WO2010033481A1 - Salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide - Google Patents
Salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide Download PDFInfo
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- WO2010033481A1 WO2010033481A1 PCT/US2009/056918 US2009056918W WO2010033481A1 WO 2010033481 A1 WO2010033481 A1 WO 2010033481A1 US 2009056918 W US2009056918 W US 2009056918W WO 2010033481 A1 WO2010033481 A1 WO 2010033481A1
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- salt
- methyl
- biphenyl
- cis
- carboxamide
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- 150000003839 salts Chemical class 0.000 title claims abstract description 35
- IYZIARNSXPGYSC-UHFFFAOYSA-N 3-phenylbenzamide Chemical compound NC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1 IYZIARNSXPGYSC-UHFFFAOYSA-N 0.000 title claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000004305 biphenyl Substances 0.000 claims description 10
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 9
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical group OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
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- MKJNSLNKUXUGAN-OKZTUQRJSA-N n-[6-[(2s,6r)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide;phosphono dihydrogen phosphate Chemical compound OP(O)(=O)OP(O)(O)=O.C1[C@@H](C)O[C@@H](C)CN1C(N=C1)=CC=C1NC(=O)C1=CC=CC(C=2C=CC(OC(F)(F)F)=CC=2)=C1C MKJNSLNKUXUGAN-OKZTUQRJSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide, as well as to pharmaceutical compositions comprising the same and methods of treatment using the same.
- the present invention is directed to salts of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3 -yl] -2 -methyl -4 ' -(trifluoromethoxy) [1,1' -biphenyl] -3 -carboxamide.
- Preferred embodiments of the present invention are directed to the hydrochloride, diphosphate and sulfate salts ofN-[6-(cis-2,6-dimethylmo ⁇ holin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifiuoromethoxy)[ 1,1 ' -biphenyl] -3 -carboxamide.
- compositions comprising:
- the present invention is also directed to a method of treating a disease which responds to modulating the activity of the hedgehog signaling pathway comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of an inventive salt of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifiuoromethoxy)[ 1 , 1 '-biphenyl] -3 -carboxamide.
- Figure 1 shows the x-ray powder diffraction pattern for N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 ' -biphenyl] -3 - carboxamide diphosphate salt.
- Figure 2 shows the x-ray powder diffraction pattern for N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1' -biphenyl] -3 - carboxamide monosulfate salt.
- Figure 3 shows the x-ray powder diffraction pattern for N-[6-(cis-2,6- dimethylmo ⁇ holin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[ 1 , 1 '-biphenyl]-3- carboxamide monohydrochloride salt.
- salt refers to a compound prepared by the reaction of an organic acid or base drug with a pharmaceutically acceptable mineral or organic acid or base; as used herein, “salt” includes hydrates and solvates of salts made in accordance with this invention. Exemplary pharmaceutically acceptable mineral or organic acids or bases are as listed in Tables 1-8 in Handbook of Pharmaceutical Salts, P.H. Stahl and CG. Wermuth (eds.), VHCA, Zurich 2002, pp. 334-345.
- salts include, but are not limited to, hydrochloride, phosphate, sulfate, mesylate, esylate and besylate salt forms.
- polymorph refers to a distinct “crystal modification” or “polymorphic form” or “crystalline form”, which differs from another with respect to x-ray powder diffraction pattern, physico- chemical and/or pharmacokinetic properties, and thermodynamic stability.
- An embodiment of the present invention is directed to salts of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 ' -biphenyl] -3 - carboxamide.
- the salt is selected from the mono hydrochloride, diphosphate and mono sulfate salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide.
- a particularly preferred embodiment of the of the present invention are the diphosphate and the mono sulfate salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,l'- biphenyl] -3 -carboxamide.
- the present invention may be used for treating carcinoma including that of the bladder (including accelerated and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non-small cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine and endocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, and skin (including squamous cell carcinoma); tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma, medulloblastoma and schwannomas; tumors of mesenchymal origin including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and other tumors including melanoma, Merkel cell carcinoma, xeroderma pigmentosum, keratoacan
- the present invention is also useful for inhibiting the growth and proliferation of hematopoietic tumors of lymphoid lineage such as leukemia, including acute lymphocytic leukemia (ALL), acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burkitts lymphoma; and hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias (CML), myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia.
- ALL acute lymphocytic leukemia
- B-cell lymphoma B-cell lymphoma
- T-cell lymphoma T-cell lymphoma
- Hodgkins lymphoma non-Hodgkins lymphoma
- N-[6-(cis-2,6-dimethylmorpholin- 4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[ 1 , 1 '-biphenyl]-3-carboxamide diphosphate precipitates out.
- the white slurry was stirred and cooled to room temp over 100 minutes.
- the slurry was then cooled to 0 ⁇ 5°C over 5 minutes and stirred for 1 hour.
- the mixture was filtered under suction and solid was washed with acetonitrile (3 x 9.4 mL).
- the drug substance was dried under vacuum at 5O 0 C for 16 hours to obtain 9.63 g of the phosphate salt (yield: 98%).
- Table 1 below shows stability measured by degradation products (or assay) and appearance color.
- DPs are analyzed by HPLC (method see Table 3). They are calculated as area-% products.
- Compositions of the mixtures in mass% are as follows.
- Mixture 1 Lactose 200 mesh / maize starch modified 1500 LM / Aerosil 200 / Magnesiumstearate 78.5:20:0.5:1 (m/m/m/m).
- Mixture 2 Mannitol / Avicel PH 102 / Cutina HR (57:38:5) (m/m/m).
- Example 5 Table 2 below shows chemical and physico-chemical characteristics.
- 0.1N HCl solution XRPD pattern XRPD pattern XRPD pattern changed, different changed, different changed, different than free base. than that of free than that of free base. base.
- the inter-subject exposure is slightly variable, especially at high dose (100 mpk). See Table 4.
- a suspension formulation of the free form and the diphosphate salt of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy)[ 1,1 ' -biphenyl] -3 - carboxamide are dosed to rat at 3 mpk and 2.1 mpk, respectively. It was found that the disphosphate salt provided a large increase in exposure (16-fold increase) compared to the free form as outline in Table 5.
- Example 9 Details about methodology, instruments and standards used in Examples 4-5
- the pH was determined by transferring approximately 10 mg of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[ 1 , 1 '-biphenyl]-3- carboxamide salt to a 20 mL vial and adding 10 mL of the corresponding buffer or water. The solutions were stirred continuously as the pH was measured.
- acetonitrile was added to dilute the 0.2% slurry to 0.1% clear solution.
- tetrahydrofuran was added to dilute the 0.2% slurry to 0.1% clear solution.
- acetonitrile was added to dilute the 0.2% slurry to 0.1% clear solution.
- acetonitrile or acetonitrile/water 50:50, v/v
- the corresponding solvent or solvent mixture was added to dilute the 0.2% slurry to 0.1% clear solution.
- the sulfate salt and diphosphate salt of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide are dosed as a suspension at 1 mg/mL in 0.5% Methyl Cellulose/0.5% Tween 80 at a dosing volume of 10 mL/kg to Wistar rats.
- the diphosphate salt was found to give 1.6x more exposure in terms of AUC (0-24 hours) ng*hr/mL when compared to the sulfate salt. Results are shown below in Table 7.
- the mean tmax for sulfate salt is shorter (2.3 hours) versus diphosphate salt (6.7 hours).
- the mean cmax/dose for phosphate is 303 and for sulfate is 244.
- the mean auc/dose for phosphate is 4850, for sulfate is 3030.
- the sulfate salt showed less exposure in-vivo (about 40% less) than the diphosphate salt.
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Abstract
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Priority Applications (27)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES09792531T ES2418485T3 (en) | 2008-09-17 | 2009-09-15 | Diphosphate salt of N- [6- (cis-2,6-dimethylmorpholin-4-yl) -pyridin-3-yl] -2-methyl-4¿- (trifluoromethoxy) - [1,1¿-biphenyl] - 3-carboxamide |
UAA201103086A UA103049C2 (en) | 2008-09-17 | 2009-09-15 | Salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
CA2736751A CA2736751C (en) | 2008-09-17 | 2009-09-15 | Salts of n-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
AU2009293444A AU2009293444B2 (en) | 2008-09-17 | 2009-09-15 | Salts of N-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'- (trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
NZ591420A NZ591420A (en) | 2008-09-17 | 2009-09-15 | Salts of n-[6-cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
PL09792531T PL2342198T3 (en) | 2008-09-17 | 2009-09-15 | A diphosphate salt of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
KR1020117008623A KR101129088B1 (en) | 2008-09-17 | 2009-09-15 | Salts of n-[6-cis-2,6-dimethylmorpholin-4-ylpyridine-3-yl]-2-methyl-4'-trifluoromethoxy[1,1'-biphenyl]-3-carboxamide |
EA201100501A EA020048B1 (en) | 2008-09-17 | 2009-09-15 | Diphosphate salt of n-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-diphenyl]-3-carboxamide and pharmaceutical composition |
JP2011527035A JP4897938B2 (en) | 2008-09-17 | 2009-09-15 | N- [6- (cis-2,6-dimethylmorpholin-4-yl) pyridin-3-yl] -2-methyl-4 ′-(trifluoromethoxy) [1,1′-biphenyl] -3-carboxamide Salt |
SI200930626T SI2342198T1 (en) | 2008-09-17 | 2009-09-15 | A diphosphate salt of n-s6-cis-2,6-dimethylmorpholin-4yl)pyridine-3ylc-2-methyl-4'-(trifluoromethoxy)s1,1'-biphenylc-3-carboxamide |
US13/061,572 US8063043B2 (en) | 2008-09-17 | 2009-09-15 | Salts of N-[6-cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide |
BR122020009045-6A BR122020009045B1 (en) | 2008-09-17 | 2009-09-15 | USE OF N-[6-CIS-2,6-DIMETHYLMORPHOLIN-4-YL]PYRIDINE-3-YL]-2-METHYL-4'-(TRIFLUORMETOXY)[1,1'-BIPHENYL]-3-CARBOXAMIDE SALTS IN THE TREATMENT OF CARCINOMA AND OTHER TUMORS |
DK09792531.7T DK2342198T3 (en) | 2008-09-17 | 2009-09-15 | Diphosphate salt of N- [6- (cis-2,6-dimethylmorpholin-4-yl) pyridin-3-yl] -2-methyl-4 '- (trifluoromethoxy) - [1,1'-biphenyl] -3-carboxamide |
BRPI0918629A BRPI0918629B8 (en) | 2008-09-17 | 2009-09-15 | n-[6-cis-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-4'-(trifluoromethoxy)[1-1'-biphenyl]-3-carboxamide salt, and pharmaceutical composition |
EP09792531A EP2342198B1 (en) | 2008-09-17 | 2009-09-15 | A diphosphate salt of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
MX2011002805A MX2011002805A (en) | 2008-09-17 | 2009-09-15 | Salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methy l-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide. |
CN200980144876.0A CN102159570B (en) | 2008-09-17 | 2009-09-15 | Salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
IL211412A IL211412A (en) | 2008-09-17 | 2011-02-24 | Diphosphate salt of n-[6-cis-2,6-dimethylmorpholin-4yl) pyridine-3yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide and pharmaceutical compositions comprising the same |
TN2011000092A TN2011000092A1 (en) | 2009-09-15 | 2011-02-24 | Salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
ZA2011/01579A ZA201101579B (en) | 2008-09-17 | 2011-03-01 | Salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
CU2011000055A CU23860B1 (en) | 2008-09-17 | 2011-03-15 | SALTS OF N- [6- (CIS-2,6-DIMETIL-MORFOLIN-4-IL) -PIRIDIN-3-IL] -2-METHYL-4 '- (TRIFLUORO-METOXI) - [1,1'-BIFENIL ] -3-CARBOXAMIDA |
MA33778A MA32717B1 (en) | 2008-09-17 | 2011-04-15 | N- [6-CIS- (2,6-DIMETHYLMORPHOLIN-4-YL) PYRIDIN-3-YL) -2-METHYL-4'- (TRIFLUOROMETHOXY) - [1,1'-BIPHENYL] -3-CARBOXAMIDE SALTS |
US13/272,814 US20120035174A1 (en) | 2008-09-17 | 2011-10-13 | Salts of N-[6-cis-2,6-Dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
HK11111044.0A HK1156628A1 (en) | 2008-09-17 | 2011-10-17 | |
US13/462,483 US20120214810A1 (en) | 2008-09-17 | 2012-05-02 | Salts of N-[6-cis-2,6-Dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
SM201300072T SMT201300072B (en) | 2008-09-17 | 2013-06-26 | N- [6- (cis-2,6-dimethylmorfolin-4-yl) pyridin-3-yl] diphosphate salt -2-methyl-4 '- (tri-fluoromethoxy) [1,1'-bifenyl] -3 -carbossammide |
HRP20130597AT HRP20130597T1 (en) | 2008-09-17 | 2013-06-27 | A diphosphate salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
Applications Claiming Priority (2)
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US9758008P | 2008-09-17 | 2008-09-17 | |
US61/097,580 | 2008-09-17 |
Related Child Applications (2)
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US13/061,572 A-371-Of-International US8063043B2 (en) | 2008-09-17 | 2009-09-15 | Salts of N-[6-cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide |
US13/272,814 Division US20120035174A1 (en) | 2008-09-17 | 2011-10-13 | Salts of N-[6-cis-2,6-Dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
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WO2010033481A1 true WO2010033481A1 (en) | 2010-03-25 |
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PCT/US2009/056918 WO2010033481A1 (en) | 2008-09-17 | 2009-09-15 | Salts of n-[6-cis-2,6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide |
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US (3) | US8063043B2 (en) |
EP (1) | EP2342198B1 (en) |
JP (2) | JP4897938B2 (en) |
KR (2) | KR101129088B1 (en) |
CN (1) | CN102159570B (en) |
AR (2) | AR073591A1 (en) |
AU (1) | AU2009293444B2 (en) |
BR (2) | BR122020009045B1 (en) |
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CL (1) | CL2011000551A1 (en) |
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CU (1) | CU23860B1 (en) |
DK (1) | DK2342198T3 (en) |
DO (1) | DOP2011000082A (en) |
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EC (1) | ECSP11010985A (en) |
ES (1) | ES2418485T3 (en) |
GE (1) | GEP20125592B (en) |
HK (1) | HK1156628A1 (en) |
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MX (1) | MX2011002805A (en) |
MY (1) | MY151100A (en) |
NI (1) | NI201100051A (en) |
NZ (1) | NZ591420A (en) |
PE (1) | PE20110292A1 (en) |
PL (1) | PL2342198T3 (en) |
PT (1) | PT2342198E (en) |
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Cited By (5)
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WO2014128661A1 (en) * | 2013-02-25 | 2014-08-28 | Novartis Ag | Oral formulation and suspension of an oncology drug |
WO2015092720A1 (en) * | 2013-12-19 | 2015-06-25 | Novartis Ag | Metabolites of sonidegib (lde225) |
WO2017157825A1 (en) | 2016-03-15 | 2017-09-21 | F. Hoffmann-La Roche Ag | Combinations of lsd1 inhibitors for use in the treatment of solid tumors |
WO2017163258A1 (en) * | 2016-03-22 | 2017-09-28 | Msn Laboratories Private Limited | Process for the preparation of n-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifiuoromethoxy) [1,1' -biphenyi]-3-carboxamide and its polymorphs thereof |
EP3279198A4 (en) * | 2015-03-30 | 2018-09-05 | Crystal Pharmatech Co., Ltd. | Crystal form of n-[6-(cis form-2,6-dimethylmorpholine-4-group)pyridine-3- group]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3- formamide monophosphate, and preparation method therefor |
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TWI433674B (en) | 2006-12-28 | 2014-04-11 | Infinity Discovery Inc | Cyclopamine analogs |
CN101993415B (en) * | 2010-09-15 | 2013-08-14 | 北京韩美药品有限公司 | Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof |
JP6796638B2 (en) | 2015-06-04 | 2020-12-09 | ペレファーム, インク.Pellepharm, Inc. | Topical formulations and their use for the delivery of hedgehog inhibitory compounds |
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DK1670785T3 (en) * | 2003-10-02 | 2010-10-18 | Pharmacia & Upjohn Co Llc | Salts and polymorphic forms of a pyrrole-substituted indolinone compound |
GB0412468D0 (en) * | 2004-06-04 | 2004-07-07 | Astrazeneca Ab | Chemical compounds |
PE20080948A1 (en) * | 2006-07-25 | 2008-09-10 | Irm Llc | IMIDAZOLE DERIVATIVES AS MODULATORS OF THE HEDGEHOG PATH |
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Cited By (10)
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WO2014128661A1 (en) * | 2013-02-25 | 2014-08-28 | Novartis Ag | Oral formulation and suspension of an oncology drug |
AU2014220339B2 (en) * | 2013-02-25 | 2016-12-01 | Sun Pharmaceutical Industries Limited | Oral formulation and suspension of an oncology drug |
US9943520B2 (en) | 2013-02-25 | 2018-04-17 | Sun Pharma Global Fze | Oral formulation and suspension of an oncology drug |
US10426781B2 (en) | 2013-02-25 | 2019-10-01 | Sun Pharma Global Fze | Oral formulation and suspension of an oncology drug |
WO2015092720A1 (en) * | 2013-12-19 | 2015-06-25 | Novartis Ag | Metabolites of sonidegib (lde225) |
EP3279198A4 (en) * | 2015-03-30 | 2018-09-05 | Crystal Pharmatech Co., Ltd. | Crystal form of n-[6-(cis form-2,6-dimethylmorpholine-4-group)pyridine-3- group]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3- formamide monophosphate, and preparation method therefor |
US10266523B2 (en) | 2015-03-30 | 2019-04-23 | Crystal Pharmatech Co., Ltd. | Crystaline forms of N-[6-(cis-2,6-dimethylmorpholine-4-yl)pyridine-3-yl]-2-Methyl-4′-(trifluoromethoxy) [1,1′-biphenyl]-3-Methanamide monophosphate, and process of preparation thereof |
WO2017157825A1 (en) | 2016-03-15 | 2017-09-21 | F. Hoffmann-La Roche Ag | Combinations of lsd1 inhibitors for use in the treatment of solid tumors |
US10265279B2 (en) | 2016-03-15 | 2019-04-23 | Oryzon Genomics, S.A. | Combinations of LSD1 inhibitors for use in the treatment of solid tumors |
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