| 摘要 |
1. gamma-crystalline form of the compound of formula (I): characterised by the following powder X-ray diffraction diagram, measured using a diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage with respect to the most intense ray): Angle 2 theta ( degree ) Inter-planar distance d (A) Intensity Relative intensity (%) 6.298 14.02 630 39.8 7.480 11.81 380 24 8.700 10.16 1584 100 9.276 9.53 318 20.1 10.564 8.37 526 33.2 11.801 7.49 54 3.4 12.699 6.96 86 5.4 13.661 6.48 178 11.2 14.095 6.28 163 10.3 14.332 6.17 290 18.3 14.961 5.92 161 10.2 15.793 5.61 128 8.1 16.212 5.46 179 11.3 16.945 5.23 80 5.1 17.291 5.12 92 5.8 17.825 4.97 420 26.5 18.100 4.90 159 10 18.715 4.74 89 5.6 19.017 4.66 118 7.4 19.362 4.58 134 8.5 19.837 4.47 133 8.4 20.609 4.31 95 6 21.232 4.18 257 16.2 21.499 4.13 229 14.5 21.840 4.07 127 8 22.129 4.01 191 12.1 22.639 3.92 137 8.6 23.000 3.86 88 5.6 23.798 3.74 147 9.3 24.170 3.68 70 4.4 25.066 3.55 167 10.5 25.394 3.50 165 10.4 26.034 3.42 84 5.3 26.586 3.35 75 4.7 27.541 3.24 74 4.7 28.330 3.15 85 5.4 29.589 3.02 96 6.1 2. Process for the preparation of the gamma-crystalline form of the compound of formula (I) according to claim 1, characterised in mat a solution of perindopril tert-butylamine salt in chloroform is heated at reflux, the solution is then cooled to 0 degree C and the solid obtained is collected by filtration. 3. Process for the preparation of the gamma-crystalline form of the compound of formula (I) according to claim 1, characterised in that a solution of perindopril tert-butylamine salt in ethyl acetate is heated at reflux, the solution is rapidly cooled, the solid thereby obtained is then collected by filtration, it is suspended in chloroform, the suspension is stirred at ambient temperature for from 5 to 10 days, and the solid is then collected by filtration. 4. Process according to either claim 2 or claim 3, characterised in that the compound of formula (1) which is wed is obtained by the following process: firstly, on the one hand, reduction of indole-2-carboxylic acid, or an alkyl ester thereof, by a process such as the use of the tin/hydrochloric add couple, followed, if an ester is obtained, by deprotection, to obtain racemic indoline-2-carboxylic add, from which the S isomer is isolated by adding the racemate to a solution of (()-alpha-methylbemylamine in a lower aliphotic alcohol, to obtain a precipitate of the salt formed by (S)-indoline-2-carboxylic acid with alpha-methylbenzylamine, which, after filtration, is dissolved in water and acidified, to lead to (S)-indoline-2-carboxylic acid, which, after filtration and washing, is subjected to catalytic hydrogenation, under a hydrogen pressure of 10 to 150 bars, preferably between 20 and 60 bars, with heating to a temperature of 30 to 100 degree C, preferably between 40 and 80 degree C, the catalyst being selected from rhodium, palladium, platinum and nickel, mixed with a support such as charcoal, to lead, after separation from the (2S, 3aR, 7aR) isomer obtained in a low proportion, by a single crystallization from a polar solvent selected from lower aliphatic alcohol, acetonitrile, ethyl acetate and dioxane, by itself or mixed with water, or mixed with each other and with water, provided that the mixture obtained forms a single phase, to optically pure (2S, 3aS, 7aS)-perhydroindote-2-carboxylic acid, which is reacted with lower aliphatic or benzylic alcohol, in the presence of an acidic esterification catalyst, to give the corresponding ester, on the other hand, (S)-L-norvaline is esterified with ethanol in the presence of an acid catalyst, to lead to (S)-ethyl norvalinate, which is condensed under catalytic hydrogenation, under a hydrogen pressure of 10 to 150 bars, the catalyst being selected from rhodium, palladium, platinum and nickel, mixed with a support such as charcoal, with pyruvic acid, to lead directly, after a single crystallization from a polar solvent selected from lower aliphatic alcohol, acetonitrile, ethyl acetate and dioxane, by itself or mixed with water, or mixed with each other and with water, provided that the mixture obtained forms a single phase, cooling and filtration, to optically pure N-[(S)-1-carbethoxybutyl]-(S)-alanine, secondly, the benzyl or lower alkyl ester of (2S, 3aS, 7aS)-perhydroindote-2-carboxylic acid is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine in an alkaline medium in the presence of a catalyst for peptide synthesis such as dicyclohexylcarbodiimide in the presence of l-hydroxybenzotriazole, to lead to the corresponding amide, which is subjected to deprotection of the carboxylic group of the heterocyclic ring, salification with tert-butylamine and crystallisation. 5. Process according to claim 2, characterised in that the concentration of the compound of formula (I) in the chloroform is from 150 to 300 g/litre. 6. Process according to claim 3, characterised in that the concentration of the compound of formula (I) in the ethyl acetate is from 70 to 90 g/litre. 7. Pharmaceutical composition comprising as active ingredient the compound according to claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers. 8. Pharmaceutical composition according to claim 7 for use as inhibitors of angiotensin I converting enzyme. 9. Pharmaceutical composition according to claim 8 for use as a medicament in the treatment of cardiovascular diseases. 10. Pharmaceutical composition according to claim 7, characterised in that it also comprises a diuretic. 11. Pharmaceutical composition according to claim 10, characterised in that the diuretic is indapamide. |
