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WO2016012470A1 - Nouvelles formes amorphes et cristallines de l'acide (3s)-4-[[(4r)-4-(2-chloro-4-fluorophényl)-5-méthoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]méthyl]morpholine-3-carboxilique - Google Patents

Nouvelles formes amorphes et cristallines de l'acide (3s)-4-[[(4r)-4-(2-chloro-4-fluorophényl)-5-méthoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]méthyl]morpholine-3-carboxilique Download PDF

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Publication number
WO2016012470A1
WO2016012470A1 PCT/EP2015/066695 EP2015066695W WO2016012470A1 WO 2016012470 A1 WO2016012470 A1 WO 2016012470A1 EP 2015066695 W EP2015066695 W EP 2015066695W WO 2016012470 A1 WO2016012470 A1 WO 2016012470A1
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WIPO (PCT)
Prior art keywords
crystalline form
xrpd
ray powder
powder diffraction
exhibits
Prior art date
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PCT/EP2015/066695
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English (en)
Inventor
Xinhui HU
Wei Zhang
Wei Li
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2016012470A1 publication Critical patent/WO2016012470A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to novel amorphous and crystalline forms of compound (I),
  • Hepatitis B is recognized as a chronic viral disease of the liver which is characterized by liver disease.
  • Inhibitors of hepatitis B virus (HBV) are useful to limit the establishment and progression of infection by HBV as well as in diagnostic assays for HBV.
  • WO2014/037480 Al disclosed HBV inhibitor compound 00, (3S)-4-[[(4R)-4-(2-chloro-4- fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- 1 , 4-dihydropyrimidin-6- yl]methyl]morpholine-3-carboxylic acid.
  • Compound (I) simultaneously has tautomer as compound (la), (3S)-4-[[(6R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- l,6-dihydropyrimidin-4-yl]methyl]moipholine-3-carboxylic acid.
  • the compound (I) and its tautomer, compound (la), have rapid transforming speed at ambient temperature, which exist as the structure of (3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-l, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid at ambient temperature.
  • Solid form is a term to describe how one compound exists as solid state which includes amorphous, polymorph, salt, co-crystal, etc. It has fundamental influences on the
  • physicochemical properties such as solubility, chemical stability, physical stability, powder properties, etc.
  • MSA Methyl sulfonic acid
  • the present disclosure relates generally to novel solid forms of compound (I), and processes to make the forms.
  • the present invention relates to polymorphs, amorphous, salts, co-crystals and methods for the synthesis of selective production of amorphous and crystalline forms of (3S)-4-[[(4R)-4-(2- chloro-4-fiuoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- 1 , 4-dihydropyrimidin-6- yl]methyl]morpholine-3-carboxylic acid.
  • an amorphous or crystalline form of compound (I) or salts, solvates or combination thereof is provided herein.
  • the XRPD pattern of amorphous form is shown in FIG. 1.
  • the amorphous or crystalline form of compound (I) is Form A, Form B,
  • Form C Form C, Form D, Form E, Form F, Form G, Form H, Form L, Form M, Form N, Form P, Form Q or a combination thereof.
  • the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.77° ⁇ 0.1°, 8.22° ⁇ 0.1°, 19.71° ⁇ 0.1°, 19.99° ⁇ 0.1°, 24.77° ⁇ 0.1° and 25.68° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.77° ⁇ 0.1°, 8.22° ⁇ 0.1°, 9.10° ⁇ 0.1°, 9.81° ⁇ 0.1°, 11.33° ⁇ 0.1°, 12.60° ⁇ 0.1°, 14.31° ⁇ 0.1°, 19.71° ⁇ 0.1°,
  • XRPD X-ray powder diffraction
  • the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 2.
  • the crystalline form is Form A which is a hydrate of compound (I).
  • Form A is a monohydrate, bihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate of compound (I).
  • the water content of Form A is from 0.5% to 10%, particularly from 2.5% to 4.5%.
  • the crystalline form is Form A with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
  • the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.42° ⁇ 0.1°, 19.62° ⁇ 0.1°, 20.42° ⁇ 0.1°, 23.03° ⁇ 0.1°, 25.51° ⁇ 0.1° and 26.65° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.42° ⁇ 0.1°, 9.34° ⁇ 0.1°, 11.72° ⁇ 0.1°, 12.63° ⁇ 0.1°, 18.67° ⁇ 0.1°, 19.62° ⁇ 0.1°, 20.42° ⁇ 0.1°, 23.03° ⁇ 0.1°, 24.04° ⁇ 0.1°, 25.51° ⁇ 0.1°, 25.99° ⁇ 0.1°, 26.65° ⁇ 0.1°, 27.74° ⁇ 0.1° and 28.36° ⁇ 0.1°.
  • the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 5.
  • the crystalline form is Form B which is an anhydrous form of compound (I).
  • the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 17.04° ⁇ 0.1 °, 20.93° ⁇ 0.1°, 21.28° ⁇ 0.1°, 22.56° ⁇ 0.1°, 24.17° ⁇ 0.1° and 24.38° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.65° ⁇ 0.1°, 12.58° ⁇ 0.1°, 14.89° ⁇ 0.1°, 17.04° ⁇ 0.1°, 19.40° ⁇ 0.1°, 20.93° ⁇ 0.1°, 21.28° ⁇ 0.1°, 22.56° ⁇ 0.1°, 23.67° ⁇ 0.1°, 24.17° ⁇ 0.1°, 24.38° ⁇ 0.1° and 24.81° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 6.
  • the crystalline form is Form C which is a co-crystal of monohydrate of compound (I) and tetrafluoroborate of compound (I).
  • the crystalline form is Form C with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 171°C ⁇ 3°C.
  • DSC differential scanning calorimetry
  • the crystalline form is Form C with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.7.
  • DSC differential scanning calorimetry
  • the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 15.74° ⁇ 0.1°, 17.20° ⁇ 0.1°, 20.46° ⁇ 0.1°, 23.43° ⁇ 0.1°, 28.38° ⁇ 0.1° and 30.88° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 15.74° ⁇ 0.1°, 17.20° ⁇ 0.1°, 20.46° ⁇ 0.1°, 21.96° ⁇ 0.1°, 23.43° ⁇ 0.1°, 24.76° ⁇ 0.1°, 28.38° ⁇ 0.1°, 30.88° ⁇ 0.1°, 31.72° ⁇ 0.1°, 32.80° ⁇ 0.1°, 33.55° ⁇ 0.1° and 37.17° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form D with the X-ray crystal structure showed in FIG. 9.
  • the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 10.
  • the crystalline form is Form D with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 216°C ⁇ 3°C.
  • the crystalline form is Form D with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.l l.
  • the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.39° ⁇ 0.1°, 7.96° ⁇ 0.1°, 9.82° ⁇ 0.1°, 20.74° ⁇ 0.1°, 22.50° ⁇ 0.1°, 23.82° ⁇ 0.1°, 24.69° ⁇ 0.1° and 26.20° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.39° ⁇ 0.1°, 7.96° ⁇ 0.1°, 9.82° ⁇ 0.1°, 12.22° ⁇ 0.1°, 16.92° ⁇ 0.1°, 20.02° ⁇ 0.1°, 20.74° ⁇ 0.1°, 21.65° ⁇ 0.1°, 22.50° ⁇ 0.1°, 23.82° ⁇ 0.1°, 24.69° ⁇ 0.1°, 26.20° ⁇ 0.1°, 27.76° ⁇ 0.1° and 28.92° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 13.
  • the crystalline form is Form E with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
  • the crystalline form is Form E with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.14.
  • DSC differential scanning calorimetry
  • the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.73° ⁇ 0.1°, 20.87° ⁇ 0.1°, 21.80° ⁇ 0.1°, 23.15° ⁇ 0.1°, 27.03° ⁇ 0.1° and 28.58° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.02° ⁇ 0.1 °, 11.73° ⁇ 0.1°, 14.89° ⁇ 0.1°, 18.36° ⁇ 0.1°, 20.87° ⁇ 0.1°, 21.80° ⁇ 0.1°, 23.15° ⁇ 0.1°, 24.44° ⁇ 0.1°, 25.35° ⁇ 0.1°, 27.03° ⁇ 0.1°, 28.58° ⁇ 0.1°, 32.21° ⁇ 0.1°, 33.52° ⁇ 0.1° and 39.03° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 16.
  • the crystalline form is Form F with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 141°C ⁇ 3°C.
  • the crystalline form is Form F with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.17.
  • the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.85° ⁇ 0.1°, 12.32° ⁇ 0.1°, 17.37° ⁇ 0.1°, 23.07° ⁇ 0.1°, 24.86° ⁇ 0.1°, 25.31° ⁇ 0.1° and 28.48° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.81° ⁇ 0.1°, 8.20° ⁇ 0.1°, 9.85° ⁇ 0.1°, 12.32° ⁇ 0.1°, 15.01° ⁇ 0.1°, 17.37° ⁇ 0.1°, 19.35° ⁇ 0.1°, 21.19° ⁇ 0.1°, 22.42° ⁇ 0.1°, 23.07° ⁇ 0.1°, 24.86° ⁇ 0.1°, 25.31° ⁇ 0.1°, 26.57° ⁇ 0.1°, 28.48° ⁇ 0.1° and 35.38° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 19.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form G with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 152°C ⁇ 3°C.
  • DSC differential scanning calorimetry
  • the crystalline form is Form G with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.20.
  • DSC differential scanning calorimetry
  • the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.88° ⁇ 0.1°, 18.31° ⁇ 0.1°, 19.94° ⁇ 0.1°, 21.49° ⁇ 0.1°, 23.12° ⁇ 0.1°, 23.91° ⁇ 0.1°, 25.69° ⁇ 0.1° and 26.83° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.88° ⁇ 0.1°, 13.23° ⁇ 0.1°, 14.42° ⁇ 0.1°, 17.69° ⁇ 0.1°, 18.31° ⁇ 0.1°, 19.94° ⁇ 0.1°, 21.49° ⁇ 0.1°, 23.12° ⁇ 0.1°, 23.91° ⁇ 0.1°, 25.69° ⁇ 0.1° and 26.83° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 22.
  • the crystalline form is Form H with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
  • the crystalline form is Form H with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.23.
  • DSC differential scanning calorimetry
  • the crystalline form is Form D, Form E, Form F, Form G or Form H, which is a hydrochloride salt of compound (I).
  • the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.29° ⁇ 0.1°, 15.86° ⁇ 0.1°, 18.99° ⁇ 0.1°, 20.88° ⁇ 0.1°, 22.96° ⁇ 0.1° and 23.30° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.29° ⁇ 0.1°, 10.56° ⁇ 0.1°, 10.95° ⁇ 0.1°, 15.86° ⁇ 0.1°, 18.99° ⁇ 0.1°, 20.88° ⁇ 0.1°, 21.19° ⁇ 0.1°, 21.71° ⁇ 0.1°, 22.96° ⁇ 0.1°, 23.30° ⁇ 0.1°, 25.02° ⁇ 0.1°, 26.84° ⁇ 0.1°, 28.29° ⁇ 0.1° and 32.36° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 30.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form L with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
  • the crystalline form is Form L with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.31.
  • DSC differential scanning calorimetry
  • the crystalline form is Form L is an ethylsulfate of compound (I).
  • the crystalline form is Form L with the X-ray crystal structure showed in FIG. 33.
  • the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.24° ⁇ 0.1°, 8.57° ⁇ 0.1°, 13.64° ⁇ 0.1°, 14.53° ⁇ 0.1°, 16.50° ⁇ 0.1°, 17.18° ⁇ 0.1°, 19.47° ⁇ 0.1° and 22.11 ° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.24° ⁇ 0.1°, 8.57° ⁇ 0.1°, 9.80° ⁇ 0.1°, 13.64° ⁇ 0.1°, 14.53° ⁇ 0.1°, 16.50° ⁇ 0.1°, 17.18° ⁇ 0.1°, 19.47° ⁇ 0.1°, 22.11° ⁇ 0.1°, 25.23° ⁇ 0.1°, 28.11° ⁇ 0.1° and 29.39° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 34.
  • the crystalline form is Form M with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 59°C ⁇ 3°C.
  • the crystalline form is Form M with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG. 35.
  • DSC differential scanning calorimetry
  • the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.62° ⁇ 0.1°, 9.22° ⁇ 0.1°, 18.50° ⁇ 0.1°, 19.05° ⁇ 0.1°, 23.14o ⁇ 0.1o and 23.88° ⁇ 0.1o.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.62° ⁇ 0.1°, 9.22° ⁇ 0.1°, 11.81° ⁇ 0.1°, 13.10° ⁇ 0.1°, 13.83° ⁇ 0.1°, 17.44° ⁇ 0.1°, 18.50° ⁇ 0.1°, 19.05° ⁇ 0.1°, 20.63° ⁇ 0.1°, 21.98° ⁇ 0.1°, 23.14° ⁇ 0.1°, 23.88° ⁇ 0.1°, 25.61° ⁇ 0.1°, 27.85° ⁇ 0.1°, 29.31° ⁇ 0.1° and 39.07° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 37.
  • the crystalline form is Form N with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 63°C ⁇ 3°C.
  • the crystalline form is Form N with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.38.
  • DSC differential scanning calorimetry
  • the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.27° ⁇ 0.1°, 12.18° ⁇ 0.1°, 17.57° ⁇ 0.1°, 18.01° ⁇ 0.1°, 22.38° ⁇ 0.1° and 23.16° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.23° ⁇ 0.1°, 11.27° ⁇ 0.1°, 12.18° ⁇ 0.1°, 15.51° ⁇ 0.1°, 16.46° ⁇ 0.1°, 17.57° ⁇ 0.1°, 18.01° ⁇ 0.1°, 21.18° ⁇ 0.1°, 22.38° ⁇ 0.1°, 23.16° ⁇ 0.1°, 24.44° ⁇ 0.1°, 29.59° ⁇ 0.1° and 31.83° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 40.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form P with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 230°C ⁇ 3°C.
  • DSC differential scanning calorimetry
  • the crystalline form is Form P with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG. 41.
  • DSC differential scanning calorimetry
  • the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.04° ⁇ 0.1°, 12.77° ⁇ 0.1°, 16.33° ⁇ 0.1°, 16.71° ⁇ 0.1°, 18.06° ⁇ 0.1° and 20.65° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.35° ⁇ 0.1°, 9.96° ⁇ 0.1°, 11.04° ⁇ 0.1°, 12.77° ⁇ 0.1°, 15.04° ⁇ 0.1°, 16.33° ⁇ 0.1°, 16.71° ⁇ 0.1°, 18.06° ⁇ 0.1°, 20.65° ⁇ 0.1°, 22.19° ⁇ 0.1°, 23.76° ⁇ 0.1°, 25.36° ⁇ 0.1°, 26.64° ⁇ 0.1°, 29.34° ⁇ 0.1° and 30.26° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 43.
  • the crystalline form is Form Q with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 191°C ⁇ 3°C.
  • the crystalline form is Form Q with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.44.
  • DSC differential scanning calorimetry
  • the crystalline form is Form M, Form N, Form P or Form Q, which is a calcium salt of compound (I).
  • composition comprising the amorphous or crystalline form disclosed herein; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • amorphous or crystalline form disclosed herein or the pharmaceutical composition for the manufacture of a medicament for the treatment or prophylaxis of a viral disease in a patient.
  • the viral disease disclosed herein is hepatitis B infection or a disease caused by hepatitis B infection.
  • a method for the treatment or prophylaxis of hepatitis B infection or a disease caused by hepatitis B infection comprises administering an therapeutically effective amount of the amorphous or crystalline form or the pharmaceutical composition disclosed herein.
  • XRPD X-ray powder diffraction
  • the relative peak height of X-ray powder diffraction (XRPD) pattern depends on many factors related to sample preparation and geometric shapes of the instrument, however peak position is insensitive to experimental details.
  • the crystalline form disclosed herein characterized by XRPD pattern with some listed peak positions essentially can also be characterized by XRPD pattern provided in the appended drawings of the present invention. According to the state of the instrument for the experiment, the error margin in 2-theta of the characteristic peaks is ⁇ 0.1 °.
  • the relative peak height of differential scanning calorimetry depends on many factors related to sample preparation and geometric shapes of the instrument, however peak position is insensitive to experimental details.
  • the crystalline form disclosed herein characterized by DSC thermogram with some listed peak positions essentially can also be characterized by DSC thermogram provided in the appended drawings of the present invention. According to the state of the instrument for the experiment, the error margin in the melting peaks is ⁇ 3°C.
  • TGA thermal gravimetric analysis
  • relative intensity refers to the intensity of a peak with respect to the intensity of the strongest peak in the XRPD pattern which is regarded as 100%.
  • the term “combination” refers to a crystalline form containing a tautomer thereof, or a crystalline form containing one or more other crystalline forms or amorphous form
  • the term “peak” refers to a feature, in a spectrum and/or data presented in a graph, that one skilled in the art would recognize as not attributable to background noise.
  • pharmaceutical composition is used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.
  • therapeutically effective amount denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease or condition or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • composition or medicament contain the amorphous or crystalline forms of the compound (I) of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the amorphous or crystalline forms of compound (I) of the invention to prepare such compositions and medicaments.
  • amorphous or crystalline forms of compound (I) of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • amorphous or crystalline forms of compound (I) of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • An embodiment therefore, includes a pharmaceutical composition comprising an amorphous or crystalline form of compound (I).
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the amorphous or crystalline form of compound (I) of the invention can be used together with interferon, pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, and Tenofovir disoproxil for the treatment or prophylaxis of HBV.
  • FIG. 1 X-ray powder diffraction pattern for Amorphous Form
  • FIG. 2 X-ray powder diffraction pattern for Form A
  • FIG. 3 DSC thermogram of Form A
  • FIG. 4 TGA diagram of Form A
  • FIG. 5 X-ray powder diffraction pattern for Form B
  • FIG. 6 X-ray powder diffraction pattern for Form C
  • FIG. 7 DSC thermogram of Form C
  • FIG. 8 TGA diagram of Form C
  • FIG. 9 X-ray crystal structure of Form C
  • FIG. 10 X-ray powder diffraction pattern for Hydrochloride Salt Form D
  • FIG. 11 DSC thermogram of Hydrochloride Salt Form D
  • FIG. 12 TGA diagram of Hydrochloride Salt Form D
  • FIG. 13 X-ray powder diffraction pattern for Hydrochloride Salt Form E
  • FIG. 14 DSC thermogram of Hydrochloride Salt Form E
  • FIG. 15 TGA diagram of Hydrochloride Salt Form E
  • FIG. 16 X-ray powder diffraction pattern for Hydrochloride Salt Form F F1G. 17 DSC thermogram of Hydrochloride Salt Form F
  • FIG. 18 TGA diagram of Hydrochloride Salt Form F
  • FIG. 19 X-ray powder diffraction pattern for Hydrochloride Salt Form G
  • FIG. 20 DSC thermogram of Hydrochloride Salt Form G
  • FIG. 21 TGA diagram of Hydrochloride Salt Form G
  • FIG. 22 X-ray powder diffraction pattern for Hydrochloride Salt Form H
  • FIG. 23 DSC thermogram of Hydrochloride Salt Form H
  • FIG. 24 TGA diagram of Hydrochloride Salt Form H
  • FIG. 25 Omitted
  • FIG. 26 Omitted
  • FIG. 27 Omitted
  • FIG. 30 X-ray powder diffraction pattern for Ethylsulfate Form L
  • FIG.31 DSC thermogram of Ethylsulfate Form L
  • FIG.32 TGA diagram of Ethylsulfate Form L
  • FIG. 33 X-ray crystal structure of Ethylsulfate Form L
  • FIG. 34 X-ray powder diffraction pattern for Calcium Salt Form M
  • FIG. 35 DSC thermogram of Calcium Salt Form M
  • FIG. 36 TGA thermogram of Calcium Salt Form M F1G. 37 X-ray powder diffraction pattern for Calcium Salt Form N
  • FIG. 38 DSC thermogram of Calcium Salt Form N
  • FIG. 39 TGA thermogram of Calcium Salt FormN
  • FIG. 40 X-ray powder diffraction pattern for Calcium Salt Form P
  • FIG. 41 DSC thermogram of Calcium Salt Form P
  • FIG. 42 TGA diagram of Calcium Salt Form P
  • FIG. 43 X-ray powder diffraction pattern for Calcium Salt Form Q
  • FIG. 44 DSC thermogram of Calcium Salt Form Q
  • FIG. 45 TGA diagram of Calcium Salt Form Q
  • FIG. 46 X-ray powder diffraction pattern for Mesylate Form J
  • FIG. 47 DSC thermogram of Mesylate Form J
  • FIG. 48 TGA diagram of Mesylate Form J
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation using 40KV tube voltage and 40mA tube currentScan range was from 4 to 40 degree 2- theta.
  • the step size was 0.0525° at a scanning speed of 6.66°/min.
  • the XRPD pattern is shown in FIG. 2. Major peaks and their related intensities in the XRPD pattern are shown in Table 1.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation using 40KV tube voltage and 40mA tube current. Scan range was from 4 to 40 degree 2 -theta. The step size was 0.0525° at a scanning speed of 6.66°/min.
  • TGA analysis TA Q5000, 25-350°C, heating rate 10°C/min.
  • Form B of compound (I).
  • Form B was formed by using Form A as prepared in Example 2 either after dehydration at high temperature (>70°C) or low humidity (0% RH), and characterized by XRPD pattern shown in FIG. 5. Major peaks and their related intensities in the XRPD pattern are shown in Table 2.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • the solid was isolated for XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of Form C of compound (I) is shown in FIG. 6. Major peaks and their related intensities in the XRPD pattern are shown in Table 3 below.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • FIG. 9 shows the X-ray structure of Form C of compound (I), indicating that Form C is a monohydrate of co-crystal formed by compound (I) and its tetrafluoroborate with a molar ratio 1:2.
  • the crystal data and structure refinement is shown in Table 4.
  • the solid precipitate was isolated for XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of hydrochloride salt Form D of compound (I) is shown in FIG. 10. Major peaks and their related intensities in the XRPD pattern are shown in Table 5.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • hydrochloride salt Form D of compound (I) has an onset melting temperature at 216°C.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • DSC analysis TA Q2000, 25-250°C, heating rate 10°C/min.
  • TGA analysis TA Q5000, 25-250°C, heating rate 10°C/min.
  • the XRPD pattern of hydrochloride salt Form F of compound (I) is shown in FIG. 16. Major peaks and their related intensities in the XRPD pattern are shown in Table 7.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-200°C, heating rate 10°C/min.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • amorphous form of compound (I) as prepared in Example 1 40 mg was weighed and transferred to a 2-mL vial. 1 mL 0.1 N HC1 was added to form slurry. The vial was mounted to a shaker and kept shaking for 1 day at room temperature. After 1 day, the slurry was removed from the vial, transferred to a 1.5mL centrifuge tube and centrifuge at 12000rpm for 5 minutes. The supernatant was removed and the residual solid was analysed using XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of hydrochloride salt Form H of compound (I) is shown in FIG. 22. Major peaks and their related intensities in the XRPD pattern are shown in Table 9.
  • XRPD Bruker D8 Advance X-ray diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 40KV and tube current was 40mA.
  • Scan range was from 4 to 40 degree 2-theta.
  • the step size was 0.05° at a scanning speed of 3°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • the XRPD pattern of ethylsulfate Form L of compound (I) is shown in FIG. 30. Major peaks and their related intensities in the XRPD pattern are shown in Table 12.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-250°C, heating rate 10°C/min.
  • FIG. 33 shows the X-ray structure of ethylsulfate Form L.
  • the crystal data and structure refinement is shown in Table 13.
  • the solid precipitate was isolated for XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of calcium salt Form M of compound (I) is shown in FIG. 34. Major peaks and their related intensities in the XRPD pattern are shown in Table 14.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • the XRPD pattern of calcium salt Form N of compound (I) is shown in FIG. 37. Major peaks and their related intensities in the XRPD pattern are shown in Table 15.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • the solid was isolated for XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of calcium salt Form P of compound (I) is shown in FIG. 40. Major peaks and their related intensities in the XRPD pattern are shown in Table 16.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-325°C, heating rate 10°C/min.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • the result of water content was 2.5%.
  • the water content of final product was determined using Karl Fischer Coulometric titration.
  • the result of water content was 3.9%.
  • the result of water content was 4.5%.
  • the solid was collected by filtration, washed with MIBK and analysed using XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of mesylate Form J of compound (I) is shown in FIG. 46. Major peaks and their related intensities in the XRPD pattern are shown in Table 10 below.
  • XRPD Bruker D8 Advance X-ray diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 40KV and tube current was 40mA.
  • Scan range was from 4 to 40 degree 2-theta.
  • the step size was 0.05° at a scanning speed of 3°/min.
  • TGA analysis TA Q5000, 25-400°C, heating rate 10°C/min.
  • Aqueous solubility was determined by suspending lOmg compound in different bio- relevant media including SGF, FaSSIF and FeSSIF. The suspension was equilibrated at 25 °C for 24 hours then the final pH was measured. The suspension was then filtered through a 0.22um PVDF filter into a 2-mL HPLC vial. The quantitation was conducted by HPLC (described in Example AD) with reference to a standard solution. The solubility results of selected novel solid forms in this invention are shown in Table 12 which showed good aqueous solubility higher than 0.5mg/mL.
  • HPLC condition is disclosed here in Table 13.

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Abstract

La présente invention concerne une nouvelle forme cristalline et amorphe du composé (I), l'acide (3S)-4-[[(4R)-4-(2-chloro-4-fluorophényl)-5-méthoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]méthyl]morpholine-3-carboxylique et des compositions pharmaceutiques comprenant leurs formes amorphes ou cristallines ou tautomères, qui peuvent être utilisées dans le traitement ou la prophylaxie d'une maladie virale chez un patient se rapportant à une infection par l'hépatite B ou à une maladie provoquée par une infection par l'hépatite B.
PCT/EP2015/066695 2014-07-25 2015-07-22 Nouvelles formes amorphes et cristallines de l'acide (3s)-4-[[(4r)-4-(2-chloro-4-fluorophényl)-5-méthoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]méthyl]morpholine-3-carboxilique WO2016012470A1 (fr)

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Cited By (75)

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Publication number Priority date Publication date Assignee Title
WO2016124126A1 (fr) * 2015-02-07 2016-08-11 Sunshine Lake Pharma Co., Ltd. Complexes et sels de dérivés de dihydropyrimidine et leur application dans des produits pharmaceutiques
CN107200733A (zh) * 2016-03-18 2017-09-26 广东东阳光药业有限公司 二氢嘧啶衍生物的晶型及其在药物中的应用
WO2017198201A1 (fr) * 2016-05-19 2017-11-23 Sunshine Lake Pharma Co., Ltd. Forme cristalline, sel et complexe de dérivé de dihydropyrimidine, et leurs utilisations en médecine
US20170342068A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
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WO2018045150A1 (fr) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Dérivés de 4,6-diamino-pyrido [3,2-d] pyrimidine en tant que modulateurs du récepteur de type toll
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US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
WO2019200247A1 (fr) 2018-04-12 2019-10-17 Precision Biosciences, Inc. Méganucléases modifiées optimisées ayant une spécificité pour une séquence de reconnaissance dans un génome du virus de l'hépatite b
WO2019204609A1 (fr) 2018-04-19 2019-10-24 Gilead Sciences, Inc. Inhibiteurs pd-1/pd-l1
WO2019211799A1 (fr) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue de dinucléotide 2'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle
WO2020014643A1 (fr) 2018-07-13 2020-01-16 Gilead Sciences, Inc. Inhibiteurs de pd-1/pd-l1
WO2020028097A1 (fr) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique
WO2020086556A1 (fr) 2018-10-24 2020-04-30 Gilead Sciences, Inc. Inhibiteurs de pd-1/pd-l1
WO2020092528A1 (fr) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Composés 6-azabenzimidazole substitués ayant une activité inhibitrice de hpk1
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WO2020178769A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides cycliques en 2'3' et leurs promédicaments
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WO2021067181A1 (fr) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Vaccins contre le virus de l'hépatite b et méthodes de traitement du vhb
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WO2021113765A1 (fr) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Méganucléases modifiées optimisées ayant une spécificité pour une séquence de reconnaissance dans un génome du virus de l'hépatite b
WO2021130638A1 (fr) 2019-12-24 2021-07-01 Carna Biosciences, Inc. Composés modulant la diacylglycérol kinase
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US11492353B2 (en) 2010-07-22 2022-11-08 Gilead Sciences, Inc. Methods and compounds for treating Paramyxoviridae virus infections
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WO2022271677A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
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US11613553B2 (en) 2020-03-12 2023-03-28 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
WO2023167944A1 (fr) 2022-03-02 2023-09-07 Gilead Sciences, Inc. Composés et méthodes pour traiter des infections virales
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WO2023239665A1 (fr) 2022-06-06 2023-12-14 Gilead Sciences, Inc. Méthodes de traitement d'infections virales y compris le sars-cov-2
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WO2025054278A1 (fr) 2023-09-06 2025-03-13 Gilead Sciences, Inc. Formes solides d'un analogue de nucléoside et leurs utilisations
WO2025072641A1 (fr) 2023-09-28 2025-04-03 Gilead Sciences, Inc. Composés et méthodes de traitement d'infections virales

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014029193A1 (fr) * 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
WO2014037480A1 (fr) * 2012-09-10 2014-03-13 F. Hoffmann-La Roche Ag Hétéroaryldihydropyrimidines d'acide 6-aminé pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014029193A1 (fr) * 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
WO2014037480A1 (fr) * 2012-09-10 2014-03-13 F. Hoffmann-La Roche Ag Hétéroaryldihydropyrimidines d'acide 6-aminé pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b

Cited By (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11492353B2 (en) 2010-07-22 2022-11-08 Gilead Sciences, Inc. Methods and compounds for treating Paramyxoviridae virus infections
US11344565B2 (en) 2014-10-29 2022-05-31 Gilead Sciences, Inc. Methods for the preparation of ribosides
US11266666B2 (en) 2014-10-29 2022-03-08 Gilead Sciences, Inc. Methods for treating Filoviridae virus infections
WO2016124126A1 (fr) * 2015-02-07 2016-08-11 Sunshine Lake Pharma Co., Ltd. Complexes et sels de dérivés de dihydropyrimidine et leur application dans des produits pharmaceutiques
US10098889B2 (en) 2015-02-07 2018-10-16 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
US11007208B2 (en) 2015-09-16 2021-05-18 Gilead Sciences, Inc. Methods for treating arenaviridae and coronaviridae virus infections
US11382926B2 (en) 2015-09-16 2022-07-12 Gilead Sciences, Inc. Methods for treating Arenaviridae and Coronaviridae virus infections
CN107200733A (zh) * 2016-03-18 2017-09-26 广东东阳光药业有限公司 二氢嘧啶衍生物的晶型及其在药物中的应用
WO2017198201A1 (fr) * 2016-05-19 2017-11-23 Sunshine Lake Pharma Co., Ltd. Forme cristalline, sel et complexe de dérivé de dihydropyrimidine, et leurs utilisations en médecine
US20170342068A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
WO2018045150A1 (fr) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Dérivés de 4,6-diamino-pyrido [3,2-d] pyrimidine en tant que modulateurs du récepteur de type toll
WO2018045144A1 (fr) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Composés modulateurs du recepteur de type toll
US10662416B2 (en) 2016-10-14 2020-05-26 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome
US11274285B2 (en) 2016-10-14 2022-03-15 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the Hepatitis B virus genome
WO2018144390A1 (fr) 2017-01-31 2018-08-09 Gilead Sciences, Inc. Formes cristallines de ténofovir alafénamide
EP4424374A2 (fr) 2017-01-31 2024-09-04 Gilead Sciences, Inc. Formes cristallines de ténofovir alafénamide
US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
US11260070B2 (en) 2017-03-14 2022-03-01 Gilead Sciences, Inc. Methods of treating feline coronavirus infections
EP4026835A2 (fr) 2017-04-20 2022-07-13 Gilead Sciences, Inc. Inhibiteurs de pd-1/pd-l1
WO2018195321A1 (fr) 2017-04-20 2018-10-25 Gilead Sciences, Inc. Inhibiteurs pd-1/pd-l1
US12030906B2 (en) 2017-05-01 2024-07-09 Gilead Sciences, Inc. Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate
US11597742B2 (en) 2017-05-01 2023-03-07 Gilead Sciences, Inc. Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate
US11266681B2 (en) 2017-07-11 2022-03-08 Gilead Sciences, Inc. Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections
US11975017B2 (en) 2017-07-11 2024-05-07 Gilead Sciences, Inc. Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
US10966999B2 (en) 2017-12-20 2021-04-06 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
EP4227302A1 (fr) 2018-02-13 2023-08-16 Gilead Sciences, Inc. Inhibiteurs de pd-1/pd-l1
WO2019160882A1 (fr) 2018-02-13 2019-08-22 Gilead Sciences, Inc. Inhibiteurs pd -1/pd-l1
WO2019165374A1 (fr) 2018-02-26 2019-08-29 Gilead Sciences, Inc. Composés de pyrrolizine substitués en tant qu'inhibiteurs de réplication du virus de l'hépatite b
WO2019195181A1 (fr) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Anticorps et leurs fragments qui se lient à la protéine x du virus de l'hépatite b
WO2019193542A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 2'3'-cycliques
US11292812B2 (en) 2018-04-06 2022-04-05 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotides
WO2019193543A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 3'3'-cycliques
WO2019193533A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 2'2'-cycliques
US11149052B2 (en) 2018-04-06 2021-10-19 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′-cyclic dinucleotides
US11788077B2 (en) 2018-04-12 2023-10-17 Precision Biosciences, Inc. Polynucleotides encoding optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
WO2019200247A1 (fr) 2018-04-12 2019-10-17 Precision Biosciences, Inc. Méganucléases modifiées optimisées ayant une spécificité pour une séquence de reconnaissance dans un génome du virus de l'hépatite b
US11142750B2 (en) 2018-04-12 2021-10-12 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
WO2019204609A1 (fr) 2018-04-19 2019-10-24 Gilead Sciences, Inc. Inhibiteurs pd-1/pd-l1
WO2019211799A1 (fr) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue de dinucléotide 2'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle
EP4234030A2 (fr) 2018-07-13 2023-08-30 Gilead Sciences, Inc. Inhibiteurs de pd-1/pd-l1
WO2020014643A1 (fr) 2018-07-13 2020-01-16 Gilead Sciences, Inc. Inhibiteurs de pd-1/pd-l1
WO2020028097A1 (fr) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique
WO2020086556A1 (fr) 2018-10-24 2020-04-30 Gilead Sciences, Inc. Inhibiteurs de pd-1/pd-l1
WO2020092528A1 (fr) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Composés 6-azabenzimidazole substitués ayant une activité inhibitrice de hpk1
WO2020092621A1 (fr) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Composés de 6-azabenzimidazole substitués en tant qu'inhibiteurs de hpk1
EP4371987A1 (fr) 2018-10-31 2024-05-22 Gilead Sciences, Inc. Composés de 6-azabenzimidazole substitués utilisés en tant qu'inhibiteurs de hpk1
WO2020178770A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 3'3'-cycliques et leurs promédicaments
WO2020178769A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides cycliques en 2'3' et leurs promédicaments
US11766447B2 (en) 2019-03-07 2023-09-26 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020178768A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue du dinucléotide 3'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle utilisé en tant que modulateur de sting
WO2020214716A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Inhibiteurs de la protéase du vih à base de 2-imino-5-oxo-imidazolidine
WO2020214663A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
WO2020214652A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
EP4458416A2 (fr) 2019-04-17 2024-11-06 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
WO2020237025A1 (fr) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Exo-méthylène-oxindoles substitués qui sont des inhibiteurs de hpk1/map4k1
WO2020263830A1 (fr) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Protéines de fusion flt3l-fc et procédés d'utilisation
WO2021011891A1 (fr) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Formulations à action prolongée de ténofovir alafénamide
WO2021034804A1 (fr) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Formulations pharmaceutiques de ténofovir alafénamide
WO2021067181A1 (fr) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Vaccins contre le virus de l'hépatite b et méthodes de traitement du vhb
EP4458975A2 (fr) 2019-09-30 2024-11-06 Gilead Sciences, Inc. Vaccins contre le vhb et méthodes de traitement du vhb
WO2021113765A1 (fr) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Méganucléases modifiées optimisées ayant une spécificité pour une séquence de reconnaissance dans un génome du virus de l'hépatite b
WO2021130638A1 (fr) 2019-12-24 2021-07-01 Carna Biosciences, Inc. Composés modulant la diacylglycérol kinase
EP4445902A2 (fr) 2019-12-24 2024-10-16 Carna Biosciences, Inc. Composés modulant la diacylglycérol kinase
US11660307B2 (en) 2020-01-27 2023-05-30 Gilead Sciences, Inc. Methods for treating SARS CoV-2 infections
WO2021154687A1 (fr) 2020-01-27 2021-08-05 Gilead Sciences, Inc. Procédés de traitement d'infections par sras cov-2
US12012431B2 (en) 2020-03-12 2024-06-18 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
US11613553B2 (en) 2020-03-12 2023-03-28 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
WO2021188959A1 (fr) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Promédicaments de nucléosides de 4'-c-substitué-2-halo-2'-désoxyadénosine et leurs procédés de fabrication et d'utilisation
US11701372B2 (en) 2020-04-06 2023-07-18 Gilead Sciences, Inc. Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs
WO2021207049A1 (fr) 2020-04-06 2021-10-14 Gilead Sciences, Inc. Formulations d'inhalation d'analogues de carbanucléosides à substitution 1'-cyano
US11491169B2 (en) 2020-05-29 2022-11-08 Gilead Sciences, Inc. Remdesivir treatment methods
US11975012B2 (en) 2020-05-29 2024-05-07 Gilead Sciences, Inc. Remdesivir treatment methods
US11903953B2 (en) 2020-05-29 2024-02-20 Gilead Sciences, Inc. Remdesivir treatment methods
WO2021262826A2 (fr) 2020-06-24 2021-12-30 Gilead Sciences, Inc. Analogues de 1'-cyano nucléoside et leurs utilisations
US11939347B2 (en) 2020-06-24 2024-03-26 Gilead Sciences, Inc. 1′-cyano nucleoside analogs and uses thereof
WO2022031894A1 (fr) 2020-08-07 2022-02-10 Gilead Sciences, Inc. Promédicaments d'analogues nucléotidiques de phosphonamide et leur utilisation pharmaceutique
WO2022046631A1 (fr) 2020-08-24 2022-03-03 Gilead Sciences, Inc. Composés phospholipidiques et leurs utilisations
EP4424372A2 (fr) 2020-08-27 2024-09-04 Gilead Sciences, Inc. Composés et procédés pour le traitement d'infections virales
WO2022047065A2 (fr) 2020-08-27 2022-03-03 Gilead Sciences, Inc. Composés et méthodes de traitement d'infections virales
US11814406B2 (en) 2020-08-27 2023-11-14 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11926645B2 (en) 2020-08-27 2024-03-12 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
WO2022081973A1 (fr) 2020-10-16 2022-04-21 Gilead Sciences, Inc. Composés phospholipidiques et leurs utilisations
WO2022087149A2 (fr) 2020-10-22 2022-04-28 Gilead Sciences, Inc. Protéines de fusion d'interleukine-2-fc et méthodes d'utilisation
WO2022241134A1 (fr) 2021-05-13 2022-11-17 Gilead Sciences, Inc. Combinaison d'un composé de modulation de tlr8 et agent thérapeutique anti-arnsi de vhb
WO2022251318A1 (fr) 2021-05-26 2022-12-01 Gilead Sciences, Inc. Formulations phospholipidiques d'analogues de carba-nucléoside 1'-cyano-substitué
WO2022271650A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2022271677A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2022271659A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271684A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2023023527A1 (fr) 2021-08-18 2023-02-23 Gilead Sciences, Inc. Composés phospholipidiques et leurs procédés de production et d'utilisation
US11845755B2 (en) 2022-03-02 2023-12-19 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
WO2023167944A1 (fr) 2022-03-02 2023-09-07 Gilead Sciences, Inc. Composés et méthodes pour traiter des infections virales
US11851438B2 (en) 2022-03-02 2023-12-26 Gilead Sciences, Inc. 1′-cyano nucleoside analogs and methods for treatment of viral infections
US12180217B2 (en) 2022-03-02 2024-12-31 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
WO2023167938A1 (fr) 2022-03-02 2023-09-07 Gilead Sciences, Inc. Composés et méthodes de traitement d'infections virales
US11780844B2 (en) 2022-03-02 2023-10-10 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
WO2023168194A1 (fr) 2022-03-03 2023-09-07 Gilead Sciences, Inc. Composés antiviraux et leurs procédés de fabrication et d'utilisation
WO2023168254A1 (fr) 2022-03-03 2023-09-07 Gilead Sciences, Inc. Composés antiviraux, leurs procédés de production et d'utilisation
WO2023239665A1 (fr) 2022-06-06 2023-12-14 Gilead Sciences, Inc. Méthodes de traitement d'infections virales y compris le sars-cov-2
WO2024006376A1 (fr) 2022-06-29 2024-01-04 Gilead Sciences, Inc. Formes solides d'un analogue nucléosidique et leurs utilisations
WO2024006461A1 (fr) 2022-06-30 2024-01-04 Gilead Sciences, Inc. Formes solides d'un analogue nucléosidique et leurs utilisations
WO2024173458A1 (fr) 2023-02-16 2024-08-22 Gilead Sciences, Inc. Composés phospholipidiques et leurs procédés de fabrication et d'utilisation
WO2025049699A1 (fr) 2023-08-31 2025-03-06 Gilead Sciences, Inc. Composés antiviraux et leurs procédés de fabrication et d'utilisation
WO2025049493A1 (fr) 2023-08-31 2025-03-06 Gilead Sciences, Inc. Composés antiviraux et leurs procédés de fabrication et d'utilisation
WO2025054278A1 (fr) 2023-09-06 2025-03-13 Gilead Sciences, Inc. Formes solides d'un analogue de nucléoside et leurs utilisations
WO2025072641A1 (fr) 2023-09-28 2025-04-03 Gilead Sciences, Inc. Composés et méthodes de traitement d'infections virales

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