DE1668734A1 - Alkyl benzoyl carbinol esters and processes for their preparation - Google Patents

Description

ALKYLBENZOYLCARBINOLESTERS AND PROCESS FOR THEIR PRODUCTION The invention relates to alkylbenzoylmethyl esters of the formula as new and valuable compounds in which Ri is a hydrocarbon radical with 3 to 10 carbon atoms, R2 is an acyl radical of a carboxylic acid with up to 10 carbon atoms or an inorganic radical which is derived from an inorganic polybasic acid by removing the OH group therefrom, and in which X is hydrogen or represents a halogen atom which is bonded in the o or m position to the radical R1 in the benzene ring.

The hydrocarbon residue in the above formula is an example of a splice a straight-chain or branched alkyl or cycloalkyl radical, e.g. B. n-propyl, isobutyl, sec-butyl, neopentyl cyclopentyl, n-hexyl, cyclopentyl, cyclohexyl, cyclohexylethyl, n-octyl, n-decyl, etc., and the radical R2 is, for example, a formyl, acetyl, valeryl, Benzoyl, furoyl, nicotinoyl, phosphonic, sulforest etc., and come as halogen for example Cl, Br and J in question.

The new alkylbenzoylmethyl derivatives of the formula (I) have a remarkable one temperature-lowering (hypothermic) or anti-inflammatory effect at lower Toxicity to warm blooded animals.

The invention includes the new alkylbenzoylmethyl derivatives of the formula (I) and a process for their production.

The compounds of the formula (I) are prepared by reacting alkylbenzoylmethyl halides of the formula in which R1 and X have the meaning already mentioned and Y is halogen (for example Cl, Br or I), with. an acid of the formula R2 - OH (III), in which R2 has the meaning already mentioned, or with a salt of this acid with a metal (e.g. Hg, Ag, Na or K) or a tertiary amine (e.g. pyridine, Trimethylamine) or a quaternary ammonium compound (e.g. trimethylbenzylammonium).

Carboxylic acids are suitable as inorganic acids of the formula (III) with up to 10 carbon atoms, e.g. B. acetic acid, propionic acid, isobuic acid, Caproic acid, cyclopentylpropionic acid, diethylaminoacetic acid, succinic acid, tartaric acid, Malic acid, nicotinic acid, isonicotinic acid, benzoic acid, salicylic acid, anthranilic acid and indole acetic acid, and inorganic polybasic acids, e.g. sulfonic acid and phosphoric acid.

The reaction according to the invention is generally carried out in an organic Solvent carried out. Suitable solvents are, for example, lower ones Alcohol-e.

Methanol and ethanol), cycloethers (e.g. tetrahydrofuran and dioxane), Ketones (e.g. acetone, methyl ethyl ketone and Cyclohexanone), halogenated Hydrocarbons, acetonitrile, dimethylformamide, dimethyl sulfoxide, pyridine, acetic acid, and propionic acid, lower fatty acids, e.g. B. acetic acid or propionic acid, can serve simultaneously as a reactant R20H and as a solvent.

The reaction temperature is suitably selected depending on the other reaction conditions, e.g. B. the reactants or the one used Solvent, chosen and is usually between room temperature (15-25 ° C) and about 150 ° C. It is recommended that the reaction be carried out under anhydrous conditions if possible perform.

Examples of alkylbenzoylmethyl derivatives of the formula (I) prepared in this way may be mentioned: p-isobutylbenzoyimethyl nicotinate p-isobutylbenzoyimethyl phosphate p-cyclohexylbenzoylmethyl acetate p-cyclohexylbenzoylmethylphosphate. -Butylbenzoylmethylphosphat p-sec-Butylbenzoylmethylnicotinat pn-pn Octylbenzoylmethylphosphat Octylbenzoylmethylnicotinat Cyclopentylmethylbenzoylmethylacetat p-p-p-Cyclopentylmethylbenzoylmethylphosphat Cyclopentylmethylbenzoylmethylnicotinat p-cyclohexyl-m-chlorbenzoylmethylacetat t, ~ p-tert-Butylbenzoylmethylacetat p-tert-Butylbenzoylmethylphosphat pn-pn Btitylbenzoylmethylacetat But-ylbenzoylmethylphosphate pn-butylbenzoylmethylniaotinate - pn-Octylbenzoylmethyl acetate p-Cyclohexyl-m-chlorobenzoylmethyl phosphate p-Cyclohexyl-m-chlorobenzoylmethyl nicotinate p-Cyclohexyl-m-chlorobenzoylmethyl acetate The compounds of the formula (I) have a temperature-lowering or anti-inflammatory effect, if they are administered to warm-blooded animals results, for example, from the following tests in which the following test compounds were used test compound A = pn-butylbenzoyl methyl acetate "B = p-isobutylbenzoyl methyl acetate 0 = p-tert-butylbenzoyl methyl acetate" D = pn-butylbenzoyl methyl phosphate t (monosodium salt) "E = p- sec-butylbenzoylmethylphosphate (monosodium salt) "F = p-tert-butylbenzoylmethylphosphate (monosodium salt) control compound = (p-ixobutylphenyl) acetic acid, known as Ibufenac.

Test 1 The temperature-lowering effect of the compounds (I) was shown MEusen found that 150 mg of the test compound per kilogram of body weight was administered intraperitoneally. The results are given in Table I, in the effectiveness is given as lowering the body temperature in @ ° C.

Table I Reduction in body temperature (° C) test time after administration, Minute connection 15 30 60 90 120 150 180 A 2, 45 2, 60 2, 10 1, 35 1.00 0.70 0.35 B 2.00 2.30 2.30 2.30 1.70 1.55 1.35 0 2, 25 2, 50 2, 00 1, 50 1, 35 1, 10 1, 10 D 1.40 1.80 1.90 1.95 1.85 1.25 1.25 E 2, 40 2, 90 2s15 1, 65 1, 10 0s45 0s20 F 2.85 3.15 1.30 0.95 0.85 0.55 0.45 control compound 1, 55 1, 65 0, 95 0, 45 0, 25 0, 10 0 Test II The anti-inflammatory effect was determined by the method given in Proc. Soo. Exp. Biol. Med., Vol.3, p. 544 (1962), is determined on edema, generated by injection of carrageenin into rats. The results are listed in Table II, where the efficacy is expressed as percent inhibition is..

Table II Percent Inhibition of Carrageenin Edema Test Compound Post-dose time, hours 1 2 3 4 5 D 37 74 70 67 65 Control compound 50 66 51 46 47 Test III The mean lethal doses (LD50) of the compounds (I) in mice when administered intraperitoneally are given in Table III. The values show that the compounds according to the invention have a very low toxicity.

Table III Compound LD50 (mg / kg) B 1,550 C 1,640 c 1,640 Control Compound 720 As the above test results show, the compounds of the formula (I) very low toxicity and remarkable temperature lowering effect.

The compounds according to the invention are suitable as antipyretic (Pyretolytic) agents or anti-inflammatory agents for warm-blooded animals. Also suppress the pain caused by inflammation.

If the radical R2 of the compound (I) is derived from an inorganic or organic polybasic acid derived by removing an OH group from this acid is, the compound (I) is a partial ester and can be salts with metals (e.g. B. sodium, potassium, magnesium,) or amines (e.g. diethylamine, triethylamine, ethylenediamine, Diethanolamine or ammonium). As far as these salts are pharmaceutically safe are used, they are used for the same purposes as the corresponding partial esters on the same molar base used.

In humans, the dosage of the compounds according to the invention is usually 500 to 2500 mg / day. The compounds (I) are generally in the form of capsules, tablets, syrups, used as injection liquid, ointments, etc.

Preferred embodiments of the invention are provided in the following Examples described in which parts by weight become parts of volume like grams to cubic centimeters behavior.

EXAMPLE 1 4.7 parts by weight of p-isobutylbenzoylmethyl iodide (melting point 60 ° C), 2.2 parts by weight of nicotinic acid and 4.5 parts by weight of triethylamine in 30 parts by volume Acetone. The mixture is left to stand for 5 hours at room temperature. One distills the acetone from, are 50 parts by volume of ether and 20 parts by volume of water to the residue and shakes the mixture.

The ether layer is extracted with 30 parts by volume of 1Q hydrochloric acid, makes the acidic solution alkaline with sodium carbonate and extracted with Xther. Man Wash the ether extract with water, dehydrate it over anhydrous sodium sulfate and distilled off the ether, 1.2 parts by weight of p-isobutylbenzoylmethylnicotinate in the form of pale yellow prisms with a melting point of 93 ° C. The hydrochloride this compound is soluble in water.

Analysis: C H N Calculated for C18H19O3N: 72.70 6.44 4.70 Found: 72.29 6.38 4.64 The starting material, p-isobutylbenzoylmethyl iodide, is for example produced by reacting p-isobutylbenzoylmethyl chloride with sodium iodide in acetone, Example 2 "To a mixture of 6.3 parts by weight of trisilver phosphate and 3.6 parts by weight 85% phosphoric acid is added to 50 parts by volume of acetonitrile and 6 parts by weight of p-isobutylmethyl iodide.

The mixture is heated under mild conditions for 4 hours Stirring at reflux, the precipitate formed is filtered off and distilled from the filtrate the acetonitrile off. The residue is mixed with water and activated carbon is added To adsorb the product on it, filter off the charcoal, wash with water and eluted with an aqueous sodium hydroxide solution. The eluate is concentrated under reduced pressure Pressure and adds acetone to the concentrate, making the Sodium salt is precipitated from p-isobutylbenzoylmethyl phosphate.

Example 3 A mixture of 4.9 parts by weight of p-cyclohexylbenzoylmethyl iodide, 15 parts by weight of sodium acetate and 150 parts by volume of acetone boil for 1 hour and distilled releases the solvent. Adds ether and water to the residue, agitates the mixture, separates the ether layer from the aqueous layer and constricts a After the addition of a-about equal volume of petroleum ether to the concentrate, the mixture is allowed to stand, whereby 1, 8 parts by weight of p-cyclohexylbenzoyl methyl acetate as colorless prisms with a melting point 77 to 78 ° C can be obtained.

The p-cyclohexylbenzoylmethyl iodide used as the starting material is made, for example, by reacting p-cyclohexylbenzoylmethyl chloride with sodium iodide made in acetone.

Example 4 49 parts by weight of p-cyclohexylbenzoylmethyl iodide are added to a slurry obtained by reacting 60 parts by weight Trisilver phosphate and 50 parts by weight of 85% phosphoric acid in 100 parts by volume of acetonitrile in the presence of 5 parts by weight of diatomaceous earth, and leaves the mixture with agitation Simmer for 3, 5 hours. After cooling, 200 parts by volume of water are added to the reaction mixture, make the mixture obtained by adding a 20% aqueous sodium hydroxide solution to prj 7, 5 and filter off the silver iodide, which has become carrified. One constricts the filtrate is poured in under reduced pressure, the acetonitrile being removed Add 120 parts by weight of activated carbon to the stand, adjust the pH to 2 with hydrochloric acid and filtered the mixture to separate the activated carbon, which is then ait Water washes until the draining wash water has a p Van-4 4. You are suspended the washed charcoal in methanol, the suspension is made by adding a 20% aqueous sodium hydroxide solution to pH 8 and et-irahiert with 2000 parts by volume Methanol. The methanol extract is concentrated under reduced pressure and acetone is added to the residue, whereby sodium p-cyclohezylbenzoylmethyl phosphate is precipitated.

The nuclear magnetic resonance spectrum of the product in D2O shows a Doublet at 4.8 #, a sign that methylene is attached to -C-P.

Ö In the manner described in the previous examples the alkylbenzoylmethyl derivatives listed in Table IV below were prepared.

Sabelle IV Bsl.'äiedepüMlEt play R R. X NMR () [2 mm Hg), ° C 5 (IH340ii2tqHa. COCH3 it" 6-PO (OH) 2 H 4,8. -COCH 135-145 CHzj -PO (OH) HR 8td) ** ~ 9 tfi e CH2 aS ~ dWe3 S 4 85 (S) * 135rt4s G tt dEfi é * SI 4 82 (S) * 155--145 t 2 a Hs- ~ Cot) g 4.85 (S) * 475 1 '6I a:::. 4I i 4 f 82 (: '' 5: i - t) ll; a E = - 4, 5 ' 15 PO (OH) E 4 j8 (d) #} tE -PO (OH 4 ' 6IjGI 14 S6'-cö6 S 4, 85 (s) * 170 'OHAOH 15 t-PO (OH) B 48 (d) 16 HO <? JCÖCH m-Cl 4 <(S * 200 trt. t 17 lige; -pö t ~ ot 4-7t &) + * w 18 t 0 + J t X * 62 <= * S = singlet ** d = doublet

Claims (25)

P atent claims 1) Compound of the formula where Rl is a hydrocarbon radical with 3 to 10 carbon atoms, R2 is an acyl radical of a carboxylic acid with up to 10 carbon atoms or an inorganic radical which is derived from an inorganic polybasic acid by removing the On group, and X is hydrogen or a halogen atom stands. 2) Compound according to claim 1, characterized in that the remainder R2 is an acetyl radical. 3) compound according to claim l, characterized in that the remainder R2 is a phosphonic residue. 4) compound according to claim 1, characterized in that the rest R2 is a nicotinoyl. rest is. O- 5) compound according to claim 3, characterized in that that the compound is in the form of pharmaceutically acceptable salts. 6) Compound according to claim 1, characterized in that the remainder Rl is an alkyl radical with 4 carbon atoms. 7) p-isobutylbenzoylmethyln @@ tinate. 8) p-isobutyl benzoyl methyl phosphate. 9) p -cyclchexylbenzoyl methyl acetate. 10) p -cyclohexylbenzoylmethyl phosphate. 11) p -cyclohexylbenzoylmethyl nicotinate. 12) p-sec-butylbenzoyl methyl acetate. 13) p-sec-butyl benzoyl methyl phosphate. 14) p-tert-butylbenzoyl methyl acetate. 15) p-tert-butyl benzoyl methyl phosphate. 1.6) p-n-Butylbenzoyl methyl acetate. 17) p-n-butyl benzoyl methyl phosphate. 18) p-iso-butylbenzoyl methyl acetate. 19) p-n-octylbenzoyl methyl acetate. 20) p-n-octylbenzoyl methyl phosphate. 21) p -cyclopentylmethylbenzoylmethyl acetate. 22) p -cyclopentylmethylbenzoylmethyl phosphate. 23) p-Cyclohexyl-m-chl. or-benzoyl methyl acetate. 24) p-Cyclohexyl-m-chloro-benzoylmethyl-phosphate. 25) Process for the preparation of alkylbenzoyimethyl derivatives of the general formula where Rl is a hydrocarbon radical with 3 to 10 carbon atoms, R2 is an acyl radical of a carboxylic acid with up to 10 carbon atoms or an inorganic radical which is derived from a polybasic organic acid by removing the OH group and in which X is hydrogen or a halogen atom is characterized in that a compound of the general formula in which-R1 and X have the meaning given above and the radical Y is a halogen atom, with an acid of the general formula R2-OH, in which R2 has the meaning given above, or is reacted with a salt thereof.