Crystal form a of NHE3 inhibitor, preparation method therefor and application thereof
Provided is crystal form A of N,N′-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16, 18-tetrazohexahexane-1,26-di-yl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl) benzene sulfonamide. The crystal form has good light stability, high-temperature stability, and high-humidity stability.
1. A crystal form A of N,N′-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl) bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl) benzene sulfonamide of formula (I), wherein the X-ray powder diffraction thereof using Cu-Kα radiation has characteristic peaks at 2θ diffraction angles of 11.1±0.2°, 19.4±0.2°, 19.9±0.2° and 22.8±0.2°,
2. The crystal form A of claim 1 , wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 8.6±0.2°, 13.2±0.2°, 13.5±0.2°, 22.1±0.2°, and 23.8±0.2°.
3. The crystal form A of claim 2 , wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 20.8±0.2°, 23.1±0.2°, 23.4±0.2°, 24.4±0.2°, and 24.9±0.2°.
4. The crystal form A of claim 3 , wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 5.9±0.2°, 6.1±0.2°, 11.8±0.2°, 15.0±0.2°, 15.5±0.2°, 16.0±0.2°, and 17.2±0.2°.
5. The crystal form A of claim 1 , wherein the crystal form A has following characteristic peaks in X-ray powder diffraction pattern:
No.
Relative
of
intensity
Peaks
2θ (°)
(%)
1
8.587
8.2
2
11.14
69.3
3
11.816
16.8
4
13.219
37.8
5
13.498
31.1
6
15.013
12.7
7
15.532
14.7
8
15.973
14.3
9
17.209
12.9
10
19.426
69.2
11
19.864
75.8
12
20.841
35.8
13
22.139
50.5
14
22.776
100
15
23.773
27.4.
6. The crystal form A of claim 1 , wherein the crystal form A has following characteristic peaks in X-ray powder diffraction pattern:
No.
Relative
of
intensity
Peaks
2θ (°)
(%)
1
5.913
7.3
2
6.098
7.6
3
8.587
8.2
4
11.14
69.3
5
11.816
16.8
6
13.219
37.8
7
13.498
31.1
8
15.013
12.7
9
15.532
14.7
10
15.973
14.3
11
17.209
12.9
12
19.426
69.2
13
19.864
75.8
14
20.442
14.4
15
20.841
35.8
16
22.139
50.5
17
22.776
100
18
23.059
26
19
23.398
25.2
20
23.773
27.4
21
24.395
30.3
22
24.934
26.4.
7. The crystal form A of claim 1 , wherein the crystal form A has an X-ray powder refraction pattern substantially as shown in FIG. 2 .
8. The crystal form A of claim 1 , wherein the crystal form A has a characteristic absorption peak in a temperature range of 140° C.-150° C. measured by differential scanning calorimetry.
9. The crystal form A of claim 1 , wherein the crystal form A has a differential scanning calorimetry curve substantially as shown in FIG. 3 .
10. The crystal form A of claim 1 , wherein the crystal form A has a weight loss of 0.4% before a temperature of 100° C. in its thermo gravimetric analysis curve.
11. The crystal form A of claim 1 , wherein the crystal form A has a thermo gravimetric analysis curve substantially as shown in FIG. 4 .
12. A method for preparing the crystal form A of claim 1 , comprising the following steps of:
dissolving amorphous N,N′-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-di-yl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl) benzene sulfonamide by adding a good solvent thereto,
performing a first cooling to room temperature, and adding a poor solvent thereto, and
performing a second cooling, followed by standing, separating out solids and drying to obtain the crystal form A.
13. The method of claim 12 , wherein the second cooling is performed at a rate of 18-24° C./min, preferably at a rate of 20° C./min.
14. The method of claim 12 , wherein the good solvent is an organic solvent selected from the group consisting of a lower alcohol, a lower ketone and a lower nitrile, and wherein the poor solvent is methyl tert-butyl ether.
15. The method of claim 14 , wherein the lower alcohol is selected from the group consisting of methanol, ethanol, isopropanol or n-butanol, and the lower ketone is acetone; and the lower nitrile is acetonitrile.
16. The method of claim 12 , wherein a volume ratio of the good solvent to the poor solvent is 1:(8-14).
17. A pharmaceutical composition, comprising the crystal form A of claim 1 and a pharmaceutically acceptable excipient.
18. A method for inhibiting NHE-mediated antiport of sodium ions and hydrogen ions in mammals or for treating a disease, comprising administering a pharmaceutically effective amount of the crystal form A of claim 1 or a pharmaceutical composition comprising the same, wherein the disease is selected from the group consisting of heart failure, chronic kidney disease, end-stage renal disease, liver disease, peroxisome proliferator-activated receptor gamma agonist-induced fluid retention, hypertension, edema, and gastrointestinal tract disorder in mammals.
19. The method of claim 18 , wherein the administering is performed orally or by rectal suppository.
20. The method of claim 18 , wherein the heart failure is congestive heart failure, and wherein the hypertension is associated with dietary salt intake; the edema is induced by chemotherapy, premenstrual fluid overload or preeclampsia; and the gastrointestinal tract disorders are gastrointestinal motility disorder, irritable bowel syndrome, chronic constipation, functional gastrointestinal tract disorders or Crohn's disease.