NZ775308B2 - Novel salt of a bcl-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same - Google Patents
Novel salt of a bcl-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the sameInfo
- Publication number
- NZ775308B2 NZ775308B2 NZ775308A NZ77530819A NZ775308B2 NZ 775308 B2 NZ775308 B2 NZ 775308B2 NZ 775308 A NZ775308 A NZ 775308A NZ 77530819 A NZ77530819 A NZ 77530819A NZ 775308 B2 NZ775308 B2 NZ 775308B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- ppm
- crystalline form
- compound
- hydrogen sulfate
- sulfate salt
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract 7
- 150000003839 salts Chemical class 0.000 title abstract 3
- 239000012664 BCL-2-inhibitor Substances 0.000 title 1
- 229940123711 Bcl2 inhibitor Drugs 0.000 title 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract 26
- 238000010586 diagram Methods 0.000 claims abstract 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract 7
- 229940126062 Compound A Drugs 0.000 claims 25
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 25
- 206010028980 Neoplasm Diseases 0.000 claims 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 5
- 238000002360 preparation method Methods 0.000 claims 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 4
- 239000003814 drug Substances 0.000 claims 4
- 208000023275 Autoimmune disease Diseases 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 210000000987 immune system Anatomy 0.000 claims 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 2
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 claims 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 2
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims 2
- 206010025323 Lymphomas Diseases 0.000 claims 2
- 208000034578 Multiple myelomas Diseases 0.000 claims 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims 2
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims 2
- 206010033128 Ovarian cancer Diseases 0.000 claims 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 2
- 206010060862 Prostate cancer Diseases 0.000 claims 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 2
- 210000004556 brain Anatomy 0.000 claims 2
- 210000000481 breast Anatomy 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 2
- 239000010949 copper Substances 0.000 claims 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims 2
- 210000004185 liver Anatomy 0.000 claims 2
- 208000003747 lymphoid leukemia Diseases 0.000 claims 2
- 230000003211 malignant effect Effects 0.000 claims 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 201000001441 melanoma Diseases 0.000 claims 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 2
- 201000002528 pancreatic cancer Diseases 0.000 claims 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 2
- 210000003932 urinary bladder Anatomy 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 238000005384 cross polarization magic-angle spinning Methods 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- -1 dimethyl-1H-pyrrolyl Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 238000001228 spectrum Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
Novel salt and related crystalline forms of Compound (A) wherein the salt is the hydrogen sulfate salt, characterised by its X-ray powder diffraction diagram, method for preparing the same and pharmaceutical compositions containing it.
Claims (8)
1.CLAIMS 1. The hydrogen sulfate salt of 5-(5-chloro{[(3S)(morpholinylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl} phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolyl)-N- (4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide (Compound A, H SO ). 5 2 2. . A crystalline form I of the hydrogen sulfate salt of 5-(5-chloro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2- dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide (Compound A, H SO ) according to claim 1, wherein the crystalline form has an X-ray powder diffraction diagram showing the following diffraction lines (Bragg's angle 2 theta, 10 expressed in degrees ±0.2°): 5.55 ; 6.62 and 7.39. 3 3. . A crystalline form I of the hydrogen sulfate salt of 5-(5-chloro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl} phenyl)-N-(5-cyano-1,2- dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide (Compound A, H SO ) according to claim 1, wherein the crystalline form has an X-ray 15 powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89. 4 4. . The crystalline form I of the hydrogen sulfate salt of Compound A according to claim 3, wherein the crystalline form has an X-ray powder diffraction diagram having the 20 following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89. 5 5. . The crystalline form I of the hydrogen sulfate salt of Compound A according to claim 4, wherein the crystalline form has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Å): Angle 2-theta Interplanar Line no. (degrees) distance (Å) 1 5.55 15.93 2 5.62 15.73 3 6.62 13.36 4 7.39 11.95 5 10.17 8.70 6 11.49 7.70 7 11.83 7.48 8 16.01 5.53 9 16.54 5.36 10 17.04 5.20 11 18.98 4.67 12 19.18 4.63 13 21.90 4.06 14 22.28 3.99 15 24.89 3.58 6 6. . The crystalline form I of the hydrogen sulfate salt of Compound A according to any one of claims 1 to 5, wherein the crystalline form has a solid-state C CP/MAS NMR 5 spectrum having the following peaks (expressed in ppm ± 0.2 ppm): 173.31 ppm, 155.32 ppm, 140.46 ppm, 139.19 ppm, 137.42 ppm, 134.68 ppm, 131.65 ppm, 131.14 ppm, 129.37 ppm, 126.32 ppm, 118.77 ppm, 117.36 ppm, 116.54 ppm, 113.61 ppm, 112.69 ppm, 110.74 ppm, 102.33 ppm, 101.45 ppm, 63.06 ppm, 57.19 ppm, 54.87 ppm, 52.06 ppm, 44.71 ppm, 43.94 ppm, 34.42 ppm, 32.89 ppm, 31.28 ppm, 30.66 ppm, 14.40 ppm, 10 13.34 ppm, 12.49 ppm and 10.50 ppm. 7. Pharmaceutical composition comprising as active ingredient the hydrogen sulfate salt of Compound A according to claim 1 in association with one or more pharmaceutically acceptable excipients. 8. Pharmaceutical composition comprising as active ingredient the crystalline form I 5 of the hydrogen sulfate salt of Compound A according to any one of claims 2 to 6 in association with one or more pharmaceutically acceptable excipients. 9 9. . Pharmaceutical composition according to claim 7 or 8 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system. 1 10 0. . Pharmaceutical composition according to claim 9, wherein the cancer is selected 10 from the bladder, brain, breast and uterus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, 15 non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer. 1 11 1. . The hydrogen sulfate salt of Compound A according to claim 1 for use as a medicament. 1 12
2. . The crystalline form I of the hydrogen sulfate salt of Compound A according to any one of claims 2 to 6 for use as a medicament. 20 1 13
3. . Process for the preparation of the crystalline form I of the hydrogen sulfate salt of Compound A according to any one of claims 2 to 6, wherein the hydrogen sulfate salt of Compound A is crystallised in a polar medium. 14. Process for the preparation of the crystalline form I of the hydrogen sulfate salt of Compound A according to claim 13, wherein the polar medium is composed of one or more solvents selected from water and alcohols. 15. Process for the preparation of the crystalline form I of the hydrogen sulfate salt of 5 Compound A according to claim 14, wherein the alcohol is ethanol. 1 16 6. . Process for the preparation of the crystalline form I of the hydrogen sulfate salt of Compound A according to claim 14, wherein the polar medium is an ethanol/water mixture. 1 17 7. . Process for the preparation of the crystalline form I of the hydrogen sulfate salt of 10 Compound A according to any one of claim 13 to 16, in which process the crystallisation is seeded using a very small amount of the crystalline form I of the hydrogen sulfate salt of Compound A. 1 18 8. . Anhydrous crystalline form of the hydrogen sulfate salt of 5-(5-chloro{[(3S) (morpholinylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl} phenyl)-N-(5-cyano-1,2- 15 dimethyl-1H-pyrrolyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolecarboxamide (Compound A, H SO ) according to claim 1, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all of the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 5.19; 5.64; 6.74; 7.14; 8.04; 8.33; 9.17; 9.40; 10.68; 11.03; 11.35; 12.18; 12.59; 13.64; 14.78; 20 15.09. 1 19 9. . The anhydrous crystalline form of the hydrogen sulfate salt of Compound A according to claim 18, wherein the anhydrous crystalline form has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 25 theta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Å): Angle 2-theta Interplanar Line no. (degrees) distance (Å) 5.19 17.03 5.64 15.66 6.74 13.12 7.14 12.39 8.04 10.99 8.33 10.61 9.17 9.64 9.40 9.41 10.68 8.29 11.03 8.02 11.35 7.79 12.18 7.26 12.59 7.03 13.64 6.49 14.78 5.99 15.09 5.87 20. Use of the hydrogen sulfate salt of Compound A according to claim 1 in the manufacture of a medicament for the treatment of cancers, auto-immune diseases and diseases of the immune system. 21. Use of the crystalline form I of the hydrogen sulfate salt of Compound A according to any one of claims 2 to 6 in the manufacture of a medicament for the treatment of cancers, auto-immune diseases and diseases of the immune system. 10 22. Use according to claim 20 or 21, wherein the cancer is selected from the bladder, brain, breast and uterus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer. 23. The hydrogen sulfate salt of Compound A according to any one of claim 1 or 11, 5 substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings. 2 24
4. . The crystalline form I of the hydrogen sulfate salt of Compound A according to any one of claims 2 to 6, or 12, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings. 10 2 25
5. . The pharmaceutical composition according to any one of claims 7 to 10, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings. 2 26
6. . Process according to any one of claims 13 to 17, substantially as herein described with reference to any example thereof and with or without reference to the 15 accompanying drawings. 2 27
7. . The anhydrous crystalline form of the hydrogen sulfate salt of Compound A according to claim 18 or 19, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings. 2 28
8. . Use according to any one of claims 20 to 22, substantially as herein described with 20 reference to any example thereof and with or without reference to the accompanying drawings. FiRure 1: X-ray powder diffraction pattern (XPRD) of the crystalline form I of Compound A, hydrogen sulfate salt Counts 10000- 5000- T T T Ki I T I 5 10 15 20 25 Position [°20] (Copper (Cu))
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP18306430 | 2018-10-31 | ||
| PCT/EP2019/079621 WO2020089281A1 (en) | 2018-10-31 | 2019-10-30 | Novel salt of a bcl-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ775308A NZ775308A (en) | 2024-04-26 |
| NZ775308B2 true NZ775308B2 (en) | 2024-07-30 |
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