. Examples of the solvent include acetone, chloroform, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, and the like. can be used. The reaction is preferably carried out in the presence of a base. Examples of the base include triethylamine, pyridine, 4-dimethylaminopyridine, dimethylaniline, and the like. can be used. The reaction temperature may range from about 15 to about 80 ° C. The reaction time may be from about 1 to about 10 hours.

Compounds of formula (III) may also be prepared from compounds of formula (IV) by reacting a halogen derivative of the protecting group with a compound of formula (IV).

The protecting group is preferably a halogenide of a compound of formula (VIII), wherein Z is halogen and ^R5 is as defined above. Examples of halogen at Z include chlorine, bromine, iodine, and the like. may.

In the above reaction, 4 equivalents of the compound of formula IV are used

1-4 equivalents of the compound of formula VIII are used. The reaction is preferably carried out with a base such as triethylamine, pyridine, dimethylaniline, and the like. - played in his presence. Examples of the solvent include dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran. dioxane, acetonitrile, etc. can be used. The reaction temperature may range from about 7 to 150 ° C, and may be from 1 to 6 hours.

When starting from a compound of the formula II ', a compound of the formula II is prepared wherein, for example, the protecting group R ⁵ ' represents a tetrahydropyranyl group with respect to an equivalent compound of the formula II *

1-5 equivalents of tetrahydropyran are used and the reaction is carried out at a temperature ranging from ice cooling to room temperature in the presence of a catalytic amount of acid for 10 minutes to several hours. Examples of the solvent include methylene chloride, chloroform, acetonitrile, tetrahydrofuran, and the like. and the acid used as the catalyst is, for example, p-toluenesulfonic acid, sulfuric acid. etc may.

When R ⁵ 'is benzyl or tert-butyl, the compound of formula (II') is first converted to the acid halide, to convert the compound of formula (IV) to the acid halide as described above, and then to the resulting acid halide with benzyl alcohol or reaction with 1 alcohol gives the desired compound of formula II.

When R ⁵ 'is trityl or benzyloxymethyl, the compound of formula II' is first converted to the sodium, potassium or silver salt or the like and the resulting salt is, for example, trityl bromide or benzyloxy. reaction with methyl chloride (II '). When R 0' is a phenacyl group, for example, phenacyl bromide is reacted with a compound of formula II ', e.g. in the presence of triethylamine. In the above reaction, for example, benzene, hexane, chloroform, dichloromethane, ethyl acerate, tetrahydrofuran, acetonitrile, and the like.

In any of the above reactions, the reaction temperature may range from ice cooling to the boiling point of the solvent used, and the reaction temperature may be about 1 to 5 hours.

From the compound of formula (II) prepared above, the compound of formula (I) may be prepared by acylation as described previously for the reaction of the compound of formula (II) with the compound of formula (V).

When the compounds of formula (I) are converted to compounds of formula (IV) by removal of the R ⁵ 'protecting group of the R ² ' group, the reactions used to remove the R ⁵ 'are selected depending on the protecting group. For example, when R ⁵ 'is tetrahydropyranyl, the reaction is carried out in, for example, tetrahydrofuran-water or acetic acid

-4195179, an acid such as hydrochloric acid, p-toluenesulfonic acid, and the like. in the presence of room temperature at room temperature for 30 minutes to 5 hours. When R ⁵ 'is benzyloxymethyl or phenacyl, the protecting group is removed by catalytic reduction, for example in the presence of a palladium catalyst at room temperature, for a period of from 1 to 10 hours. When R ⁵ 'is tert-butyl or trityl, the reaction is carried out with an acid such as hydrochloric acid, trifluoroacetic acid, formic acid, p-toluenesulfonic acid, and the like. - in the presence of ice at a temperature of about 50 ° C for about 1-5 hours.

The compounds of formula (I) obtained by the above processes are isolated from the reaction mixture and are known, for example, by recrystallization, chromatography, and the like. - clean it.

Salts of starting compounds and end products are preferably pharmaceutically acceptable salts, such as alkali metal salts such as sodium or potassium salts, and salts of organic or inorganic acids such as hydrochloric, sulfuric, phosphoric, fumaric, maleic or oxalic acids.

The starting compounds of formula (II) wherein R ² is carboxyl may be prepared according to the procedure described in EP 80 371 or in an analogous manner.

Compounds of formula (I) wherein R ² is carboxyl or (IX), hereafter referred to as (Γ), significantly antagonize the analgesic slow-reacting substance (SRS-A). It is a group of chemical mediators that cause bronchial and other smooth muscle contraction.

SRS-A is produced in the body by a variety of stimuli, such as immune responses, and is considered to be an effective mediator of bronchospasm in immediate allergies, such as allergic asthma. , etc. and it is known that the activity of LTD and LTC is nearly identical in human bronchial muscles and that the LTD has a greater muscle tightening effect than LTC in guinea pig ileum [S. E. Dahlen et al., Natura 288, 484 (1980); Lewis, R.A., et al., Biochemical and Biophysical Research Communications 96, 271 (1980). The SRS-A antagonizing activity of the active compounds can be investigated in guinea pig ileum [R. A. Appleton et al., 1977, Journal of Medical Chemistri, 37, 371, and whereas SRS-A is the name of LTC, LTD, et al. and the ratio of these is uncertain, it is advisable to test the antagonist effect with synthetic SRS-A.

The SPS-A antagonizing activity of the compounds of formula (I) was performed using synthetic LTD ₄ as described below and it was found that bronchoconstriction induced by intravenous injection of synthetic leukotriene D ₄ (LTD ₄ ) in certain guinea pigs (I '). Compounds of formula (II) were more potent than Compound A when administered orally to guinea pigs prior to administration of L.TD ₄ .

Pharmacological Activity Assay 1) Assay for SRS-A antagonizing activity

The study was performed on guinea pigs weighing approximately 400 g (Hartley strain, male and female), divided into groups of 6 to 10 and bronchoconstriction induced by LTD _{4 using} the Konzett-Rössler method [Konzett H. and Rössler R. Naunyn Schmiedebergs Archive for Experimentelle Pathologie und Pharmacologie 195, 71-74 (1940)]. Guinea pigs were placed supine under urethane anesthesia (1.5 g / kg, i.p.) and the trachea was incised and ligated with an artificial respirator (Rodent Respirator Model 680, Harvard Apparatus Company, USA) using a cannula. The branched tube from the above tracheal cannula was connected to a Bronchospasm Transducer (Model 7020, Ugobasil Biological Research Apparatus, Italy). In addition to loading pressure of 4-7 ml of air / breath, 70 breaths / / min and 10 ₂ 0 cm- lungs recorded in the volume of air flow Rectigraph-8S-sel (San-ei Sokki Co. LTD., Japan) via a transducer.

Following intravenous administration of mg / kg gallamine triethiodide, LTD ₄ dissolved in physiological saline is administered intravenously at 10 µg / kg and the bronchoconstriction induced is recorded for 15 minutes. Test compounds are suspended in 5% gum arabic solution or dissolved orally in water at a dose volume of 0.2 ml / kg body weight 1 hour prior to administration of LTD ₄ . LTD ₄ is administered via a cannula inserted into the cervical vein, dissolved in physiological saline, prepared from LTD ₄ stock solution in methanol at -70 ° C in methanol.

The results are shown in Table 1 below

-5195179

Table I

Compound R ¹ C0- R ² X ID ₅₀ (po) (µmol / kg) ^X Example 1 CH ₅ -CO- COOH Br 47 of compound control H COOH Br 146 The compound

ID50 (50% Inhibitor Dose): Individual values are determined from the relationship between the dose and the% reduction in airway flow at the time when maximal effect is observed, i.e., 30 seconds after LTD4 administration.

Control Compound A: Compound of Formula I as disclosed in European Patent Application Publication No. 80,371

2) Toxicity

The acute toxicity of the compound prepared in Example 1 was investigated in mice.

Five groups of male mice (JckICR strain) of average weight 30 g each, 5 weeks old, were treated with the test compound. The compound prepared in Example 1 was suspended in a 5% gum arabic solution and administered orally in a dose volume of 0.2 ml / 10 g body weight.

It has been found that the compound of the present invention when administered at an oral dose of 500 mg / kg does not cause any symptoms attributable to the compound. After 7 days the animals were necropsied and no lesions were observed.

According to the above result, the compounds of formula (Γ) have low toxicity.

Due to the above properties of the compounds of formula (Γ), the active ingredients of the pharmaceutical formulations are diseases attributable to SRS-A, e.g. used to treat. For example, as an active ingredient in anti-asthma and anti-inflammatory agents, the compounds of formula (T) and their salts may be administered orally or parenterally to the mammal to be treated, e.g.

In pharmaceutical compositions for oral use, the compounds of formula (ó) or their salts are formulated with a pharmaceutically acceptable carrier, excipient or diluent such as lactose, starch, cellulose derivatives, stearic acid, magnesium stearate, saccharose, capsules, granules, pellets, liquids, syrups, etc. - for30 may. Pharmaceutical formulations for parenteral administration are prepared by preparing a compound of formula (Γ) or a salt thereof with pharmaceutically acceptable carriers, diluents or other excipients such as white petrolatum, hydrophilic ointment base, oily base, glyceride, polyethylene glycol, and the like. Mixed and formulated as an ointment, suppository, aerosol, inhalation or injection, etc. formulated. The various dosage forms may be prepared by conventional pharmaceutical techniques.

Compounds of formula (I) wherein R ² is a carboxyl group (R ² ') protected by a protecting group (R ⁵ ') other than the general formula (VI) and n, R ³ , and R ⁴ are as defined above, i.e. Compounds of Formula (I) - They are useful as intermediates in the preparation of compounds of formula (I) above.

The invention is further illustrated by the following non-limiting Examples ⁵⁵ .

Reference Example 1

In a manner analogous to that described in European Patent Publication No. 80,731, the following ve60 kits are prepared:

(1) 3- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -4-bromo-benzoic acid methyl ester, m.p. 108-110 ° C (recrystallization solvent: acetone) ether); gg (2) 3- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -4-bromobenzoic acid, m.p. 6195179 and 146-149 ° C (solvent used for recrystallization: aqueous alcohol).

Reference Example 2

In analogy to the procedure described in European Patent Publication No. 80,371, the following compounds were prepared:

(1) Methyl 2- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -5-bromobenzoic acid, m.p. 71-73 ° C (recrystallization solvent: acetone) -ether);

(2) 2- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -5-bromo-benzoic acid, m.p. 157-158 ° C (recrystallization solvent: aqueous alcohol).

Reference Example 3 (1) A mixture of 1.2 g of 3-fluoro-4-hydroxybenzoic acid, 20 ml of ethanol and 1 ml of concentrated sulfuric acid was refluxed for 13 hours, then concentrated and extracted with chloroform. The extract was washed with aqueous sodium bicarbonate solution, dried and the solvent was distilled off. 1.3 g of ethyl 3-fluoro-4-hydroxybenzoic acid are obtained in crystalline form, m.p. 79-80 ° C.

(2) 600 mg of 3-fluoro-4-hydroxybenzoic acid ethyl ester, 1.15 g of 4- (3-chloropropoxy) -2-hydroxy-3-propylacetophenone, 450 mg of potassium carbonate, 550 mg. of potassium iodide (2 ml) and dimethylformamide (2 ml) was stirred vigorously at 80-90 ° C for 4.5 hours. Ethyl acetate was added to the reaction mixture and insoluble materials were removed by filtration. The filtrate was concentrated and the residue was recrystallized from methanol. Ethyl 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-fluorobenzoic acid (1.3 g) is obtained in crystalline form, m.p. 87-88 ° C.

(3) 1.3 g of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-fluorobenzoic acid ethyl ester, 8 ml of ethanol and 1 g of sodium hydroxide. the mixture is refluxed in 5 ml of water for 40 minutes. Ethanol is distilled off from the reaction mixture. The residue was dissolved in water and the solution was acidified with dilute hydrochloric acid to give a crystalline solid. Recrystallization from ethanol gave 1.06 g of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-fluorobenzoic acid as a crystalline solid, m.p. 165-166 ° C.

(4) A solution of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-fluorobenzoic acid (220 mg) in chloroform (2 mL) with thionyl chloride (0.4 mL) was refluxed for 20 minutes. refluxing the solvent and removing the solvent under reduced pressure. Toluene was added to the residue and the solvent was removed under reduced pressure. To the residue were added 5 ml of acetone, 70 mg of 3-dimethylaminopropanol and 0.25 ml of triethylamine and the mixture was refluxed for 0.5 hours. The precipitated colorless crystalline precipitate was filtered off and the filtrate was concentrated. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was evaporated and hexane was added to the cooled residue. 140 mg of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-fluorobenzoic acid 3-dimethylaminopropyl ester are obtained in the form of colorless crystals, m.p. 55-56 ° C. C.

EXAMPLE 1 4- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid (2 g) was dissolved in a mixture of pyridine (ml) and acetic anhydride (10 ml). The solution was heated at 100-120 ° C for 14 hours and then concentrated. The residue was dissolved in chloroform. The solution was washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was chromatographed on a silica gel column. Elution was carried out with hexane: ethyl acetate (3: 1, 2: 1, 1: 1), and finally ethyl acetate. The ethyl acetate fractions were combined and concentrated. The residue was crystallized from chloroform to give 1.0 g of 4- [3- (3-acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid, m.p. 155-156 ° C.

2- [3- (3-Acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -5-bromobenzoic acid is also prepared as described above, m.p. 125-127 ° C (recrystallization solvent: acetone). -ether).

Example 2

A mixture of 2.0 g of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid, 10 ml of pyridine and 10 ml of propionic anhydride at 100-110 ° C is obtained. After heating for 30 hours, the solvent was distilled off. The residue was dissolved in chloroform and the solution was washed with dilute hydrochloric acid and water. The solution was dried over sodium sulfate and chromatographed on a silica gel column. Elution was carried out with a 5: 1 mixture of chloroform and ethyl acetate. The eluate was evaporated and the residue was recrystallized from hexane.

1.77 g of 4- [3- (4-acetyl-3-propionyloxy-2-propylphenoxy) propoxy] -3-bromobenzoic acid are obtained, m.p. 136-137 ° C.

Example 3 il) A mixture of 2 g of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid in 20 ml of chloroform and 5 ml of thionyl chloride for 30 minutes. reflux and evaporate the chloroform. The residue was dissolved in acetone (40 mL). The solution is 500 mg

3- (Ν, Ν-Dimethylamino) -1-propanol and 4 ml of triethylamine were added. The mixture was stirred at room temperature for 2 hours. The precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed on a silica gel column. Elution was carried out with ethyl acetate followed by 10: 1 ethyl acetate: triethylamine. The solvent was evaporated from the eluate. The residue was recrystallized from hexane. 1.8 g of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid 3- (Ν, Ν-dimethylamino) -propyl ester are obtained. in crystalline form, m.p. 71-72 ° C.

-7195179 (2) Dissolve 1 g of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid 3- (Ν) in a mixture of 5 ml of pyridine and 5 ml of acetic anhydride. , .Beta.-dimethylamino) -propyl ester. The solution was stirred at 110-120 ° C for about 18 hours and then concentrated. The residue was chromatographed on a silica gel column. Elution is carried out with ethyl acetate and the eluate is evaporated. The resulting oily residue was dissolved in ether and anhydrous oxalic acid in ether was added. The resulting crystalline material is filtered off, washed with ethanol and then isopropyl ether and dried. 866 mg

4- [3- (4-Acetyl-3-acetoxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid 3- (Ν, Ν-dimethylamino) -propyl ester monooxalate is obtained, m.p. 141-142 ° C.

Example 4 (1) 1.35 g of 4- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3-bromobenzoic acid are dissolved in 30 ml of methylene chloride. To the solution was added 0.9 mL of dihydropyran and 5 mg of p-toluenesulfonic acid monohydrate. After stirring at room temperature for 30 minutes, another 30 ml of methylene chloride was added. The resulting solution was washed with aqueous sodium bicarbonate solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by chromatography on a silica gel column. Elution is carried out with chloroform. 1.4 g of tetrahydropyranyl of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid are obtained in the form of a colorless oil. NMR (CDC1 ₃₎ delta: 0.88 (3H, t), 2.38 (2H, m), 2.53 (3H, s), 2.62 (2H, t), 3.7 to 4 , 1 (2H, m), 4.29 (4H, t), 6.18 (1H, s), 6.47 (1H, d, J = 9Hz), 6.91 (1H, d, J = 8 Hz), 7.54 (1H, d, J = 9Hz), 8.00 (1H, dd, J = 2 and 8Hz), 8.23 (1H, d, J = 2Hz).

(2) 1.4 g of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid tetrahydropyranyl ester are dissolved in 20 ml of methylene chloride. To the solution were added 6 ml triethylamine and 15 mg

4-Dimethylaminopyridine was added and acetic anhydride (5 ml) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes and then methanol (5 mL) was added. After allowing the mixture to stand for a while, 50 ml of chloroform was added. The mixture was washed with 5% aqueous sodium bicarbonate solution, then water, and dried over sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography. 4- (3- (3-Acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-bromo-benzoic acid tetrahydropyranyl ester ( ₃ g) was obtained as a colorless oil. NMR (CDCl3) δ: 0.87 (3H, t), 2.34 (3H, s), 2.47 (3H, s), 4.29 (4H, t), 6.18 (1H, br s), 6.79 ( 1H, d, J = 9Hz), 6.90 (1H, d, J = 8Hz), 7.68 (1H, d, J = 9Hz),

7.99 (1H, dd J = 2 and 8 Hz), 8.23 (1H, d, J = 2 Hz).

(3) 1.3 g of 4- [3- (3-acetoxy-4-acetyl-2-propyl)

Phenoxypropoxy] -3-bromobenzoic acid tetrahydropyranyl ester is dissolved in 10 ml tetrahydrofuran. To the solution was added 1 ml of 1N hydrochloric acid solution, allowed to stand at room temperature for one hour, and then 60 ml of chloroform was added. The mixture was washed well with water and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was crystallized from isopropyl ether and then recrystallized from aqueous ethanol. 0.7 g of 4- [3- (3-acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-bromo-benzoic acid is obtained in crystalline form, m.p. 155-156 ° C.

(4) 3- [3- (3-Acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -4-bromo-benzoic acid, m.p. 137-139 ° C (recrystallization solvent: aqueous alcohol).

Example 5

124 mg 4- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-fluoro-benzoaza-3-dimethyl-aminopropyl ester with 1 ml dichloromethane, 0.5 ml To a solution of triethylamine and a catalytic amount of 4-dimethylaminopyridine was added 0.38 ml of acetic anhydride. The mixture was stirred vigorously at room temperature for 1.5 hours. Methanol (2 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, the solution was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dissolved in ether and a saturated ethereal oxalic acid solution was added until no more precipitate formed. The precipitate was filtered off and washed with ether. 180 mg of 4- [3- (3-acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-fluorobenzoic acid 3-dimethylaminopropyl-1-ester mono oxalate are obtained, m.p. 167 ° C.

Example 6

1.0 g of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-chlorobenzoic acid, prepared as described in European Patent Publication No. 80,371,

To a mixture of 4.6 ml triethylamine, 8 mg 4-dimethylaminopyridine and 6 ml dichloromethane at 5-7 ° C

Acetic anhydride (3.1 ml) was added and the mixture was stirred vigorously for 80 minutes. Methanol (5 mL) was added dropwise to quench the excess acetic anhydride. The mixture was concentrated, the oily residue was poured into ice water and the precipitate was filtered off. Recrystallization from ethanol-water gave 975 mg of 4- [3- (3-acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-chloro-benzoic acid as white crystals, m.p. 146-148 ° C.

Example 7 (1) To a solution of 903 mg of 4- [3- (4-acetyl-3-hydroxy-2-p-opyl-phenoxy) -propoxy] -3-bromobenzoic acid in 100 ml of dichloromethane was added 5 drops of concentrated sulfuric acid. isobutene was bubbled into the mixture for 30 minutes under ice-cooling. The mixture was allowed to stand at room-8195179 in a closed vessel for 2 days. Sodium bicarbonate was added to the reaction mixture and nitrogen gas was bubbled through to remove isobutene. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography eluting with 9: 1 hexane: ethyl acetate. The eluate was concentrated under reduced pressure. 4- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid tert-butyl ester (660 mg) is obtained as a light brown oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ: 0.90 (3H, t,

J = 7Hz), 1.29-1.72 (2H, m), 1.56 (9H, s), 2.21-2.74 (4H, m), 2.54 (3H, s), 4.28 (2H, t, J = 6Hz), 4.30 (2H, t, J = 6Hz), 6.48 (1H, d, J = 9Hz), 6.88 (1H, d, J = 8 Hz), 7.57 (1H, d, J = 9 Hz),

7.90 (1H, dd, J = 2 and 8 Hz), 8.14 (1H, d, J = 2 Hz), 12.72 (1H, s).

(2) 660 mg of 4- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid tert-butyl ester were treated as described in Example 5. 4- [3- (3-Acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-bromo-benzoic acid tert-butyl ester (610 mg) is obtained as a light brown oily substance.

NMR (CDC1 ₃₎ δ: 0.88 (3H, t,

J = 7Hz), 1.32-1.70 (2H, m), 1.57 (9H, s), 2.20-2.65 (4H, m), 2.33 (3H, s), 2 , 45 (3H, s), 4.13-4.40 (4H, m), 6.78 (1H, d, J = 9Hz), 6.86 (1H, d, J = 8Hz), 7 , 67 (1H, d, J = 9Hz), 7.88 (1H, dd, J = 2 and 8Hz), 8.13 (1H, d, J = 2Hz).

(3) To a solution of 1.5 g of 4- [3- (3-acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid tert-butyl ester in 10 ml of dioxane at 20 ° C. 10 ml of cold 2N hydrochloric acid in dioxane are added with stirring. The reaction mixture was warmed to room temperature and stirred for 30 minutes. Another 10 ml of cold 2N hydrochloric acid in dioxane was added. The mixture was stirred for 1.5 hours and then concentrated under reduced pressure. The residue was dissolved in chloroform (30 mL) and the solution was washed with water (30 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in isopropyl ether. The solution is treated with activated carbon and hexane is added to the solution. The precipitated crystals were filtered off, purified by column chromatography on silica gel and recrystallized from aqueous ethanol. 0.35 g of 4- [3- (3-acetoxy-4-acetyl-2-propylphenoxy) -propoxy] -3-bromobenzoic acid is obtained in the form of a colorless crystalline solid, m.p. 154-156 ° C.

Example 8

A mixture of 4- [3- (3-acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-bromobenzoic acid (200 mg) in chloroform (2 mL) and thionyl chloride (0.4 mL) was heated under reflux for 20 minutes. boil then concentrate. Acetone (5 mL) and 3-dimethylaminopropanol (300 mg) were added to the residue and the mixture was refluxed for 0.5 h. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography and the eluted oil was dissolved in ether. Oxalic acid solution was added to the solution. 4- [3- (3-Acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-bromo-benzoic acid 3-dimethylaminopropyl-ester monooxalate (200 mg), m.p. 141-142 ° C. C.

Example 9

700 mg of 4- (3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3-fluorobenzoic acid, 25 ml of dichloromethane, 2 ml of triethylamine, 2 ml of acetic anhydride and A mixture of catalytic amount of 4-dimethylaminopyridine was stirred at ice-cooled to room temperature for 6.5 hours, methanol (2 ml) was added and stirred for 30 minutes. Recrystallization gave 4- [3- (3-acetoxy-4-acetyl-2-propyl-phenoxy) -propoxy] -3-fluorobenzoic acid (723 mg) in crystalline form, m.p. 144-145 ° C.

Claims (12)

A process for the preparation of a novel benzoic acid derivative of formula (I) wherein R ¹ is C 1 -C 4 alkyl, R ² is carboxyl, C 1 -C 6 alkoxycarbonyl, tetrahydropyranyloxycarbonyl, or di. (C 1 -C 4) alkylamino (C 1 -C 6) alkoxycarbonyl, and X is a halogen atom or a salt thereof, characterized in that ^a ) a compound of formula II wherein R ² and X are as defined in the preamble, or a salt thereof with an acylating agent of formula V wherein R ¹ and Y is a leaving group - or (b) a compound of formula (IV), which is a narrower group of compounds of formula (I), wherein R ¹ and X are as defined herein, or salts thereof, wherein X is as defined above. or a salt thereof is reacted with a reactant suitable for the introduction of a R ⁵ 'protecting group, the resulting compound of formula II', wherein X is as defined above and R ² 'is a R ⁵ ' protected carboxyl group, is a compound of formula (V). with an acylating agent of the formula wherein R ¹ is as defined above and Y is a leaving group, and the resulting compound of formula (I ') wherein R ¹ , R ² ' and X are phen9 -9195179 ti - R ⁵ 'is deprotected and optionally i) compounds of the general formula (III) which are a narrower group of the compounds of the formula I in which R ¹ and X are as defined in the above and R ² 'is a (C 1-6) alkoxycarbonyl group, tetrahydropyranyloxy; -carbonyl group or di (C 1 -C 4) alkylamino (C 1 -C 6) alkoxycarbonyl group or a salt of a compound of formula (IV): wherein R ¹ and X are as defined herein - or a salt thereof for the introduction of a (1-6C) alkoxycarbonyl group, a tetrahydropyranyloxycarbonyl 1 group or a di (1-4C) alkylamino (1-6C) alkoxycarbonyl group with a reagent, or ii) being a narrower group of the compounds of formula (I), (IV) compounds of the formula: - wherein ^R1 and X are as defined above - or their salts for preparing a general k (I ") pletű compound - wherein R 'and X are as defined above and R ^2' is R ⁵ 'carboxyl protecting group - removing the protecting group. (Priority: 25.09.1985) 2. A process for the preparation of a benzoic acid derivative of the Formula I wherein R ¹ is C 1 -C 4 alkyl, R ² is carboxyl, C 1 -C 6 alkoxycarbonyl, tetrahydropyranyloxycarbonyl, or di ( (C 1 -C 4) alkylamino (C 1 -C 6) alkoxycarbonyl, and X is a halogen atom and salts thereof, characterized in that a compound of the formula II in which R ² and X are as defined in the preamble, or a salt thereof with an acylating agent of the formula V in which R ¹ and Y is a leaving group - and optionally i) a compound of formula III which is a narrower group of compounds of formula I, wherein R ¹ and X are as defined above and R ² 'is (C 1 -C 6) alkoxycarbonyl, tetra hydropyranyl; an oxycarbonyl group or a di (C 1 -C 4 alkyl) amino (C 1 -C 6) alkoxycarbonyl group or a salt thereof, wherein R ¹ and X are or a salt thereof (C 1 -C 6) alkoxycarbonyl, tetrahydropyranyloxycarbonyl or di (C 1 -C 4) alkylamino (C 1 -C 6) alkoxycarbonyl as defined herein. or (ii) reacting a compound of formula (I), which is a narrower group of compounds of formula (I), wherein R ¹ and X are as defined herein, or a salt thereof (I "). The compound of formula I, wherein R ¹ and X are carboxyl groups as defined herein and R ² 'is R ⁵ ' protected, is deprotected. (Priority: 10/30/1984) 3. A method according to claim 2 for preparing a compound of formula (I) wherein ^R1 is methyl, characterized in that using the compound of formula ¹ wherein A is a methyl group (V), R acylating agent. (Priority: 30.10.1984) 4. A method according to claim 2 for preparing a compound of formula (I), R ² represents a carboxy group, characterized in that using the compound of formula ² is carboxy (II) having R as a starting material. (Priority: 30.10.1984) A process according to claim 2 for the preparation of compounds of formula I wherein R ² is a group of formula IX wherein π is 2 to 4 and R ³ and R ⁴ are independently 1 to 3 C 1 -C 4 alkyl, characterized in that the starting material is a compound of formula II wherein R ² is as defined in the preceding disclosure. (Priority: 30.10.1984) 6. A process according to claim 2 for the preparation of compounds of formula (I) wherein X is bromine, wherein the starting material is a compound of formula (II) wherein X is bromine. (Priority: 30.10.1984) 7. Process for the preparation of compounds of general formula (IV) according to claim 2, wherein R ¹ is methyl, wherein the starting material is a compound of formula (I ') wherein R ¹ is methyl. (Priority: 30.10.1984) 8. Process according to claim 2 for the preparation of compounds of formula (IV) wherein X is bromine, wherein the starting material is compound of formula (I ') wherein X is bromine. (Priority: 30.10.1984) 9 according to claim 1 b) a process for preparing compounds of formula wherein R ¹ is a methyl group (IV), characterized in that using the compound of formula ¹ wherein A is a methyl group (V), R acylating agent. (Priority: 25.09.1985) Process b) according to claim 1, for the preparation of compounds of formula IV wherein X is bromine, characterized in that a compound of formula (ΙΓ) wherein X is bromine is used as starting material. .Priority: 25.09.1985.) -10195179 11. A process for the preparation of a pharmaceutical composition comprising the compounds of formula (I) according to claim 1, wherein R ¹ and X are as defined in claim 1 and R ² is carboxyl or (IX). wherein n is 2 to 4 and R ³ and R ⁴ are each independently C 1 -C 3 alkyl or a pharmaceutically acceptable salt thereof, mixed with a carrier and / or other excipients commonly used in the preparation of a medicament to form a medicament. (Priority: 25.09.1985) 12. A process for the preparation of a pharmaceutical composition, wherein a compound of formula (I) according to claim 2, wherein R ¹ and X are as defined in claim 2, and R ² is carboxyl or (IX). is a group of formula and the latter formula, n is 2-4, and R ³ and R ⁴ Reporting independently 1 - converted or carrier and / or diluent pharmaceutically acceptable salts commonly used in the pharmaceutical preparation in admixture with a pharmaceutical - C3 AL10 alkyl.