FI82689B - PHARMACEUTICAL FORM OF PHARMACOLOGICAL PROPERTIES 2-ETHOXY-4- / N- (1- (2-PIPERIDINO-PHENYL) -3-METHYL-1-BUTYL) -AMINOCARBONYLMETHYL / BENZOESYR B-OCH C-FORM. - Google Patents

Abstract

1. Two new solid forms of 2-ethoxy-4-[N-(1-(2-piperidino- phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, the form designated (B) being characterised by the melting point of 140-142 degrees C and by the IR(KBr) spectrum according to Figure B' and the form designated (C) being characterised by a melting point of 75-85 degrees C and by the IR(KBr) spectrum according to Figure C'.

Description

1 82689

The process for the preparation of pharmacologically valuable forms B and C of 2-ethoxy-4- [N - ((2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonyl-methyl] -benzoic acid - Förfarande för fram-ställning av pharmacologiskt 2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoicyrase B- and C-form

EP-A2-0.147850, July 10, 1985, does not describe 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl] butyl) aminocarbonylmethyl] benzoic acid, which melting point 90-92 ° C (acetone / petroleum ether; form (A)). This compound is then obtained according to Example 11 by catalytic hydrogenation of 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-buten-1-yl) aminocarbonylmethyl] benzoic acid; it, like its physiologically acceptable acid addition salts and enantiomers, has valuable pharmacological properties. Namely, they affect the metabolism of intermediates, in particular they have a hypoglycemic effect.

Surprisingly, it has now been found that the same compound, namely 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid, is further obtained in solid form by crystallization from other solvents. or solvent mixtures. Form (B) having a melting point of 140-142 ° C is obtained by crystallization from a mixture of ethanol and water; the foamy form (C) with a melting range of 75-85 ° C is obtained from a 1: 1 methanol adduct (melting point: 85-90 ° C) which precipitates on crystallization from methanol by heating at 60 ° C under vacuum (5 torr) phosphorus on pentoxide to remove methanol.

The forms in the soluble state are identical, as unambiguously indicated by the corresponding leaching spectra, e.g. IR-. . spectra in methylene chloride (see Figures A, B and C).

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In contrast, in solid form, the forms differ in their melting properties and in the spectra of the solid, for example in terms of the corresponding IR-KBr spectra (see Figures A ', B' and C ').

To measure IR absorption, Forms (A), (B) and (C) were dissolved in methylene chloride (40 mg substance / ml methylene chloride) or rotated well with potassium bromide and then hydraulically compressed into a tablet (approximately 1 mg substance / 300 mg KBr).

In the case of solutions, the IR spectra were measured with an IR spectrometer (Perkin-Elmer, type 299) in a sodium chloride cuvette (layer thickness 0.2 mm) compared to pure methylene chloride solution and, in the case of potassium bromide extrudates, with an IR spectrometer (Perkin-Elmer, type 298) compared to air.

The forms can be converted into each other by recrystallization and drying, respectively. Thus, the lower melting form (A) is obtained by recrystallization of the higher melting form (B) from acetone / petroleum ether and the higher melting form (B) is obtained by recrystallization of the lower melting form (A) from ethanol / water. Recrystallization of the higher melting form (B) from methanol gives a 1: 1 adduct with methanol and removal of the methanol gives a foamy form (C),

Regardless of the nature of the process used for the synthesis of the process according to the invention, a higher melting or lower melting form or a foamy form can also be prepared, if desired, by selecting a suitable solvent or solvent mixture during crystallization and by corresponding drying. This is of practical importance for solid forms, whether or not galenic excipients are used with them in drugs, especially for lowering blood sugar in the treatment of type II diabetes; the different solid forms may then have different shelf life 3 82689 and / or different resorption properties in vivo and thus result in a different biological effect.

According to the invention, 2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid is obtained by the method described above, not in the European Publication Notice, preferably however, by reacting 3-methyl-1- (2-piperidinophenyl) -1-butylamine with a compound of the general formula

HOOC-CH2- ^ ^ - W

OC 2 H 5 W is a carboxy group or a carboxyl group protected by a protecting group, or a reactive derivative thereof optionally prepared in a reaction mixture, followed, if necessary, by cleavage of the deprotected protecting group and further solid forms (B) and (C) by crystallization and finally recrystallization and / or or by drying, respectively.

Suitable reactive derivatives of the compound of the above general formula are, for example, their esters such as methyl, ethyl or benzyl ester, their thioesters such as methylthio or ethylthioester, their halides such as acid chloride, their anhydrides or imidazolides.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide. , Ν'-dicyclohexylcarbodiimide, Ν, Ν'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or amino for example in the presence of phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine which can simultaneously act as solvents, at temperatures between -25 and 250 ° C, preferably between -10 ° C and the boiling point of the solvent used. The reaction can also be carried out without a solvent. In addition, the water formed during the reaction can be separated azeotropically by distillation, for example by heating with toluene in a water separator, or by adding a desiccant such as magnesium sulfate or a molecular sieve.

If necessary, the subsequent cleavage of the protecting group is best carried out hydrolytically, conveniently either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, water, methanol, methanol. in isopropanol or water / dioxane at temperatures between -10 and 120 ° C, for example between room temperature and the boiling point of the reaction mixture.

The tert-butyl protecting group may also be cleaved by heat, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and most preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid or phosphoric acid, phosphoric acid.

In addition, the benzyl group used as a protecting group can also be hydrogenolytically cleaved off in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

The post-crystallization takes place in situ from the ethanol / water reaction mixture or, as the final recrystallization, by dissolving in an ethanol / water mixture, optionally by heating and cooling, and possibly by trituration and / or seeding (Form B), or by dissolving in acetone, and adding petroleum ether. (Form A) or by dissolving (possibly heating) in methanol, then cooling and triturating and / or inoculating and heating the isolated solid methanol adduct, preferably in vacuo, in the presence of a desiccant such as phosphorus pentoxide (Form C).

The new compound obtained can be further converted into its salts, in particular its physiologically acceptable salts with inorganic or organic acids or also bases. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, ethanolate, ethinic acid, ethinic acid, ethinic acid, calendroxide, sodium hydroxide, potassium hydroxide, potassium hydroxide, ethylenediamine or lysine.

The compounds used as starting materials are obtained by methods known from the literature.

It has already been mentioned above that the new compound has valuable. . pharmacological properties, namely the effect on the metabolism of intermediates, but in particular the hypoglycaemic effect.

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Compounds A = 4- [N- (1- (2-piperidinophenyl) -1-ethyl) aminocarbonylmethyl] benzoic acid sodium salt (e.g. 10, EP-A-0.058.779), B * 4- [N- (1- (2-piperidino-phenyl) -1-propyl) -aminocarbonylmethyl] -benzoic acid (e.g. 9, EP-A-0.058.779), C = 4- [N- (1- ( 2-Piperidino-phenyl) -2-methyl-1-propyl) -aminocarbonylmethyl] -benzoic acid (e.g. 29, EP-A-0.058.779) and D = 4- [N- (1- (2-piperidino) -phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid (e.g. 25, EP-A-0.099.017) was compared to E * 2-ethoxy-4- [N- (1- (2-piperidino-phenyl) ) -3-Methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid 1. Antihypertensive effect

The hypoglycemic effect of the test substance was studied in self-reared female rats weighing 180-220 g and fasted for 24 hours before the start of the experiment. Immediately before the start of the experiment, the test substance was suspended in 1.5% methylcellulose and applied via the gastric tube.

Blood was drawn immediately before and 1, 2, 3, and 4 hours after application of the substance, respectively, from the retro-orbital venous plexus. From this, 50 μl of protein in 0.5 ml of 0.33 N perchloric acid were removed and centrifuged. Glucose was determined from the supernatant by the hexo kinase method using an analytical totometer. Statistical 7 82689 evaluation was performed by t-test using p = 0.05 as the significance limit.

The values obtained are shown in the following table as a percentage of the controls.

Table I

r ~ mg7k <r 0.5 mg / kg

Total 1234 1234 diste_hour _hour- Λ -35 -25 -11 n.s. -17 -15 n.s. socalled

B -27 -28 -18 -18 C -19 -19 -16 “19 n.s. -18 -16 -14 D -44 -35 -26 -18 _E ___- 45 -44 -47 -43

Table II

: 0.200 mg / kg 0.100 mg / kg 0.030 mg / kg

Compound Compound Compound

Hour_D_E_D_E_D_E_ 1 -28 - - “43 -28 -19 2 -22 - - -39 -22 -39 ;; 3 -13 - -38 -13 -38: 4_n. s _-_ -36_n. p ._- 34_ 2. Acute toxicity Ί Self-grown female and male mice weighing 20 to 26 g were tested for toxicity after a single oral dose (suspension in 1% methylcellulose) with a 14-day observation period:

Substance_orienting acute toxicity_ crystalline form B_> 1000 mo / kq p.q (6 animals died 0) s 82689

Due to their pharmacological properties, the compound according to the invention and its physiologically acceptable salts are suitable for the treatment of diabetes mellitus. For this purpose, it is possible to process, possibly in combination with other active ingredients, into conventional galenic formulations, such as tablets, granules, capsules, powders or suspensions. The single dose for adults is then 1-50 mg, preferably 2.5-20 mg, 1 or 2 times a day.

The following examples further illustrate the invention:

Note:

Melting points were determined Electro Thermal R - melting point apparatus for visually observing the other side of the molten glass tube of the sample material.

Example 1 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

To a solution of 2.9 g (11.9 mMol) of 3-methyl-1- (2-piperidino-phenyl) -1-butylamine in 29 ml of acetonitrile is added successively 3 g (11.9 mMol) of 3 -ethoxy-4-ethoxycarbonyl-phenylacetic acid, 3.7 g (14.3 mMol) of triphenylphosphine, 3.3 ml (23.8 mMol) of triethylamine and 1.15 ml (11.9 mMol) of carbon tetrachloride. It is then stirred for 15 hours at room temperature, the solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water. The organic extract is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by flash chromatography on silica gel (toluene / acetone = 10/1).

Yield: 4.9 g (85% of theory),

M.p .: 143-145 ° C (petroleum ether) 9 82689

Calc .: C 72.47 H 8.39 N 5.83

Found: 72.37 8.45 6.07

Example 2 Higher Melting Form of 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid (B)

Stir a mixture of 4.7 g (9.7 mMol) of 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester and 14.7 ml of 1N sodium hydroxide in 47 ml of ethanol, for 2 hours at 60 [deg.] C., then neutralized with 14.7 ml of ΙΝ-hydrochloric acid and cooled to 0 [deg.] C. The precipitated colorless crystals are filtered off, washed with ice water and a small amount of ice-cold ethanol and dried at 100 ° C / l torr.

Yield: 3.9 g (88% of theory)

M.p .: 140-142 ° C

Found: C 71.65 H 8.02 N 6.19

Calc .: 71.90 8.08 6.34

On recrystallization from ethanol / water (2/1), the melting point remains the same.

Example 3 Lower melting form (A) of 2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid 1.0 g of 2-ethoxy-4 The higher melting form (B) of [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid is dissolved in 5 ml of acetone at room temperature and 5 ml of petroleum ether (60-70 ° C). During trituration, crystallization gradually occurs. An additional large amount of petroleum ether is added and, after crystallization, is filtered off. Wash with petroleum ether and dry the almost colorless crystals for two hours at 60 ° C / 0.1 torr.

Yield: 0.7 g

M.p .: 95-98 ° C (clear from 135 ° C)

Lask. C 71.65 H 8.02 N 6.19 Obtained 71.80 8.04 5.92 The spectra of this form (see Figures A and A ') are identical to the melting point of form (A) already described in the aforementioned non-public European publication. 90-92 ° C, with spectra.

Example 4 Higher Melting Form of 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid (B)

1.0 g of the lower-melting form (A) of 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid is dissolved by heating in a steam bath to 10 ml. ethanol / water (2/1). It is then cooled to 0 ° C, whereupon crystallization occurs. Perform, wash with a small amount of ice-cold ethanol and dry at 100 ° C / l torr. Yield: 0.8 g M.p .: 140-142 ° C

Example 5 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid foam form (C) 1.5 g of 2-ethoxy-4- [N- (1- (2-Piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid, higher melting form (B) is dissolved in 5 ml of methanol with heating. It is then cooled by trituration to 0 ° C. The precipitated crystals are filtered off, washed with a small amount of cold methanol and dried for 2 hours at 60 ° C / 0.1 torr. Adduction yield (with 1 x CH 3 OH): 1.2 g

M.p .: 85-90 ° C

Lask. (x 1 CH 3 OH): C 69.39 H 8.32 N 5.78

Found 69.20 8.20 5.92

The above adduct is converted to the methanol-free foam form (C) by heating for 24 hours at 60 ° C / 5 torr on phosphorus pentoxide.

Melting range: 75-85 ° C

Found C 71.65 H 8.02 N 6.19 Calcd. 71.82 8.06 6.03 • · »·« • * • «•« • · • «*« * * «- •» • * -

Claims (2)

A process for the preparation of pharmacologically valuable 2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -amycarbonylmethyl] benzoic acid (B) form with sp = 140 - 142 ° C and (C) form with sp = 75 - 80 ° C, characterized in that the (B) form is crystallized by dissolving 2-ethoxy-4- [n- (1- (2-piperidino) phenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid in ethanol / water (2: 1) and the (C) form are crystallized by dissolving 2-ethoxy-4- [N- (1- (2-piperidino) -phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] benzoic acid in methanol and the obtained crystals are dried at 60 ° C in vacuo. Process according to Claim 1, characterized in that 2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] benzoic acid is prepared by adding 3-methyl-1 - (2-piperidino-phenyl) -1-butylamine react with a carboxylic acid of the general formula H00C-CH2 - P formed reactive derivatives, and if needed, the protecting group used is cleaved.