Thermodynamically stable crystalline hydrochloride of (r)- (-)-2-{n-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol - 2-yl)butyl] aminomethyl}-chroman

 

(57) Abstract:

The invention relates to a new, more thermodynamically stable crystalline form of the hydrochloride of (R)-(-)-2-{N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-chroman. We offer hydrochloride were characterized by physico-chemical parameters in the claims. It is not converted even at high air humidity ( relative humidity 85%, room temperature). On this basis, the proposed hydrochloride are particularly well suited for solid pharmaceutical compositions of 5-HT1A-agonistic activity, used for the treatment and prevention of, for example, stroke. 6 C.p. f-crystals, 6 ill.

The invention relates to salts derived aminomethylpropanol, in particular to thermodynamically stable crystalline hydrochloride of (R)-(-)-2-{ N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] aminomethyl}-chroman.

In the European patent 352 613 (example 92 N) describes hydrochloride (R)-(-)-2-{ N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] -aminomethyl}chromane formula:

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It has a melting point of 192 - 194oC. On the basis of its properties as a 5-HT1 is edstac, in particular for the treatment and prevention of neuronal degenerations due to ischemic effects such as stroke.

Discovered that the famous hydrochloride is metastable and high humidity (relative humidity 85%, room temperature) can be partially transformed. On this basis, it is only partly suitable for use in pharmaceutical compositions.

The task of the invention to provide a more stable crystalline hydrochloride known aminomethylpropanol.

This problem is solved proposed thermodynamically stable crystalline hydrochloride of (R)-(-)-2-{N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)-butyl]aminomethyl}chromane.

Proposed according to the invention hydrochloride is not converted even at high air humidity (relative humidity 85%, room temperature). On this basis, it is particularly well suited for solid pharmaceutical compositions with 5-HT1A-agonistic activity.

Proposed according to the invention hydrochloride is characterized by the following physico-chemical parameters:

1. Melting point proposed under the Fig is UP>Is the transformation in the solid phase (endothermic peak in thermogram of differential scanning calorimetry; Fig.1). The heat of transformation is 24 j/,

2. X-ray diffraction pattern (see Fig.2) [2]::

9,7; 11,5; 12,3; 12,6; 13,4; 14,5; 15,7; 16,8; 16,9; 17,5; 18,3; 19,4; 20,4; 22,5; 22,6; 23,2; 24,0; 24,4; 24,7; 24,9; 25,8; 26,0; 26,3; 26,9; 27,4; 27,9; 28,4; 27,7; 29,2; 29,3; 29,8; 30,1; 31,1; 31,8; 32,6; 33,9; 34,1; 34,3; 34,7; 35,1; 35,3; 35,7; 36,2; 36,4; 36,7; 37,0; 37,4; 37,6.

3. The infrared spectrum (Fig.3) [cm-1]:

621, 672, 680, 716, 731, 743, 752, 783, 800, 835, 849, 876, 897, 910, 927, 940, 987, 1010, 1021, 1044, 1059, 1106, 1137, 1153, 1179, 1197, 1213, 1242, 1248, 1288, 1305, 1320, 1348, 1373, 1408, 1445, 1458, 1488, 1585, 1603, 1690, 1733, 2389, 2424, 2448, 2541, 2571, 2673, 2701, 2785, 2847, 2873, 2999, 2930, 2949, 2961, 2993, 3025, 3073, 3097, 3189, 3444.

4.13C-NMR spectrum of the solid (Fig.4) [M. D.]:

159, 158, 153, 137, 135, 134, 133, 130, 128, 126, 121, 120, 118, 117, 116, 115, 72, 55, 54, 50, 49, 40, 39, 27, 26, 25, 23.

5. The spectrum in the far infrared region (see Fig.5) [cm-1]:

105, 121, 152, 169, 195, 224, 247, 286, 300, 335, 345, 391, 410, 420, 426, 455, 485.

6. Raman spectrum (see Fig.6) [cm-1]:

9, 105, 119, 142, 174, 234, 286, 309, 348, 393, 419, 487, 513, 587, 595, 623, 644, 680, 739, 763, 988, 1016, 1033, 1062, 1158, 1181, 1223, 1245, 1288, 1307, 1321, 1351, 1379, 1394, 1411, 1433, 1462, 1476, 1600, 1613, 1736, 2869, 2900, 2933, 2963, 2983, 2991, 3028, 3044, 3061, 3082.

By its physical-chemical parameters (melting properties according to differe the solid body, spectrum in the far-infrared and Raman spectrum (see Fig. 1-6/ proposed according to the invention hydrochloride distinctly different from known hydrochloride.

Proposed according to the invention the crystalline hydrochloride get, in General, what is known hydrochloride are suspended in water or inert organic substances, such as, for example, lower alcohols, ketones or alkanes up to achieve the desired degree of conversion, particularly preferably up to quantitative transformation in the proposed according to the invention crystalline form. Typically, this transformation occurs at temperatures 0-35oC, preferably at 30oC. the resulting crystals are separated and removal of existing solvent is dried at room temperature in vacuum or at elevated temperature to constant weight.

Proposed according to the invention the crystalline hydrochloride in a known manner transferred in conventional dosage forms of 5-HTlA-agonistic activity, and the preferred dosage forms in which the crystalline active substance is in the solid state, as, for example, tablets, coated tablets, pills, granules is ispolzovanie inert nontoxic pharmaceutically suitable carriers and excipients. Proposed according to the invention the pharmaceutical composition contains a proposed according to the invention a stable crystalline hydrochloride in an effective amount.

The following examples illustrate how to get proposed according to the invention a stable crystalline hydrochloride.

Example 1

Getting the seed crystal

0.5 g known metastable hydrochloride (R)-(-)-2-{N-[4-(1,1-dioxide-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] aminomethyl} chromane suspended in 8 ml of a mixture of acetone with methanol in the ratio of 7:1 and stirred for 5 days at room temperature. The precipitate is filtered off and dried in vacuum at room temperature to constant weight. To test for the quantitative turning off the infrared spectrum.

Example 2

0.5 g known metastable hydrochloride (R)-(-)-2-{N-[4-(1,1-dioxide-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] aminomethyl} chromane suspended in 7 ml of a mixture of acetone with ethanol in a ratio of 6:1. In the suspension making the product of example 1 diluted and stirred for 5 days at 0oC. the Precipitate is filtered off and dried in vacuum at room temperature until constant the industry.

Example 3

0.5 g known metastable hydrochloride (R)-(-)-2-{N-[4-(1,1-dioxide-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] aminomethyl} chromane suspended in 6 ml of a mixture of acetone with ethanol in a ratio of 2:1. In the suspension making the product of example 1 diluted and stirred for 5 days at room temperature. The precipitate is filtered off and dried in vacuum at room temperature to constant weight. To test for the quantitative turning off the infrared spectrum.

Example 4

1.7 g known metastable hydrochloride (R)-(-)-2-{N-[4-(1,1-dioxide-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] aminomethyl} chromane suspended in 14 ml of a mixture of acetone with ethanol in a ratio of 6:1. In the suspension making the product of example 1 diluted and stirred for 6 days at room temperature. The precipitate is filtered off and dried in vacuum at room temperature to constant weight. To test for the quantitative turning off the x-ray diffraction pattern.

Example 5

0.4 g known metastable hydrochloride (R)-(-)-2-{N-[4-(1,1-dioxide-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] aminomethyl} chromane suspended in 7 ml of a mixture of acetone with ethanol rela/SUP>C. the Precipitate is filtered off and dried in vacuum at room temperature to constant weight. To test for the quantitative turning off thermogram of differential scanning calorimetry.

Example 6

0.5 g known metastable hydrochloride (R)-(-)-2-{N-[4-(1,1-dioxide-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] aminomethyl} chromane suspended in 10 ml of isopropanol. In the suspension making the product of example 1 diluted and stirred for 6 hours at room temperature. The precipitate is filtered off and dried in vacuum at room temperature to constant weight. To test for the quantitative turning off thermogram of differential scanning calorimetry.

1. Thermodynamically stable crystalline hydrochloride of (R)-(-)-2-{ N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl] aminomethyl} -chroman.

2. Thermodynamically stable crystalline hydrochloride under item 1, which converted approximately at 60oWith the warmth of turning 24 Joule/year

3. Thermodynamically stable crystalline hydrochloride by PP. 1 and 2, characterized by the following x-ray diffraction data [2]:

4. Thermodynamically stable crystalline hydrochloride by PP. 1-3, characterized by the following data of the infrared spectrum [cm-1] :

621, 672, 680, 716, 731, 743, 752, 783, 800, 835, 849, 876, 897, 910, 927, 940, 987, 1010, 1021, 1044, 1059, 1106, 1137, 1153, 1179, 1197, 1213, 1242, 1248, 1288, 1305, 1320, 1348, 1373, 1408, 1445, 1458, 1488, 1585, 1603, 1690, 1733, 2389, 2424, 2448, 2541, 2571, 2673, 2701, 2785, 2847, 2873, 2999, 2930, 2949, 2961, 2993, 3025, 3073, 3097, 3189, 3444.

5. Thermodynamically stable crystalline hydrochloride by PP. 1-4, characterized by the following data13C-NMR spectrum of the solid (Fig. 4) [M. D. ] :

159, 158, 153, 137, 135, 134, 133, 130, 128, 126, 121, 120, 118, 117, 116, 115,

72, 55, 54, 50, 49, 40, 39, 27, 26, 25, 23.

6. Thermodynamically stable crystalline hydrochloride by PP. 1-5, characterized by the following data spectrum in the far infrared region [cm-1] :

105, 121, 152, 169, 195, 224, 247, 286, 300, 335, 345, 391, 410, 420, 426, 455, 485.

7. Thermodynamically stable crystalline hydrochloride by PP. 1-6, characterized by the following data of the Raman spectrum [cm-1] :

9, 105, 119, 142, 174, 234, 286, 309, 348, 393, 419, 487, 513, 587, 595, 623, 644, 680, 739, 763, 988, 1016, 1033, 1062, 1158, 1181, 1223, 1245, 1288, 1307, 1321, 1351, 1379, 1394, 1411, 1433, 1462, 1476, 1600, 1613, 1736, 2869, 2900, 2933, 2963, 2983, 2991, 3028, 3044, 3061, 3082.

 

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